Tenascin in denervated human muscle

Tenascin is a large oligomeric glycoprotein of the extracellular matrix. Its location is limited in innervated muscle tissues. We investigated immunohistologically, using two monoclonal antibodies (mab) against Tenascin, biopsied denervated human muscle of children and adults. Tenascin was present in the interstitial space among denervated muscle fibres. Accumulation of Tenascin in denervated adult muscle tissue was frequent, accumulation in denervated muscle tissue of children was sparse and weak. The two antibodies reacted correspondingly. Tenascin was not only found in the vicinity of atrophic muscle fibres, but also close to normally sized fibres, suggesting an early stage of denervatio…

Genotype-phenotype correlations in nemaline myopathy caused by mutations in the genes for nebulin and skeletal muscle alpha-actin.

We present comparisons of the clinical pictures in a series of 60 patients with nemaline myopathy in whom mutations had been identified in the genes for nebulin or skeletal muscle alpha-actin. In the patients with nebulin mutations, the typical form of nemaline myopathy predominated, while severe, mild or intermediate forms were less frequent. Autosomal recessive inheritance had been verified or appeared likely in all nebulin cases. In the patients with actin mutations, the severe form of nemaline myopathy was the most common, but some had the mild or typical form, and a few showed other associated features such as intranuclear rods or actin accumulation. Most cases were sporadic, but in ad…

Morphology of experimentally denervated and reinnervated rat facial muscle I. Histochemical and histological findings

The morphological changes in rat facial muscles were evaluated after permanent denervation and were compared with findings after immediate reinnervation. Thirty rats underwent transection of the left and right facial nerves immediately followed by hypoglossal-facial nerve anastomosis on the right side (muscular reinnervation) and removal of 8-10 mm of the facial plexus on the left side (permanent muscular denervation). Levator labii muscle samples of both sides were collected sequentially at 2, 6, 7, 10, 20, and 24 weeks after surgery and submitted to routine histological and enzyme histochemical staining procedures. In normal levator labii muscles a typical "chessboard" pattern was found, …

Cap disease uncapped

With the advent of enzyme histochemistry and electron microscopy, the new nosographic group of congenital myopathies hailed as ‘‘new myopathies’’ [1] was established, largely based on morphological features in biopsied muscle specimens although clinically early (congenital) onset and mild progression were also attributed to these childhood myopathies. When molecular investigations of patients with hereditary neuromuscular diseases began, earlier classifications based on clinical, morphological, and metabolic criteria started to quake, most conspicuously observed in the group of limb girdle muscular dystrophy or limb girdle muscular syndrome, which now comprise seven autosomal dominant (LGMD…

The Neuronal Ceroid-Lipofuscinoses. Recent Advances

The neuronal ceroid lipofuscinoses (NCLs) represent a group of neurodegenerative disorders characterised by progressive visual failure, neurodegeneration, epilepsy and the accumulation of an autofluorescent lipopigment in neurons and other cells. The main childhood subtypes are infantile (INCL;CLN1), classical late infantile (LINCL;CLN2) and juvenile NCL (J NCL; CLN3), distinguished on the basis of age of onset, clinical course and ultrastructural morphology, and recently genetic analysis. In addition several variant forms of the disease complex have been described as well as a rare adult onset form. Advances in both genetics and biochemistry have led to the identification of the genes for …

Introduction

A sphenoorbital encephalocele — clinical, radiological, and morphological findings

We report here on congenital sphenoorbital encephalocele which could not be disclosed by computed tomography including contrast medium application or by orbital sonography. Surgery and histological examination were necessary to establish correct the diagnosis.

Neonatal form of nemaline myopathy, muscle immaturity, and a microvascular injury.

An infant with a neonatal form of nemaline myopathy showed ultrastructural features of muscle immaturity. Immaturity was characterized by an abnormal presence of myotubes, as well as cells in clusters within a common basement membrane and a great number of satellite cells adhering to very small muscle fibers. In addition, degenerative changes and a severe microvascular lesion were observed. The pathologic findings in the muscle of this patient were those of neonatal nemaline myopathy complicating severe microvascular injury, possibly induced by an unknown toxic agent. ( J Child Neurol 1990;5:122-126).

Desmin-related neuromuscular disorders

Desmin, the intermediate filament protein of skeletal muscle fibers, cardiac myocytes, and certain smooth muscle cells, is a member of the cytoskeleton linking Z-bands with the plasmalemma and the nucleus. The pathology of desmin in human neuromuscular disorders is always marked by increased amounts, diffusely or focally. Desmin is highly expressed in immature muscle fibers, both during fetal life and regeneration as well as in certain congenital myopathies, together with vimentin. Desmin is also enriched in neonatal myotonic dystrophy and small fibers in infantile spinal muscular atrophy. Focal accretion of desmin may be twofold, in conjunction with certain inclusion bodies, cytoplasmic an…

Electrophysiological findings of neuronal ceroid lipofuscinosis in heterozygotes.

Nineteen obligate heterozygotes, 8 individuals at risk of being heterozygote, and 10 patients afflicted with four different forms of neuronal ceroid lipofuscinosis were examined electrophysiologically. The group of obligate heterozygotes was compared to age-matched control groups. Statistically significant differences were found between scotopic b-wave amplitudes, P-ERG amplitudes, and EOG light peaks of the obligate carriers of the juvenile type and the control subjects. The photopic L-ERGs and the latencies of the VEPs were mostly within the normal range. The findings represent the first evidence of functional ophthalmological changes in obligate carriers of neuronal ceroid lipofuscinosis…

Myopathic form of arthrogryposis and microcirculation lesion.

A microvascular lesion characterized by extensive platelet aggregation, thrombosis, vascular damage with hemorrhages was found in the muscle of a 2-month-old boy with a myopathic form of the arthrogryposis syndrome. The lesion morphologically resembled the vascular leakage seen in immunologically mediated tissue injury. A degradative effect of proteases released during platelet and neutrophil aggregation on the muscle and joints is suggested.

MRI in DNM2-related centronuclear myopathy: Evidence for highly selective muscle involvement

Dynamin 2 has recently been recognized as a causative gene for the autosomal dominant form of centronuclear myopathy (dominant centronuclear myopathy). Here we report an affected father and daughter with dynamin 2 related AD CNM with predominantly distal onset of weakness. In addition to the diagnostic central location of myonuclei the muscle biopsy also showed core-like structures. Muscle MRI in the lower leg revealed prominent involvement of the soleus, but also of the gastrocnemius and the tibialis anterior whereas in the thigh there was a consistent pattern of selective involvement of adductor longus, semimembranosus, biceps femoris, rectus femoris, and vastus intermedius with relative …

ACUTE INFANTILE SPINAL MUSCULAR ATROPHY

Biopsy as well as autopsy studies of a child who died 8 weeks after birth from the acute infantile form of spinal muscular atrophy revealed classical morphological changes, including degeneration and loss of motoneurons in the spinal cord, loss of large myelinated fibres in anterior roots and neurogenic atrophy in muscle. New ultrastructural findings include massive muscle cell elimination by apoptosis with the formation of membrane-bound muscle cell fragments, apoptotic bodies. In addition, numerous immature muscle fibres were observed. The morphological findings raise the possibility that in a severely growth-retarded muscle, the process of muscle cell apoptosis removes the peripheral tar…

The Eighth Meryon Society Lecture read at Worcester College, Oxford on 2 July, 2004

Progress in neuropathology of the neuronal ceroid lipofuscinoses.

Abstract Since the last, 6th, International Congress on Neuronal Ceroid-Lipofuscinoses, neuropathological advances in neuronal ceroid lipofuscinoses (NCL) have been made in several areas: (1) In adult NCL (ANCL) lipopigments have now been repeatedly confirmed to contain subunit c of mitochondrial ATP synthase and even sphingolipid activators (saposins). ANCL lipopigments have also been confirmed in extracerebral tissues including skin, skeletal muscle, and spleen, but not yet lymphocytes (2). Among circulating blood cells not only B cells and subclasses of T lymphocytes, i.e., CD4 + , CD8 + , and CD56 cells, but also monocytes have been found to contain NCL lipopigments, indicating that thi…

156th ENMC International Workshop: desmin and protein aggregate myopathies, 9-11 November 2007, Naarden, The Netherlands.

Primary desminopathies.

•  Introduction •  Desmin is an essential component of the extrasarcomeric cytoskeleton in striated muscle cells •  Distal myopathy,cardiac arrhythmias,cardiomyopathy:classical criteria of primary desminopathies •  Sub-sarcolemmal and cytoplasmic desmin-positive protein aggregates:the morphological hallmark of primary and secondary desminopathies •  The spectrum of pathogenic desmin gene mutations •  The molecular pathogenesis of primary desminopathies: some answers gained,but even more questions raised •  Diagnostic work-up to distinguish primary from secondary desminopathies •  Treatment and clinical management of primary desminopathy patients Abstract Mutations of the human desmin gene o…

Chronic progressive external ophthalmoplegia with a novel mitochondrial DNA deletion and a mutation in the tRNALEU(UUR) gene

Large-scale deletions and point mutations of the mitochondrial DNA are generally accepted as being involved in the pathogenesis of diseases associated with mitochondrial encephalomyopathies such as Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia (CPEO). We screened suspected patients using polymerase chain reaction techniques, Southern blot analyses, and muscle biopsy specimens. We report on a novel 4,953-base pair deletion associated with a familial occurrence of a tRNA Leu(UUR) T3250C point mutation in a young female patient clinically diagnosed with CPEO. This deletion is not flanked by direct repeats, so slip replication and homologous recombination do not seem li…

Immunolocalization of Tenascin-C in Human Type II Fiber Atrophy

Tenascin-C is a multifunctional extracellular matrix glycoprotein with stimulatory and anti-adhesive or inhibitory properties for axon growth. Its location and discontinuous expression are restricted in innervated muscle tissues. Tenascin-C accumulated interstitially among human denervated muscle fibers and close to normal-sized fibers. To expand our knowledge of the expression of tenascin-C in human neuromuscular disorders, we investigated immunohistologically 20 human muscle specimens with type II myofiber atrophy of children and adults. Tenascin-C immunoreactivity in adult type II atrophy was frequent, and accumulation in children was sparse and weak. In both groups, tenascin-C immunorea…

SIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome.

Marinesco-Sjogren syndrome is a rare autosomal recessive multisystem disorder featuring cerebellar ataxia, early-onset cataracts, chronic myopathy, variable intellectual disability and delayed motor development. More recently, mutations in the SIL1 gene, which encodes an endoplasmic reticulum resident co-chaperone, were identified as the main cause of Marinesco-Sjogren syndrome. Here we describe the results of SIL1 mutation analysis in 62 patients presenting with early-onset ataxia, cataracts and myopathy or combinations of at least two of these. We obtained a mutation detection rate of 60% (15/25) among patients with the characteristic Marinesco-Sjogren syndrome triad (ataxia, cataracts, m…

Ultrastructural myopathology in the molecular era.

