• Kenneth Raymond

SORD-Deficiency: Decoding This Newly Discovered and Confusing CMT Subtype

Updated: 5 days ago

Exploring What Makes SORD-Deficiency CMT So Different from Every Other CMT Subtype, and Discussing Why SORD-Deficiency is CMT

"Everyone has high sorbitol. That's part of this disease. We do know that sorbitol level does drive the disease severity. Why is that important? Because, with AT-007 treatment, we're reducing sorbitol levels. So, it's important to know that sorbitol is driving this disease and how high or low your sorbitol levels are makes a difference in terms of how quickly and aggressively the disease will progress." --Shoshana Shendelman, PhD, Founder, Applied Therapeutics

Charcot-Marie-Tooth disease, or what is CMT, is an inheritable peripheral nervous system disease with no current treatment or cure. The peripheral nervous system comprises all the nerves that lie outside of the brain and spinal cord except the optic nerves, and CMT can affect all of them (including the optic nerves for some). CMT is not an easy disease to describe. CMT is a heterogeneous multisystem disease (heterogeneous (het-eh-row-jeh-nay-us) = many different causes and the presentation can be different for everybody). CMT is a peripheral neuropathy (neuro- = nerve, -pathy = disease) that is actually a peripheral polyneuropathy because CMT affects more than one peripheral nerve at a time rather than just one nerve (poly- = many/more than one, mono- = one (polyneuropathy vs. mononeuropathy)). CMT is also a neuromuscular disease because the disease of the peripheral nerves causes symptoms to present in muscles (neuro- = nerve, -muscular = affects skeletal muscle). CMT, however, is not a muscle disease. If this isn’t confusing enough, the name doesn’t help. It gets easier, though, when we know the name’s origin.

CMT gets its name from the three doctors who first described it in 1886: Jean-Martin Charcot (1825-1893), Pierre Marie (1853-1940), both from France, and Howard Henry Tooth (1856-1925) from England. Today, CMT as a disease name has evolved into an umbrella term that refers to many different sensory and/or motor neuropathies, axonopathies, myelinopathies, and neuronopathies (Pisciotta & Shy, 2018) (Bansagi, et al., 2017). In its infancy, however, CMT described a disease that causes only lower leg muscle weakness and atrophy, or what is aptly called, “peroneal muscle atrophy.” Over time, however, CMT has revealed itself to be profoundly more diverse with reaches far beyond the lower legs (multisystem).

The Age of Discovery

First described in 1886, the cause for CMT wasn’t discovered until more than one-hundred years later. In 1991, researchers announced and published the first cause of CMT, a duplication of a tiny segment of chromosome 17 (17p11.2 – 17p12), which they concluded is responsible for causing CMT1A (Raeymaekers, et al., 1991). A year later, this discovery was narrowed down to the exact gene—an extra copy of the PMP22 gene that’s present when the tiny chromosome 17p11.2-p12 segment is duplicated (Patel, et al., 1992). At the time, researchers believed there might only be a small handful of additional causes to find and this thing would be figured out. CMT, however, has proven itself to be, perhaps, the most complicated disease there is.

Scientists have now discovered CMT-causing mutations in more than 120 genes. Mutations in these genes cause more than 150 individual CMT subtypes (Raymond, 2022). New discoveries are happening every year, and there’s no signs of slowing down. Scientists estimate that we are only about halfway to finding all genes that have CMT-causing mutations (Shy, 2020). However, some estimate that we might be closer after the recent discovery of SORD-deficiency (Züchner, 2021).

Sorbitol cyclone. This double-helix-shaped cyclone of sweetener packets depicts the detrimental effect of increased sorbitol levels on peripheral nerves, caused by biallelic mutations in the sorbitol dehydrogenase (SORD) gene.

Gracing the May 2020 cover of Nature Genetics, a truly prestigious achievement, researchers announced the discovery of a new CMT subtype caused by autosomal recessive mutations in the SORD gene (Cortese, et al., 2020). The investigators who make CMT subtype genetic discoveries get to name their discovery. The name they choose becomes known as the subtype name. Rather than choosing a conventional CMT name like CMT1K or CMT4M, for example, the investigators who discovered the CMT-causing mutations in the SORD gene chose to call it, simply, “SORD-deficiency.”

