Determining jitter values in the very young by use of the e-norms methodology.

INTRODUCTION: The diagnosis of myasthenia gravis in very young infants is a challenging one. In young infants, stimulated single-fiber electromyography (StimSFEMG) is the most appropriate technique, but it has serious limitations due to the absence of reference values in this subpopulation. Here we present our efforts to derive a reference range of jitter in a patient cohort of infants <3 years of age using the extrapolated norms, or e-norms, technique. METHODS: The e-norms method was used to calculate jitter mean consecutive difference (MCD) descriptive statistics for children <3 years of age. RESULTS: The e-norms derived jitter upper MCD limit was 45 µs in children <1 year, 33 µs in those <2 years, and 26 in those <3 years of age. CONCLUSION: In the absence of jitter reference values for the very young, the e-norms method can be used as an alternative to derive these values from laboratory cohorts. Muscle Nerve 55: 51-54, 2017.

DOK7 congenital myasthenic syndrome in childhood: early diagnostic clues in 23 children.

Mutations in DOK7 are a common cause of congenital myasthenia. Treatment with ephedrine or salbutamol is effective, but diagnosis is often delayed. The aim of our study was to find early clues to the diagnosis of DOK7 congenital myasthenic syndrome. We included 23 children of 20 families. Onset of symptoms ranged from birth to age 3 years. 13 presented at birth with feeding difficulties, 11 with stridor (documented vocal cord palsy in 7), 3/11 with hypotonia/poor head control. Weakness was more pronounced proximally in all, axial in early presenting infants. Muscle biopsy showed non-specific features in 15/16, type 1 fibre predominance in 14/16, areas devoid of oxidative enzyme activity in 7/16. Muscle imaging was normal in 8/10, 2/10 showed mild non-specific changes. A diagnostic clue suggesting CMS rather than myopathy was the discrepancy between muscle imaging or histology findings compared with the degree of weakness. Repetitive nerve stimulation and stimulation single fibre electromyography were pathological in 9/17 and 13/14, respectively. In conclusion, stridor and feeding difficulties at birth or progressive weakness despite normal milestones in infancy point to the diagnosis and should lead to neurophysiological and genetic investigation. Fatigability can be absent or easily missed in the first years of life.

Impaired neuromuscular transmission and response to acetylcholinesterase inhibitors in centronuclear myopathies.

Many clinical features of autosomal centronuclear myopathies (CNM) and X-linked myotubular myopathy (XLMTM) are common to congenital myasthenic syndromes (CMS). We describe three children whose clinical and electrophysiological findings originally suggested CMS, in whom CNM was diagnosed pathologically, though not yet genetically characterised. A fourth case, with XLMTM, also showed electrophysiological features of a neuromuscular transmission defect. Three (including the XLMTM case) showed improved strength with acetylcholinesterase inhibitor treatment. We also studied neuromuscular junction structure and function in the MTM1 knockdown zebrafish model of XLMTM, demonstrating abnormal neuromuscular junction organization; anticholinesterase therapy resulted in marked clinical response. These observations suggest that a neuromuscular transmission defect may accompany CNM and contribute to muscle weakness. Muscle biopsy should be considered in infants suspected to have CMS, especially if treatment response is incomplete, or no CMS gene mutation is identified. Treatment with acetylcholinesterase inhibitors may benefit some CNM patients. This warrants further confirmation.

A new analytical method to diagnose congenital myasthenia with stimulated single-fiber electromyography.

Stimulated single-fiber electromyography (SSF-EMG) is useful to assess neuromuscular junction (NMJ) abnormalities in children. Conventionally mean consecutive difference (MCD) analysis measures the jitter for each muscle-fiber potential. We present a new algorithm that analyzes the entire SSF-EMG waveform. Cross-correlational coefficients (between 0-1.0) are calculated for consecutive pairs of 100 SSF-EMG waveforms obtained at each needle position in orbicularis oculi, and averaged. A lower normal limit (0.722, mean -3 SD) was established from 123 SSF-EMG samples in 10 adult control subjects, and applied to SSF-EMG data from 23 children referred for a suspected myasthenic syndrome. Results were compared with MCD analysis and related to the final clinical diagnosis. Our results showed that compared with conventional MCD measurement, the new algorithm had better specificity (87% vs. 53%) but similar sensitivity (88% for both). These findings indicate that the cross-correlational method is a useful predictor of NMJ dysfunction in children.