Charcot–Marie–Tooth Disease With Episodic Rhabdomyolysis Due to Two Novel Mutations in the β Subunit of Mitochondrial Trifunctional Protein and Effective Response to Modified Diet Therapy

Abstract

A 29-year-old female experienced chronic progressive peripheral neuropathy since childhood and was diagnosed with Charcot–Marie–Tooth disease (CMT) at age 15. She developed recurrent, fever-induced rhabdomyolysis (RM) at age 24. EMG studies showed decreased amplitude of compound muscle action potential, declined motor conductive velocity, and absence of sensor nerve action potential. Acylcarnitine analysis revealed elevated C16-OH, C18-OH, and C18:1-OH. Muscle biopsy showed scattered foci of necrotic myofibers invaded by macrophages, occasional regenerating fibers, and remarkable muscle fiber type grouping. Whole-exome sequencing identified two novel heterozygous mutations: c.490G>A (p.G164S) and c.686G>A (p.R229Q) in HADHB gene encoding the β-subunit of mitochondrial trifunctional protein (MTP). Reduction of long-chain fatty acid via dietary restrictions alleviated symptoms effectively. Our study indicates that the defect of the MTP β-subunit accounts for both CMT and RM in the same patient and expands the clinical spectrum of disorders caused by the HADHB mutations. Our systematic review of all MTPD patients with dietary treatment indicates that the effect of dietary treatment is related to the age of onset and the severity of symptoms.

Case report: Mitochondrial trifunctional protein deficiency caused by HADHB gene mutation (c.1175C>T) characterized by higher brain dysfunction followed by neuropathy, presented gadolinium enhancement on brain imaging in an adult patient

“…l-carnitine (3 g/day) was also administrated. ( 5 ). 1 year after treatment commencement, the MMSE score was 26/30, and FAB score was 11/18.…”

“…MTP deficiency presents heterogeneous clinical phenotypes varying from early-onset life-threatening cardiomyopathy, hypoketotic hypoglycemia, and liver failure to a late-onset form with myopathy, recurrent rhabdomyolysis, and peripheral neuropathy ( 3 ). In some late-onset cases, the symptoms of peripheral neuropathy are similar to those of Charcot–Marie–Tooth disease (CMT) ( 4 , 5 ). Additionally, some cases are complicated by hypoparathyroidism ( 6 , 7 ).…”