Abnormal Somatosensory Evoked Potentials Indicate Compressive Cervical Myelopathy in Mucopolysaccharidoses

Compressive myelopathy at the cranio-cervical junction is a complication of mucopolysaccharidoses (MPS). To detect cervical myelopathy we recorded median and posterior tibial nerve SEPs in 15 patients aged 2.4 - 33.4 years (median 8.8 years) with MPS I-S (n = 3), MPS IVA (n = 8) and MPS VI (n = 4). In addition to the cortical waveforms we recorded the subcortical median nerve SEPs N13b and P13 generated near the cranio-cervical junction and the lemniscal P30 after posterior tibial nerve stimulation. MRI studies in 13 subjects revealed spinal cord compression at the cranio-cervical junction in 10 patients; 5 patients had an increased signal intensity on the T2-weighted initial MRI indicating…

Cardiac manifestations of Anderson-Fabry disease: results from the international Fabry outcome survey.

Aims Anderson–Fabry disease (AFD) is an uncommon X-linked disorder caused by deficient activity of the lysosomal enzyme α-galactosidase A. The Fabry Outcome Survey is a European database designed to monitor the long-term efficacy and safety of enzyme replacement therapy (ERT) with agalsidase alfa. The aim of this study was to determine the prevalence and characteristics of cardiac disease in AFD patients. Methods and results Clinical and laboratory data were available in 714 patients from 11 countries (mean age 35 ± 17 years, 369 women, 336 treated). The prevalence of angina was 23 vs. 22%; palpitations and arrhythmias 27 vs. 26%; exertional dyspnoea 23 vs. 23%; and syncope 2 vs. 4%, in wom…

Prenatal diagnosis and carrier detection in mucopolysaccharidosis type II by mutation analysis. A 47,XXY male heterozygous for a missense point mutation.

Identification of iduronate-2-sulphatase (IDS) gene mutations in patients with mucopolysaccharidosis type II (MPS II, Hunter syndrome) allows fast and reliable carrier detection and prenatal diagnosis. We describe here three cases of prenatal diagnosis by direct detection of the gene mutation. In addition to two affected male fetuses from two different families, a 47,XXY fetus carrying both the normal and the mutant allele was diagnosed in a third family. The latter pregnancy was carried to term and the child is obviously not affected by MPS II.

Source document verification in the Mucopolysaccharidosis Type I Registry

Purpose The Mucopolysaccharidosis Type I (MPS I) Registry is an international observational database that tracks the natural history and the outcomes of patients with MPS I. The Registry was a regulatory requirement following the approval of laronidase enzyme replacement therapy for MPS I in 2003. All data are collected voluntarily after informed consent from the patient or family. Data are checked through queries, monthly reviews, and electronic audits to identify missing, inconsistent, or invalid data. This analysis sought to determine overall data accuracy in the Registry through source document verification (SDV). Methods Two phases of SDV were performed. In each phase, Registry data we…

Correction: Corrigendum: Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome

CORRIGENDUM: Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome

A 15-Year Perspective of the Fabry Outcome Survey

Abstract The Fabry Outcome Survey (FOS) is an international long-term observational registry sponsored by Shire for patients diagnosed with Fabry disease who are receiving or are candidates for therapy with agalsidase alfa (agalα). Established in 2001, FOS provides long-term data on agalα safety/efficacy and collects data on the natural history of Fabry disease, with the aim of improving clinical management. The FOS publications have helped establish prognostic and severity scores, defined the incidence of specific disease variants and implications for clinical management, described clinical manifestations in special populations, confirmed the high prevalence of cardiac morbidity, and demon…

123 MOLECULAR GENETIC ANALYSIS IN HUNTER DISEASE

Clinical and biochemical studies have revealed a great phenotypic variability in mucopolysaccharidosis type II (Hunter disease), probably due to different mutations in the IDS gene that has been localized in Xq28. Using a cDNA probe containing almost the entire coding region of the human IDS gene, we performed a molecular analysis on 7 patients with Hunter disease. In one patient, a complete deletion of the IDS coding sequences was found. Another patient had structural alterations of the IDS gene including a partial deletion. In 5 patients, however, after restriction digestion of the DNA by PstI and TaqI and Southern hybridization with the IDS cDNA, the audiographic patterns obtained were s…

Central corneal thickness in mucopolysaccharidosis II and VI.

Objective To describe the ultrasonographically detected central corneal thickness (CCT) in patients with Type II and VI mucopolysaccharidosis (MPS) and its impact on applanation tonometry and glaucoma detection. Methods Twenty-eight patients with MPS (19 MPS II, nine MPS VI) underwent pachymetric investigation of CCT. Additionally, ultrasound measurements of axial length of the globe, slit-lamp evaluation with semiquantitative grading of corneal clouding, applanation tonometry, and assessment of refractive error were performed. Results Median average corneal thickness was 534.5 microm (range, 491.5-579.0 microm) in the MPS II and 547.0 microm (range, 492.5-693.05 microm) in the MPS VI group…

Diagnostic efficacy of the fluorometric determination of enzyme activity for Pompe disease from dried blood specimens compared with lymphocytes-possibility for newborn screening.

