Charcot-Marie-Tooth disease (CMT) is the most common cause of inherited peripheral neuropathy, with an estimated frequency of 1/2500. We studied a large family with 17 patients affected by the axonal form of CMT (CMT2). Analysis of the 15 genes or loci known to date was negative. Genome-wide genotyping identified a CMT2 locus in 16q21-q23 between D16S3050 and D16S3106. The maximum two-point LOD score was 4.77 at theta = 0 for marker D16S3050. Sequencing of candidate genes identified a unique mutation, c.986G>A (p.Arg329His), affecting a totally conserved amino acid in the helical domain of cytoplasmic alanyl-tRNA synthetase (AlaRS). A second family with the same mutation and a different founder was then identified in a cohort of 91 CMT2 families. Although mislocation of mutant Arg329His-AlaRS in axons remains to be evaluated, experimental data point mostly to a quantitative reduction in tRNA(Ala) aminoacylation. Aminoacylation and editing functions closely cooperate in AlaRS, and Arg329His mutation could also lead to qualitative errors participating in neurodegeneration. Our report documents in 18 patients the deleterious impact of a mutation in human cytoplasmic AlaRS and broadens the spectrum of defects found in tRNA synthetases. Patients present with sensory-motor distal degeneration secondary to predominant axonal neuropathy, slight demyelination, and no atypical or additional CNS features.

We evaluated prospectively the occurrence of seizures within 15 days of a first stroke or transient ischemic episode in 1,640 patients to study relation between seizures and type of stroke. Seizures occurred in 90 patients (5.4%), including 36 (4.4%) of 814 with infarct owing to atheroma, 21 (16.6%) of 126 with infarct owing to cardiogenic embolus, 3 (1%) of 273 owing to lacunar infarct, 5 (1.9%) of 259 owing to transient ischemic attack (TIA), 21 (16.2%) of 129 owing to supratentorial hematoma, and 4 (16.6%) of 24 owing to subarachnoid hemorrhage. Thirteen (14.6%) of 89 subcortical infarcts were associated with seizures. Seizures were the initial sign of stroke in 80 (89%) of 90 cases and were usually single and partial. Seizure symptoms were most often motor, sensory, or visual.

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We report on a patient with a severe, rare neonatal form of non-dystrophic myotonia. The patient presented with facial dysmorphism, muscle hypertrophy, severe constipation, psychomotor delay, and frequent cold-induced episodes of myotonia and muscle weakness leading to severe hypoxia and loss of consciousness. Muscle biopsy was non-specific and electromyography revealed intense generalized myotonia. The myotonic episodes improved after introducing oral mexiletine and maintaining room temperature at 28 degrees C. The patient died at 20 months of age following a bronchopulmonary infection. A previously undescribed de novo heterozygous c.3891C > A change, which predicts p.N1297K in the SCN4A gene. Mutations within the voltage-gated sodium channel alpha-subunit gene (SCN4A) have been described in association with several phenotypes including paramyotonia congenita, hyperkalemic or hypokalemic periodic paralysis, and potassium-aggravated myotonias. The cold-sensitive episodes of stiffness followed by weakness suggested the diagnosis of channelopathy in our patient. However, her neonatal onset, the triggering of severe episodes by exposure to modest decreases in temperature, involvement of respiratory muscles with prolonged apnea, early-onset muscle hypertrophy, psychomotor retardation, and fatal outcome are evocative of a distinct clinical subtype. Our observation expands the phenotypic spectrum of sodium channelopathies.