Abstract
The rare autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) is associated with mutations in the RAB7A gene, involved in the late endocytic pathway. CMT2B is characterized by predominant sensory loss, ulceromutilating features, with lesser-to-absent motor deficits. We characterized clinically and genetically a family harboring a novel pathogenic RAB7A variant and performed structural and functional analysis of the mutant protein. A 39-year-old woman presented with early-onset walking difficulties, progressive distal muscle wasting and weakness in lower limbs and only mild sensory signs. Electrophysiology demonstrated an axonal sensorimotor neuropathy. Nerve biopsy showed a chronic axonal neuropathy with moderate loss of all caliber myelinated fibers. Next-generation sequencing (NGS) technology revealed in the proband and in her similarly affected father the novel c.377A>G (p.K126R) heterozygous variant predicted to be deleterious. The mutation affects the biochemical properties of RAB7 GTPase, causes altered interaction with peripherin, and inhibition of neurite outgrowth, as for previously reported CMT2B mutants. However, it also shows differences, particularly in the epidermal growth factor receptor degradation process. Altogether, our findings indicate that this RAB7A variant is pathogenic and widens the phenotypic spectrum of CMT2B to include predominantly motor CMT2. Alteration of the receptor degradation process might explain the different clinical presentations in this family.
Highlights
IntroductionAutosomal dominant axonal Charcot–Marie–Tooth disease type 2B (CMT2B) largely overlaps with hereditary sensory-autonomic neuropathies (HSANs) as it is characterized by predominant sensory loss, high frequency of ulcer formations and amputations, with variable motor deficits [1,2,3,4,5,6,7,8,9,10].Affected patients show severe distal sensory loss for pain and touch, reduced-to-absent deep tendon reflexes, foot deformities, and sometimes distal wasting and weakness mainly in lower limbs [1,2,3,4,5,7,8,9,10]
We report a family with a novel Charcot-Marie-Tooth type 2B (CMT2B) phenotype with motor predominance and absence of ulcers and mutilations, carrying a novel pathogenic RAB7 variant (c.377A>G, p.K126R) which is absent in global databases, affects a highly conserved amino-acid in the GTPase domain of Rab7, is predicted to be pathogenic by in silico analysis, and is transmitted as an autosomal dominant trait
The proband (III-1) (Figure 1A), a 39-year-old female, at age 14 years started complaining of calf muscle cramps, progressive walking difficulties, distal muscle wasting and weakness, recurrent ankle sprains and balance issues
Summary
Autosomal dominant axonal Charcot–Marie–Tooth disease type 2B (CMT2B) largely overlaps with hereditary sensory-autonomic neuropathies (HSANs) as it is characterized by predominant sensory loss, high frequency of ulcer formations and amputations, with variable motor deficits [1,2,3,4,5,6,7,8,9,10].Affected patients show severe distal sensory loss for pain and touch, reduced-to-absent deep tendon reflexes, foot deformities, and sometimes distal wasting and weakness mainly in lower limbs [1,2,3,4,5,7,8,9,10]. Autosomal dominant axonal Charcot–Marie–Tooth disease type 2B (CMT2B) largely overlaps with hereditary sensory-autonomic neuropathies (HSANs) as it is characterized by predominant sensory loss, high frequency of ulcer formations and amputations, with variable motor deficits [1,2,3,4,5,6,7,8,9,10]. CMT2B is caused by heterozygous mutations in RAB7A, with five mutations (L129F, K157N, N161T/I, V162M) reported in patients from eleven families [1,2,3,4,5,7,8,9,10], all displaying the characteristic ulcero-mutilating phenotype with variable motor involvement (Table 1). RAB7A, hereafter referred to as RAB7, is a member of the Rab family of small GTPases involved in the regulation of vesicular trafficking between early endosomes and lysosomes, controlling transport to the degradative compartments in the endocytic pathway and lysosome biogenesis [14]
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