The “First Treatable CMT Disease” is Neither CMT Nor a Disease


This article at CMT News isn’t strictly correct in calling SORD Deficiency a type of CMT. CMT is a disease that causes disabilities. SORD Deficiency is, well, a deficiency that causes a type of CMT or a diseased outcome resembling types of CMT that may lead to disability. It might be easier to say the hereditary SORD Deficiency causes a type of neuromuscular disease that’s clinically similar to the CMT family.

These ‘D’ words — “Deficiency” and “Disease” — are related but distinct and easily confused. Add “Disability” and it gets really messy, as Jackie Leech Scully reflects in “What is a Disease?” This is a great essay published in EMBO Reports in 2004; check it out for a patients’ perspective on these key medical terms.

Getting Definitions Right

The term “CMT” or “Charcot-Marie-Tooth Disease” has worn out its welcome

A deficiency involves a lack or insufficient level of a key nutrients, hormones, enzymes, etc. A deficiency may do physical damage and even cause death. A deficiency can lead to a disease, and a disease is defined as an injurious chronic condition caused by some other agent or mechanism, such as a deficiency like SORD which causes (but in itself isn’t) a type of) CMT.

So, it’s most accurate to say CMT is a hereditary (but not necessarily inherited) neuromuscular disease (HNMD) or a Distal Hereditary Motor Neuropathy (dHMN), or a Hereditary Motor/Sensory Neuropathy (HMSN). All of these terms are used today as umbrellas for diseases including all types of CMT.

Scrapping “CMT” and Its Obsolete “Types”

Some have argued the term “CMT” or “Charcot-Marie-Tooth Disease” has worn out its welcome as a mashup of three 19th-century doctors’ names. It is not descriptive of anything useful for understanding the disease or spreading awareness about it. More significantly, the CMT classification into types and subtypes is passing into obsolescence. This classification is based on the often inaccurate and misleading distinctions between axonal, demyelinating, and intermediate (both axonal and demyelinating) nerve damage presenting clinical symptoms that have defined the disease.

Photo of racoon with labels: "featherless" and "biped" — "This is a man."

A 2018 proposal (Magy et al) to update the classification of inherited neuropathies garnered the support of a majority of the 107 international CMT specialists and is recognized in the current 2023 revision of GeneReviews’ Charcot-Marie-Tooth Hereditary Neuropathy Overview. (This is a publication that has been updated regularly since 1998 to kep pace with CMT research.) I believe Magy et al’s proposal will slowly prevail as “CMT” fades in usage by geneticists, neurologists, and clinicians dealing with the disease. The main resistance is likely to be charities and funding organizations like the CMTA that have wedded their brand and marketing to the “CMT” name — up until they decide to make the change. That would certainly help shift the field if they were to take the lead rather than be drawn along later. It’s hard to see the downside of having a bigger tent for patients, donors, reseachers, and other people who have more in common and more to gain from working and thinking together.

CMT Type classifications are based on misleading and often inaccurate distinctions between axonal, demyelinating, and intermediate (both axonal and demyelinating) nerve damage.

It’s important to think outside the CMT box. In the past and still today in places where CMT specialists are rare, anyone presenting CMT-like clinical symptoms is likely to be diagnosed with this vaguely defined disease in the absence of a differential diagnosis. Differential diagnoses for CMT are not commonly examined in my experience, although they do exist, and the recently formed MD Canada-funded NMD4C (Neuromuscular Disease Network for Canada) is doing a lot of good work in this regard.

The Post-CMT Future

The pre-human genome project classification of CMT types and subtypes was based on clinical assessments and then nerve conduction velocity testing. These limited assessments are now being augmented (and will likely be replaced) by primarily genetic testing, family history, and more precise tissue and chemical tests that are emerging.

Take, for example, the recently (2014) discovered CMT2S. CMT2S is only one neuromuscular disorder connected to mutations in the IGHMBP2 gene, like SMARD1. While the symptoms and impacts differ, they share a common genetic root. Research for cures and therapies — and simply how neuromuscular diseases are studied and taught — seem likely to benefit more from “lumping” them together based on genetic commonalities than splitting them apart for their clinical differences.

Or consider other recent discoveries in the field of CMT research. Mutations on the COQ7 gene can impair the production and create a deficiency of Coenzyme Q10 (CoQ10). That deficiency leads to a likely treatable form of distal hereditary motor neuropathy — which previously would have been identified as a kind of CMT disease.

SORD Deficiency is similar. Mutations on the SORD gene can impair production of Sorbitol Dehydrogenase, an enyme that processes sorbitol. Without the enzyme, the sorbitol (a type of carbohydrate called a sugar alcohol, or polyol) builds up and damages nerves. That nerve damage is responsible for clinical outcomes that look like CMT and related neuromuscular diseases.

CoQ10 and Sorbitol Dehydrogenase deficiencies are not diseases or CMT. Their discovery is helpful not just for people who have them but for how they encourage careful definitions, rethinking, and reclassification in CMT research. That’s the effect these new discoveries have had on my thinking about CMT since I first wrote about SORD here, here, and for the Hereditary Neuropathy Foundation. (I was also tested for the SORD mutation since I have CMT2 symptoms but no genetic matches for known CMT mutations or any family members with similar symptoms.)

SORD (and COQ7) won’t be classified as new types of CMT but unique genetic sites of treatable deficiencies that can be prevented from causing distal hereditary motor neuropathy or neuromuscular disease. It will be an interesting twist if CMT-related research does away with “CMT disease” not just by finding cures and treatements but by changing how naming and classification works in neurological pathology! There won’t be anymore “CMT,” there will be dHMN and NMDs. Maybe like “Lou Gehrig’s Disease” and ALS people will understand both the scientific and the popularized names.

Update: Applied Therapeutics has a drug, AT-007, that’s being fast-tracked in clinical trials for treating SORD Deficiency and some other rare neurological diseases. It appears to cut sorbitol levels in half for people afected by SORD Deficiency. This article calls SORD Deficiency and another deficiency/disorder a “disease” rather than the potential causes of diseases, but it doesn’t mention CMT, and neither do any other sources I’ve seen about SORD Deficiency and possible treatments outside the CMT community.

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