AUTOSOMAL RECESSIVE AND X-LINKED FORMS OF CHARCOT-MARIE-TOOTH DISEASE IN CHILDHOOD

Introduction: There are now more than 30 identified genes and 44 loci for the various forms of hereditary neuropathies. Hereditary sensory and motor neuropathy (HMSN; Charcot-Marie-Tooth disease;CMT) is commonly divided into demyelinating forms (including dominantly inherited subtypes – CMT1, and autosomal recessive forms – CMT4) and axonal neuropathies (CMT2), which can be inherited in both dominant (AD) and recessive (AR) fashion. A rarer X-linked form is designated CMTX.

Objective: In this paper, the recently elucidated recessive forms of CMT, such as those due to lamin, EGR2, N-myc DRGI, periaxin, GDAP1 and myotubularin mutations (HMSN with myelin outfolding) as well as giant axonal neuropathy and severe infantile axonal neuropathy with respiratory failure (SMARD) will be examined. X-linked CMT will be compared.

Results: In a biopsy series of 260 cases of peripheral neuropathy in children aged 16 years and under, over 30% of cases were likely to have been due to AR inheritance but precise identification of the genetic cause was relatively infrequent. Clinical and histopathological clues to the precise etiology will be described.

Ten X-linked HMSN (CMTX) patients (2 biopsies) were also identified. Five of the ten patients had known connexin mutations (Val35Met, His73Fs, Gly159Ser, Ser182Thr and Met34Thr). Clinical findings included pes cavus, severe hand and foot weakness, pathologic fractures and gait abnormalities. One female patient had moderate hearing impairment with no clinical features of neuropathy. Nerve conduction velocities and amplitudes were typically more affected in the lower than in the upper limbs. Nerve biopsies showed predominance of axonal degeneration, with some segmental demyelination and onion bulb formation.

Conclusions: AR and X-linked forms of CMT are relatively common in childhood. Their precise characterisation is often elusive but can be assisted by a systematic examination of clinical, neurophysiological and histopathologic clues leading to appropriate DNA studies.

Keywords: Recessive; CMT; CMTX