Compound heterozygous mutations of the TNXB gene cause primary myopathy.

Complete deficiency of the extracellular matrix glycoprotein tenascin-X (TNX) leads to recessive forms of Ehlers-Danlos syndrome, clinically characterized by hyperextensible skin, easy bruising and joint hypermobility. Clinical and pathological studies, immunoassay, and molecular analyses were combined to study a patient suffering from progressive muscle weakness. Clinical features included axial and proximal limb muscle weakness, subclinical heart involvement, minimal skin hyperextensibility, no joint abnormalities, and a history of easy bruising. Skeletal muscle biopsy disclosed striking muscle consistency and the abnormal presence of myotendinous junctions in the muscle belly. TNX immunostaining was markedly reduced in muscle and skin, and serum TNX levels were undetectable. Compound heterozygous mutations were identified: a previously reported 30kb deletion and a non-synonymous novel missense mutation in the TNXB gene. This study identifies a TNX-deficient patient presenting with a primary muscle disorder, thus expanding the phenotypic spectrum of TNX-related abnormalities. Biopsy findings provide evidence that TNX deficiency leads to muscle softness and to mislocalization of myotendinous junctions.

Axon cytoskeleton ultrastructure in chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION: To detail the extent and pattern of axon cytoskeleton alterations in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Nerve biopsies from 7 cases of CIDP, including 4 cases with severe fiber loss, were compared with 5 controls by morphometric transmission electron microscopy (TEM). RESULTS: Despite demyelination of single fibers, myelin ultrastructure was otherwise normal. Contrary to immunolabeling, TEM revealed a decrease in neurofilament (NF) density in every case, although there were pronounced variations among fibers even in the same sample. The NF decrease reached the same extent in large- and small-diameter fibers. It was observed in normally myelinated fibers, suggesting they were demyelinated at a distance from the section. Minimal inter-NF distance increased roughly inversely to NF density. Microtubules increased in 3 cases previously characterized by increased growth-associated protein (GAP-43) immunolabeling. CONCLUSION: These data demonstrate the severity and constancy of axonal lesions, and especially of NF, in residual fibers in our cases of CIDP.

The neural substrates of script knowledge deficits as revealed by a PET study in Huntington's disease.

INTRODUCTION: Previous neuropsychological investigations have suggested that both the prefrontal cortex and the basal ganglia are involved in the management of script event knowledge required in planning behavior. METHODS: This study was designated to map, the correlations between resting-state brain glucose utilization as measured by FDG-PET (positron emission tomography) and scores obtained by means of a series of script generation and script sorting tasks in 8 patients with early Huntington's disease. RESULTS: These patients exhibited a selectively greater impairment for the organizational aspects of scripts compared to the semantic aspects of scripts. We showed significant negative correlations between the number of sequencing, boundary, perseverative and intrusion errors and the metabolism of several cortical regions, not only including frontal, but also posterior regions. CONCLUSION: Our findings suggest that, within the fronto-striatal system, the cortical frontal regions are more crucial in script retrieval and script sequencing than the basal ganglia.

Mitochondrial dysfunction and pathophysiology of Charcot-Marie-Tooth disease involving GDAP1 mutations.

Charcot-Marie-Tooth (CMT) disease represents a large group of clinically and genetically heterogeneous disorders leading to inherited peripheral neuropathies affecting motor and sensory neurons. Mutations in the ganglioside-induced differentiation-associated-protein 1 gene (GDAP1), which encodes a protein anchored to the mitochondrial outer membrane, are usually associated with the recessive forms of CMT disease and only rarely with the autosomal dominant forms. The function of GDAP1 is not fully understood but it plays a role in mitochondrial dynamics by promoting fission events. We present an overview of GDAP1 and the corresponding protein together with the complete spectrum of the 41 gene mutations described so far. We examine the relationship between the genotype and the phenotype in the various forms of CMT disease related to GDAP1 mutations, and discuss the pathophysiological hypotheses that link peripheral neuropathies to mitochondrial dysfunction and GDAP1 mutations. The meta-analysis of the literature reveals the great heterogeneity of phenotypic presentations and shows that the recessive forms of CMT disease, i.e. CMT4A and AR-CMT2, are far more severe than the dominant form, i.e. CMT2K. Among patients with recessive forms of the disease, those carrying truncating mutations are more seriously affected, often becoming wheelchair-bound before the end of the third decade. At the neuronal level, GDAP1 mutations may lead to perturbed axonal transport and impaired energy production as in other neurodegenerative diseases due to mutations in genes involved in mitochondrial dynamics.

Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation.

