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PubMed2006

Aggregation and proteasome: the case of elongated polyglutamine aggregation in spinal and bulbar muscular atrophy.

Aggregates, a hallmark of most neurodegenerative diseases, may have different properties, and possibly different roles in neurodegeneration. We analysed ubiquitin-proteasome pathway functions during cytoplasmic aggregation in polyglutamine (polyQ) diseases, using a unique model of motor neuron disease, the SpinoBulbar Muscular Atrophy. The disease, which is linked to a polyQ tract elongation in the androgen receptor (ARpolyQ), has the interesting feature that ARpolyQ aggregation is triggered by the AR ligand, testosterone. Using immortalized motor neurons expressing ARpolyQ, we found that a proteasome reporter, YFPu, accumulated in absence of aggregates; testosterone treatment, which induced ARpolyQ aggregation, allowed the normal clearance of YFPu, suggesting that aggregation contributed to proteasome de-saturation, an effect not related to AR nuclear translocation. Using AR antagonists to modulate the kinetic of ARpolyQ aggregation, we demonstrated that aggregation, by removing the neurotoxic protein from the soluble compartment, protected the proteasome from an excess of misfolded protein to be processed.

Animals↗
PubMedDate not supplied

Late-onset X-linked recessive spinal and bulbar muscular atrophy.

A family is described in which five males have late-onset facial weakness, dysarthria, dysphagia, and slowly progressive proximal weakness. Electrodiagnostic studies and muscle biopsy were compatible with spinal muscular atrophy. This family appears quite similar to several previously reported families with late-onset X-linked recessive spinal and bulbar muscular atrophy. Because of the relative homogeneity of this particular phenotype of spinal muscular atrophy, a single metabolic derangement was sought. Three obligate carriers were studied, and no abnormality was detected. A further family with this condition is briefly discussed.

Aged↗
PubMed2002

[Progressive spinal amyotrophy type I or Werdnig-Hoffman disease. Apropos of 5 cases in Dakar (Senegal)].

Type I spinal muscular atrophy or Werdnig-Hoffman disease is rarely described in black populations. We report five such cases diagnosed in a paediatric outpatient clinic in Dakar. We conducted a retrospective study relating to patients examined for hypotonia progressing since birth for whom the electromyogram had made it possible to confirm an involvement of the peripheral nerve without nerve conduction anomaly. Mean age of diagnosis was 12.3 +/- 7.6 months. Respiratory distress was noted for 2 patients. A family background of similar symptomatology was found in 1 case and consanguinity in 2 cases. Only 1 case of death occurred whereas the 4 other patients were lost to follow-up. The diagnosis of spinal muscular atrophy must be considered in the presence of any severe hypotonia in infants.

Child, Preschool↗
PubMed1982

Increased collagen synthesis by Duchenne myogenic clones.

Myogenic cell clones were grown in triplicates from 3 patients with Duchenne muscular dystrophy, 5 with late onset myotonic dystrophy, 2 with spinal muscular atrophy, 6 male children controls, 4 adult controls and 6 normal aborted fetuses (10-12 weeks old). The clones from patients with myotonic dystrophy and spinal muscular atrophy had normal collagen synthesis. The fetal clones showed 3.3-fold lower values than control clones for [3H] extracellular (medium) hydroxyproline, while intracellular [3H] hydroxyproline levels showed normal values. Analysis of [3H] proline incorporation demonstrated a 4-fold increase in [3H] hydroxyproline released into the medium of Duchenne myogenic cell clones while intracellular [3H] hydroxyproline levels showed normal values. The collagen turnover of Duchenne clones was normal. These results strongly suggest that the increased amount of collagen present in Duchenne dystrophic muscle is related to the primary defect of the disease and is not due to secondary replacement fibrosis.

Adult↗
PubMed2000

Subcellular localization and axonal transport of the survival motor neuron (SMN) protein in the developing rat spinal cord.

The subcellular localization of the survival motor neuron (SMN) protein, encoded by the spinal muscular atrophy determining gene, was investigated in motor neurons of the developing and adult rat spinal cord by light and electron microscopy immunocytochemistry. The experiments were carried out with a panel of anti-SMN antibodies, all recognizing an SMN-specific protein band at 39 kDa in HeLa cells and rat spinal cord protein extracts. SMN protein expression decreased during postnatal spinal cord development, but it remained unchanged in distribution and intensity in motor neurons at all ages examined. SMN protein was mainly organized in immunoreactive aggregates sparse in the nucleoplasm and cytoplasm of both mature and developing motor neurons, and it was more rarely localized within the endoplasmic reticulum and in apposition to the external mitochondrial membrane. Most strikingly, the SMN protein was found in association with cytoskeletal elements in spinal dendrites and axons, where it was particularly evident during postnatal development. The present findings suggest that SMN protein may be transported via axoplasmic flow in maturing neurons. Given the RNA-binding activity of SMN, the SMN protein could be involved in the transport of specific mRNAs in axons and dendrites of motor neurons. The reduced transport of specific mRNAs within motor neurons during development could play a role in the motoneuronal degeneration and impaired axonal sprouting observed in spinal muscular atrophy.

