CHCHD10 variant p.(Gly66Val) causes axonal Charcot-Marie-Tooth disease

Abstract

Objective: We describe the phenotype consistent with axonal Charcot-Marie-Tooth disease type 2 (CMT2) in 4 families with a c.197G>T (p.(Gly66Val)) variant in CHCHD10.

Methods: We sequenced the CHCHD10 gene in a cohort of 107 families with CMT2 of unknown etiology. The patients were characterized by clinical examination and electroneuromyography. Muscle MRI and biopsy of the muscle or nerve were performed in selected cases. Neuropathologic autopsy was performed in 1 case.

Results: The c.197G>T variant in CHCHD10 was found in 6 families, 4 of which included multiple individuals available for detailed clinical study. Variants in this gene have recently been associated with amyotrophic lateral sclerosis-frontotemporal dementia, mitochondrial myopathy, or spinal muscular atrophy Jokela type (SMAJ), but not with CMT2. Our patients had a late-onset distal axonal neuropathy with motor predominance, progressing to involve sensory nerves. Neurophysiologic and neuropathologic studies confirmed the diagnosis of sensorimotor axonal neuropathy with no loss of anterior horn neurons. Muscle biopsies showed occasional cytochrome c oxidase-negative fibers, combined with small amounts of mitochondrial DNA deletions.

Conclusions: CHCHD10 c.197G>T (p.(Gly66Val)) is a cause of sensorimotor axonal neuropathy. This gene should be considered in patients presenting with a pure CMT2 phenotype, particularly when motor symptoms predominate.

Figure 1. Pedigrees and sequencing

(A) Pedigrees of the studied families are shown. Asterisks indicate individuals who were studied genetically, and arrows denote index patients. The CHCHD10 variant c.197G>T (p.(Gly66Val)) segregated with the disease phenotype. (B) Chromatograms of the index patient from each family are shown with the c.197G>T change indicated (arrow); a normal control sequence is shown at the bottom.

Figure 2. Analysis of muscle and nerve histopathology and muscle mtDNA deletions

(A) Representative muscle biopsy shows a cytochrome c oxidase (COX)-negative blue fiber in the middle; slightly above it to the left is a single concave atrophic fiber. Above the lower margin in the middle is a small group atrophy with moderately atrophic fibers, and basally, in the left corner, a small group with very small fibers is seen (asterisks). Frozen section, COX-succinate dehydrogenase activity stain, original magnification 200×, scale bar 50 µm. (B) Long range PCR on total muscle DNA was performed to detect mitochondrial DNA (mtDNA) deletions from patients and 2 control individuals without mtDNA deletions (Ctrl-1 and Ctrl-2). As a positive control, we used muscle DNA from a patient with progressive external ophthalmoplegia (PEO) caused by a variant in the RRM2B gene. The PCR primers were designed to overlap the 4977 bp common deletion between positions 13447-13459 and 8470-8482 and yielded a PCR product of ∼8 kb from undeleted mtDNA (arrow). The 8-kb band was readily detected in controls and patients. The patient with PEO had multiple smaller bands corresponding to deleted mtDNA molecules. Similar deletion bands were observed at lower intensity in patients F2:II-2, F1:IV-3, F14:III-1, and F1:III-9. This suggested that low levels of mtDNA deletions were present in many but not all of our patients. SM denotes size marker (GeneRuler 1 kb DNA ladder), H2O denotes negative control (water substituted for template). (C) High power field of sural nerve biopsy from autopsy material of patient F1:III-9 demonstrates subtotal loss of large myelinated fibers (arrow) with no marked hypertrophic changes, regenerative fiber groups, or demyelination. Plastic section, toluidine blue staining, original magnification 400×, scale bar 25 µm.