Peripheral myelin protein 2 – a novel cluster of mutations causing Charcot-Marie-Tooth neuropathy

The proband is a 37-year old Bulgarian female (A.III-1) reporting a family history of CMT consistent with autosomal dominant inheritance, with both an affected parent and grandparent (Figs. 1a, 2a). The disease onset of patient A.III-1 was in childhood, with delayed walking at the age of 18 months with frequent falls (Table 1). She had always run slower compared to her peers. She has had difficulties in stepping on her heels and toes since the age of 2–3 years. Foot deformities (high arched feet, thin calves) became apparent in the first decade of life. During her teens proximal muscle weakness in the lower limbs was noticed with difficulties in climbing stairs. The patient was referred to the department of neurology at the age of 20 and was followed up for 17 years. From the age of 29 years she started having weakness in the distal hand muscles with impairment of the fine movements, as well as tingling in the fingers bilaterally. Neurophysiological examinations from four consecutive tests, performed in 2001, 2011, 2016 and 2018 are presented in Table 2. Nerve conduction studies (NCS) were consistent with severe demyelination and secondary axonal degeneration. There are absent sensory responses in both upper and lower limbs. At the age of 37 years the compound muscle action potentials (CMAPs) in the lower limbs were unobtainable. In the upper limbs, CMAPs had severely reduced CV, prolonged distal latencies and low amplitudes. Needle EMG showed scattered fibrillation potentials and neurogenic motor unit action potentials.

The proband’s parent (A.II-2) started to walk at the age of 1 year with frequent falls. Foot deformities (high arched feet, thin calves) became apparent in the first decade of life. From the age of 34 years the patient reported weakness in the distal hand muscles with impairment of the fine movements. Neurological examination at the last follow-up (age 34) is presented in Table 1. NCS displayed a demyelinating pattern with secondary axonal degeneration in the lower limbs.

Lower limb musculature of patient A.III-1 was examined using magnetic resonance imaging (MRI) (Fig. 2b-e). The lateral compartments of the calves, including peroneus longus and brevis muscles were more severely affected, followed by extensor digitorum brevis and tibialis anterior muscles. The posterior compartment of the calves seemed relatively preserved. At thigh level the muscles were preserved as well, with slight changes visible in semimembranosus and semitendinosus muscles.

The proband (B.II-2) is a German individual who was adopted at the age of 1.5 years. The patient first exhibited a slight clumsiness with children’s gymnastics at the age of 2–3 years (Table 1). Foot deformities (pes varus) were observed at the age of 10 years, leading to walking impairment. After consultation with a child neurologist at youth, B.II-2 first presented in the neurological outpatient clinic at the age of 37 years. At that time, the patient complained of slightly progressive walking impairment and exercise induced muscle cramps in the upper limbs. The neurological examination was consistent with polyneuropathy with a predominant involvement of the lower limbs. The patient underwent surgical correction of foot deformity on the left side at the age of 41. When last examined at the age of 44, the motor and sensory deficits had not progressed significantly. B.II-2 was able to walk 2–3 km with orthopaedic shoes but without further aids. NCS performed at the age of 37 years showed a moderate reduction of motor and sensory amplitudes as well as conduction velocities in the lower limbs and markedly prolonged F-wave latencies, consistent with a primarily demyelinating pathology most pronounced on proximal parts of the motor nerve (Table 2). These remained without any major changes in the examination seven years later, at age 44.

The older sibling (B.II-1, also adopted) was reported to present with foot deformities and slight clumsiness since the age of 2–3 years. Since these complaints have not interfered with everyday activities, the individual was followed up at the age of 46 years. Patient B.II-1 revealed similar, albeit milder clinical features with pes varus deformity more pronounced on the right side, an inability to walk on heels, areflexia, but absence of muscle atrophy or sensory deficits (Table 1). As an additional clinical feature, B.II-1 had suffered from recurrent generalized seizures with an onset at the age of 12 years, which reduced markedly upon therapy with valproic acid. NCS revealed only discreet abnormalities with prolonged F-wave latencies in the lower and upper limbs, suggesting a focal demyelinating pathology at the level of the roots or the proximal parts of the motor nerves, but mostly normal motor and sensory amplitudes and conduction velocities. Interestingly, the CVs of the sensory nerves in the upper limbs were normal, while the amplitudes of SNAPs were decreased, suggesting axonal damage. The CVs of the median and ulnar nerves were decreased with normal amplitudes and distal latencies of CMAPs (Table 2).

Both adopted sibs originate from the same biological parents. One of them (B.I-2) was reported to have had a similar disease but no clinical data were available.