Electron microscopy is an essential component of myopathology, both in diagnostics and research of neuromuscular diseases. Although recently reduced in the diagnostic armamentarium, it has greatly been expanded to mouse models in research. Mostly it is descriptive, but a few additional techniques in combination with transmission electron microscopy have been employed. Foremost among them is immunoelectron microscopy, which assists in guiding molecular analysis in hereditary conditions, but may be vital in diagnostics of certain acquired entities, e.g., undulating tubules in dermatomyositis and in those congenital myopathies where genes and mutations remain to be identified, as in cylindrica…

Localization of the giant axonal neuropathy gene to chromosome 16q24

Giant axonal neuropathy (GAN) is a degenerative disorder of the peripheral nerves that is inherited as an autosomal recessive trait, presenting in early childhood and progressing to death, usually by late adolescence. Diagnosis is made by peripheral nerve biopsy, in which a striking pathological finding is seen--fibers distorted by giant axonal swellings filled with densely packed bundles of neurofilaments (the primary intermediate filament in neurons), with segregation of other axoplasmic organelles. In addition to disorganized neurofilaments in nerve, disorganization of other members of the intermediate filament family of proteins is seen in other tissues; this implies that the underlying…

In-frame deletion in the seventh immunoglobulin-like repeat of filamin C in a family with myofibrillar myopathy.

Myofibrillar myopathies (MFMs) are an expanding and increasingly recognized group of neuromuscular disorders caused by mutations in DES, CRYAB, MYOT, and ZASP. The latest gene to be associated with MFM was FLNC; a p.W2710X mutation in the 24th immunoglobulin-like repeat of filamin C was shown to be the cause of a distinct type of MFM in several German families. We studied an International cohort of 46 patients from 39 families with clinically and myopathologically confirmed MFM, in which DES, CRYAB, MYOT, and ZASP mutations have been excluded. In patients from an unrelated family a 12-nucleotide deletion (c.2997_3008del) in FLNC resulting in a predicted in-frame four-residue deletion (p.Val…

Prenatal diagnosis of infantile neuronal ceroid-lipofuscinosis: a combined electron microscopic and molecular genetic approach.

Based on two unrelated index patients afflicted with INCL, fetal chorion tissues were studied from subsequent pregnancies of the two respective mothers resulting in the prenatal diagnosis of INCL in two of the three pregnancies. Documentation of INCL was based on electron microscopy and DNA studies of the biopsied chorion tissue, later confirmed in the two affected fetuses after termination of their pregnancies by demonstrating INCL-specific lipopigments in post-mortem tissues, in the liver of both aborted fetuses and, additionally, in spleen and skeletal muscle of one of the affected fetuses. The autolysis of the aborted tissues, however, precluded a systematic documentation of all affecte…

A case of lipogranulomatosis Farber: some clinical and ultrastructural aspects

A 20-month-old girl showed typical clinical signs of Farber disease: hoarseness since birth, and periarticular subcutaneous painful nodules. Complete deficiency of acid ceramidase activity was found in cultured skin fibroblasts. An electron microscopic examination of a dermal nodule disclosed pathognomonic tubular inclusions in histiocytes. In epidermal cells zebra-body-like and needle-like lysosomal inclusions were found. Their ultrastructure is different from that of the intrahistiocytic lysosomal inclusions. Probably three clinical types of Farber disease may be distinguished according to the symptomatology and the course of the disease: a severe type, an intermediate type and a relative…

Late infantile neuronal ceroid lipofuscinosis: Quantitative description of the clinical course in patients withCLN2 mutations

We examined 26 individuals with clinical and electron microscopic signs of late infantile neuronal ceroid lipofuscinosis (LINCL). In 22 cases, we found both pathogenic alleles. Sixteen patients exclusively carried either one or a combination of the two common mutations R208X and IVS5-1G > C. In the remaining cases, four missense mutations could be detected, of which R127Q, N286S, and T353P represent novel, previously not described alleles. A clinical performance score was developed by rating motor, visual, and verbal functions and the incidence of cerebral seizures in 3-month intervals during the course of the disease. A Total Disability Score was derived by summing up the single scores for…

7th International Congress on Neuronal Ceroid‐Lipofuscinoses (NCL‐98) 13–16 June 1998, Dallas, USA

121st ENMC International Workshop on Desmin and Protein Aggregate Myopathies. 7–9 November 2003, Naarden, The Netherlands

The 121st European Neuromuscular Centre (ENMC)sponsored International Workshop on ‘DESMIN and Protein Aggregate Myopathies’, attended by 16 active participants from France, Germany, Poland, Spain, Sweden, the United Kingdom and the USA, was actually the fourth one in a row addressing the pathology of the muscle fibre intermediate filament desmin, its associated and similar diseases, all four [1–3] organized by Michel Fardeau and Hans H. Goebel. In his introduction, the chairman, Hans H. Goebel (Mainz), recorded the evolution of ‘Protein Aggregate Myopathies (PAM)’ which are marked by the accumulation of diverse proteins within muscle fibres as a morphologic hallmark in separate myopathies w…

The 8th International Congress on Neuronal Ceroid Lipofuscinoses (Batten Disease) ‐ NCL 2000 20 ‐ 24 September, 2000 Oxford, United Kingdom

Dementia in the Neuronal Ceroidlipofuscinoses

Dementia is defined as a decline in cognitive abilities such as impairment of memory, reasoning, behaviour, attention, motivation and effectiveness. The term usually implies that normal mature mental capability was achieved before, and it is therefore mostly ascribed to adult patients.

Giant axonal neuropathy and leukodystrophy

Abstract An 11-year-old Persian boy, born to consanguineous parents, manifested a progressive gait abnormality beginning at 5 years of age. A severe cerebellar disorder developed with associated dysfunction of the peripheral nervous system, but no sign of mental impairment. The sensory and motor nerve conduction velocities were greatly reduced, especially in the lower extremities. Cerebrospinal fluid protein was normal. Computed tomography and magnetic resonance imaging revealed leukoencephalopathy, especially in the cerebellum, but also in periventricular areas. The diagnosis of giant axonal neuropathy was established by biopsy of the sural nerve. The few previous histologic examinations h…

Desmin-related myopathies

Desmin-related myopathies are marked by accumulation of desmin, which is often familial and associated with cardiomyopathy. When multifocal this excess is characterized by inclusions such as cytoplasmic or spheroid bodies, when disseminated the excess is called granulofilamentous material. Excess of desmin might represent an abnormal type of protein metabolism.

Sural nerve biopsy studies in leigh's subacute necrotizing encephalomyelopathy

Peripheral neuropathy marked by reduced nerve conduction velocities was found in four unrelated children, between the ages of 15 months and 9 years, whose autopsies revealed Leigh's subacute necrotizing encephalomyelopathy. Sural nerve biopsies disclosed primary demyelination and remyelination, as well as loss of myelinated and unmyelinated axons. The use of morphometric and electron microscopic studies shows that these techniques may reveal peripheral neuropathy in Leigh's disease more often than light microscopic methods alone.

Workshop on the genetic and molecular basis of the neuronal ceroid lipofuscinoses London, UK, 13–16 November 1997

Expression of cell adhesion molecules in inflammatory myopathies.

We examined the expression of cell adhesion molecules in 25 cases of inflammatory myopathies. Inflammatory myopathies showed upregulation of adhesion molecules. ICAM-1 was strongly expressed on endothelial cells as well as on fibroblasts and infiltrating leukocytes while the expression of VCAM-1, similar in its distribution, was much weaker. A few muscle fibers in polymyositis revealed sarcolemmal labeling for ICAM-1. ELAM-1 showed only weak expression on vessels. The inflammatory cellular infiltrates contained varying amounts of cells bearing the VCAM-1 ligand VLA-4 and the ELAM-1 ligand SLeX as well as large amounts of cells expressing LFA-1 alpha and beta, ligands of ICAM-1.

Morphological studies in canine (Dalmatian) neuronal ceroid-lipofuscinosis.

Dalmatian dogs may develop a neuronal or generalized ceroid-lipofuscinosis (NCL) which strongly resembles that seen in English setters, especially as to the ultrastructural changes and ubiquity of the stored lipopigments and the retinal pathology, while differing clinically from the disorder of English setters in that the disease has a longer course of up to 5 or 6 yr. Clinical onset is at about age 6 months; however, an unequivocal morphological diagnosis is possible between the 4th and 5th month of life in biopsied skin. Detailed data of additional investigations are in progress and are awaiting later publication. Thus, NCL in the Dalmatian dog, though not yet as thoroughly investigated a…

Human NCL Neuropathology

AbstractThe neuronal ceroid lipofuscinoses (NCL) currently encompass fourteen genetically different forms, CLN1 to CLN14, but are all morphologically marked by loss of nerve cells, particularly in the cerebral and cerebellar cortices, and the cerebral and extracerebral formation of lipopigments. These lipopigments show distinct ultrastructural patterns, i.e., granular, curvilinear/rectilinear and fingerprint profiles. They contain−although to a different degree among the different CLN forms−subunit C of ATP synthase, saposins A and D, and beta-amyloid proteins. Extracerebral pathology, apart from lipopigment formation, which provides diagnostic information, is scant or non-existent. The ret…

Extracerebral biopsies in neurodegenerative diseases of childhood

Abstract Among the numerous neurodegenerative diseases in children few may allow morphological diagnosis by extracerebral biopsy. These encompass neurometabolic conditions, foremost lysosomal disorders, but also peroxisomal and mitochondrial diseases marked by disease- or group-specific organelles. Largely, these neurometabolic conditions can also be diagnosed by biochemical and increasingly by molecular genetic techniques. However, there are a few neurodegenerative diseases which do not allow either biochemical or molecular genetic diagnosis and, thus, rely on biopsy of extracerebral tissues, so-called ‘essential’ biopsies to achieve a diagnosis during the patient's life. Among these few d…

A new familial congenital myopathy in children with desmin and dystrophin reacting plaques.

