Vikas Sharma (name changed) brought in his 2-year-old son, Avinash (name changed), to Dr Krishnakumar Shah, Senior Paediatric Neurologist, Lilavati Hospital and Research Center at Mumbai, for a regular check-up. Upon examination, Dr Shah observed that Avinash was lagging in some of his milestones. While Avinash was cognitively on track, he was still unable to walk. On talking more with the father, Dr Shah realized that Vikas also had had a similar motor delay and in fact had not started walking until he turned 5 years old. He also has a wide base gait and foot drop, just like his father, Mohan (Avinash’s grandfather), before him. Vikas was now concerned whether his son, Avinash, also has the same problem as himself and his father, Mohan, before him. However, he did not know what they were suffering from.
With this family history, Dr Shah did some further neurophysiological investigations and found that both Vikas and Avinash were showing signs of peripheral neuropathy in the hands as well as the legs. Nerve conduction and electromyography tests performed in father and son indicated that they had some sort of a hereditary sensory-motor neuropathy. Dr Shah also had videos taken of Vikas and Mohan to understand the similarities between their abnormal gait. Based on these test results and clinical assessment of gait, autosomal dominant, Charcot-Marie-Tooth (CMT) disease was suspected, and Vikas was counselled to undergo genetic testing. Genetic results for both Vikas and Avinash came positive for mutations in the gene encoding for myelin protein zero or the MPZ gene, suggesting that all three generations have CMT type 1B.
CMT1B is one type amongst a wide variety of inherited peripheral neuropathies that encompass the CMT disease. Clinical features include a slowly progressive weakness and atrophy of the distal limb muscles. In addition, foot drop and steppage gait are also common features of the CMT disease. While clinical manifestations are similar amongst all the neuropathies, CMT disease is further categorized based on the affected gene. Over 100 genes have so far been identified as being involved in causing these hereditary muscle weakness and sensory loss disorders. While 1 in 2,500 are affected by any one of the CMT diseases, only 1 in 30,000 are specifically affected by CMT 1B. Once clinically assessed via nerve electrophysiological tests and confirmed via genetic
testing, currently approved treatment options include physiotherapy and occupational therapy. Since CMT disease is a slowly progressive neurodegenerative disorder, periodic follow-ups are required. Symptomatic treatment with pain management can substantially help in improving the quality of life. Further, several clinical trials have been undertaken and are currently being carried out using various drugs as potential treatment options. However, currently, no cure is available.
With technological advances, a very promising therapy option is the advent of gene therapy. Sarepta Therapeutics, Inc. has announced a clinical trial slated to start in 2019 using gene therapy, albeit
for the more common CMT1A. Type 1A version is most often caused due to an extra copy of the PMP22 gene, which encodes for the peripheral myelin protein 22. A group of researchers has previously shown that overexpression of neurotrophin NT-3 significantly improves nerve regeneration and myelination and can lead to improvements in mouse models of CMT 1A. Should this therapy be successful, alternate gene therapy options are likely to hold promise for other CMT disease types as well.
Talking about the possibilities for the Sharma family, Dr Shah says: “For Mr. Mohan, time has run out; however, he has been lucky to have led a more or less normal life. For Vikas too, a permanent cure may not be in sight, but for Avinash, the possibility of a cure in the near future is bright. Only time can tell whether it will arrive in time to prevent him from carrying this disorder to the next generation.”