Pompe disease is a rare, autosomal-recessive disorder which results from a defect in the lysosomal enzyme acid alpha-glucosidase (GAA). The onset of this disease is highly variable, with infantile types being the most severe. Traditionally, lymphocytes, fibroblasts or muscle biopsies were necessary for enzyme activity measurement, because these materials do not express maltase-glucoamylase (MGA) that interferes with the assay. Recently, acarbose was found to inhibit MGA activity selectively, so that dried blood became accessible for GAA assessment.To evaluate the diagnostic efficacy of GAA measurement in dried blood specimens (DBSs) in comparison with lymphocytes. If DBSs provided reliable …

Thirty-four novel mutations of the GLA gene in 121 patients with Fabry disease

Fabry disease (FD) is an X-chromosomal disorder caused by mutations in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A. We performed mutation screening on a cohort of 121 patients including 84 male and 37 female index cases and identified a total of 90 different mutations, 34 of which are reported for the first time here. Both point mutations (74.4%) and 'short length' rearrangements (25.6%) were found, including missense (54.4%), nonsense (14.4%), and splice site point mutations (5.6%), deletions (17.8%) or insertions/duplications (5.6%) of a few nucleotides, and complex rearrangements including larger deletions (2.2%). GLA mutations were identified in 82 (97.6%) of the 84…

Long-term follow-up of endurance and safety outcomes during enzyme replacement therapy for mucopolysaccharidosis VI: Final results of three clinical studies of recombinant human N-acetylgalactosamine 4-sulfatase

Abstract The objective of this study was to evaluate the long-term clinical benefits and safety of recombinant human arylsulfatase B (rhASB) treatment of mucopolysaccharidosis type VI (MPS VI: Maroteaux-Lamy syndrome), a lysosomal storage disease. Fifty-six patients derived from 3 clinical studies were followed in open-label extension studies for a total period of 97–260 Weeks. All patients received weekly infusions of rhASB at 1mg/kg. Efficacy was evaluated by (1) distance walked in a 12-minute walk test (12MWT) or 6-minute walk test (6MWT), (2) stairs climbed in the 3-minute stair climb (3MSC), and (3) reduction in urinary glycosaminoglycans (GAG). Safety was evaluated by compliance, adve…

Cardiac manifestations of Anderson-Fabry disease in heterozygous females.

AbstractObjectivesWe sought to define the prevalence of cardiac involvement in female patients with Anderson–Fabry disease (AFD).BackgroundAnderson–Fabry disease is a rare inborn X-linked lysosomal storage disorder. Globotriaosylceramide (Gb3), the major substrate of the deficient α-galactosidase A enzyme, accumulates progressively in vulnerable cells, including the cardiovascular system. It has been believed that heterozygous females have less cardiac involvement than hemizygous males with AFD.MethodsWe performed two-dimensional echocardiographic examinations of female patients heterozygous for AFD.ResultsSince 1997, a total of 55 female patients (mean age, 39.6 years; range, 6.1 to 70.8 y…

Adenoids of patients with mucopolysaccharidoses demonstrate typical alterations.

Abstract Objective Tonsillar hypertrophy caused by the progressive accumulation of partially degraded glycosaminoglycans (GAGs) within the cells is a typical symptom in patients with mucopolysaccharidoses (MPS). We studied the tissue of adenoids and tonsils of patients suffering from MPS with special regard to characteristic morphological features serving as possible markers for diagnosis. Methods Adenoids of 87 patients and tonsils of 4 patients with MPS (2 patients with MPS I, 7 MPS II, 5 MPS IV and 10 MPS VI and 63 controls) and controls were examined. Examinations were repeated in a blinded manner by two pathologists. Results The key feature observed was a subepithelial “clearing” on sc…

Increase in left ventricular mass index and acroparesthesia incidence in children with Fabry disease correlates with their GLA mutation

Neuraminidase deficiency presenting as non-immune hydrops fetalis

A newborn infant with oedema, ascites and hepatosplenomegaly is described. In ascites fluid foamy macrophages were found, in a liver biopsy cytoplasmic inclusions and membrane-bound vacuoles were seen. Furthermore the child excreted excessive amounts of sialic acid-rich oligosaccharides in the urine, and therefore a neurovisceral degenerative disorder was assumed. The diagnosis of sialidosis was confirmed by enzymatic assay in cultured fibroblasts, in which a complete deficiency of the lysosomal enzyme neuraminidase could be demonstrated. After recurrent septicaemias the child became dystrophic and died at the age of 6 months. Our case is compared with sialidosis observed by other authors, …

Comment: Why are females with Fabry disease affected?

Thromboembolic events in Fabry disease and the impact of factor V Leiden

Although several reports suggest an increased thromboembolic event rate, especially regarding strokes and TIAs at early age in patients with Fabry disease (FD), the risk for patients with FD to experience these events, the clinical relevance of additional risk factors including the concurrence of factor V Leiden (FVL), and the benefit of enzyme replacement therapy (ERT) regarding these events remain unclear.Three hundred four consecutively recruited patients with FD were evaluated for their lifetime occurrence of thromboembolic events such as stroke, TIA, deep vein thrombosis, and pulmonary embolism. The thromboembolic risk was determined in patients with FD and concurrent FVL, and the impa…

Orthopedic manifestations in patients with mucopolysaccharidosis type II (Hunter syndrome) enrolled in the Hunter Outcome Survey.

Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a rare, inherited disorder caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase. As a result of this deficiency, glycosaminoglycans accumulate in lysosomes in many tissues, leading to progressive multisystemic disease. The cardiopulmonary and neurological problems associated with MPS II have received considerable attention. Orthopedic manifestations are common but not as well characterized. This study aimed to characterize the prevalence and severity of orthopedic manifestations of MPS II and to determine the relationship of these signs and symptoms with cardiovascular, pulmonary and central nervous system involvemen…

Molecular analysis of Gaucher disease: distribution of eight mutations and the complete gene deletion in 27 patients from Germany

Gaucher disease is the most common lysosomal storage disease with a high prevalence in the Ashkenazi Jewish population but it is also present in other populations. The presence of eight mutations (1226G, 1448C, IVS2+1. 84GG, 1504T, 1604T, 1342C and 1297T) and the complete deletion of the beta-glucocerebrosidase gene was investigated in 25 unrelated non-Jewish patients with Gaucher's disease in Germany. In the Jewish population, three of these mutations account for more than 90% of all mutated alleles. In addition, relatives of two patients were included in our study. Restriction fragment length polymorphism analysis and sequencing of PCR products obtained from DNA of peripheral blood leukoc…