In 5 children with a progressive congenital myopathy representing 3 different families, unusual histological, immunohistochemical and ultrastructural changes in skeletal muscle have been found. Histologically, this myopathy was characterized by the presence of fine hyaline plaques devoid of oxidative as well as ATPase enzyme activities. At the ultrastructural level plaques were composed of helical filaments and amorphous dense material. Helical filament storage corresponded to strong desmin as well as ubiquitin immunoreactivity. In addition they were also dystrophin positive. The exclusive appearance of desmin, ubiquitin and dystrophin positive plaques in muscle specimens from 5 children em…

Progressive cerebellar ataxia in juvenile GM 2 -gangliosidosis type Sandhoff

M2 Polarized Macrophages and Giant Cells Contribute to Myofibrosis in Neuromuscular Sarcoidosis

The etiopathogenesis of sarcoidosis, a systemic granulomatous disease, still remains obscure. A multitude of organs have been described to be affected in systemic sarcoidosis. Skeletal muscles may also be affected, leading to myalgia and weakness. A workup of the specific immune response with emphasis on the macrophage response is provided herein. Affected muscle tissue from seven patients with systemic sarcoidosis was analyzed and compared with that from seven patients with other myopathies containing macrophagocytic infiltration. Monocytes/macrophages and giant cells in granulomas of muscle tissue from patients with sarcoidosis show a status of alternative activation (M2) based on their e…

Frontotemporal dementia: the post-tau era.

As scientists have begun to decipher the molecular genetic bases of hereditary frontotemporal dementia (FTD), it has become clear that the biology of these human neurodegenerative diseases has a complexity not previously suspected. FTD has been found to be linked to several chromosomal loci including those in chromosome 9, chromosome 17, and chromosome 3. The article by Guyant-Marechal et al. in this issue of Neurology reports the clinical, pathologic, and molecular characteristics of a form of FTD associated with inclusion body myopathy and Paget disease of the bone observed in members of two families and expands our knowledge on genetically determined FTD.1 The disorder is associated with…

Ultrastructural Pathology of Eccrine Sweat Gland Epithelial Cells in Globoid Cell Leukodystrophy

Three of four children were recognized by deficient β-galactocerebrosidase activities as having globoid cell leukodystrophy inclusions in sweat gland epithelial cells, similar in ultrastructure to those seen in Schwann cells. This observation in globoid cell leukodystrophy emphasizes the need to include sweat gland epithelial cells in examinations of skin in globoid cell leukodystrophy, as well as in any neurometabolic disorder. ( J Child Neurol 1993;8:171-174).

Magnetic resonance imaging in primary cerebral neuroblastoma

Ultrastructural study of the retina in late infantile metachromatic leukodystrophy.

The autopsy of a 2-year-old girl revealed a clinically unrecognized metachromatic leukodystrophy (MLD) due to an aryl-sulfatase A deficiency, characteristically affecting the central and peripheral nervous system by demyelination and by accumulation of metachromatic material. The retina though reported clinically as normal, showed the same demyelinating process in the optic nerve including the papilla but an additional intraneuronal storage of MLD-typical lysosomal residual bodies in ganglion cell perikarya of the retina. Cells of the bipolar and photoreceptor layers as well as pigment epithelial cells were not affected by MLD-specific lysosomal storage. Thus, sulfatides seem to play a part…

An ultrastructural study on retinal neural and pigment epithelial cells in ovine neuronal ceroid-lipofuscinosis.

Ovine neuronal ceroid-lipofuscinosis represents another well studied model for human neuronal ceroid-lipofuscinosis (NCL). Accumulation of abnormal lipopigments in various retinal neurons, and loss of photoreceptors are similar to the lesions in human juvenile NCL and indicate that the sheep is a suitable model in which to study the pathogenesis of both NCL lipopigment formation and retinopathia pigmentosa. However, this latter process is not as advanced in NCL-diseased sheep as in human patients but far more obvious than in canine NCL in which retinopathy cannot be unequivocally documented. Ovine NCL shares with canine NCL peculiar lamellar inclusions in retinal pigment epithelial cells wh…

Congenital myopathies at their molecular dawning

The introduction and application of molecular techniques have commenced to influence and alter the nosology of congenital myopathies. Long-known entities such as nemaline myopathies, core diseases, and desmin-related myopathies have now been found to be caused by unequivocal mutations. Several of these mutations and their genes have been identified by analyzing aggregates of proteins within muscle fibers as a morphological hallmark as in desminopathy and actinopathy, the latter a subtype among the nemaline myopathies. Immunohistochemistry has played a crucial role in recognizing this new group of protein aggregate myopathies within the spectrum of congenital myopathies. It is to be expected…

Childhood neuromuscular disease with rimmed vacuoles

A 5-year-old boy suffered from a slowly progressive non-familial neuromuscular disease, clinically marked by generalised muscle weakness, atrophy and hypotonia, a "myopathic" EMG and mildly elevated CK values. His gastrocnemius muscle showed marked myopathy, type I fibre predominance, and numerous "rimmed" vacuoles. This boy's condition is regarded as a childhood neuromuscular disease with rimmed vacuoles.

The neuronal ceroid-lipofuscinoses: A historical introduction

AbstractThe neuronal ceroid-lipofuscinoses (Batten disease) collectively constitute one of the most common groups of inherited childhood onset neurodegenerative disorders, and have also been identified in many domestic and laboratory animals. The group of human neuronal ceroid-lipofuscinoses currently comprises 14 genetically distinct disorders, mostly characterised by progressive mental, motor and visual deterioration with onset in childhood or adolescence. Abnormal autofluorescent, electron-dense granules accumulate in the cytoplasm of nerve cells, and this storage process is associated with selective destruction and loss of neurons in the brain and retina. The present paper outlines near…

AN ULTRASTRUCTURAL STUDY OF THE RETINA IN HUMAN LATE INFANTILE NEUROAXONAL DYSTROPHY

A case involving a girl who died at 11 years of age and who had developed normally until the age of 18 months, at which time further psychomotor maturation stopped and then regressed, is reported. The patient appeared hypotonic and showed loss of deep tendon reflexes, as well as bulbar signs and increasing immobility. Visual impairment resulted in blindness at the age of 7 years. Her disease was diagnosed as late infantile neuroaxonal dystrophy (LINAD) after examination of sural nerve biopsy samples and after autopsy. Under electron microscopy, retinal axons were filled with tubulocisternal profiles and occasional large lamellar clefts close to or distant from synaptic complexes. These lesi…

Leigh syndrome due to compound heterozygosity of dihydrolipoamide dehydrogenase gene mutations. Description of the first E3 splice site mutation.

Item does not contain fulltext A boy with recurrent episodes of hypoglycaemia and ataxia, microcephaly, mental retardation, permanent lactic acidaemia, intermittent 2-oxoglutaric aciduria as well as elevation of serum branched chain amino acids was diagnosed with dihydrolipoamide dehydrogenase (E3) deficiency. Analysis of genomic DNA revealed compound heterozygosity for two novel mutations: I393T in exon 11, located at the interface domain of the protein and possibly interfering with its dimerisation, and IVS9+1G>A located at a consensus splice site. A heterozygous polymorphism was also detected. In the patient's cDNA the I393T mutation and the polymorphism appeared to be homozygous, indica…

Familial mixed congenital myopathy with rigid spine phenotype

We describe a father and daughter with a rigid spine syndrome and proximal myopathy. The index patient was a 42-year-old man, who died from respiratory failure after a lifelong, slowly progressive proximal myopathy and a rigid spine phenotype. This was morphologically characterized by cytoplasmic bodies, increased desmin, features of reducing-body myopathy, and sarcoplasmic and intranuclear tubulofilamentous inclusions. These cases are characterized by an early onset and possibly autosomal-dominant inheritance, with associated complex structural hallmarks of both desmin-related and inclusion body myopathies. Together they may be defined as a complex mixed congenital myopathy with a rigid sp…

Immune-mediated necrotizing myopathy is characterized by a specific Th1-M1 polarized immune profile.

Immune-mediated necrotizing myopathy (IMNM) is considered one of the idiopathic inflammatory myopathies, comprising dermatomyositis, polymyositis, and inclusion body myositis. The heterogeneous group of necrotizing myopathies shows a varying amount of necrotic muscle fibers, myophagocytosis, and a sparse inflammatory infiltrate. The underlying immune response in necrotizing myopathy has not yet been addressed in detail. Affected muscle tissue, obtained from 16 patients with IMNM, was analyzed compared with eight non-IMNM (nIMNM) tissues. Inflammatory cells were characterized by IHC, and immune mediators were assessed by quantitative real-time PCR. We demonstrate that immune- and non–immune-…

Cytoplasmic body myopathy revisited.

Desmin – Protein Surplus Myopathies, 96th European Neuromuscular Centre (ENMC)-sponsored International Workshop held 14–16 September 2001, Naarden, The Netherlands

Protein Aggregation in Muscle Fibers and Respective Neuromuscular Disorders

Protein aggregation in muscle fibers may be a nonspecific phenomenon such as occurring in cores or ragged red fibers. However, it may also be a disease-specific and disease-significant phenomenon constituting protein aggregate myopathies (PAMs). These may be divided into two classes: The first one is marked by impaired extralysosomal degradation of proteins, catabolic PAM, encompassing desmin-related myopathies. Mutant proteins, that is, desmin, myotilin, or α-B crystallin, defy protein degradation, aggregate and associate with other proteins within muscle fibers, hence marking desminopathies, myotilinopathies, and α-B crystallinopathies. A second class of PAM encompasses those apparently a…

Autosomal recessive micrencephaly with simplified gyral pattern, abnormal myelination and arthrogryposis.

The clinical courses, neuroimaging and muscle biopsy findings of two infants born to an inbred Arab family are described. They had a syndrome of micrencephaly with simplified gyral pattern, abnormal myelin formation and arthrogryposis. Increased variation of fiber size was seen in the muscle biopsy, creatine kinase, however was normal. Large areas of muscle were replaced by adipofibrous tissue. The infants had dysmorphic features consistent with the fetal akinesia/hypokinesia sequence. The abnormalities were suggestive of microlissencephaly probably associated with a dysgenetic process in the muscles. The syndrome showed an autosomal recessive inheritance.

A morphometric study on sural nerves in metachromatic leucodystrophy.

This study reexamines peripheral neuropathy in infantile, juvenile and adult metachromatic leuco-dystrophy. A computer-assisted method was used which gives more detailed information on abnormal fibre structure from scatter diagrams of the g ratio (axon diameter/fibre diameter). The data show marked and statistically significant reductions in sheath thickness, particularly for the thick myelinated fibres, and most severe in the juvenile and adult forms. This is interpreted as evidence of remodelling of virtually the entire fibre population, without a clear-cut selectivity for either thin or thick fibres.

Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy

Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies showed a severe block in autophagosomal clearance in muscle a…

Morphologic diagnosis in neuronal ceroid lipofuscinosis.

Morphologic pathology in NCL is marked by two processes, the interaction of which has not yet been completely clarified: 1) degeneration of nerve cells, foremost in the cerebral cortex, resulting in considerable cerebral atrophy in early childhood forms, likely responsible for clinical and neuroradiological findings; 2) widespread accumulation of autofluorescent lysosomal lipopigments of varying ultrastructure, the demonstration of which is still largely responsible for diagnostic recognition of an individual patient's NCL. Numerous tissues and organs are available for biopsy, among them brain (historical), rectum (still favoured by some), skeletal muscle and peripheral nerves (largely by c…

Hearing loss in facioscapulohumeral dystrophy.

