シャルコー・マリー・トゥース病

BACKGROUND: Charcot-Marie-Tooth disease 1A (CMT1A) and Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome (CANVAS)/Replication Factor Complex subunit 1 (RFC1)-related disease affect large nerve fibers, but small fiber dysfunction may contribute to pain and dysautonomia. We applied a multimodal protocol, including potentials elicited by a micropatterned electrode targeting intraepidermal nerve endings, to characterize small fiber involvement. METHODS: In this cross-sectional study, healthy controls (HC) and patients with CMT1A or RFC1 disease underwent neurologic examination, autonomic assessment with the composite autonomic symptom score-31 (COMPASS-31) and compound autonomic dysfunction test (CADT), electrochemical skin conductance (ESC), nociceptive evoked potentials (NEPs), pain-related evoked potentials (PREPs), somatosensory evoked potentials (SEPs), and skin biopsy. RESULTS: Twenty-one patients with CMT1A, 16 with RFC1 disease, and 21 HC were included. Neuropathic pain occurred in 33% of CMT1A and 81% of RFC1 patients. Dysautonomia was prominent in RFC1 disease, with abnormal CADT scores in 94%, COMPASS-31 scores of 7-46, and abnormal ESC in 63%, compared with 24% in CMT1A. N40 NEP latencies were prolonged in both patient groups versus HC (p<0.001), with absent responses in 33% and 44%, respectively. PREPs showed prolonged N2 latencies in CMT1A (p=0.003), with absent N2 responses in 57%; in RFC1 disease, N2 responses were absent in 50%. Skin biopsy showed length-dependent intraepidermal nerve fiber density loss in CMT1A and severe non-length-dependent epidermal denervation in RFC1 disease. DISCUSSION: Multimodal assessment integrating ESC, NEPs, PREPs, and skin biopsy identifies distinct Aδ- and C-fiber dysfunction patterns in CMT1A and RFC1 disease and may support phenotyping and small-fiber biomarker development in peripheral neuropathies.

Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy with significant clinical and genetic heterogeneity. CMT typically affects distal musculature or peripheral nerves in younger patients. Imaging is not required for diagnosis but may help distinguish other disease processes similar to CMT. We describe a case of a middle-aged patient with extensive osseous, muscular, and peripheral nerve imaging abnormalities that prompted neurologic and genetic evaluation, leading to a diagnosis of CMT type 1A (CMT1A). We correlate radiographic, computed tomography (CT), and magnetic resonance imaging (MRI) findings with neurophysiologic and genetic testing results. This case highlights the role of multimodality imaging in CMT1A.

INTRODUCTION/AIMS: Small fiber involvement in Charcot-Marie-Tooth disease (CMT) is incompletely characterized. We evaluated corneal small fiber parameters and immune cell density in common CMT subtypes, which are predominantly demyelinating neuropathies, using in vivo corneal confocal microscopy (IVCCM). METHODS: Sixteen patients with genetically confirmed hereditary demyelinating neuropathies (PMP22-related CMT1A/HNPP and CMTX1) and 32 healthy controls underwent IVCCM. Corneal nerve fiber density (CNFD), length (CNFL), branch density (CNBD), tortuosity (CNFT), and Langerhans cell density were quantified. Clinical severity was assessed with the Charcot-Marie-Tooth Neuropathy Score (CMTNS). Neuropathic pain was defined as painDETECT ≥ 19 or ongoing treatment. RESULTS: Patients showed reduced CNFD compared with controls (20.8 ± 10.7 vs. 26.1 ± 5.3 fibers/mm2; p = 0.024). Subgroup analysis demonstrated significant reductions in CNFD (p = 0.001), CNFL (p = 0.006), and CNBD (p = 0.040) in PMP22-related neuropathies, whereas CMTX1 patients did not differ from controls. CNFD, CNFL, and CNBD correlated inversely with CMTNS. Patients with neuropathic pain exhibited lower CNFD (10.5 ± 8.8 vs. 25.4 ± 7.9 fibers/mm2, p = 0.009), CNFL (9.8 ± 3.9 vs. 16.2 ± 2.8 mm/mm2, p = 0.002), and CNBD (9.9 ± 11.8 vs. 32.7 ± 19.2 branches/mm2, p = 0.030) than painless patients. Langerhans cell density did not differ between groups. DISCUSSION: PMP22-related neuropathies demonstrate significant corneal small fiber loss without increased Langerhans cell density, suggesting a predominantly structural phenotype without evidence of increased corneal immune activation. IVCCM may serve as a noninvasive biomarker of small fiber involvement and disease severity.

Charcot-Marie-Tooth disease is an inherited peripheral neuropathy marked by progressive loss of motor and sensory function. GDAP1 mutations are implicated in Charcot-Marie-Tooth disease, but the precise mechanism is not fully understood. This study aims to decipher the underlying genetic variant and its functional consequences in a consanguineous Indian family with two children (an 8-year-old boy and 3-years old girl) who presented with progressive motor and sensory limb involvement secondary to severe distal axonal neuropathy. Whole-exome sequencing identified a novel homozygous frameshift variant (c.503_504delAG) in GDAP1 in proband that was segregated among the family members. Patient-derived fibroblasts demonstrated complete loss of protein expression and swollen mitochondria with disrupted cristae in the cultured fibroblasts of affected individuals. Altered mitochondrial membrane potential with elevated reactive oxygen species levels, and significantly reduced ATP production and oxygen consumption rate in affected individuals compared to unaffected parents and controls, indicated impaired mitochondrial bioenergetics. We report a novel GDAP1 frameshift variant that disrupts mitochondrial structure and bioenergetics, underscoring GDAP1's role in mitochondrial quality control. However, the other downstream mechanisms implicated in axonal degeneration remains to be elucidated.

Charcot-Marie-Tooth (CMT) disease is the collective term for the most common inherited peripheral neuropathies, affecting both motor and sensory nerves. A typical CMT patient presents with slowly progressive distal muscle weakness and atrophy that primarily involves the small foot muscles, peroneal muscles, and, often later, the muscles of the hands and forearms. Foot deformities, most commonly pes cavus and claw toes, are common and can lead to gait impairments. In this paper, we report a patient with an intermediate CMT (CMT-Int) type carrying a novel pathogenic variant in the MPZ gene combined with type 2 diabetes. The patient's initial symptoms included a gradual onset of muscle wasting, weakness, and sensory impairment in the lower limbs. Electrophysiological findings suggested widespread peripheral nerve damage affecting both sensory and motor fibers, with a predominant demyelinating pattern accompanied by axonal damage. Genetic testing identified a previously unreported heterozygous mutation in the MPZ gene, specifically c.548G > A, p.Trp183∗. This alteration results in the replacement of the 183rd amino acid (tryptophan) by a stop codon. This premature stop codon is predicted to escape nonsense-mediated mRNA decay, resulting in a C-terminally truncated protein that may exert a dominant-negative effect. Although a different variant affecting the same codon (c.549G > A, p.Trp183∗, VCV000917145.1) has been documented, this particular pathogenic mutation has not been previously recorded. After being diagnosed with CMT, the patient developed type 2 diabetes following pancreatic cyst surgery in September 2022. The presence of both conditions exposed her peripheral nerves to congenital structural abnormalities combined with the metabolic consequences of chronic hyperglycemia and local ischemia, thereby exacerbating nerve injury.