Farber disease (acid ceramidase deficiency) epidemiology: literature review and patient cohort data indicate moderate and attenuated phenotypes are likely underrepresented in the medical literature and are underdiagnosed

<p>Cardio- Renal Outcomes With Long- Term Agalsidase Alfa Enzyme Replacement Therapy: A 10- Year Fabry Outcome Survey (FOS) Analysis</p>

Purpose Following the publication of 5-year agalsidase alfa enzyme replacement therapy (ERT) outcomes data from the Fabry Outcome Survey (FOS), 10-year data were analyzed. Patients and methods FOS (ClinicalTrials.gov identifier: NCT03289065) data (April 2001 to August 2018) were retrospectively analyzed. Estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) were analyzed after treatment start (baseline) for patients with ≥3 measurements, including baseline and year 10. Results Median (range) age (years) of the evaluable treated renal cohort at treatment start was 48.8 (17.9-67.3) for females (n=62), 34.4 (18.0-66.8) for males (n=90). With eGFR ≥60 mL…

Clinical outcomes in idursulfase-treated patients with MPS II: 3-year data from the Hunter Outcome Survey (HOS)

Measuring patient experiences in Fabry disease: validation of the Fabry-specific Pediatric Health and Pain Questionnaire (FPHPQ)

Abstract Introduction Common symptoms for children with Anderson-Fabry Disease (FD) such as acroparaesthesia and gastrointestinal manifestations can only be objectively assessed in patients using a valid instrument. To date, no such instrument exists. Methods A preliminary 40-item measure of symptoms and experience with FD, the Fabry-specific Paediatric Health and Pain Questionnaire (FPHPQ) was developed, but lacked a formal assessment of its measurement properties. The FPHPQ was used in the Fabry Outcome Survey (FOS), a registry for all patients with a confirmed diagnosis of FD who are receiving agalsidase alfa, or are treatment naïve and who are managed by physicians participating in FOS.…

Progressive cerebellar ataxia in juvenile GM 2 -gangliosidosis type Sandhoff

Insights into the management of patients with MPS II: Key findings following 10years of the Hunter Outcome Survey (HOS)

Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey.

Background Fabry disease is a rare X-linked disorder caused by deficient activity of the enzyme alpha-galactosidase A. This produces progressive lysosomal accumulation of globotriaosylceramide throughout the body, leading to organ failure and premature death. Aim Here, we present the clinical manifestations of Fabry disease in children enrolled in FOS--the Fabry Outcome Survey--a European database of the natural history of Fabry disease and the effects of enzyme replacement therapy with agalsidase alfa (Replagal). Methods Currently, there are 545 patients in FOS, from 11 European countries. We analysed the baseline demographic and clinical characteristics of 82 of these patients (40 boys, 4…

Determination of globotriaosylceramide in plasma and urine by mass spectrometry

Abstract Background: Fabry disease is an X-chromosomally inherited lysosomal storage disorder leading to accumulation of glycosphingolipids, mainly globotriaosylceramide (ceramide-trihexoside, Gb3). Concentrations of Gb3 in plasma and urine have been used to diagnose Fabry disease and to monitor enzyme replacement therapy with recombinant α-galactosidase. Methods: Gb3 was purified from plasma or urine by combined liquid extraction/protein precipitation and solid-phase extraction, and was detected by flow-injection analysis electrospray mass spectrometry (MS) using multi-reaction-monitoring. Calibration was performed via standard addition using C17-Gb3 as internal standard. The most abundant…

Disease manifestations and X inactivation in heterozygous females with Fabry disease

Aim: Fabry disease is an X-linked lysosomal storage disorder characterized by an accumulation of neutral glycosphingolipids in multiple organ systems caused by α-galactosidase A deficiency due to mutations in the GLA gene. The majority of heterozygous females show the characteristic signs and symptoms of the disease, and some of them are severely affected. The current hypothesis for the occurrence of disease manifestations in females is skewed X inactivation favouring the mutant GLA allele. Method: We analyzed the patterns of X inactivation in the leukocytes of 28 biochemically and genetically characterized symptomatic Fabry disease heterozygotes and their correlation with clinical and bioc…

The heart and cardiovascular system in patients with Morquio syndrome type A

Mitral and aortic regurgitation in 84 patients with mucopolysaccharidoses

In echocardiographic and necropsy studies nodular thickening of the mitral valve and, less frequently, of the aortic valve has been found in 60%-90% of patients with mucopolysaccharidoses (MPS). Little is known about the haemodynamic consequences of these morphological changes. In this study 84 unselected patients with different enzymatically proven MPS and 84 age and sex matched, healthy persons were studied prospectively by colour Doppler flow mapping. The patients' age ranged from 1 to 47 years (median 8.1 years). Mitral and aortic regurgitation were defined as a holosystolic or holodiastolic jet originating from the valve into the left atrium or the left ventricular outflow tract, respe…

HETEROGENEITY OF METATROPIC DYSPLASIA

Metatropic dysplasia is a neonatally manifest entity that is characterized clinically by a rapidly progressing kyphoscoliosis leading to severe shortening of the originally long trunk ("metatropism"). Major radiographic features include flattening and defective ossification of the vertebral bodies, a narrow thorax and a marked hypoplasia of the basilar portions of the ilia with crescent-shaped iliac crests. There is some evidence of genetic heterogeneity. From five personal observations and from a review of the literature we conclude that metatropic dysplasia comprises at least three genetic entities: (1) a nonlethal type with autosomal recessive transmission; (2) a nonlethal dominant type …

Mutational analysis of 105 mucopolysaccharidosis type VI patients

Mucopolysaccharidosis type VI (MPS VI; Maroteaux-Lamy syndrome) is a lysosomal storage disorder caused by mutations in the N-acetylgalactosamine-4-sulfatase (arylsulfatase B, ARSB) gene. ARSB is a lysosomal enzyme involved in the degradation of the glycosaminoglycans (GAG) dermatan and chondroitin sulfate. ARSB mutations reduce enzyme function and GAG degradation, causing lysosomal storage and urinary excretion of these partially degraded substrates. Disease onset and rate of progression is variable, producing a spectrum of clinical presentation. In this study, 105 MPS VI patients—representing about 10% of the world MPS VI population—were studied for molecular genetic and biochemical parame…

Enzyme replacement therapy in Fabry disease: Comparison of agalsidase alfa and agalsidase beta

Critical assessment of chitotriosidase analysis in the rational laboratory diagnosis of children with Gaucher disease and Niemann-Pick disease type A/B and C.