Bilateral sloping high frequency hearing loss of 20–90 dB was found in six out of ten patients with infantile or adolescent onset FSHD. In all cases the basic defect could be traced to the cochlea. The outer hair cells of the basal turn are predominantly affected. In 20 patients with various other forms of muscular dystrophy or neuromuscular disorders with an FSH distribution, no sensorineural hearing loss was found. Myopathology of FSHD patients extended from mild to severe, often showing inflammatory infiltrates and type I fibre atrophy, without unequivocal differences between the two groups with and without hearing loss. It is concluded that cochlear dysfunction is a specific and frequen…

Nuclear actin aggregation is a hallmark of anti-synthetase syndrome-induced dysimmune myopathy

Objective: To analyze antisynthetase syndrome–associated myositis by modern myopathologic methods and to define its place in the spectrum of idiopathic inflammatory myopathies (IIMs). Methods: Skeletal muscle biopsies from antisynthetase syndrome–associated myositis and other IIMs from different institutions worldwide were analyzed by histopathology, quantitative PCR, and electron microscopy. Results: Myonuclear actin filament inclusions were identified as a unique morphologic hallmark of antisynthetase syndrome–associated myositis. Nuclear actin inclusions were never found in dermatomyositis, polymyositis, sporadic inclusion body myositis, autoimmune necrotizing myopathy associated with si…

Fetal akinesia caused by a novel actin filament aggregate myopathy skeletal muscle actin gene (ACTA1) mutation.

We report a female newborn, diagnosed with fetal akinesia in utero, who died one hour after birth. Post-mortem muscle biopsy demonstrated actin-filament myopathy based on immunolabelling for sarcomeric actin, and large areas of filaments, without rod formation, ultrastructurally. Analysis of DNA extracted from the muscle disclosed a novel de novo heterozygous c.44G>A, GGC>GAC, 'p.Gly15Asp' mutation in the ACTA1 gene. Analysis of the location of the mutated amino-acid in the actin molecule suggests the mutation most likely causes abnormal nucleotide binding, and consequent pathological actin polymerization. This case emphasizes the association of fetal akinesia with actin-filament myopathy.

Surplus protein myopathies.

Abstract Certain muscular dystrophies are marked by absence or reduction of mutant proteins, foremost dystrophinopathies and sarcoglycanopathies. Conversely, other sporadic and familial neuromuscular conditions are marked by a surplus of proteins present in a granular or filamentous form, such as desmin-related myopathies, actinopathy and, perhaps, hyaline body myopathy. This emerging group of congenital myopathies is clinically, immunohistochemically, and genetically diverse. Clinically, early- and late-onset diseases with variable courses are described. Immunohistochemically, mutant gene-related and other proteins have been identified by immunohistochemistry. Mutations in the desmin and α…

Introduction: Recent Advances in Hereditary Neuromuscular Diseases of Childhood

6th International Congress on Neuronal-Ceroid-Lipofuscinosis (NCL-96), June 8–11, 1996, Gustavelund, Finland

Duchenne muscular dystrophy and idiopathic hyperCKemia segregating in a family

A 7-month-old boy with gross motor delay and failure to thrive presented with rhabdomyolysis following an acute asthmatic episode. During hospitalization an electrocardiographic conversion to a Wolff-Parkinson-White type 1 (WPW) pattern took place. Duchenne muscular dystrophy (DMD) was suspected based on elevated creatine kinase (CK) serum levels, muscle biopsy, and family history. The diagnosis was confirmed by molecular analysis, which documented a deletion corresponding to cDNA probe 1-2a in the dystrophin gene, in the propositus and in an affected male cousin of his mother. "Idiopathic" hyperCKemia was found in the propositus, his father, and 5 of his relatives. We suggest that the unus…

Reducing Body Myopathy with Cytoplasmic Bodies and Rigid Spine Syndrome: A Mixed Congenital Myopathy

At the age of five years a male child started to develop a progressive rigid spine, torsion scoliosis, and flexion contractures of his elbows, knees, hips, and ankles owing to severe proximal and distal muscle weakness. He had three muscle biopsies from three different muscles at ages 7, 11, and 14 years, respectively. Myopathologically, these muscle tissues contained numerous inclusions which, at the ultrastructural level, turned out to be reducing bodies and cytoplasmic bodies, often in close spatial proximity. Similar histological inclusions, although not further identified by histochemistry and electron microscopy, were seen in his maternal grandmother's biopsied muscle tissue who had d…

Congenital Myopathies in the New Millennium

Few medical disciplines have benefited so enormously from the molecular revolution as myology. Whereas the congenital myopathies have flourished from enzyme histochemistry and electron microscopy, defining individual congenital myopathies by structural abnormalities, genetic research has only recently focused on congenital myopathies. However, a number of congenital myopathies have been molecularly elucidated: central and multiminicore diseases, nemaline myopathy, myotubular myopathy, and congenital myopathy marked by aggregation of proteins, giving rise to the concept of protein aggregate myopathies, to which now desminopathies, α-B crystallinopathies, selenoproteinopathy, myotilinopathy,…

Desmin pathology in neuromuscular diseases

Desmin is an intermediate filament protein that in striated muscle is normally located at Z-bands, beneath the sarcolemma, and prominently at neuromuscular junctions. It is abundant during myogenesis and in regenerating fibers, but decreases in amount with maturation; in regenerating and denervated muscle fibers it is co-expressed with vimentin. Aggregates of desmin occur as nonspecific cytoplasmic bodies or cytoplasmic spheroid complexes, similar to the aggregates of keratin filaments in Mallory bodies or the neurofilament aggregates in Lewy bodies. In all three instances, alpha-B crystallin may be associated with desmin. There are now increasing numbers of neuromuscular disorders in which…

Infantile neuroaxonal dystrophy: Diagnosis by skin biopsy

A child who shows progressive motor and mental deterioration after the first year of life, who has pyramidal signs, marked muscle hypotonia, but no seizures, suggests to have infantile neuroaxonal dystrophy (INAD). Beyond the age of two years, the EEG also entails characteristic findings. Diagnosis may be obtained by an ultrastructural examination of biopsied skin. The respective clinical and morphological findings are recorded and illustrated from four patients in this report.

Mutations in the β-tropomyosin (TPM2) gene – a rare cause of nemaline myopathy

Nemaline myopathy is a clinically and genetically heterogeneous muscle disorder. In the nebulin gene we have detected a number of autosomal recessive mutations. Both autosomal dominant and recessive mutations have been detected in the genes for alpha -actin and alpha -tropomyosin 3. A recessive mutation causing nemaline myopathy among the Old Order Amish has recently been identified in the gene for slow skeletal muscle troponin T. As linkage studies had shown that at least one further gene exists for nemaline myopathy, we investigated another tropomyosin gene expressed in skeletal muscle, the beta -tropomyosin 2 gene. Screening 66 unrelated patients, using single strand conformation polymor…

Practical application of electron microscopy to neuromuscular diseases.

Concerning individual neuromuscular conditions, electron microscopy may be considered “essential,” “helpful,” or “wasteful.” “Essential” electron microscopy should provide a clear diagnosis, because of the disease specificity of the ultrastructural findings, in particular as to inclusions within muscle fibers, such as cylindrical spirals and reducing bodies. Electron microscopy may be “helpful” in detecting ultrastructural features preceding typical light microscopic findings, for instance, undulating tubules in endothelial cells. Congenital, metabolic, and inflammatory myopathies may often be more easily and more reliably diagnosed by means of the electron microscope. Diagnostically “waste…

Myopathy with hexagonally cross-linked crystalloid inclusions: delineation of a clinico-pathological entity.

A novel myopathy characterized by hexagonally cross-linked tubular arrays has been reported in five patients. We studied the clinical and histopathological features of five additional unrelated patients with this myopathy. Patients experienced exercise intolerance with exercise-induced myalgia and weakness, without rhabdomyolysis. One patient additionally presented mild permanent pelvic girdle muscle weakness. Age at onset varied between 13 and 56 years. The inclusions were eosinophilic on H and E, bright red with modified Gomori’s trichrome stains, present in type 2 fibers, and revealed immunoreactivity selectively for a caveolin-3-antibody. Ultrastructurally, the inclusions showed a highl…

Immunohistochemistry of primary central nervous system malignant rhabdoid tumors: report of five cases and review of the literature

Malignant rhabdoid tumors (MRT) are characterized by a typical light microscopic morphology with uniformly round tumor cells, vacuolated cytoplasm with occasional round, hyaline intracytoplasmic, periodic acid-Schiff-positive inclusions, vesicular nuclei with prominent nucleoli and positive immunoreactivity for vimentin. The histogenesis of MRT is controversial. Five cases of primary central nervous system (CNS) rhabdoid tumors in children are presented. Immunohistochemical, light and electron microscopic features are compared with primary CNS malignant rhabdoid tumors reported in the literature. Expression of various neurofilaments in our cases of primary CNS rhabdoid tumors was prominent …

Cell Death and Oxidative Damage in Inflammatory Myopathies

There is evidence that muscle fibers in denervating disorders and muscular dystrophies undergo apoptosis. In 21 patients with autoimmune inflammatory myopathies, we found no features of muscle fiber apoptosis such as DNA fragmentation or expression of apoptosis-related proteins. However, muscle fibers in myositis displayed distinct up-regulation of inducible and neuronal nitric oxide synthase (NOS). While inducible NOS was distinctly up-regulated on the sarcolemma of all kinds of muscle fibers neuronal NOS displayed increased expression in the sarcoplasm of damaged as well as atrophic muscle fibers. There were no disease-specific patterns in the different myositis subtypes. Enhanced express…

Adult polyglucosan body myopathy.

This report describes a sporadic late-onset myopathy in two unrelated adults which was marked by polyglucosan inclusions surrounded by abnormally structured mitochondria, the latter finding a localized, possibly reactive phenomenon. The polyglucosan material was characterized by a battery of histochemical and enzyme histochemical techniques; revealed common antigenicity with Lafora bodies, corpora amylacea and muscle fiber inclusions in types IV and VII glycogenoses; and contained ubiquitin. Additional lectin histochemical and associated digestion preparations disclosed the presence of alpha-glycosyl residues as apparently the sole carbohydrate component in polyglucosan bodies while the abo…

Nemaline myopathy with intranuclear rods--intranuclear rod myopathy.

