Peripheral neuropathies: SAQ

This boy presents the textbook phenotype of Charcot-Marie-Tooth disease: a slowly progressive distal neuropathy with pes cavus, hammer toes, inverted-champagne-bottle leg wasting, absent ankle jerks, large-fibre sensory loss, steppage gait, and an affected parent. The uniform slowing of the median motor conduction velocity to 28 metres per second across all nerves without conduction block confirms a demyelinating inherited neuropathy, and the affected father establishes the autosomal dominant inheritance pattern. ^[1]

Question 1 (10 marks)

Outline your diagnostic approach, the specific investigations you would request, and how you would classify and confirm the diagnosis. ^[1]

The clinical picture is diagnostic of a hereditary motor and sensory neuropathy, and the uniform slowing to 28 metres per second places it in the CMT1 demyelinating family. The nerve conduction velocity threshold of thirty-eight metres per second separates demyelinating CMT1, with uniform slowing, from axonal CMT2, with preserved velocity and reduced amplitudes. The absence of patchy, non-uniform conduction block argues against an acquired demyelinating neuropathy such as CIDP, which is the critical treatable differential to exclude. ^[1][8]

The first genetic test for a child with uniform demyelinating slowing is a PMP22 duplication and deletion analysis by multiplex ligation-dependent probe amplification, which diagnoses CMT1A and HNPP. If positive for the duplication, this confirms CMT1A, which accounts for around half of all Charcot-Marie-Tooth disease and is caused by a one-point-four-megabase duplication on chromosome seventeen discovered by Lupski in 1991. If the duplication test is negative, a next-generation sequencing hereditary neuropathy panel covering MPZ, GJB1, MFN2, and dozens of other genes is the next step. ^[2][9]

I would examine the father formally, because his mild pes cavus and reduced ankle jerks confirm the autosomal dominant inheritance and strengthen the case for CMT1A. I would take a three-generation family history, asking about high arches, foot drop, abnormal gait, ankle sprains, and orthopaedic foot surgery, and I would arrange cascade genetic testing of affected relatives. The importance of excluding CIDP is that it is treatable with immunotherapy while CMT is not, and the Fernandez-Garcia study showed that a significant fraction of children referred for genetic neuropathy testing have an acquired demyelinating process. ^[9]