Clinical, neurophysiological and morphological study of dominant intermediate Charcot-Marie-Tooth type C neuropathy.

Dominant intermediate Charcot-Marie-Tooth neuropathy subtype C (DI-CMTC) was associated with mutations in the YARS gene, encoding tyrosyl-tRNA synthetase, in two large unrelated Bulgarian and US pedigrees and one sporadic case. Here for the first time we describe the clinical, neurophysiological and histopathological features, and phenotypic differences between these two DI-CMTC families. Twenty-one affected individuals from the US family and 27 from the Bulgarian family were evaluated. The mean age of onset in US subjects was 10.7 years in men and 7.3 years in women, while in the Bulgarian participants it was 18.2 years in men and 33.7 years in women. The course was slowly progressive. Extensor digitorum brevis atrophy was uniform. Atrophy and/or weakness of upper and lower limb muscles were found in over 50 % of the subjects. Nerve conduction studies (NCS) were abnormal in all US adults and five of six children and all Bulgarian patients except one asymptomatic 25-year-old man. Median motor NCS were in the range of 29.5-45.6 m/s in the US family and 24.7-57.8 m/s in the Bulgarian family. Sural sensory nerve action potentials were absent in 14/21 and 4/12 NCS from adult US and Bulgarian participants, respectively. Analysis of sural nerve biopsies from US patients revealed age-dependent morphological changes of axonal degeneration, absence of onion bulbs, and <10 % fibers with segmental remyelination. Our findings provide further insights into the diagnosis and pathology of intermediate CMT. They also extend the phenotypic spectrum of peripheral neuropathies associated with aminoacyl-tRNA synthetase mutations.

Loss-of-function mutations in HINT1 cause axonal neuropathy with neuromyotonia.

Inherited peripheral neuropathies are frequent neuromuscular disorders known for their clinical and genetic heterogeneity. In 33 families, we identified 8 mutations in HINT1 (encoding histidine triad nucleotide-binding protein 1) by combining linkage analyses with next-generation sequencing and subsequent cohort screening of affected individuals. Our study provides evidence that loss of functional HINT1 protein results in a distinct phenotype of autosomal recessive axonal neuropathy with neuromyotonia.

Early clinical and electrophysiologic features of the two most common autosomal recessive forms of Charcot-Marie-Tooth disease in the Roma (Gypsies).

Our recent studies of the genetic epidemiology of neuromuscular disorders in Gypsies in Bulgaria have revealed that two private disorders, hereditary motor and sensory neuropathy type Lom and hereditary motor and sensory neuropathy type Russe, account for most cases of Charcot-Marie-Tooth disease in this population. In this study, we examined the clinical and electrophysiologic manifestations of the two disorders in childhood, aiming to identify the distinctive features that allow early differential diagnosis. The study included 13 patients, aged between 2 and 15 years. The childhood clinical manifestations of both neuropathies were similar, although they tended to be more severe in hereditary motor and sensory neuropathy type Lom. The nerve conduction velocities in hereditary motor and sensory neuropathy type Lom were lower than in hereditary motor and sensory neuropathy type Russe. Brainstem auditory evoked potentials were abnormal in hereditary motor and sensory neuropathy type Lom, even at an early age, and normal in hereditary motor and sensory neuropathy type Russe. Although electrophysiologic data provide a more reliable differentiation than clinical data, the definitive diagnosis should rely on genetic testing. (J Child Neurol 2006;21:20-25).

Mutation screening of the N-myc downstream-regulated gene 1 (NDRG1) in patients with Charcot-Marie-Tooth Disease.

In a previous study, we have shown that N-myc downstream-regulated gene 1 (NDRG1), classified in databases as a tumor suppressor and heavy metal-response protein, is mutated in hereditary motor and sensory neuropathy Lom (HMSNL), a severe autosomal recessive form of Charcot-Marie-Tooth (CMT) disease. The private founder mutation R148X, causing HMSNL in patients of Romani ethnicity, has so far remained the only molecular defect linking NDRG1 to a specific disease phenotype. Here we report the first study aiming to assess the overall contribution of this gene to the pathogenesis of peripheral neuropathies, in cases where the most common causes of CMT disease have been excluded. Sequence analysis of NDRG1 in 104 CMT patients of diverse ethnicity identified one novel disease-causing mutation, IVS8-1G>A (g.2290787G>A), which affects the splice-acceptor site of IVS8 and results in the skipping of exon 9. The phenotype of the IVS8-1G>A homozygote was very closely related to that of HMSNL patients. In addition, we have detected homozygosity for the known R148X mutation in two affected individuals. Mutations in NDRG1 thus accounted for 2.88% of our overall group of patients, and for 4.68% of cases with demyelinating neuropathies. No other variants were identified in the coding sequence, whereas 12 single nucleotide polymorphisms were observed in the introns. Hum Mutat 22:129-135, 2003.