Laboratory diagnosis of lysosomal storage disorders, especially sphingomyelinase deficiency (Niemann–Pick disease type A/B) and Niemann–Pick disease type C (NPC) can be challenging. We therefore aimed to analyse the feasibility of first-step screening with specific chitotriosidase cut-off values in children ≤ 10 years of age with visceral organomegaly (hepatomegaly, splenomegaly, or hepatosplenomegaly) in whom a storage disorder was suspected. We conducted a retrospective, cross-sectional, referral, single-centre study to assess diagnostic test properties in 106 individuals. Median chitotriosidase activity was 12 655 nmol/h per ml (interquartile range 4693–20982) in Gaucher disease (GD); 78…

Diagnose und Therapie des Morbus Gaucher Aktuelle Empfehlungen der deutschen Therapiezentren im Jahr 2000

Hintergrund: Beim Morbus Gaucher handelt es sich um die haufigste Sphingolipidose, deren Vorkommen zwischen 1 : 40 000 (in Zentraleuropa) und 1 : 2 000 (in einigen ausereuropaischen Landern, zum Beispiel Israel) variiert. Zugrunde liegt dieser Speichererkrankung ein autosomal-rezessiv vererbter Defekt der Glucocerebrosidase, der zu einem verminderten Abbau der Sphingolipide fuhrt. Die akuten und chronischen neuronopathischen Verlaufsformen (fruher als Gaucher-Typen 2 und 3 bezeichnet) sind mit 5 bis 10% in Mitteleuropa und Deutschland seltener als die nicht neuronopathische Variante (fruher als Gaucher-Typ 1 bezeichnet). Klinisch ist der Morbus Gaucher charakterisiert durch die Kernsymptome…

An 18-month-old girl with hoarseness, stiff joints and subcutaneous nodules

Development of a Scoring System to Evaluate the Severity of Craniocervical Spinal Cord Compression in Patients with Mucopolysaccharidosis IVA (Morquio A Syndrome).

BackgroundAs spinal cord compression at the craniocervical junction (CCJ) is a life-threatening manifestation in patients with mucopolysaccharidosis (MPS) IVA, surgical decompression should be performed before damage becomes irreversible. We evaluated the diagnostic value of several examinations for determining the need for decompression surgery.MethodsWe retrospectively analysed results of clinical neurological examination, somatosensory evoked potential (SEP) and magnetic resonance imaging (MRI) in 28 MPS IVA patients. A scoring system - based on the severity of findings - was used to compare results of patients with and without indication for decompression surgery. Individual test scores…

Molecular basis of mucopolysaccharidosis type II: Mutations in the iduronate-2-sulphatase gene

A number of mutations in the X-chromosomal human iduronate-2-sulphatase gene have now been identified as the primary genetic defect leading to the clinical condition known as Hunter syndrome or mucopolysaccharidosis type II. The mutations that are tabulated include different deletions, splice-site and point mutations. From the group of 319 patients thus far studied by Southern analysis, 14 have a full deletion of the gene and 48 have a partial deletion or other gross rearrangements. All patients with full deletions or gross rearrangements have severe clinical presentations. Twenty-nine different "small" mutations have so far been characterised in a total of 32 patients. These include 4 nons…

Idursulfase treatment of Hunter syndrome in children younger than 6 years: results from the Hunter Outcome Survey.

Purpose: To use the Hunter Outcome Survey, an international database, to assess the safety and effectiveness of enzyme replacement therapy with idursulfase in patients with Hunter syndrome who started treatment before 6 years of age. Methods: The study population included all patients enrolled in the Hunter Outcome Survey who started idursulfase infusions (0.5 mg/kg every other week) before 6 years of age and who had at least one follow-up examination recorded. Results: The study population included 124 patients, younger than 6 years, who had a mean age at start of idursulfase of 3.6 ± 1.6 years (mean ± SD). The mean duration of treatment was 22.9 ± 14.6 months. A total of 69 infusion-relat…

Acid ceramidase deficiency: Farber lipogranulomatosis, spinal muscular atrophy associated with progressive myoclonic epilepsy and peripheral osteolysis

Abstract An inherited deficiency of the lysosomal enzyme ceramidase leads to accumulation of the sphingolipid ceramide in several organs such as skin, liver, brain and other tissues, resulting in a broad spectrum of clinical manifestations. The most common form, called Farber lipogranulomatosis, is characterized by subcutaneous skin nodules and a progressive hoarseness, in many cases also the central nervous system is affected. A lethal hydrops fetalis represents the most severe form. A ceramidase deficiency was also found in a few patients in whom neurological symptoms such as spinal muscular atrophy and myoclonus epilepsy dominated the clinical picture, in other adult patients peripheral …

Proteoglycan synthesis by cultured human chondrocytes.

