New Gene (PSAT1) Linked to Treatable CMT-like Outcomes

DNA Model - DNA Molecule, Griffin & George Ltd, Motorised, 1965

Two new and treatable cases of peripheral neuropathy reported in children raise more questions about the definition and diagnosis of CMT types.

But is it really CMT then?

Steve Bryson at CMT News has a nice breakdown of new findings in China reported in Pediatric Neurology that some variants (mutations) in the PSAT1 gene [NIH, GeneCards] can result in a cluster of symptoms commonly associated with the CMT family of polyneuropathy/neuromuscular diseases.

There are several unusual and interesting features of these two pediatric CMT cases where mobility was seriously impaired in the feet and legs — and in one case also the hands and arms. Curiously, the researchers identified these cases as “axonal CMT,” but they did not call it CMT2. Other of their findings noted demyelination was also at work, and all the major symptoms were treatable because the mechanism of the disease appears to be an enzyme deficiency, as in the recently discovered SORD Deficiency that also leads to CMT-like outcomes.

The first thing to catch my eye in this study is that some already-known variants on PSAT1 cause severe problems in the central nervous system (CNS), but in these two newly documented cases, that didn’t happen. Instead, the results were deemed consistent with “axonal CMT” and affected only the peripheral nervous system’s sensory and motor nerves. Mobility was severely impacted however, but in different ways in the two teenagers. One was suffering from malnutrition, and both had a nasty skin disorder, ichthyosis.

Clear, accurate language matters in medicine, science, and everywhere else. My vote is for hereditary neuromuscular wasting (or atrophy) because it very clearly states the major effect of all types of CMT: your motor nerves fail and the muscles they connect to weaken and die.

The second unusual feature of these cases is that “a nerve biopsy showed reduced density of myelinated nerve fibers, and electron microscopy revealed signs of axon damage and death.” In nerve conduction tests, “absent or reduced responses” were found. Typically CMT1 is associated with demyelination and reduced responses on nerve conduction velocity (NCV) tests, and CMT2 are associated with axonal damage and relatively normal nerve conduction. While these two primary types of CMT have been sharply delineated over the years, in reality all types of CMT involve some degree of damage to both axons and myelin, which is what has been reported in the new Chinese pediatric cases.

A third item of interest is that both patients’ conditions were treatable and improved with serine supplements, even though both children showed normal levels of serine in blood tests! I don’t know what to make of that.

An Unusual Disease Mechanism

What is serine, and how do these newly reported PSAT1 mutations bring about CMT symptoms? That isn’t entirely clear, but it sounds like an enzyme production deficiency is being identified as the likely cause.

PSAT1 is critical to the production of the PSAT enzyme, Phosphoserine aminotransferase or PSAT for short. PSAT is necessary for the production of serine, an amino acid. Serine deficiency disorders typically lead to really awful outcomes in early childhood development, far worse than what the children experienced in these reported novel CMT cases. I wonder if their deficiency kicked in late enough to hurt them less.

As we’ve seen with SORD gene variants that make it impossible to synthesize an enzyme the body needs to process sorbitol — which in turn leads to nerve damage and CMT-like symptoms from an excess of sorbitol — the PSAT1 variants make it impossible to synthesize an enzyme the body needs to produce an amino acid. In the first case, rather than associating SORD mutations with a type of CMT, clinicians have begun identifying it as a “SORD Deficiency.” So let me make a prediction! People with the PSAT1 mutations that produce CMT-like outcomes seem likely to be diagnosed with a PSAT or “Serine Deficiency.” Along with SORD, PSAT can cause a deficiency/disorder adjacent to or overlapping with the CMT/HNMD/dHMN disease types.

Naming is Hard

Why are there so many different names and classifications for CMT? Because there are many, many different causes of peripheral neuropathies. New expressions of CMT and similar diseases are still being discovered, and their genetic causes are slowly being identified.

While an acquired neuropathy can result in more or less the same symptoms and outcomes as a type of CMT, to qualify as a true CMT diagnosis, there must be a genetic cause, and most of these haven’t been found yet. But as more genetic variants leading to CMT-like outcomes are found, it’s apparent their mechanisms for damaging the nervous system can differ greatly. Some cause deficiency disorders that are or may be treatable. This might qualify them for inclusion in a different diagnostic category rather than a new or existing type/subtype of Charcot Marie Tooth disease.

I’ve said before it’s likely “CMT” may be reaching the end of its usefulness as a name. It’s a very non-descriptive term compared to hereditary (or accidental) neuromuscular atrophy, distal or peripheral hereditary motor neuropathy (impacting the lower and/or upper extremities most), and peroneal neuropathy (specific leg muscles). These are all diseases from inherited or de novo genetic mutations.

The new Chinese study I’ve reviewed here also brings attention to the unhelpfulness of overly emphasizing “axonal” and “demyelinating” categories in CMT diagnosis. Hopefully more precise language will be used in the future.

Clear, accurate language matters in medicine, science, and everywhere else. My vote is for hereditary neuromuscular wasting (or atrophy) because it very clearly states the major effect of all types of CMT: your motor nerves fail and the muscles they connect to weaken and die. In many if not all types of CMT, this damage occurs system-wide and also affects the brain. Respiratory involvement is common even if it’s rarely severe. All of it gets only worse over time and with age as muscles are weakening anyway.

I’ve got a big backlog of 30+ drafts of posts like this I’ve meant to develop and write about CMT research news and my own CMT experiences and questions. So, I’m joining a #clickpublish challenge to try to get out one post per day. We’ll see how it goes!

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