Hereditary spastic paraplegia refers to a genetically heterogeneous syndrome. We identified five members of a family suffering from a late-onset spastic paraplegia-like disorder, carrying the homoplasmic m.9176 T>C mutation in the mitochondrial ATP6 gene. The clinical severity of the disease observed in the family was correlated with the biochemical and assembly defects of the ATP synthase. The m.9176 T>C mutation has been previously associated to Leigh syndrome or familial bilateral striatal necrosis. Other factors such as modifying genes may be involved in the phenotypic expression of the disease. The family belongs to the mitochondrial haplogroup J, previously shown to play a role in modulating the phenotype of mitochondrial diseases and be associated with longevity. Moreover other nuclear modifying genes or environmental factors may contribute to the disease phenotype. This finding extends the genetic heterogeneity of the hereditary spastic paraplegia together with the clinical spectrum of mutations of the ATP6 gene.

Papilloedema and MRI enhancement of the prechiasmal optic nerve at the acute stage of Leber hereditary optic neuropathy.

The authors report a case of one patient from a family carrying the homoplasmic Leber hereditary optic neuropathy (LHON) G11778A mitochondrial DNA mutation with papilloedema 9 months prior to the acute stage of LHON and still present at the onset of visual loss. During the vision loss, the MRI demonstrated a T2 hyperintensity and an enhancement of the prechiasmal left optic nerve, suggesting the existence of an inflammatory mechanism. A retrospective review of the chart of two others members of the same family, with bilateral optic disc oedema at onset of the vision loss, suggests that the relationship of papilloedema and acute phase of LHON may not be just a coincidence, at least in this family. The visual loss related to LHON could have been triggered in the setting of the chronic papilloedema, associated with the intracranial hypertension.

Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K).

Mutations in GDAP1, an outer mitochondrial membrane protein responsible for recessive Charcot-Marie-Tooth disease (CMT4A), have also been associated with CMT2K, a dominant form of the disease. The three CMT2K patients we studied carried a novel dominant GDAP1 mutation, C240Y (c.719G > A). Mitochondrial respiratory chain complex I activity in fibroblasts from CMT2K patients was 40% lower than in controls, whereas the tubular mitochondria were 33% larger in diameter and the mitochondrial mass was 20% greater. Thus, besides the regulatory role GDAP1 plays in mitochondrial network dynamics, it may also be involved in energy production and in the control of mitochondrial volume.

Script representation in patients with Alzheimer's disease.

We examined script representation in 26 patients with Alzheimer's disease (AD) compared to 31 healthy elderly subjects (HE). Participants were asked to sort cards describing actions belonging to eight scripts according to the script to which they belonged and according to their order of execution. Each script included actions which were low in centrality and distinctiveness (non-central actions and non-distinctive actions--NCA & NDA), and which were high in centrality (central actions--CA), distinctiveness (distinctive actions--DA), centrality and distinctiveness (central actions and distinctive action--CA & DA). These actions were presented in three conditions. In the first condition (scripts with headers--SH), the 43 actions belonging to three different scripts were given with each script header written on separate cards. The second condition (scripts without headers--SwH) used 46 actions belonging to three other scripts, but no script header was provided. In the third condition (scripts with distractor header--SDH), the 28 actions belonging to two other scripts were given with each script header and a distractor header written on separate cards. The results showed that performance of subjects with AD was significantly lower in all conditions. Overall, AD patients made significantly more sequencing errors than HE subjects. AD patients also committed significantly more sorting errors than HE subjects for all types of actions (NCA & NDA, CA, DA, CA & DA). These data are consistent with the view that AD produces impairment of both the syntactic and semantic dimensions of script representation.

[Executive functioning and normal aging: a study of arithmetic word-problem-solving]. / Fonctionnement exécutif et vieillissement normal : étude de la résolution de problèmes numériques.

UNLABELLED: Recent studies suggest that executive functions are among the first cognitive functions to decline with normal aging. METHODS: We studied the effect of age on executive functions using a set of 13 arithmetic word problems including 9 problems of increasing complexity which were solvable in 2, 3, 4 operations, and 4 aberrant problems. Three groups participated in the study: 18 young, 18 adult and 18 elderly participants. RESULTS: The results showed that elderly participants were more impaired to resolve complex arithmetic word problems, without deficit in their ability to eliminate aberrant problems. CONCLUSION: The current elderly sample has a dissociated pattern of performance similar to that of some patients with frontal lobe lesions. In these patients, relations were found between the inability to generate correct algorithms of resolution for arithmetic word problems of increasing complexity and lesions in the dorsolateral prefrontal cortex, and between the impaired inhibition of unsolvable word problems and lesions in the orbitofrontal regions. We suggest that cognitive aging could be better interpreted in terms of changes in some frontal systems rather than in all-encompassing frontal deterioration.