Iliac crest biopsies are important in the detection of human skeletal dysplasias. Therefore, culture of these cells may serve as a valuable method for studying proteoglycan metabolism in chondrocytes of individuals with skeletal abnormalities. Morphological and biochemical studies were performed on human iliac crest chondrocytes grown in monolayer and in agarose gels. Two proteoglycan populations of different hydrodynamic size and glycosaminoglycan composition were synthesized by cells grown in monolayer. Chondrocytes cultured in an agarose gel for 2 weeks synthesized proteoglycans identical to those of the native tissue with respect to hydrodynamic size and glycosaminoglycan chain length. …

Measuring patient experiences in fabry disease: validation of the Fabry Outcome Survey (FOS) paediatric health and pain questionnaire

Psychiatrische und neuropsychologische Auffälligkeiten bei Patienten mit Morbus Fabry: Literaturübersicht

Fabry Disease (FD) is an X-linked lysosomal storage disorder (prevalence about 1 : 100 000) caused by a genetic defect associated with a lack of alpha-galactosidase A (alpha-GAL) enzyme activity. As a consequence, neutral glycosphingolipides can not be cleaved and metabolized, and accumulate in lysosomes of several tissues, particularly in vascular endothelium and smooth muscle cells. The most prominent symptoms comprise pain attacks and acroparesthesia, angiokeratoma, corneal opacity, renal and cardiac dysfunction, hypo- and anhidrosis, gastrointestinal symptoms, and cerebrovascular dysfunction with vertigo, headache, and cerebral ischemia. Characteristic symptoms of FD can occur in male a…

Neuropsychiatric symptoms and brain structural alterations in Fabry disease

Background:  Neuropsychiatric symptoms (NPS), mainly cognitive deficits up to dementia and depressive syndromes have been described repeatedly in Fabry disease (FD). However, examinations regarding the pattern, extent, and frequency of the NPS in FD are still lacking. Moreover, the relationship between NPS and brain structural alterations in FD is unknown. The aim of this study was 1) to characterize NPS in a relatively large cohort of adult subjects with FD, and 2) to explore the association of cognitive performance and depressive syndromes with the FD-typical brain structural findings. Methods:  Twenty-five Fabry patients (age 36.5 ± 11.0) with mild to moderate disease involvement and 20 …

Quantification of the Fabry marker lysoGb3 in human plasma by tandem mass spectrometry

Morbus Fabry is a hereditary metabolic disorder with low prevalence and late clinical manifestation. A defect in the α-galactosidase gene leads to lysosomal accumulation of the glycolipid globotriaosylceramide (Gb3). Gb3 may be used for monitoring of enzyme replacement therapy (ERT), but diagnostic sensitivity is limited. Recently, globotriaosylsphingosine (lysoGb3) was introduced as a promising new marker with significantly better sensitivity. For Fabry diagnosis, clinical studies and possible therapy monitoring, we established a fast and reliable LC-MS/MS assay for quantification of lysoGb3 in human plasma. Protein precipitation and glycolipid extraction from EDTA plasma was performed usi…

The Role of Next-Generation Sequencing in the Diagnosis of Lysosomal Storage Disorders

Next-generation sequencing (NGS) panels are used widely in clinical diagnostics to identify genetic causes of various monogenic disease groups including neurometabolic disorders and, more recently, lysosomal storage disorders (LSDs). Many new challenges have been introduced through these new technologies, both at the laboratory level and at the bioinformatics level, with consequences including new requirements for interpretation of results, and for genetic counseling. We review some recent examples of the application of NGS technologies, with purely diagnostic and with both diagnostic and research aims, for establishing a rapid genetic diagnosis in LSDs. Given that NGS can be applied in a w…

Lysosomal storage disorder in non-immunological hydrops fetalis (NIHF) - more common than assumed? Report of four cases with transient NIHF and a review of the literature

Abstract Background Lysosomal storage disorders (LSD) are a rare cause of non immunological hydrops fetalis (NIHF) and congenital ascites. The reported incidence is about 1%. The incidence of idiopathic NIHF is estimated to be about 18%. Patients and methods We report four cases with transient hydrops fetalis resulting from LSD and performed a literature review on LSD with NIHF and congenital ascites in combination. Results At present, 12 different LSDs are described to be associated with NIHF or congenital ascites. Most patients had a family history of NIHF, where the preceding sibling had not been examined. A diagnostic approach to the fetus with NIHF due to suspected LSD either in utero …

Long-term effectiveness of agalsidase alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis

Outcomes from 5 years of treatment with agalsidase alfa enzyme replacement therapy (ERT) for Fabry disease in patients enrolled in the Fabry Outcome Survey (FOS) were compared with published findings for untreated patients with Fabry disease. Data were extracted from FOS, a Shire-sponsored database, for comparison with data from three published studies. Outcomes evaluated were the annualized rate of change in estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) as well as time to and ages at a composite morbidity endpoint and at death. FOS data were extracted for 740 treated patients who were followed for a median of ~ 5 years. Compared with no trea…

The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents.

Fabry disease (FD) is a debilitating progressive multisystem X-linked lysosomal storage disorder. It was generally believed that the disease affects only adult males. Through systematic pedigree analysis, we identified 35 paediatric FD patients (age 1 to 21 years, mean 12.6 years) in 25 families. Predominant signs in this cohort were: acroparesthesia, hypohidrosis, and cornea verticillata. Neurological and psychological changes, such as tinnitus, recurrent vertigo, headache, diminished level of activity, fatigue, and depression were often observed. Angiokeratoma and gastrointestinal symptoms were frequent. Some patients also showed cardiac abnormalities. Six children and adolescents (three …

Functional and genetic characterization of the non-lysosomal glucosylceramidase 2 as a modifier for Gaucher disease.

Background: Gaucher disease (GD) is the most common inherited lysosomal storage disorder in humans, caused by mutations in the gene encoding the lysosomal enzyme glucocerebrosidase (GBA1). GD is clinically heterogeneous and although the type of GBA1 mutation plays a role in determining the type of GD, it does not explain the clinical variability seen among patients. Cumulative evidence from recent studies suggests that GBA2 could play a role in the pathogenesis of GD and potentially interacts with GBA1. Methods: We used a framework of functional and genetic approaches in order to further characterize a potential role of GBA2 in GD. Glucosylceramide (GlcCer) levels in spleen, liver and brain…

Enzyme replacement therapy for mucopolysaccharidosis VI: evaluation of long-term pulmonary function in patients treated with recombinant human N-acetylgalactosamine 4-sulfatase.

