Charcot–Marie–Tooth disease type 2J with MPZ Thr124Met mutation: clinico-electrophysiological and MRI study of a family

Abstract

The purpose of the present study was to describe clinico-electrophysiological features and lower limb muscle MRI findings in a CMT2J pedigree due to MPZ Thr124Met mutation. We examined the proband, aged 56 years, and her affected daughter and son, aged 30 and 29 years. Disease severity in terms of ability to walk and run was established using a nine-point functional disability scale (FDS). We administered the CMT neuropathy score (CMTNS) based on patient's symptoms, neurologic examination and neurophysiologic testing. All three patients had non-symptomatic Adie's pupil. The proband and her son presented with late-onset lower limb sensorimotor neuropathy and pes cavus; the proband's daughter had no signs of polyneuropathy. FDS score was 4 in the proband, 2 in her son, and 0 (normal) in her daughter. In both symptomatic patients, electrophysiological study showed a pattern of length-dependent axonal neuropathy mainly involving lower limb nerves; this was normal in the other patient. CMTNS was 18 in the proband, 12 in her son, and 0 (normal) in her daughter. MRI of foot and leg musculature was normal in the proband's daughter, whereas the other two patients showed massive fatty atrophy of intrinsic foot musculature, extensive and diffuse fatty atrophy of leg muscles in the proband, and mild distally accentuated fatty infiltration of calf muscles in her son. Muscle edema, detected only in the proband's son, was present in 7 out of 22 (33%) of visualized leg muscles, whereas contrast enhancement occurred in 6 of them. The reported mutation may manifest with either isolated Adie's pupil or pupil abnormalities with late-onset sensorimotor length-dependent axonal polyneuropathy, though the presence of pes cavus might indicate an earlier onset. MRI examination helps to delineate an accurate extent of muscle involvement in the disease.

Long-term Analyses of Innervation and Neuromuscular Integrity in the Trembler-J Mouse Model of Charcot-Marie-Tooth Disease

“…Furthermore, it is feasible that distal muscles of the hind paws were more affected, which could have impacted performance on the Rotarod. Consistent with this hypothesis, magnetic resonance imaging studies of CMT1A patients with minimal disease phenotype detected selective involvement of intrinsic foot muscles (42). …”

Reduced penetrance in hereditary motor neuropathy caused by TRPV4 Arg269Cys mutation

“…In our pedigree we found three gene mutation carriers (Arg269Cys), of which two at the age beyond the average age of disease onset and not showing any clinical signs of the disease. Furthermore, detailed electrophysiological evaluation was normal, and MRI of foot and lower-leg musculature did not reveal fatty atrophy; even the most distal muscles, constantly involved in subclinical CMT1A or CMT2A [3,6,16], exhibited normal appearance. We interpret that these unaffected mutation carriers are prototypic examples of non-penetrance.…”

“…In CMT2J some carriers of Thr124Met mutation in MPZ gene exhibited Adie's pupil with no polyneuropathic signs [9,16]. In a pedigree with MPZ Lys236del mutation causing adult-onset CMT1 phenotype, one gene mutation carrier aged 15 years had normal neurologic examination except for mildly reduced vibration sense, and normal nerve electrophysiologic findings [28].…”

Compound Charcot-Marie-Tooth disease: a kindred with severe hereditary neuropathy, pupil abnormalities and a novel MPZ mutation

“…It is therefore understandable that our probands suffered from early onset severe neuropathy with significant disability. Clinical variability exists in family members with the same MPZ mutation 5. Their mother was unaffected despite being a carrier of the MPZ mutation, and it was possible that she could develop symptoms later in life.…”