KLHL40-related nemaline myopathy with a sustained, positive response to treatment with acetylcholinesterase inhibitors

Abstract

Congenital myopathies are a group of inherited muscle disorders characterized by hypotonia, weakness and a non-dystrophic muscle biopsy with the presence of one or more characteristic histological features. Neuromuscular transmission defects have recently been reported in several patients with congenital myopathies (CM). Mutations in KLHL40 are among the most common causes of severe forms of nemaline myopathy. Clinical features of affected individuals include fetal akinesia or hypokinesia, respiratory failure, and swallowing difficulties at birth. Muscle weakness is usually severe and nearly half of the individuals have no spontaneous antigravity movement. The average age of death has been reported to be 5 months in a recent case series. Herein we present a case of a patient with a nemaline myopathy due to KLHL40 mutations (c.604delG, p.Ala202Argfs*56 and c.1513G>C, p.Ala505Pro) with an impressive and prolonged beneficial response to treatment with high-dose pyridostigmine. Myasthenic features or response to ACEI have not previously been reported as a characteristic of nemaline myopathy or KLHL40-related myopathy.

Treating pediatric neuromuscular disorders: The future is now

“…The other is the demonstration in animal models of MTM1 and DNM2 related CNM of abnormalities in the structure of the neuromuscular junction (Dowling, Joubert et al, ; Gibbs et al, ). Of note, positive response to pyridostigmine has been additionally described in several single case studies including: (1) a patient with TPM2 mutation and cap myopathy (Rodriguez Cruz et al, ); (2) a patient with TPM3 mutation and congenital fiber‐type disproportion (Munot et al, ); and (3) in a patient with KLHL40 mutation and nemaline myopathy (Natera‐de Benito et al, ). Thus pyridostigmine (typically at 7 mg/kg/day though reported at significantly higher doses as well) may represent a therapeutic with potential benefit across the spectrum of congenital myopathies.…”

Current and future therapeutic approaches to the congenital myopathies

“…Supported by preclinical data in a mouse model of ACTA1-related NM [90], a pilot study in 5 patients with NM suggested a beneficial effect of l-tyrosine, with reduced fatigue and improvement of drooling [111]. A recent report of a single case with severe KLHL40-related NM suggested a sustained beneficial response to the acetylcholinesterase inhibitor pyridostigmine [112], indicating an associated neuromuscular transmission defect potentially amenable to treatment, corresponding to observations in other congenital myopathies, in particular the CNMs (see above).…”

Identification ofKLHL40mutations by targeted next-generation sequencing facilitated a prenatal diagnosis in a family with three consecutive affected fetuses with fetal akinesia deformation sequence

“…Thus, in our case, the maternal history of recurrent elective abortions associated with obvious FADS features had prompted the search for mutations in genes associated with FADS. Of note, a recent report has suggested that neonate with KLHL40 ‐related NM may favorably respond to early treatment with high‐dose pyridostigmine after birth . Thus, an early definitive molecular diagnosis can also facilitate early treatment.…”