Pulmonary function is impaired in untreated mucopolysaccharidosis type VI (MPS VI). Pulmonary function was studied in patients during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB; rhN-acetylgalactosamine 4-sulfatase). Pulmonary function tests prior to and for up to 240 weeks of weekly infusions of rhASB at 1 mg/kg were completed in 56 patients during Phase 1/2, Phase 2, Phase 3 and Phase 3 Extension trials of rhASB and the Survey Study. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and, in a subset of patients, maximum voluntary ventilation (MVV), were analyzed as absolute volume in liters. FEV1 and FVC showed little change f…

Measuring corneal clouding in patients suffering from mucopolysaccharidosis with the Pentacam densitometry programme

Aim To identify a means to objectively measure corneal clouding in patients with mucopolysaccharidosis in a prospective controlled clinical trial. Methods Corneal haze was assessed by slit lamp examination and measured using the densitometry programme of the Pentacam, a rotating Scheimpflug camera in 33 mucopolysaccharidoses (MPS) patients and 32 controls. Results Pentacam measurements were available in 31 right and 31 left eyes of 32 patients and in 32 left and right eyes of 32 subjects in the control group. Slit lamp findings correlated very well with corneal density measurements (Spearman correlation right eye (OD)/left eye (OS)=0.782/0.791). MPS patients had higher density units (median…

Clinical course of sly syndrome (mucopolysaccharidosis type VII).

WOS: 000377110800007

Clinical and neuroradiological findings in classic infantile and late-onset globoid-cell leukodystrophy (Krabbe disease)

In the present study the clinical course and imaging of early and late-onset forms of Krabbe disease are analyzed. We report on 11 patients with a biochemical diagnosis of galactosyl ceramide β-galactoside deficiency. Two presented as the classic infantile form and died within the second year of life. In 9 children the first clinical signs, such as gait difficulties and visual failure, started after age 2 years. All these patients developed slow regression of motor and mental capacities, and most of them died within their first decade. In patients of both groups computed tomography (CT) and magnetic resonance imaging (MRI) were performed. In the late-onset form, hypodensities of the central…

Downregulation of alpha-galactosidase A upregulates CD77: functional impact for Fabry nephropathy.

Anderson-Fabry disease, an inherited deficiency in the lysosomal enzyme alpha-galactosidase A, is characterized by the progressive accumulation of globotriaosylceramide (Gb3), also known as CD77. We sought to clarify the pathogenesis of Fabry disease by establishing a cell model of this disorder. The expression of alpha-galactosidase A was transiently silenced by RNA interference in HK2 and primary human renal epithelial cells and stably silenced in HK2 cells by retroviral transfection with small hairpin RNA. All of the silenced cells had histological similarities to cells of patients with Fabry disease. The cells had reduced viability, significant accumulation of intracellular Gb3, and a m…

Thalamic hyperdensity — is it a diagnostic marker for Sandhoff disease?

Sandhoff disease, also known as GM2-gangliosidoses variant 0, is caused by the deficient activity of both hexosaminidase A and hexosaminidase B. We report a 15-month-old boy diagnosed with Sandhoff disease by demonstrating the enzyme deficiency. The interesting finding was bilateral thalamic hyperdensity on the CT scan. The hyperdensity in all previously published cases was homogeneous and symmetric and limited to the thalamus; the cause still remains unknown. We suggest that the finding of dense thalami may be useful as a specific diagnostic criterion for the GM2-gangliosidoses and especially for Sandhoff disease.

Clinical outcomes after 3 years of idursulfase treatment in patients with MPS II: data from the Hunter Outcome Survey (HOS)

Deletion of the Hunter gene and both DXS466 and DXS304 in a patient with mucopolysaccharidosis type II.

Hunter syndrome is an X-linked mucopoly-saccharidosis due to deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS). A cDNA clone containing the entire coding region of the human IDS gene, mapped in Xq28, has been used as molecular probe to study a patient with Hunter syndrome. A submicroscopic deletion has been detected that spans the IDS gene as well as DXS466 and DXS304, 2 loci mapped probably not more than 900 kb from the IDS locus. A detailed clinical description of the patient is provided and his phenotype is compared to that of other patients with IDS deletion described recently. By following the segregation of a restriction fragment length polymorphism at the IDS locus in th…

Prevalence and characterization of cardiac involvement in Hunter syndrome.

To assess the prevalence of cardiovascular signs and symptoms in a large group of patients with Hunter syndrome, an X-linked metabolic disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase.The Hunter Outcome Survey was established to characterize the natural history of Hunter syndrome and to assess the response to enzyme replacement therapy. Echocardiographic and electrocardiographic examination results were available for 102 patients who were enzyme replacement therapy-naïve in the Hunter Outcome Survey (median age at examination, approximately 8 years) as of Jan 23, 2009.The most common cardiovascular finding was valve disease, which was present in 63% of patients.…

Brain structural alterations in Fabry disease: ROI-based and voxel-based analyses of diffusion tensor imaging parameters

Hunter disease before and during enzyme replacement therapy.

