Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

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ObjectiveTo determine the relative contribution of inhibitory and facilitatory circuits in the development of cortical hyperexcitability in amyotrophic lateral sclerosis (ALS).MethodsIn this cross-sectional study, cortical excitability was assessed in 27 patients with ALS, and results compared to 25 healthy controls. In addition, a novel neurophysiologic measure of cortical function, short-interval intracortical facilitation (SICF), was assessed reflecting activity of the facilitatory circuits.ResultsThere was a significant increase in SICF (ALS −18.51 ± 1.56%, controls −8.52 ± 1.21%, p < 0.001) in patients with ALS that was accompanied by a reduction of short-interval intracortical inhibition (ALS 3.94 ± 1.29%, controls 14.23 ± 1.18%, p < 0.001) and cortical silent period duration (p = 0.034). The index of excitation, a biomarker reflecting the contribution of inhibitory and facilitatory circuit activity, was significantly increased in patients with ALS (82.79 ± 6.01%) compared to controls (36.15 ± 3.44, p < 0.001), suggesting a shift toward cortical excitation. Increased excitation correlated with upper motor neuron signs (R2 = 0.235, p = 0.016) and greater functional disability as reflected by a correlation with the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised score (R2 = 0.335, p = 0.002).ConclusionsThe present study established that cortical hyperexcitability is a key contributor to ALS pathophysiology, mediated through dysfunction of inhibitory and facilitatory intracortical circuits. Therapies aimed at restoring the cortical inhibitory imbalance provide novel avenues for future therapeutic targets.

We assessed the clinicopathological features of nine patients with pure autonomic neuropathy, that is, neuropathy without sensory or motor deficits. The duration from symptom onset to diagnosis ranged from 1 month to 13 years. Of eight patients in whom serum antiganglionic acetylcholine receptor antibody was determined, four were positive. All patients who tested positive for this antibody manifested widespread autonomic dysfunction, with the exception of one patient who only experienced orthostatic hypotension. However, patients who were negative for the antiganglionic acetylcholine receptor antibody presented with partial autonomic failure. One of these patients had diffuse parasympathetic failure and generalized hypohidrosis but no orthostatic hypotension, which is clinically compatible with postganglionic cholinergic dysautonomia. Electron microscopic examination revealed a variable degree of reduction in unmyelinated fibers. Compared with normal controls, the patients had a significantly increased density of collagen pockets (p < 0.05). Additionally, the percentage of Schwann cell subunits with axons (out of the total number of Schwann cell subunits associated with unmyelinated fibers) was significantly decreased (p < 0.01). The density of unmyelinated fibers tended to decrease with increasing time between the onset of autonomic symptoms and biopsy (p < 0.05). In conclusion, the clinical and pathological features of pure autonomic neuropathy vary in terms of progression, autonomic involvement, presence of the antiganglionic acetylcholine receptor antibody, and loss of unmyelinated fibers.