Data show this new CMT subtype, SORD-deficiency, is the most common autosomal recessive CMT subtype, affecting approximately 3,000 CMTers in the US, approximately 4,000 CMTers in Europe, and approximately 60,000 worldwide—accounting for 10% of all axonal CMT cases. (Shendelman, 2022). For context, CMT in whole affects approximately 135,000 in the US, approximately 180,000 in Europe, and just over 3 million globally.

Scientists have a firm grasp on the SORD gene and the biochemical function it’s responsible for. The biochemical process the SORD gene is a part of is implicated in diabetes and other diseases, and scientists have been studying this implication for decades. There was already pharmaceutical expertise in this area when scientists made the SORD-deficiency discovery. Because of this, researchers feel this might be the first truly treatable CMT subtype (CMTA, 2021).

What is SORD-Deficiency?

Also known as SORD-deficiency CMT, or SORD-CMT, or just SORD, whichever we call it, SORD-deficiency is a CMT subtype (Shendelman, 2022). Specifically, SORD-CMT is an axonal CMT subtype, and as an axonal subtype, it fits within the CMT2 nerve conduction and symptom profile. SORD-CMT is mostly a motor neuropathy (primarily affects the motor nerves), but there can be sensory nerve involvement. A likely description on a nerve conduction study (NCS) report would be along the lines of length-dependent axonal motor polyneuropathy (or sensorimotor polyneuropathy if there is also sensory nerve involvement). What is CMT2?

CMT is clinically divided into two main groups according to nerve conduction study results (NCS): CMT1, classified as demyelinating, and CMT2, classified as axonal. These are differentiated by their respective nerve conduction profiles. Clinically, CMT1 has nerve conduction velocities (speeds) that are slower than 38 meters/second (and usually slower than 25 meters/sec) and amplitudes (signal strength) that are somewhat reduced; and CMT2 has velocities that are faster than 38 meters/second with significantly reduced amplitudes (Dyck, Lambert, & Mulder, 1963) (El-Abassi, 2014) (Stojkovic, 2016). Although these are basic and general rules-of-thumb, how CMT is clinically diagnosed without the benefit of a genetic confirmation is typically based on these criteria. Then, once the underlying genetic cause is identified, the diagnosis transitions to the subtype associated with the identified gene mutation. The genetic diagnosis, however, might not remain a CMT1 or a CMT2 classified subtype, such as CMT1B or CMT2D, for example.

CMT1 is a group of ten demyelinating subtypes as determined by nerve conduction. However, there are twenty-eight demyelinating subtypes. CMT2 is a group of thirty-six CMT subtypes, but there are 114 axonal subtypes (Experts in CMT, 2022). Of these 114, there are twenty-three subtypes that have a dHMN name— eighteen dHMN subtypes plus five dSMA subtypes (dHMN and dSMA are synonymous (Inherited Neuropathies Consortium (INC), 2021)). dHMN is the acronym for Distal Hereditary Motor Neuropathy and dSMA is the acronym for Distal Spinal Muscular Atrophy. Despite the names, the CMT experts consider these to be CMT (Bird, 1998, Updated 2022) (Bansagi, et al., 2017). What is dHMN?

The subtypes of dHMN are a length-dependent motor neuronopathy, meaning the issue originates within the motor neuron of the peripheral nerves and affects the longest peripheral motor nerves first and more severally than the shorter ones (the nerves that control the muscles of the feet and lower legs vs. the nerves that control the muscles of the hands, for example). The motor nerves are the nerves that control muscles and movement. Sometimes truncated to just HMN (Hereditary Motor Neuropathy), there is little to no sensory nerve involvement, and these subtypes exhibit an axonal CMT nerve conduction profile. As such, the dHMN subtypes are classified as axonal CMT and are therefore often clinically diagnosed as CMT2. Sometimes, however, dHMN (aka HMN, aka dSMA) is the clinical diagnosis when NCS results show a length-dependent axonal CMT and when there is only motor nerve involvement. This will be important in a moment.

As a general rule-of-thumb, symptoms associated with CMT2 are typically length-dependent, again, meaning the longer nerves are often affected before the shorter ones, and often more severely. Typically, the lower legs and feet are more severely affected than the hands. Symptom onset can occur at any point in life. Nerve conduction can be quite variable from nerve to nerve and even side to side. How does SORD-CMT fit within this CMT2/axonal CMT classification?

