title: Muscle biopsy findings in a child with NALCN gene mutation.
abstract: Mutation in NALCN (Sodium leak channel, non-selective) gene in humans has been shown to present with a wide spectrum of clinical manifestations including neurodevelopmental impairment, hypotonia and congenital contractures. Distinctive features including episodic ataxia and neuroaxonal dystrophy have also been reported. In this case report, we describe the muscle biopsy findings of a 3-year-old boy who presented with congenital arthrogryposis, hypotonia and developmental delay who has a heterozygous de novo C.965T>C (p.1332T) variant in the NALCN gene found by expanded whole exome sequencing (WES). Distal arthrogryposis and ulnar deviation of hands were prominent findings, which have been shown to be associated with de novo heterozygous mutations in this gene. He also presented with brief paroxysmal episodes of tremulousness; however, he has not clearly had episodes of episodic ataxia. Initial work-up including extensive genetic and metabolic tests was normal except for mildly elevated multiple metabolites in urine, suggestive of mild dysfunction of multiple mitochondrial enzymes. Muscle biopsy findings revealed ragged red fiber changes on trichrome staining and an increased number of mitochondria with non-specific crystalloid like inclusions ultrastructurally. The biochemical and muscle biopsy findings are suggestive of a possible mitochondrial bioenergetic dysfunction. The association of NALCN gene with secondary mitochondrial dysfunction remains unclear.
authors.affiliation: Center for Pediatric Neurology, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Indu
authors.initials: I
authors.lastname: Sivaraman
authors.affiliation: Center for Pediatric Neurology, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Neil R
authors.initials: NR
authors.lastname: Friedman
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA; Department of Anatomic Pathology, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Electronic address: praysor@ccf.org.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Prayson
mesh_terms: D001706:Biopsy; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins; D009154:Mutation / Q000235:genetics*; D052097:Quadriceps Muscle / Q000473:pathology*; D015222:Sodium Channels / Q000235:genetics*
chemical_list: D007473:Ion Channels; D008565:Membrane Proteins; C544681:NALCN protein, human; D015222:Sodium Channels
keywords: Arthrogryposis; Mitochondrial myopathy; Muscle biopsy; NALCN; Ragged red fiber