Among the different nosological forms of nemaline/rod myopathy, one morphological variant is marked by intranuclear rods in addition to sarcoplasmic rods. Such patients fall into two categories: firstly, adults and secondly, young infants suffering from the severe form. Intranuclear rods indicate unfavourable prognosis. Recently, intranuclear rods without sarcoplasmic rods have also been encountered. Intranuclear rods, largely solitary, are often found large in size with the ultrastructural lattice pattern of sarcoplasmic rods and Z-disks. They contain alpha-actinin and actin. The origin of intranuclear rods is still enigmatic. Their presence within nuclei without sarcoplasmic rods points t…

Esthesioneuroblastoma: Ultrastructural, immunohistological and biochemical investigation of one case

A case of esthesioneuroblastoma, the pathological diagnosis of which almost always causes great difficulties, was investigated ultrastructurally, biochemically, and immunohistologically, using antibodies against the five known types of intermediate filaments [keratin, vimentin, desmin, glial fibrillary acidic protein (GFAP) and neurofilaments]. The tumour cells did not react with antibodies against any of the five intermediate filament proteins. Ultrastructural investigations showed dense cored secretory granules in the cytoplasm and cell processes. Thus, immunohistology offers by "exclusion" a differential diagnosis to avoid often misdiagnosed tumours (undifferentiated carcinomas, embryona…

Storage Diseases: Diagnostic Position

Storage diseases are metabolic multiorgan conditions, which may be divided into lysosomal and nonlysosomal diseases. Disorders of the lysosomal type require electron microscopy for morphological diagnosis. It is the metabolic substrate that determines involvement of the cell type or organ in the individual storage disease, allowing extracerebral biopsies, for instance, in the neuronal ceroid-lipofuscinoses (NCL). A hierarchy of tissues biopsied for diagnosis can be based on easy accessibility: blood lymphocytes, skin, conjunctiva, rectum, skeletal muscle. Lysosomal diseases are divided into vacuolar and nonvacuolar ones. NCL display variegated ultrastructural patterns. Drugs may induce lyso…

Desmin-related myopathy with mallory body-like inclusions is caused by mutations of the selenoprotein N gene

Desmin-related myopathies (DRMs) are a heterogeneous group of muscle disorders, morphologically defined by intrasarcoplasmic aggregates of desmin. Mutations in the desmin and the alpha-B crystallin genes account for approximately one third of the DRM cases. The genetic basis of the other forms remain unknown, including the early-onset, recessive form with Mallory body-like inclusions (MB-DRMs), first described in five related German patients. Recently, we identified the selenoprotein N gene (SEPN1) as responsible for SEPN-related myopathy (SEPN-RM), a unique early-onset myopathy formerly divided in two different nosological categories: rigid spine muscular dystrophy and the severe form of c…

Spheroid body myopathy revisited

Having reported spheroid body myopathy from Indiana (IN) inherited in an autosomal-dominant fashion several years ago, we now describe additional findings from the Oregon branch—briefly recorded earlier—and confirm earlier studies in another clinically affected IN member of this kinship demonstrating identical spheroid bodies within the myopathic muscle specimens. The spheroid bodies also contained increased amounts of desmin, α-B crystallin, and ubiquitin within muscle fibers. Our studies now have established that spheroid body myopathy is a member of the growing family of desminopathic neuromuscular conditions. © 1997 John Wiley & Sons, Inc. Muscle Nerve20:1127–1136, 1997

Infantile intranuclear rod myopathy.

This report concerns three unrelated floppy infants, two girls and one boy, each biopsied at the age of 1 month. They were hypotonic since birth and required artificial ventilation. The two girls died at the ages of 4 and 3½ months, respectively, the boy is still alive at the age of 2 years, but requires assisted ventilation. Each of the three infants showed, by muscle biopsy, abundant intranuclear rods, the boy and one girl also had sarcoplasmic rods, which were not present in the other girl's muscle. Absence of sarcoplasmic rods, but the presence of intranuclear rods could also be documented in her autopsied muscle. Using an antibody against α-actinin, immunoelectron microscopy showed re…

Secondary reduction in calpain 3 expression in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy (primary dysferlinopathies).

Made available in DSpace on 2016-10-10T03:52:18Z (GMT). No. of bitstreams: 5 Secondary reduction in calpain 3 expression in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy.pdf: 167085 bytes, checksum: b445ec059ea2d0f06bd4fa913354872a (MD5) license_url: 52 bytes, checksum: 2f32edb9c19a57e928372a33fd08dba5 (MD5) license_text: 24259 bytes, checksum: f1f24f769b03eb8f9cd3f53c1090841c (MD5) license_rdf: 24658 bytes, checksum: 9d3847733d3c0b59c7c89a1d40d3d240 (MD5) license.txt: 1887 bytes, checksum: 445d1980f282ec865917de35a4c622f6 (MD5) Previous issue date: 2000 Dysferlin is the protein product of the gene (DYSF) that is defective in patients with limb girdle muscular dy…

Ultrastructural studies of the retina in infantile neuronal ceroid-lipofuscinosis.

A 9-year-old boy who had died of infantile neuronal ceroid-lipofuscinosis had experienced retina-derived visual failure. Ophthalmologically and morphologically, his retina was severely atrophic and scarred by a dense fibrillary gliosis while photoreceptor cells had completely disappeared, cells of the bipolar layer had decreased in number and had become atrophic beyond cytologic recognition. Retinal pigment epithelial cells had undergone either atrophy or proliferation. Disease-specific granular lipopigments had accumulated in perikarya and processes of remaining cells and were infrequently associated with melanin within huge melanolipofuscin bodies and RPE cells of sessile and migrating na…

Gene-Related Protein Surplus Myopathies

Numerous muscular dystrophies, such as dystrophinopathies, sarcoglycanopathies, and emerino- and laminopathies, are marked by the absence or reduction of mutant transsarcolemmal or nuclear proteins. In addition to these recently identified minus-proteinopathies, there are a growing number of plus-proteinopathies among neuromuscular disorders marked by a surplus or excess of endogenous proteins within muscle fibers of different, i.e., nontranssarcolemmal and nonnuclear types. These proteins are often filamentous; for example, desmin and actin accrue in respective desmin-related myopathies, among which are entities marked by mutant desmin, true desminopathies, and actinopathy, the latter ofte…

Molecular, oncologic, and therapeutic spectrum of von Hippel-Lindau disease

Topical Review: Progress in Desmin-Related Myopathies

Desmin-related myopathies are sporadic and familial neuromuscular conditions of considerable clinical heterogeneity uniformly marked by the pathologic accretion of desmin, often in a filamentous fashion. A large variety of other proteins, some of them cytoskeletal, also accrue. Morphologically, two types may be distinguished, one characterized by inclusions such as cytoplasmic and spheroid bodies or desmin-dystrophin plaques and another marked by granulofilamentous material. The genetic spectrum of desmin-related myopathies is quite diverse in that missense mutations and deletions in the desmin gene and a missense mutation in the α-B crystallin gene have been detected and several genes on o…

Recent Advances in the Morphology of Myositis

Summary Myositis in man may be divided into infectious and non-infectious forms. The myopathologist more often deals with the latter forms which comprise dermatomyositis/polymyositis, inclusion body myositis, mixed connective tissue disease/collagenoses, and granulomatous myopathies. Modern morphological techniques as enzyme-histochemistry, electron microscopy, immunohistology, and morphometry are of different value in various forms of myositis, but are often indispensable techniques in up-to-date diagnostic work up of a myositis.

Congenital cytoplasmic body myopathy: case report.

Novel γ-sarcoglycan-mutation affects cardiac function and N-terminal dystrophin expression

Retinopathia Pigmentosa Plus - the Value of Ultra-Structural Examination of the Human Retina

Retinopathia pigmentosa is more widely, but somewhat incorrectly known as Retinitis pigmentosa (RP). Its course as a primary exclusively retinal disease follows autosomal-dominant, autosomal-recessive, or X-linked recessive modes of inheritance, or it may be sporadic. However, a progressive retinopathy, also called tapeto-retinal degeneration, may also be associated with numerous disorders: retinopathia pigmentosa plus (RPP). Among these RPP are those which form part of certain syndromes, e.g. Laurence-Moon-Bardet-Biedl syndrome, the Hallgren syndrome, the Marinesco-Sjogren syndrome, to name a few. Other RPP are associated with disorders of different organs, the skin, e.g. Werner disease, t…

A mild juvenile variant of type IV glycogenosis.

The mild juvenile form of type IV glycogenosis, confirmed by a profound deficiency of the brancher enzyme in tissue specimens is reported from three Turkish male siblings who, foremost, suffered from chronic progressive myopathy. Muscle fibers contained polyglucosan inclusions of typical fine structure, i.e. a mixture of granular and filamentous glycogen. They reacted strongly for myophosphorylase, but were resistant to diastase. These inclusions were ubiquitinated and reacted with antibody KM-279 which previously has been shown to bind to Lafora bodies, corpora amylacea and polyglucosan material in hepatic and cardiac cells of type IV glycogenosis as well as polyglucosan body myopathy with…

Neurometabolische Krankheiten mit neuropathologischen Befunden

Nach einer Darstellung allgemeiner Klassifikationsprinzipien und praktisch-diagnostischer Empfehlungen werden die Morphologie, Biochemie und Klinik zahlreicher neurologischer Krankheiten mit Stoffwechseldefekt besprochen. Wesentliche Krankheitsgruppen umfassen lysosomale Krankheiten (Gangliosidosen, Leukodystrophien, Sphingolipidosen, Mukolipidosen, Oligosaccharidosen, Mukopolysaccharidosen, Zeroidlipofuszinosen), peroxisomale Krankheiten, Mitochondriopathien, Polyglucosankrankheiten, Stoffwechselstorungen der Aminosauren und Krankheiten des Kupferstoffwechsels. Dabei wird besonderer Wert auf die Differentialdiagnose gelegt.

Workshop 6: Immunohistochemistry of Proteins in Neuromuscular Disorders

Immunelectronmicroscopic characterization of T4 and T8 lymphocytes and natural killer cells in neuronal ceroid-lipofuscinosis.

CD4+, CD8+, and CD56+ cells were isolated with the immunomagnetic separation technique from peripheral blood mononuclear cells (PBMC) of 3 patients with neuronal ceroid-lipofuscinosis : one patient each with infantile (INCL), late infantile (LINCL), and juvenile (JNCL) neuronal ceroid-lipofuscinoses, all studied by light (LM) and electron (EM) microscopy. To compare the pathology of these cells with affected cells in other types of lysosomal diseases, the separation was also performed with PBMC of 1 patient with mucolipidosis (ML) type II, 2 patients with mucopolysaccharidosis (MPS) type I, and 4 patients with MPS type III. Disease-specific lysosomal inclusions were identified in CD4+, CD8+…

Topical Review: The Neuronal Ceroid-Lipofuscinoses

The neuronal ceroid-lipofuscinoses, a group of progressive neurodegenerative diseases in children and in adults, have now been recognized for some 90 years, and the childhood forms represent one of the largest groups of progressive neurodegenerative diseases in children. Apart from a core group of major clinical forms—the infantile, the late-infantile, the juvenile, and the adult forms—numerous atypical patients afflicted with neuronal ceroid-lipofuscinosis have now been identified, constituting 10% to 20% of all patients with neuronal ceroid-lipofuscinosis. These "atypical" patients have, over the past 10 years, prompted the suggestion of 15 atypical variants or minor syndromes, many of th…

Myopathology of non-infectious inflammatory myopathies - the current status.

