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

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.

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Charcot-Marie-Tooth disease type 2CC due to NEFH variants causes a progressive, non-length-dependent, motor-predominant phenotype

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2021-327186 ◽

2021 ◽

pp. jnnp-2021-327186

Author(s):

Menelaos Pipis ◽

Andrea Cortese ◽

James M Polke ◽

Roy Poh ◽

Jana Vandrovcova ◽

...

Keyword(s):

Age Of Onset ◽

Muscular Atrophy ◽

Disease Type ◽

Lower Limbs ◽

Reading Frame ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Neurophysiological Studies ◽

History Of ◽

Tooth Disease

ObjectiveNeurofilaments are the major scaffolding proteins for the neuronal cytoskeleton, and variants in NEFH have recently been described to cause axonal Charcot-Marie-Tooth disease type 2CC (CMT2CC).MethodsIn this large observational study, we present phenotype–genotype correlations on 30 affected and 3 asymptomatic mutation carriers from eight families.ResultsThe majority of patients presented in adulthood with motor-predominant and lower limb-predominant symptoms and the average age of onset was 31.0±15.1 years. A prominent feature was the development of proximal weakness early in the course of the disease. The disease progressed rapidly, unlike other Charcot-Marie-Tooth disease (CMT) subtypes, and half of the patients (53%) needed to use a wheelchair on average 24.1 years after symptom onset. Furthermore, 40% of patients had evidence of early ankle plantarflexion weakness, a feature which is observed in only a handful of CMT subtypes. Neurophysiological studies and MRI of the lower limbs confirmed the presence of a non-length-dependent neuropathy in the majority of patients.All families harboured heterozygous frameshift variants in the last exon of NEFH, resulting in a reading frameshift to an alternate open reading frame and the translation of approximately 42 additional amino acids from the 3' untranslated region (3′-UTR).ConclusionsThis phenotype–genotype study highlights the unusual phenotype of CMT2CC, which is more akin to spinal muscular atrophy rather than classic CMT. Furthermore, the study will enable more informative discussions on the natural history of the disease and will aid in NEFH variant interpretation in the context of the disease’s unique molecular genetics.

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Mitochondrial trifunctional protein deficiency: an adult patient with similar progress to Charcot-Marie-Tooth disease

Rinsho Shinkeigaku ◽

10.5692/clinicalneurol.cn-000976 ◽

2017 ◽

Vol 57 (2) ◽

pp. 82-87 ◽

Cited By ~ 1

Author(s):

Yuki Yamamoto ◽

Naoko Matsui ◽

Yu Hiramatsu ◽

Yoshimichi Miyazaki ◽

Hiroyuki Nodera ◽

...

Keyword(s):

Adult Patient ◽

Protein Deficiency ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Mitochondrial Trifunctional Protein ◽

Tooth Disease

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Clinical and genetic characteristics of Charcot–Marie–Tooth disease type 4D (type Lom) in Russia

Neuromuscular Diseases ◽

10.17650/2222-8721-2020-10-2-39-45 ◽

2020 ◽

Vol 10 (2) ◽

pp. 39-45

Author(s):

A. F. Murtazina ◽

O. A. Shchagina ◽

T. B. Milovidova ◽

E. L. Dadali ◽

G. E. Rudenskaya ◽

...

Keyword(s):

Age Of Onset ◽

Disease Type ◽

Pathogenic Variant ◽

Genetic Characteristics ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Pathogenic Variants ◽

European Part Of Russia ◽

Ndrg1 Gene ◽

Tooth Disease

Introduction. Charcot–Marie–Tooth disease type 4D is a hereditary demyelinating neuropathy, that occurs with the high frequency in patients of Roma origin. It is characterized by early onset at the age of 2–10 years and hearing impairment, manifested by the 3rd decade of life.Aim of the study. To describe the clinical and genetic characteristics of Charcot–Marie–Tooth disease type 4D in Russian patients of Roma origin.Materials and methods. For 14 probands from unrelated families of Roma origin with a clinical diagnosis of Charcot–Marie–Tooth disease, genetic tests for the pathogenic variants c. 442C>T in the NDRG1 gene and c. 3325C>T in the SH3TC2 gene was carried out. For 8 patients with Charcot–Marie–Tooth disease type 4D, detailed clinical and electrophysiological examination was performed.Results. In 11 families of Roma origin, the c. 442C>T pathogenic variant in the NDRG1 gene in a homozygous state was detected, which accounted for 79 % all observed Roma patients with Charcot–Marie–Tooth disease. There are 12 of the 14 tested families live in the European part of Russia, 7 of them are from nearby regions. The average age of onset was 3.3 years. The first symptom in 7 of 8 patients was gait disturbances. At the time of examination (age range 6–19 years), all patients showed marked hypotrophy and weakness of the feet, lower leg, hands muscles, feet deformities, reduction or loss of tendon reflexes.Discussion. Due to the detection of only one pathogenic variant in most Russian patients of Roma origin with Charcot–Marie–Tooth disease, the knowledge of the ethnicity of a proband with early myelinopathy can significantly simplify the confirmation of the diagnosis on the molecular level.

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