Mucopolysaccharidosis type II (Hunter disease) is a lysosomal storage disease attributable to X-linked deficiency of the enzyme α-L-iduronate-sulfatase. Because of this deficiency, glycosaminoglycanes accumulate in various tissues and body fluids. We describe three patients representing the broad spectrum of Hunter disease and their response to enzyme replacement therapy. Patient 1 did not manifest central nervous system involvement, patient 2 manifested moderate neurologic disease, and patient 3 had already manifested a severe neurologic course during early infancy. In all patients, improvements in visceral organ size, physical capacity, and gastrointestinal functioning were reported. More…

Pathophysiologische Aspekte hirnstruktureller Veränderungen bei Morbus Fabry: Literaturübersicht

Fabry Disease (FD) is a rare X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A (alpha-GAL) enzyme activity. Neutral glycosphingolipides (esp. Gb3) accumulate in lysosomes of several tissues, particularly in vascular endothelium and smooth muscle cells. Cerebral manifestations that might be mainly due to progressive cerebrovascular dysfunction, are one major and often life-threatening burden of the disease. We reviewed the present literature concerning brain structural alterations in FD and discuss the possibly relevant underlying pathophysiological aspects of these disturbances. Cerebrovascular events (TIA, stroke) occur in FD at a rather early age. In female…

Splice donor site mutation in the lysosomal neuraminidase gene causing exon skipping and complete loss of enzyme activity in a sialidosis patient.

Sialidosis is a lysosomal storage disease caused by the deficiency of K K-N-acetylneuraminidase (NEU1; sialidase), the key enzyme for the intralysosomal catabolism of sialylated glycoconjugates. We have identified a homozygous transversion in the last intron (IVSE +1 Gs C) in neu1 of a sialidosis patient. Sequencing of the truncated cDNA revealed an alternatively spliced neu1 transcript which lacks the complete sequence of exon 5. Skipping of exon 5 leads to a frameshift and results in a premature termination codon. This is the first description of an intronic point mutation causing a complete deficiency of the lysosomal neuraminidase activity. fl 2001 Federation of Euro- pean Biochemical S…

Farber disease: design of the first observational and cross-sectional cohort study capturing retrospective and prospective data on the natural history and phenotypic spectrum of patients, including novel methodologies for assessment of disease-specific symptoms

Voxel based analyses of diffusion tensor imaging in Fabry disease

Background: Fabry disease (FD) is a lysosomal storage disorder that is associated with marked cerebrovascular disease. Conventional MRI shows an extensive load of white matter lesions (WMLs) already at an early stage in FD. Objective: Investigator independent and sensitive quantification of brain structural changes in clinically affected men and women with FD. Methods: The authors performed a voxel-based analysis of diffusion tensor images (DTI) in 25 FD patients and 20 age-matched normal controls. Results: DTI revealed significant increases of cerebral white matter diffusivity (MD) in FD patients that were pronounced in the periventricular white matter. Even the subgroup of patients withou…

Molecular analysis in patients with mucopolysaccharidosis type II suggests that DXS466 maps within the Hunter gene

Hunter disease is an X-linked mucopolysaccharidosis caused by deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS). Using the IDS cDNA and DNA probes corresponding to loci flanking the IDS locus, we performed molecular genetic studies in two patients with Hunter syndrome. An interstitial deletion spanning the middle part of the IDS gene was found in the first patient. The second patient carries a gross gene rearrangement that can be detected after HindIII or EcoRI digestion of genomic DNA, and is similar to that found recently in seven unrelated Hunter patients. Our data suggest that the structural aberration observed is a partial intragenic inversion. As the same altered hybridiz…

75 The hunter outcome survey (HOS): A registry of mucopolysaccharidosis II patients

Enzyme replacement and gene therapy for mucopolysaccharidoses: current progress and future directions

Introduction: Mucopolysaccharidoses (MPS) are lysosomal storage disorders caused by the deficiency of enzymes that are responsible for the stepwise degradation of complex carbohydrates, the glycosaminoglycans. Whereas in the past the treatment of MPS consisted mainly of palliative care, enzyme replacement therapy (ERT) is now possible for some MPS disorders, and in the future many other therapeutic options will become available.Areas covered: This review, based on personal experience and the currently available literature, will give an overview on the efficacy and limitations of ERT and will discuss new therapeutic approaches, such as anti-inflammatory drugs, substrate reduction therapy, ch…

Mutation analyses in 17 patients with deficiency in acid β-galactosidase: three novel point mutations and high correlation of mutation W273L with Morquio disease type B

An inherited deficiency in beta-galactosidase can result in GM1 gangliosidosis, with several phenotypes of generalized or chronic psychomotor deterioration, as well as in Morquio disease type B, a characteristic mucopolysaccharidosis free of neurological symptoms. We performed mutation analyses in 17 juvenile and adult patients from various European regions with a deficiency in beta-galactosidase and skeletal abnormalities. Fifteen of these had the Morquio B phenotype and have remained neurologically healthy until now while the two others exhibited psychomotor retardation of juvenile onset. A two-base substitution (851-852TG--CT; W273L) was present in 14 of the 15 Morquio B cases. Even if o…

Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome.

Purpose: This study evaluated the safety and effectiveness of long-term enzyme replacement therapy with idursulfase (recombinant human iduronate-2-sulfatase) in patients with Hunter syndrome. Methods: All 94 patients who completed a 53-week double-blinded study of idursulfase enrolled in this open-labeled extension study and received intravenous idursulfase at a dose of 0.5 mg/kg weekly for 2 years, and clinical outcomes and safety were assessed. Results: No change in percent predicted forced vital capacity was seen, but absolute forced vital capacity demonstrated sustained improvement and was increased 25.1% at the end of the study. Statistically significant increases in 6-minute walking t…

Enzyme replacement therapy with agalsidase alfa in pregnant women with Fabry disease

Ocular Changes in Patients With Mucopolysaccharidosis I Receiving Enzyme Replacement Therapy

Objective To describe the progression of ocular changes in patients with mucopolysaccharidosis I receiving enzyme replacement therapy. Methods Three male and five female patients with mucopolysaccharidosis I were followed up for 4 years while undergoing enzyme replacement therapy with α-L-iduronidase (Aldurazyme). Visual acuity, corneal clouding, intraocular pressure, ophthalmoscopy, and optic disc measurements were performed yearly. Results Vision remained stable in 5 patients and deteriorated by at least 2 Snellen lines in 3 patients. Deterioration in 2 of these patients was related to progressive corneal clouding. Visual acuities improved in 1 patient after bilateral penetrating keratopl…