Besides the classical inflammatory myopathies (IM), dermatomyositis (DM), polymyositis, and inclusion body myositis, the much larger spectrum of IM includes focal and nodular myositis, granulomatous myositis, macrophagic myofasciitis, graft vs. host myositis, eosinophilic myositis, and other immune-associated conditions, some of them only recently described. In addition, paraneoplastic, statin-induced and critical illness myopathies have been considered immune-associated IM. Infectious, i.e., bacterial, viral, and parasitic IM are much less frequent in the northern hemisphere. In IM, muscle biopsy is an essential diagnostic procedure to initiate therapy. The myopathological spectrum encompa…

Lysosomal and Peroxisomal Disorders. Recent Advances: Introduction

Desmin‐related Myopathies

Outstanding progress in elucidating the pathology of muscular disorders at light and electron microscopic levels has allowed the identification of proteins involved in pathological alterations. This, in turn, has led to discoveries of multiple genes and mutations associated with previously poorly understood conditions. An unexpected result is that phenotypically similar and pathogenetically related neuromuscular disorders are associated with mutations in one or the other of several interacting proteins. Keywords: desmin-related myopathy; distal myopathy; cardiomyopathy; desmin and alpha-B crystallin gene mutations; functional analysis; molecular pathogenesis; genotype–phenotype correlations

Macrophagic myofasciitis in a 3-month-old child

Macrophagic myofasciitis (MMF) is a rare inflammatory myopathy which occurs after injection of aluminium-containing vaccines against hepatitis B virus (HBV), hepatitis A virus, and tetanus toxoid. Most of the cases reported are from France and are adult patients. We report a rare case of MMF in a 3-month-old male child of Indian origin. He was immunized for HBV at birth after which he developed generalized hypotonia, and central nervous system and peripheral nervous system manifestations at 1 month of age. Muscle biopsy showed typical features of MMF and aluminium could be detected in the muscle biopsy macrophages by ultrastructural examination and LAMMA technique. Our case is the youngest …

Protein aggregation in congenital myopathies.

Protein aggregation in congenital myopathies may be encountered among different myofibrillar myopathies such as granulofilamentous myopathy, cytoplasmic body myopathy, or spheroid body myopathy, which are designated as αB crystallinopathy, desminopathy, and myotilinopathy, respectively, according to the respective mutant proteins. Caps in cap disease and reducing bodies in reducing body myopathy were disclosed to contain numerous proteins. The multitude of diverse proteins aggregating within muscle fibers suggests impaired extralysosomal degradation of proteins, a disturbance of catabolism. The lack of different proteins accruing, but the mutant ones at an early age of affected patients in …

Myxoma of the orbit: a clinicopathologic report.

A 27-year-old white man developed proptosis of his left eye over a period of 2 years. It was associated with vertical diplopia and displacement of the left globe down and laterally. Ultrasonography showed a cystic mass in the superior orbital region. Computed tomography (CT) demonstrated a solid, well-defined lesion behind the globe displacing the optic nerve medially. A transfrontal craniotomy revealed a nodular mass in the posterior and superior orbit, which extended anteriorly up to the globe. Histopathology, immunohistochemistry, and transmission electron microscopy proved the tumor to be a myxoma.

Hamartoma of the triceps surae muscle.

A 9-year-old, otherwise healthy girl presented with a 5-year history of pain in her right calf with retarded growth and development of an equinus contracture of her right leg. Magnetic resonance imaging showed an irregular mass with heterogeneous enhancement after contrast in her right triceps surae muscles, especially the soleus. Histological studies of this triceps surae muscle tissue revealed a haphazard distribution of adipose and connective tissue, striated and smooth muscle cells, vessels and lymphoid follicles, as well as nerve bundles which, together, were considered components of a hamartoma.

Internalized myofiber capillaries: Observations on their origin and clinical features

Internalized capillaries limited to type 1 muscle fibers were noted in seven patients. They occurred in each case in association with a similar admixture of neurogenic and myopathic features that included atrophic and hypertrophic fibers, internal nuclei, fiber splitting, and endomyseal and perimyseal fibrosis. Internalized capillaries in enlarged type 1 fibers arose from fiber splits on step section study of four patients. They occurred in the gastrocnemius, quadriceps, and soleus muscles from patients with a variety of disorders that included Becker dystrophy, diabetes mellitus and strenuous leg activities, Achilles tendon rupture, and myotonic dystrophy. Exercise-induced myalgias were no…

Neuronal ceroid-lipofuscinoses: The current status

In view of the epidemiological connotation of childhood neuronal ceroid-lipofuscinosis (NCL) as one of the most frequent progressive lysosomal diseases and neurodegenerative disorders in children, the recognition of the individual clinical forms of childhood NCL is still based on invasive diagnostic electronmicroscopy which, currently, may be applied also for prenatal diagnosis. Like other inherited disorders, the NCL group has finally also benefited from the genetic breakthroughs of localization of the genes for infantile NCL and juvenile NCL on chromosomes 1 and 16, respectively. This review concerns recent advances in morphological studies, broadening of the clinical spectrum of childhoo…

Intermediate Filament Diseases: Desminopathy

Desminopathy is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins, desmin and alphaB-crystallin. The inheritance pattern in familial desminopathy is characterized as autosomal dominant or autosomal recessive, but many cases have no family history. At least some and likely most sporadic desminopathy cases are associated with de novo DES mutations. The age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Typically, the illness presents with lower and later upper limb muscle weakness slowly spreading to involve truncal, neck-flexor, facial and bulba…

Neuropathology of neurometabolic diseases in children with epilepsy.

Neurometabolic diseases are largely hereditary ones. They encompass lysosomal, peroxisomal, mitochondrial, and polyglucosan diseases as well as amino and organic acidemias/acidurias. Neuropathologically, the entire brain may be affected, i.e. pan-encephalopathy, the grey matter, preferentially being called polioencephalopathy or, when lesions might predominate in white matter, leukoencephalopathies/leukodystrophies. An important issue are extracerebral biopsies that facilitate or allow in vivo diagnosis and may be achieved by electron microscopy. Modern neuropathological techniques may retroactively be applied to archival tissues and those of modern mouse models.

Cytokine expression profile in idiopathic inflammatory myopathies.

Cytokines have been shown to be potent inducers of major histocompatibility complexes (MHC) class I and II as well as of cell adhesion molecules in muscle tissue cultures, indicating that cytokines may play a role in mediating muscle fiber damage in inflammatory myopathies. We found in 21 cases of autoimmune myositis various amounts of inflammatory cells expressing interleukin (IL)-1 alpha and -beta, IL-2, IL-4, tumor necrosis factor (TNF) -alpha and -beta, and interferon (IFN)-gamma and its receptor. Muscle fibers displayed enhanced expression of IL-1 alpha and -beta, IL-2, and TNF-alpha. Upregulation of cytokines was strongest at sites of cellular infiltration typical for the respective m…

Actin-related myopathy without any missense mutation in the ACTA1 gene.

Actinopathies are defined by missense mutations in the ACTA1 gene coding for sarcomeric actin, of which some 70 families have, so far, been identified. Often, but not always, muscle fibers carry large patches of actin filaments. Many such patients also have nemaline myopathy, qualifying actinopathies as a subgroup of nemaline myopathies. This article concerns a then newborn, now 21/2-year-old boy, the first and single child of nonconsanguineous parents, who was born floppy, requiring immediate postnatal assisted ventilation. A quadriceps muscle biopsy revealed large patches of thin myofilaments reacting at light and electron microscopic levels with antibodies against actin but only a few s…

Prophylactic Implantable Cardioverter Defibrillator Placement in a Sporadic Desmin Related Myopathy and Cardiomyopathy

Desminopathy is a neuromuscular disorder associated with the accumulation of the protein desmin. This article reports a case of a man with a mutation in the desmin gene suffering from cardiomyopathy and skeletal myopathy. This patient underwent implantable cardioverter defibrillator (ICD) implantation for prognostic considerations and subsequently developed a sustained ventricular tachycardia (SVT). While nonsustained VTs (NSVT) have previously been reported, this is the first time that a SVT could be seen in a patient with this disease.

Current state of clinical and morphological features in human NCL.

The neuronal ceroid lipofuscinoses (NCL) are large group of autosomal recessive lysosomal storage disorders with both enzymatic deficiency and structural protein dysfunction. Previously, diagnosis of (NCL) was based on age at onset clinicopathological (C‐P) findings described 4 forms, classified as infantile (INCL) (2), late‐infantile (LINCL) (5), juvenile (JNCL) (6), and adult (ANCL) most patients with NCL have progressive ocular and cerebral dysfunvtion, including cognitive/motor dysfunction and uncontrolled seizures. After reviewing 520 patients with NCL, we found that about 104 (20%) did not fit this classification of NCL With further research, 4 additional forms have been recognized: F…

Apoptosis-related Proteins in Skeletal Muscle Fibers of Spinal Muscular Atrophy

There is evidence that apoptosis in spinal muscular atrophies (SMA) is not restricted to motor neurons but also affects muscle fibers. Studying the expression of several apoptosis-associated proteins we found constant expression of bax in muscle fibers, which promoted cell death. The expression of bax correlated with defective innervation of muscle fibers was also indicated by upregulation of N-CAM. While in early-onset SMA atrophic as well as normo- and hypertrophic muscle fibers displayed expression of bax, muscle fibers in late-onset SMA and peripheral neuropathies showed bax-expression only in atrophic fibers. Other investigated apoptosis-associated factors comprised interleukin-1 beta …

Intranuclear nemaline rod myopathy

The clinical, pathologic, and genetic findings of a boy with intranuclear nemaline rod myopathy are described. Serial muscle biopsies revealed myocyte nuclei containing inclusions that were immunoreactive for α-actinin and increased with age. Genetic analysis revealed a Val163Leu ACTA1 mutation previously associated with nemaline rod myopathy. Although initially delayed, he has reached all milestones and remains stable. These findings suggest intranuclear rods may increase with time and do not necessarily imply a poor prognosis. Muscle Nerve, 2006

Protein surplus myopathies and other rare congenital myopathies.