Ring chromosome 17 epilepsy may resemble that of ring chromosome 20 syndrome.

A four-year-old boy with ring chromosome 17 presenting with early-onset, pharmacoresistant epilepsy underwent repeated 24-hour video-EEG monitoring and cytogenetic analyses, including fluorescent in situ hybridization with telomeric and locus-specific probes of chromosome 17. Epilepsy was characterized by nocturnal motor seizures and by prolonged diurnal electrical status epilepticus. The 46, XY, r (17) karyotype was observed in the majority of cell lines. Fluorescent in situ hybridization revealed a deletion at the 17p telomere on the ring chromosome, whereas the 17q telomere and the Miller-Dieker lissencephaly locus were undeleted. The epileptic syndrome observed in this case of ring chromosome 17 resembles the one described in the ring chromosome 20 syndrome, raising the question of the specificity and the pathogenesis of ring chromosome epileptic syndromes. [Published with videosequences].

Executive functions in normal aging: an examination of script sequencing, script sorting, and script monitoring.

We explored the effect of age on executive functions by using script-sequencing and script-sorting tasks. Older participants (n = 39), relative to young subjects (n = 40), committed more errors in script sequencing. However, there was no difference in performance between elderly and young subjects in excluding irrelevant items. These results suggest that aging generates impairment in the ability to produce temporally coherent sequences without deficit in the ability to eliminate distractors in the action domain. We proposed that the sequencing difficulties in elderly participants could be due to working-memory and shifting deficits mediated by changes in the dorsolateral prefrontal cortex.

A second pedigree with autosomal dominant nemaline myopathy caused by TPM3 mutation: a clinical and pathological study.

The slow alpha-tropomyosin (TPM3) gene has to date been associated with few cases of both dominant and recessive nemaline myopathies. We report the identification of a p.Arg167His mutation in a four-generation family presenting with a mild classical form of the disease. Clinically, there was no correlation between the age at presentation and the severity of the disease. The dominant-negative p.Arg167His mutation is a recurrent mutation, previously reported in one sporadic case. Histological studies showed discrepancy between the two reports. While a type II fibre predominance was described in the sporadic case, we observed an almost complete type I fibre predominance. This study emphasizes the variability in histopathological phenotypes seen with TPM3 mutations.

Diagnosis of myotubular myopathy in the oldest known manifesting female carrier: a clinical and genetic study.

X-linked myotubular myopathy is a congenital myopathy due to mutation in the MTM1 gene, encoding myotubularin. Most of the affected male neonates die early of respiratory failure. The female carriers are usually asymptomatic. The authors report a novel MTM1 mutation in a 77-year-old woman. She presented with progressive ptosis since childhood, proximal limb weakness, and a severe restrictive respiratory dysfunction with a hemidiaphragmatic paresis, leading to death at 84 years of age. The muscle biopsy showed centrally nucleated fibers and mitochondrial abnormalities. A stop mutation Leu498X in MTM1 gene was identified in the proband and in her two healthy daughters. The X-inactivation pattern was random in the proband's blood and muscle DNA, and in blood DNA from her two unaffected MTM1 mutation carrier daughters. Two large heteroplasmic deletions were also detected in the muscle mitochondrial DNA of the propositus, raising the question of their putative impact on the phenotype.

Refsum's disease may mimic familial Guillain Barre syndrome.

Refsum's disease is a rare autosomal recessive disorder with clinical features including retinitis pigmentosa, anosmia, deafness, chronic sensory-motor neuropathy, ataxia and the accumulation of phytanic acid in blood plasma and body tissues. We report the occurrence of Refsum's disease in two sisters, both presenting with acute demyelinating polyneuropathy mimicking the familial Guillain Barre syndrome. Thus, when GBS is suspected, particularly in cases of familial recurrence as well as in atypical cases of acute polyneuropathy, the diagnosis of Refsum's disease should be considered, looking for other features of the disease and, if appropriate, testing plasma phytanic acid levels.

Myotilinopathy in a family with late onset myopathy.

Mutations in titin are well known cause of late onset autosomal dominant distal myopathy. Mutations in another sarcomeric protein, myotilin, were first identified in two families with dominant limb girdle muscular phenotype. Recently, however, myotilin mutations have been associated with more distal phenotypes in patients with late onset myofibrillar myopathy. We report here a multigenerational French family in which gene sequencing identified a S60F myotilin mutation in all patients with full penetrance despite very late onset. The family was originally reported as a distal myopathy but intrafamilial variability was remarkable with proximal or distal muscle weakness or both. Extended morphological characteristics of muscle biopsy findings in myotilinopathy indicate that immunohistochemistry may be important for selection of molecular genetic approach in myofibrillar myopathy.