Search results for "Leukodystrophy"

2015

Objective Pelizaeus–Merzbacher disease (PMD) is a progressive and lethal leukodystrophy caused by mutations affecting the proteolipid protein (PLP1) gene. The most common cause of PMD is a duplication of PLP1 and at present there is no curative therapy available. Methods By using transgenic mice carrying additional copies of Plp1, we investigated whether curcumin diet ameliorates PMD symptoms. The diet of Plp1 transgenic mice was supplemented with curcumin for 10 consecutive weeks followed by phenotypical, histological and immunohistochemical analyses of the central nervous system. Plp1 transgenic and wild-type mice fed with normal chow served as controls. Results Curcumin improved the moto…

Transporteurs ABC peroxysomaux et adrénoleucodystrophie liée au chromosome X

2012

X-linked adrenoleukodystrophy (X-ALD) is a complex neurodegenerative disease associated with mutations in the ABCD1 gene, which encodes for a peroxisomal ABC transporter. Thanks to the efforts of the ELA foundation and to the recent successes of gene therapy published in Science in 2009, X-ALD is better known but still remains poorly understood. The exact role of ABCD1 and its homologs, as well as the exact link between the biochemical and metabolic peroxisomal defects and the clinical symptoms of the disease remain to be elucidated. This review summarizes the knowledge concerning the subfamily D of the ABC transporter family and concerning X-ALD, the most frequent peroxisomal disorder.

The Inflammatory Response in Acyl-CoA Oxidase 1 Deficiency (Pseudoneonatal Adrenoleukodystrophy)

2012

Among several peroxisomal neurodegenerative disorders, the pseudoneonatal adrenoleukodystrophy (P-NALD) is characterized by the acyl-coenzyme A oxidase 1 (ACOX1) deficiency, which leads to the accumulation of very-long-chain fatty acids ( VLCFA) and inflammatory demyelination. However, the components of this inflammatory process in P-NALD remain elusive. In this study, we used transcriptomic profiling and PCR array analyses to explore inflammatory gene expression in patient fibroblasts. Our results show the activation of IL-1 inflammatory pathway accompanied by the increased secretion of two IL-1 target genes, IL-6 and IL-8 cytokines. Human fibroblasts exposed to very-long-chain fatty acids…

Effect of dietary polyunsaturated fatty acids on the expression of peroxisomal ABC transporters

2008

Abstract Peroxisomal ABC transporters encoded by the ABCD genes are thought to participate in the import of specific fatty acids in the peroxisomal matrix. ABCD1 deficiency is associated with X-linked adrenoleukodystrophy (X-ALD), the most frequent peroxisomal disorder which is characterized by the accumulation of saturated very-long-chain fatty acids (VLCFA). ABCD2 (the closest homolog of ABCD1) and ABCD3 have been shown to have partial functional redundancy with ABCD1; only when overexpressed, they can compensate for VLCFA accumulation. Other lipids, for instance polyunsaturated fatty acids (PUFA), should be possible candidate substrates for the ABCD2 and ABCD3 gene products, ALDRP and PM…

A novel compound heterozygous mutation in GALC associated with adult-onset Krabbe disease: case report and literature review

2021

Krabbe disease (KD) is a rare autosomal recessive lipid storage leukodystrophy. It is caused by deficient enzyme activity resulting from mutations of the β-galactocerebrosidase (GALC) gene. KD is distinguished into subtypes based on the age of onset; these are early infantile, late infantile, juvenile, and adult-onset. We report a case of a 47-year-old Caucasian man with a 2-year history of muscle atrophy and weakness in both hands associated with pyramidal signs and mild spasticity in the lower limbs. An extensive work-up led this motor neuron disease-like disorder to be diagnosed as adult-onset KD. The patient was found to be compound heterozygous for two GALC mutations (p.G286D and p.Y49…

Aspartoacylase-lacZ knockin mice: an engineered model of Canavan disease.

2011

Canavan Disease (CD) is a recessive leukodystrophy caused by loss of function mutations in the gene encoding aspartoacylase (ASPA), an oligodendrocyte-enriched enzyme that hydrolyses N-acetylaspartate (NAA) to acetate and aspartate. The neurological phenotypes of different rodent models of CD vary considerably. Here we report on a novel targeted aspa mouse mutant expressing the bacterial β-Galactosidase (lacZ) gene under the control of the aspa regulatory elements. X-Gal staining in known ASPA expression domains confirms the integrity of the modified locus in heterozygous aspa lacZ-knockin (aspa(lacZ/+)) mice. In addition, abundant ASPA expression was detected in Schwann cells. Homozygous (…

Giant axonal neuropathy and leukodystrophy

1991

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…

Impact of 7-Ketocholesterol and Very Long Chain Fatty Acids on Oligodendrocyte Lipid Membrane Organization: Evaluation Via LAURDAN and FAMIS Spectral…

2011

International audience; In the context of multiple sclerosis and X-linked adrenoleukodystrophy, 7-ketocholesterol (7KC) and very long chain fatty acids (C24:0, C26:0) are supposed to induce side effects respectively on oligodendrocytes which are myelin (which is a lipoproteic complex) synthesizing cells. The effects of 7KC (25, 50 mu M), C24:0 and C26:0 (10, 20 mu M) on cell viability and lipid membrane organization were investigated on 158N murine oligodendrocytes. Concerning 7KC and fatty acids (at 20 mu M only):1) cell growth was strongly inhibited; 2) marked induction of cell death was revealed with propidium iodide (PI); 3) no apoptotic cells were found with C24:0 and C26:0 (absence of…

Dehydroepiandrosterone up-regulates the Adrenoleukodystrophy-related gene (ABCD2) independently of PPAR alpha in rodents

2007

International audience; X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disease caused by mutations in the ABCD1 gene, which encodes a peroxisomal ABC transporter, ALDP, supposed to participate in the transport of very long chain fatty acids (VLCFA). The adrenoleukodystrophyrelated protein (ALDRP), which is encoded by the ABCD2 gene, is the closest homolog of ALDP and is considered as a potential therapeutic target since functional redundancy has been demonstrated between the two proteins. Pharmacological induction of Abcd2 by fibrates through the activation of PPARa has been demonstrated in rodent liver. DHEA, the most abundant steroid in human, is described as a PPARa activat…

Axonal pathology of the skin in infantile neuroaxonal dystrophy.

1987

Ultrastructural studies on the skin of two patients affected by infantile neuroaxonal dystrophy (INAD) were performed to evaluate its diagnostic value and to discuss the etiology of INAD. While the majority of terminal axons around intradermal glands were dystophic consisting of tubulomembranous and tubulovesicular profiles sometimes accompanied by synaptic vesicles, there were only few dystophic axons inside intradermal nerve bundles. These observations suggest that the primary lesion of INAD is located in terminal and presynaptic axons. Therefore, terminal axons have to be investigated when a diagnostic skin biopsy is performed in INAD.