The protein surplus myopathies have emerged as a newly recognized subgroup of morphologically defined myopathies within the spectrum of congenital myopathies because of the accumulation of protein aggregates, some of them mutant proteins. Currently, nosologic, including molecular criteria include desmin-related myopathies, actinopathies, and hereditary inclusion body myopathies, whereas hyaline body myopathy is still a putative form of protein surplus myopathy because of lack of any molecular data. The congenital myopathies (CM), foremost including nemaline and myotubular myopathies, have given evidence that, despite their epidemiologic rarity, the molecular age has dawned in CM and has eve…

Electron microscopic studies on skin and lymphocytes in early juvenile neuronal ceroid-lipofuscinosis.

Skin and lymphocytes of three patients with early juvenile neuronal ceroid-lipofuscinosis (NCL) were ultras trueturally investigated. Fingerprint profiles (FPP), isolated and I or mixed with curvilinear profiles (CLP), in various dermal cells and large, usually single lipopigments delineated by a trilaminar membrane and filled with a granular matrix, FPP and occasionally lipid droplets in lymphocytes were observed in all three patients. Characteristic lipopigments in lymphocytes are an important feature to differentiate between early juvenile NCL and late infantile and juvenile NCL.

Camptocormia associated with focal myositis in multiple-system atrophy

Camptocormia (CC) or pronounced forward flexion of the trunk is a common symptom of Parkinson's disease. We describe 2 patients with probable, respectively possible multiple-system atrophy and CC. Magnetic resonance imaging of the erector trunci showed focal patchy hyperintensities with gadolinium enhancement and muscle biopsy was indicative of variably pronounced focal myositis. CC was progressive and the major handicap for both patients after 1 and 1.5 years of follow-up, respectively. The therapeutic response was poor. Similarities with the dropped-head syndrome suggest that the muscle pathology may be either the primary cause of CC, a focal reaction to the CC posture, or a coincident sy…

Electron microscopic observation of tonsillar tissue as a diagnostic aid in early juvenile neuronal ceroid-lipofuscinosis.

An electron microscopic observation in a tonsil of a patient with early juvenile neuronal ceroid-lipofuscinosis (NCL) demonstrated characteristic lipopigments in lymphocytes, i.e., fingerprint profiles (FPP) and granular matrixes. While numerous FPP, curvilinear profiles (CLP) and granular matrixes were found in reticulo-endothelial and plasma cells, tonsillar lymphocytes contained only FPP and granular matrixes as seen in circulating lymphocytes. These findings suggest that a tonsil biopsy, an easy and simple technique, may provide more reliable information than a skin biopsy not only for the diagnosis of but also for differentiating the clinical forms of childhood NCL.

A series of West European patients with severe cardiac and skeletal myopathy associated with a de novo R406W mutation in desmin.

Desminopathy is a familial or sporadic cardiac and skeletal muscular dystrophy associated with mutations in desmin. We have previously characterized a de novo desmin R406W mutation in a patient of European origin with early onset muscle weakness in the lower extremities and atrioventricular conduction block requiring a permanent pacemaker. The disease relentlessly progressed resulting in severe incapacity within 5 years after onset. We have now identified three other patients with early onset rapidly progressive cardiac and skeletal myopathy caused by this same desmin R406W mutation. The mutation was present in each studied patient, but not in their parents or other unaffected family member…

Expression Profile of Stress Proteins, Intermediate Filaments, and Adhesion Molecules in Experimentally Denervated and Reinnervated Rat Facial Muscle

The immunohistochemical profiles of ubiquitin, heat shock protein 70, alpha-B-crystallin, desmin, vimentin, neural cell adhesion molecule (N-CAM), and tenascin in rat facial muscle were studied after permanent denervation by transection of the facial plexus on one side and compared with findings after immediate reinnervation by hypoglossal-facial nerve anastomosis subsequent to transection on the contralateral side. Levator labii muscle samples were collected sequentially at 2, 6, 7, 10, 20, and 24 weeks after surgery. Normal levator labii muscle fibers showed physiological expression of desmin and alpha-B-crystallin. Denervated rat facial muscle displayed distinct up-regulation of ubiquiti…

The metalloproteinase-disintegrin ADAM10 is exclusively expressed by type I muscle fibers.

ADAM10 (Kuzbanian) is a member of a recently discovered family of membrane-anchored metalloproteinases with a complex and conserved domain structure. In part, these metalloproteinases have been implicated in muscle formation. Herein the expression pattern of ADAM10 in human skeletal muscle was studied. ADAM10 was found to be present in human myoblasts and to be exclusively expressed in type I fibers, suggesting that it may be critical in muscle fiber differentiation.

Morphology of Skeletal Muscle

Skeletal muscle makes up the largest organ of the body, by both volume and weight, comprising more than 40 %. More than 500 diseases concern muscle tissue, the majority of which originate in muscle, others secondarily affect the muscle, foremost by denervation. The functional and structural dependence of skeletal muscle on innervation—that is, the peripheral and central nervous systems—renders muscle tissue unique and adds a dimension to the nosology, more obviously than in other organs. Therefore, diseases affecting muscle are also termed neuromuscular diseases. Within the nosological spectrum of the muscle parenchyma, which encompasses hereditary and acquired conditions, muscular dystroph…

Autophagic vacuolar myopathy is a common feature of CLN3 disease

Abstract Objective The neuronal ceroid lipofuscinoses (NCL) are genetic degenerative disorders of brain and retina. NCL with juvenile onset (JNCL) is genetically heterogeneous but most frequently caused by mutations of CLN3. Classical juvenile CLN3 includes a rare protracted form, which has previously been linked to autophagic vacuolar myopathy (AVM). Our study investigates the association of AVM with classic, non‐protracted CLN3. Methods Evaluation of skeletal muscle biopsies from three, non‐related patients with classic, non‐protracted and one patient with protracted CLN3 disease by histology, immunohistochemistry, electron microscopy, and Sanger sequencing of the coding region of the CLN…

Neuronal ceroid-lipofuscinosis--late-infantile or Jansky-Bielschowsky type--revisited.

Among the now eight genetic types of neuronal ceroid-lipofuscinoses (NCL), CLN1 to CLN8, CLN2 is considered classic late-infantile NCL. It was originally described by Janský in a family of eight children with four of them affected [Janský J (1908) Sborn Lek 13:165-196] and, subsequently, by Bielschowsky in a family of three children each of whom was affected, and, hence, termed Janský-Bielschowsky type of NCL. Earlier, archival studies of Bielschowsky's original post-mortem tissue blocks had documented accumulation of autofluorescent lipopigments with a curvilinear ultrastructure. In a subsequent study, described here, immunohistochemical absence of the CLN2-related lysosomal enzyme tripept…

Myofibrillar disorganization characterizes myopathy of camptocormia in Parkinson’s disease

Camptocormia is a highly disabling syndrome that occurs in various diseases but is particularly associated with Parkinson’s disease (PD). Although first described nearly 200 years ago, the morphological changes associated with camptocormia are still under debate and the pathophysiology is unknown. We analyzed paraspinal muscle biopsies of 14 PD patients with camptocormia and compared the findings to sex-matched postmortem controls of comparable age to exclude biopsy site-specific changes. Camptocormia in PD showed a consistent lesion pattern composed of myopathic changes with type-1 fiber hypertrophy, loss of type-2 fibers, loss of oxidative enzyme activity, and acid phosphatase reactivity …

When tubules aggregate

Within muscle fibres, tubules appear as microtubules, transverse tubules, and different components of the sarcotubular system, the latter consisting of longitudinal tubules and lateral or terminal sacs which, at special junctional connections, are situated on both sides of transverse tubules forming triads. Pathological structures related to the transverse tubules are honeycomb structures, both the transverse tubules and the honeycomb ones being labelled by extracellularly applied lanthanum [1] or potassium ferrocyanide [2], thus, indicating an open connection between the interior of the muscle fibres and the extracellular space. Dyads or multiple incomplete or complete forms of triads, pen…

Mitochondrial myopathy with lactic acidosis and deficient activity of muscle succinate cytochrome-c-oxidoreductase

A male infant had severe muscular hypotonia from birth. Recurrent vomiting with dehydration and severe metabolic acidosis complicated the course. Elevated lactate (up to 12.3 mmol/l; n less than 2), pyruvate (0.4 mmol/l; n less than 0.05) and alanine levels were found in serum with an abnormal lactate/pyruvate ratio (greater than 30; n less than 15). In urine the concentrations of lactate, pyruvate, alanine and of several intermediates of the citric acid cycle were increased. In muscle, numerous disseminated "ragged red fibres" were found by light microscopy; muscle fibres were found to contain subsarcolemmal aggregates of mitochondria, lipid droplets and glycogen by electromicroscopical me…

Diagnosis of the neuronal ceroid lipofuscinoses: An update

Abstract For the majority of families affected by one of the neuronal ceroid lipofuscinoses (NCLs), a biochemical and/or genetic diagnosis can be achieved. In an individual case this information not only increases understanding of the condition but also may influence treatment choices and options. The presenting clinical features prompt initial investigation and also guide clinical care. The clinical labels “infantile NCL”, “late infantile NCL” and “juvenile NCL”, therefore remain useful in practice. In unusual or atypical cases ultra-structural analysis of white blood cells or other tissue samples enables planning and prioritisation of biochemical and genetic tests.This review describes cu…

Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy

Muscle contraction results from the force generated between the thin filament protein actin and the thick filament protein myosin, which causes the thick and thin muscle filaments to slide past each other. There are skeletal muscle, cardiac muscle, smooth muscle and non-muscle isoforms of both actin and myosin. Inherited diseases in humans have been associated with defects in cardiac actin (dilated cardiomyopathy and hypertrophic cardiomyopathy), cardiac myosin (hypertrophic cardiomyopathy) and non-muscle myosin (deafness). Here we report that mutations in the human skeletal muscle alpha-actin gene (ACTA1) are associated with two different muscle diseases, 'congenital myopathy with excess o…

Immune-mediated rippling muscle disease with myasthenia gravis: a report of seven patients with long-term follow-up in two.