Animals↗
PubMed2003

Severe infantile neuropathy with diaphragmatic weakness and its relationship to SMARD1.

A group of 13 patients with early onset diaphragmatic palsy in association with a progressive neuropathy is presented. All eight of those tested were found to have mutations in the same gene encoding the immunoglobulin mu-binding protein 2 (IGHMBP2) in patients with spinal muscular atrophy (SMA) with respiratory distress type 1. Six out of these eight patients had either homozygous or compound heterozygous mutations, and two had only a single heterozygous mutation. Detailed analysis of the clinical picture and the neurophysiological and histopathological findings indicated that these patients shared similar characteristics, which were further developed as a set of diagnostic criteria. Some of the most striking of these were early onset of respiratory compromise, a markedly low birth weight, very slow motor nerve conduction velocities and a general decrease in the size of myelinated fibres on sural nerve biopsy. Extensive histological examination of the spinal cord in one patient failed to find any evidence of an SMA. Four out of the five not tested genetically were positive for all diagnostic criteria. None of the cases of early onset neuropathies or spinal muscular atrophies with early respiratory failure reviewed in the literature shares the exact characteristics, but many do have very close similarities. Their classification varies, but the discovery of mutations in IGHMBP2 in cases that are variously classified as SMA plus or severe infantile neuropathy with respiratory distress points to a need for the search for this genetic defect to be widened to include both groups. The fact that we identified other, similar cases of neuropathy and early respiratory failure with and without IGHMBP2 mutations suggests genetic as well as clinical heterogeneity in these infants. It is possible that infants that do not have mutations in the IGHMBP2 gene will be found to have mutations in a similar functioning gene.

Axons↗
PubMed2000

Fatal infantile X-linked neuropathy.

We report a pedigree with severe X-linked neuropathy that occurs in male infants and results in death, typically by 2 years of age. The proband of our report was weak with preserved mentation. He underwent extensive evaluation, which revealed abnormal nerve conduction studies, neurogenic changes on muscle biopsy, a decreased number of large myelinated fibers and rare onion bulb formations on nerve biopsy, negative gene testing for spinal muscular atrophy, CMT1a, and CMTX1 and a normal brain magnetic resonance image. The proband's mother, an obligate carrier, had normal nerve conduction studies. Male infants with a spinal muscular atrophy phenotype but normal genetic studies should be evaluated for this fatal X-linked neuropathy.

Adult↗
PubMedDate not supplied

[Clinical analysis of late infantile form of muscular atrophy].

Clinical analysis of 47 cases of late infantile spinal muscular atrophy is reported. In 25.5% of cases mothers reported weak fetal movements in pregnancy and low muscular tonus after birth, these signs predicted early manifestation of the disease. In 89,2% of cases the first signs of the disease appeared within the first 3 years of life. Delayed motor development in infancy was observed in 59.6%. Immobilization developed between the ages of 2 and 18 years, usually after 7 years of disease duration, and it was not correlated with the age of onset of the first signs of the disease. Mental development was normal in 81.5% of cases. Familial character of the disease was found in 51.1% of cases and in some of them intrafamilial variability was observed.

Adolescent↗
PubMed2002

Cytochrome c oxidase deficiency due to a novel SCO2 mutation mimics Werdnig-Hoffmann disease.

BACKGROUND: Mutations in the SCO2 gene have been associated with fatal cardioencephalomyopathy. OBJECTIVE: To report a novel SCO2 mutation with prominent spinal cord involvement mimicking spinal muscular atrophy (Werdnig-Hoffmann disease). PATIENT AND METHODS: An infant girl presented at birth with generalized weakness, hypotonia, and lactic acidosis. At 1 month of age she developed hypertrophic cardiomyopathy and died of heart failure 1 month later. Neuroradiological studies were unremarkable. Muscle biopsy specimens showed groups of atrophic and hypertrophic fibers, but mutation screening of the SMN gene was negative. Histochemical and biochemical studies of respiratory chain complexes were performed, and the whole coding region of the SCO2 gene was sequenced. RESULTS: Findings from muscle histochemistry studies showed virtually undetectable cytochrome c oxidase activity, but normal succinate dehydrogenase reaction. Biochemical analysis in muscle confirmed a severe isolated cytochrome c oxidase deficiency. Pathologic findings of the brain were unremarkable, but the ventral horns of the spinal cord showed moderate-to-severe loss of motor neurons and astrocytosis. Sequencing of the SCO2 gene showed the common E140K mutation, and a novel 10 base-pair duplication of nucleotides 1302 to 1311, which disrupts the reading frame of the messenger RNA and gives rise to a truncated protein. CONCLUSION: The SCO2 mutations should be considered in the differential diagnosis of children with spinal muscular atrophy without mutations in the SMN gene.

Amino Acid Sequence↗