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]

Question 2 (10 marks)

Discuss your management plan, the prognosis you would give the family, and the precautions you would advise for future anaesthesia and chemotherapy. [6]

The management of Charcot-Marie-Tooth disease is supportive and multidisciplinary, guided by the Yiu 2022 clinical practice guideline for paediatric Charcot-Marie-Tooth disease. No disease-modifying therapy has proven effective for CMT1A, and the ascorbic acid trials showed no benefit. I would fit this boy with custom-moulded ankle-foot orthoses to correct the foot drop, stabilise the ankle, reduce falls, and improve the steppage gait. I would start physiotherapy for Achilles and hamstring stretching, strengthening, and balance training, and arrange podiatry for foot care and footwear modification. I would assess and treat neuropathic pain with gabapentin or pregabalin, which affects a significant minority of children with CMT. [6]

I would tell the family that the prognosis is one of slow progression over decades with preservation of ambulation and a normal life expectancy. Most children with CMT1A remain ambulant into late adulthood with orthotic support, and the Fridman natural history study confirmed that the disease burden is driven by foot and hand weakness, sensory loss, and pain rather than by life-threatening complications. I would explain the autosomal dominant inheritance and the one in two recurrence risk, and I would arrange genetic counselling for the family, including cascade testing of relatives and future reproductive planning. In adolescence, I would consider orthopaedic surgery for fixed foot deformity, such as tendon transfer or osteotomy, and I would plan a structured transition to adult neurology. [7]

I would advise the critical precaution that vincristine can unmask or severely worsen Charcot-Marie-Tooth disease and cause irreversible neuropathy. If this boy ever needs vincristine for cancer treatment, the oncology team must be informed of the diagnosis so that an alternative agent is used or the dose is modified. I would also advise careful padding and positioning under anaesthesia, because the nerves are vulnerable to compression, and a total intravenous anaesthesia technique is preferred. [11]