We report seven patients with immune-mediated rippling muscle disease (iRMD) and AChR-antibody positive myasthenia gravis (MG) without germline caveolin-3 gene mutations. We describe the follow-up of two patients and the clinical features of five new patients (1 female, 4 male, aged 32 to 69 years). These presented with significant generalized, exercise-induced and electrically-silent muscle rippling with myalgia, combined with generalized MG. In two of the seven patients, MG appeared before iRMD. Mediastinal imaging excluded thymic alterations in all, although two had other coincident tumours. Myalgia and rippling were aggravated by acetylcholinesterase-inhibitor treatment. Generalized MG …

Abnormal Lipopigments and Lysosomal Residual Bodies in Metachromatic Leukodystrophy

Ultrastructurally, metachromatic leukodystrophy (MLD) is marked by characteristic features such as herringbone, prismatic and tufaceous patterns which are typically encountered within oligodendrocytes of the central nervous system (CNS) and in Schwann cells (PNS). These patterns can be documented in late infantile, juvenile, and adult forms. In the latter, aging of the ailing individual adds another component, the accumulation of lipopigments which are marked by an opaque supposedly lipid droplet and a granular component. While MLD-specific lysosomal residual bodies occur in myelinforming cells, lipopigments accrue in neurons and to a lesser degree in astrocytes. MLD represents a unique exa…

Isocortical Pathology in Type C Niemann-Pick Disease

A case of Niemann-Pick disease was examined with Golgi preparations and a transparent Golgi impregnation counterstained for intraneuronal pigment deposits. There was a specific type of storage of unmetabolized substrate restricted to certain nerve cell types. The most conspicuous changes in the isocortex were: 1) dilated axonal segments in layer IIIab pyramidal cells filled with storage material; the volume of these axonal expansions often exceeded that of the soma; 2) distension of layer IIIc, layer V, and layer VIa pyramidal cell perikarya with storage material; 3) new formation, elongation, and vertical orientation of basal dendrites in layer V pyramidal cells; 4) well-preserved pyramida…

Expression of different isoforms of nitric oxide synthase in experimentally denervated and reinnervated skeletal muscle.

Denervated muscle fibers express enhanced levels of stress and apoptosis-associated proteins and undergo apoptosis. In experimentally denervated and reinnervated rat facial muscle, we now evaluate changes in the expression patterns of different isoforms of nitric oxide synthase (NOS)-generating nitric oxide (NO), which mediates oxidative stress and apoptosis. Physiological expression of NOS corresponds to a constant sarcolemmal staining pattern for neuronal NOS (nNOS) and a patchy sarcolemmal and weak sarcoplasmic labeling for the endothelial NOS-isoform, with no expression for inducible NOS (iNOS). Denervated muscle displayed distinct downregulation of nNOS with preserved expression of dys…

Congenital myopathy and epidermolysis bullosa due to PLEC variant

Abstract We report on an adult Turkish patient with mild myopathy with a fiber-type disproportion and mitochondrial disorganization caused by genetic variants in the plectin gene (PLEC). Molecular genetic panel testing revealed two homozygous variants in PLEC (NM_000445.4): c.8306C>G (p.Pro2769Arg) and c.7506 + 5C>G (p. ?) that were classified as variants of unknown significance (class 3) following ACMG guidelines for variant classification in genetic diagnostics. A thorough reassessment of the patient revealed mild skin blistering (epidermolysis bullosa simplex, EBS). This illustrates the importance of deep phenotyping of neuromuscular patients.

Morphological studies on CLN2

Electron microscopic, fluorescence microscopic, and immunohistochemical studies earlier performed on archivalcerebral tissue from Max Bielchowsky's original three patients revealed curvilinear bodies rich in subunit C of mitochondrial ATP synthase (SCMAS). Recent progress in the elucidation of CLN2, i.e. identification of the defective lysosomal enzyme tripeptidyl-peptidase I (TPP-I) and mutations in the CLN2 gene have further corroborated earlier data. Immunohistochemically the absence of the TPP-I protein could be confirmed in the archival tissues using pathological controls. Unlike biochemistry, immunohistochemistry enables examination of these archival tissues elucidating the causative …

Experimental emetine myopathy: enzyme histochemical, electron microscopic, and immunomorphological studies.

Ipecac, containing emetine hydrochloride, is used by patients with anorexia nervosa to induce vomiting. Its chronic usage may result in a myopathy and a cardiomyopathy, the former marked by cytoplasmic bodies. We studied myopathological changes after daily injections of female Wistar rats with emetine hydrochloride intraperitoneally for periods of 4, 5, 9, and 10 weeks. the extensor digitorum longus muscle and the soleus muscle showed core-like lesions, streaming of the z-discs, nemaline bodies, cytoplasmic bodies, and spheroid cytoplasmic bodies. Immunomorphological studies revealed increased amounts of desmin. During a period of repair, i.e., 2, 4, and 6 weeks after termination of emetine…

Protein aggregate myopathies.

Protein aggregate myopathies (PAMs) based on the morphologic phenomenon of aggregation of proteins within muscle fibers may occur in children (selenoproteinopathies, actinopathies, and myosinopathies) or adults (certain myofibrillar myopathies and myosinopathies). They may be mutation related, which includes virtually all childhood forms but certain other forms as well, or sporadic, which are largely seen in adults. Their classification as myofibrillar or desmin-related myopathies, actinopathies, or myosinopathies is based on the identification of respective mutant proteins, most of them components of the sarcomeres. Recognition of PAM requires muscle biopsy and an extensive immunohistochem…

Congenital myopathies with inclusion bodies: a brief review

Abstract Based on morphological abnormalities, congenital myopathies can be classified into several categories: (1) enzyme histochemically abnormal appearance without structural pathology, e.g. congenital fibre type disproportion or congenital fibre type uniformity; (2) abnormally placed nuclei, e.g. myotubular and centronuclear myopathies; (3) disruption of normal intrinsic structures, largely sarcomeres, e.g. central cores and minicores; (4) abnormal inclusions within muscle fibres. Several such inclusions are derived from pre-existing structures, most notably rods or nemaline bodies. Other derivatives of Z-band material are cytoplasmic bodies and possibly related inclusions as spheroid b…

Structural congenital myopathies (excluding nemaline myopathy, myotubular myopathy and desminopathies): 56th European Neuromuscular Centre (ENMC) sponsored International Workshop December 12–14, 1997, Naarden, The Netherlands

Incidence of neuronal ceroid-lipofuscinoses in West Germany: Variation of a method for studying autosomal recessive disorders

The incidence of neuronal ceroid-lipofuscinoses (NCL) in West Germany was determined using a novel method which is applicable to other autosomal recessively inherited diseases. Questionnaires were sent to all pediatric departments (answer rate 189/276, 68%), schools for the blind (39/46, 85%), and neuropathological institutes (15/22, 68%). Diagnoses were accepted only when based on firm clinical and/or electron microscopic criteria; 207 such identified patients were sorted according to year of birth. Plotting the cumulative number of new cases per year against the year of birth resulted in a slightly S-shaped curve. Before the year 1962, the curve is relatively flat, probably due to ineffic…

Actinopathies and Myosinopathies

The currently recognized two forms of "anabolic" protein aggregate myopathies, that is, defects in development, maturation and final formation of respective actin and myosin filaments encompass actinopathies and myosinopathies. The former are marked by mutations in the ACTA1 gene, largely of the de novo type. Aggregates of actin filaments are deposited within muscle fibers. Early clinical onset is often congenital; most patients run a rapidly progressive course and die during their first 2 years of life. Myosinopathies or myosin storage myopathies also commence in childhood, but show a much more protracted course owing to mutations in the myosin heavy chain gene MYH7. Protein aggregation co…

Human pathology in NCL

AbstractIn childhood the neuronal ceroid lipofuscinoses (NCL) are the most frequent lysosomal diseases and the most frequent neurodegenerative diseases but, in adulthood, they represent a small fraction among the neurodegenerative diseases. Their morphology is marked by: (i) loss of neurons, foremost in the cerebral and cerebellar cortices resulting in cerebral and cerebellar atrophy; (ii) an almost ubiquitous accumulation of lipopigments in nerve cells, but also in extracerebral tissues. Loss of cortical neurons is selective, indiscriminate depletion in early childhood forms occurring only at an advanced stage, whereas loss of neurons in subcortical grey-matter regions has not been quantit…

Macrophagic myofasciitis plus (distinct types of muscular dystrophy).

Macrophagic myofasciitis (MMF) is a well-known lesion following vaccination with aluminium-containing vaccines. It has abundantly been reported in adults and several times in children, often in single patients or in rather small cohorts. Only few of these published reports on children have shown distinct myopathology of another neuromuscular disease except for MMF. Indications for biopsy often were nondescript clinical features in children, such as hypotonia or delay in motor development but, apparently, never that of suspected MMF. Thus, in previous reports as well as in our two patients, encountering MMF in the biopsied tissue specimens was coincidental. Our two unrelated patients with MM…

Novel slow-skeletal myosin (MYH7) mutation in the original myosin storage myopathy kindred

Abstract Myosin storage myopathy (OMIM 608358), a congenital myopathy characterised by subsarcolemmal, hyaline-like accumulations of myosin in Type I muscle fibres, was first described by Cancilla and Colleagues in 1971 [Neurology 1971;21:579–585] in two siblings as ‘familial myopathy with probable lysis of myofibrils in type I muscle fibres'. Two mutations in the slow skeletal myosin heavy chain gene ( MYH7 ) have recently been associated with the disease in other families. We have identified a novel heterozygous Leu1793Pro mutation in MYH7 in DNA from paraffin sections of one of the original siblings. This historical molecular analysis confirms the original cases had myosin storage myopat…

Characteristic morphologic manifestation of CADASIL, cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy, in skeletal muscle and skin.

Aluminum in a baby's muscle.

Muscular alteration in agyria with pyramidal tract anomaly

A 4-year-old boy with a history of muscular hypotonia, mental retardation, microcephaly, and generalized convulsions was found at autopsy to have agyria, agenesis of the anterior commissure and posterior corpus callosum as well as an abnormal decussation of pyramidal tracts which descended in the spinal dorsal columns. Postmortem muscular alterations included type IIc fiber hypertrophy and type I fiber grouping, variably expressed in individual muscles and intramuscular fascicles. This may represent a developmental delay compatible with a gestational age between the 34th and 40th week. These studies also indicate the importance of examining (a) multiple samples of postmortem muscles and (b)…

De Novo prion aggregates trigger autophagy in skeletal muscle

ABSTRACT In certain sporadic, familial, and infectious prion diseases, the prion protein misfolds and aggregates in skeletal muscle in addition to the brain and spinal cord. In myocytes, prion aggregates accumulate intracellularly, yet little is known about clearance pathways. Here we investigated the clearance of prion aggregates in muscle of transgenic mice that develop prion disease de novo . In addition to neurodegeneration, aged mice developed a degenerative myopathy, with scattered myocytes containing ubiquitinated, intracellular prion inclusions that were adjacent to myocytes lacking inclusions. Myocytes also showed elevated levels of the endoplasmic reticulum chaperone Grp78/BiP, su…

July 2003: 62-year-old female with progressive muscular weakness

The July 2003 Case of the Month (COM). A 62-year-old female patient experienced progressive muscular weakness over the last ten years, involving shoulder and pelvic girdle muscles, paraspinal and facial muscles. A biopsy was taken from the left deltoid muscle where hepatitis vaccination had taken place 4 weeks previously. The specimen revealed macrophagic myofasciitis due to the injection of aluminium-bound vaccines. The finding can be reproduced experimentally by injecting vaccines in rats. The pathomechanism is supposed to involve immune stimulation due to long term persistence of the adjuvant. Macrophagic myofasciitis has been suggested to occasionally cause myopathy but is supposed to b…