Acid Ceramidase Deficiency

Abstract A deficiency of the lysosomal enzyme ceramidase leads to accumulation of the sphingolipid ceramide in several organs such as skin, liver, brain and other tissues, resulting in a broad spectrum of clinical manifestations. The most common form, called Farber lipogranulomatosis, is characterized by subcutaneous skin nodules and a progressive hoarseness, in many cases also the central nervous system is affected. A lethal hydrops fetalis represents the most severe form. A ceramidase deficiency was also found in a few patients in whom neurological symptoms such as spinal muscular atrophy and myoclonus epilepsy dominated the clinical picture. In the ceramidase gene, which has been mapped …

Prevalence of Uncontrolled Hypertension in Patients With Fabry Disease

Background Fabry disease is a rare X-linked disease arising from deficiency of α-galactosidase A. It results in early death related to renal, cardiac, and cerebrovascular disease, which are also important outcomes in patients with elevated blood pressure (BP). The prevalence of uncontrolled hypertension, as well as the effect of enzyme replacement therapy on BP, in patients with Fabry disease is unknown. Methods We examined uncontrolled hypertension (systolic BP [SBP] ≥130 mm Hg or diastolic BP [DBP] ≥80 mm Hg) among 391 patients with Fabry disease who were participating in the Fabry Outcome Survey (FOS). Results Uncontrolled hypertension was present in 57% of men and 47% of women. In patie…

Mucopolysaccharidosis Type VII (Sly disease) survivors

treatment. Onset of neurological symptoms at age 8 and in adolescence. Pair 4: L.M. died at age 5 months due to liver failure. P.M. (7 years): earlyinfantile form, despite treatment start at age 2 progressive neurological deterioration. Pair 5: R.K.: late-infantile form, untreated, died at age 9 due to progressive neurological involvement. M.K.: late infantileform, start of treatment at age 5, died at age 13 due to epileptic encephalopathy. These cases reveal that disease onset and progression in siblings with NPC vary, and that miglustat can slow disease progression.

Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa.

Globotriaosylceramide concentrations were assessed as potential predictors of change from baseline after 12 months by estimated glomerular filtration rate and left-ventricular mass index using pooled data from three randomized, placebo-controlled agalsidase alfa trials and open-label extensions of patients with Fabry disease.Males (aged 18 years or older) with Fabry disease received agalsidase alfa (0.2 mg/kg every other week for 12 months). A backward-elimination approach evaluated potential predictors (baseline estimated glomerular filtration rate and left-ventricular mass index; age at first dose; baseline and change from baseline at 12 months of globotriaosylceramide (urine, plasma); ur…

Treatment strategies for lysosomal storage disorders.

Over the past several years the number of treatments available for patients with lysosomal storage disorders has rapidly increased. Haematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction, and chaperone therapies are currently available, and gene therapies and other treatments are rapidly advancing. Despite remarkable advances, the efficacy of most of these therapies is limited, particularly because the treatments are usually initiated when organ damage has already occurred. To circumvent this limitation, screening in newborn infants for lysosomal storage disorders has been introduced in many countries. However, this screening is complicated by the broad cl…

Development and testing of new screening method for keratan sulfate in mucopolysaccharidosis IVA.

Mucopolysaccharidosis IVA (MPS IVA), a progressive lysosomal storage disease, causes skeletal dysplasia through excessive storage of keratan sulfate (KS). We developed an ELISA-sandwich assay that used a MAb specific to KS. Forty-five blood and 59 urine specimens from MPS IVA patients (ages 1–65 y) were analyzed to determine whether KS concentration is a suitable marker for early diagnosis and longitudinal assessment of disease severity. Blood specimens were obtained from patients categorized as phenotypically severe (n = 36) and milder (n = 9). Urine specimens were also analyzed from patients categorized as severe (n = 56) and milder (n = 12), respectively. Blood KS levels (101–1525 ng/mL)…

A 4-year study of the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa in 36 women with Fabry disease

Although Fabry disease is X linked and considered to affect primarily male hemizygotes, female heterozygotes may experience all the signs and symptoms of this metabolic disorder. This prospective, single-center, open-label, clinical trial was performed to evaluate the long-term response of female patients with Fabry disease to enzyme replacement therapy.Symptomatic women (average age = 47 years) enrolled in this 4-year study were treated with agalsidase alfa (Replagal, Shire HGT, Inc.) at a dose of 0.2 mg/kg, every other week for 4 years (N = 36). Clinical and biochemical assessments were conducted at 12-month intervals.The Mainz Severity Score Index, a measure of total disease burden, was …

Fetal presentation of Morquio disease type A.

A fetus with mucopolysaccharidosis type IV A (Morquio type A) is described. The family had one affected child exhibiting symptoms of classical Morquio A disease, and late in the subsequent pregnancy prenatal diagnosis was requested. At 23 weeks' gestation, moderate ascites was detected by detailed ultrasound scan and keratan sulphate was found in the amniotic fluid. The pregnancy was terminated by prostaglandin induction and the diagnosis of mucopolysaccharidosis type IV A was confirmed by demonstration of a deficiency of N-acetylgalactosamine-6-sulphate (GalNac-6-S) sulphatase in cultured amniotic cells and in post-mortem fibroblast cultures. The activities of beta-galactosidase and arylsu…

Influence of retinol on human chondrocytes in agarose culture

Vitamin A and its congeners, collectively called retinoids, are known to have teratogenic potential and have induced craniofacial and limb malformations in numerous animal species. More importantly, retinoids are recognized as teratogenic to fetuses of pregnant women who have taken such preparations for dermatologic disorders. Information gathered from the study of animal models suggests that retinoids interfere with cartilage differentiation. If chondrogenesis in limb development is disturbed it may contribute to limb reductions and malformations. In vitro studies using various animal systems have shown that cartilage matrix macromolecules are altered to resemble those secreted by mesenchy…