SORD-CMT symptom onset is usually in the second decade, typically by about 17 years old (CMTA, 2022). Symptoms are basically that of a motor-predominant CMT2 and/or dHMN, affecting only the motor nerves, in a length-dependent manner, with little to no sensory nerve involvement, and include difficulty with walking, frequent tripping, lower leg weakness, foot deformities, progressing to the need for mobility aids (leg bracing); and later on, hand weakness, for example. However, some can have upper limb sensory and motor involvement early on in their disease course.

Although SORD-CMT is classified as an axonal CMT, some SORD-CMTers have nerve conduction that is more consistent with intermediate CMT (Record, et al., 2022). Intermediate CMT is a group of CMT subtypes as determined by NCS results. Intermediate CMT nerve conduction doesn’t necessarily comport with demyelinating CMT or with axonal CMT, it is somewhere in between, it is intermediate (El-Abassi, 2014). Intermediate CMT does not denote disease severity and refers only to nerve conduction. Regardless of the nerve conduction profile a CMTer who has SORD-CMT might have, SORD-CMT is classified as an axonal CMT subtype.

CMTers who have SORD-CMT are often clinically diagnosed with either CMT2 or with dHMN (or HMN, and some possibly dSMA) based on symptoms and especially on NCS results. Past genetic testing for these CMTers failed to identify a conclusive genetic cause for their CMT. SORD-CMT and its cause were discovered and published only in 2020. Prior to this, the SORD gene was not part of any CMT genetic test. Nobody knew about this gene’s connection to CMT.

Several commercial genetic testing companies moved quickly to offer SORD testing within a year of the initial discovery of its role in CMT. However, SORD genetic testing is not yet a part of the neuromuscular or neuropathy gene panels that are used in CMT genetic testing. So, physicians need to specifically order the SORD genetic test if they suspect a patient might have SORD-CMT (SORD genetic testing resources are discussed in Diagnosing SORD-CMT). Why this name, “SORD,” and why the caps lock?

This Gene has a Name, and Its Name is “SORD” (for short)

Genes have both a long-form name and a short-form called a symbol. The symbol is an abbreviation of the long-form gene name. The HUGO Gene Nomenclature Committee is the entity who manages these names and symbols. The "SORD" in SORD-deficiency is short for SORBITOL DEHYDROGENASE. Where SORBITOL DEHYDROGENASE is the gene name, SORD is the gene symbol (HGNC, 2022). It’s customary to write the gene name in all caps but is not required in literature. The gene symbol, however, is always written in all caps.

The SORD gene codes for an enzyme aptly called sorbitol dehydrogenase (the gene provides the genetic code that makes the enzyme and provides the genetic instructions for how the enzyme functions). An enzyme is a biological catalyst (causes a biochemical change). SORD belongs to a group of enzymes called dehydrogenases. Dehydrogenases are a group of enzymes that each catalyze (change/convert) a compound to another by removing hydrogen atoms (de-hydrogen-ates, ergo de-hydro-gen-ace). Specific to the SORD gene, sorbitol dehydrogenase is the enzyme that converts sorbitol to fructose by removing a hydrogen atom from sorbitol. This action converts (changes) sorbitol to fructose. This is the important part in the context of SORD-CMT, and it all starts with glucose.

The Less Traveled Path[way] of SORD-CMT

Glucose is one of many different simple sugars. When we talk about blood sugar, we're talking about glucose. In biochemistry, anything ending in "ose" is a simple sugar. The body metabolizes (converts to energy) these simple sugars through various biochemical processes. Glucose is metabolized in many ways, and each is referred to as a pathway. Each of these pathways convert glucose to other sugars which are then, eventually, used by the cell for energy.

The majority of glucose is converted to other substances that are used by the cell for energy via the hexokinase pathway. The hexokinase pathway is the biochemical chain reaction that converts hexoses to energy. As complicated as this might sound, you don’t have to be a biologist to know what all this is and how it works in the context of SORD-CMT

"Medicine makes sense once we understand what the words are saying." --Medicosis Perfectionalis

Hexokinase (hex-oh-kye-nace) is an enzyme that phosphorylates hexoses. Phosphorylates means "to add a phosphate group to a substance." A hexose is any sugar that contains six carbon atoms (hex- = six, -ose = sugar). These are referred to as six-carbon sugars. In biochemistry, "kinase" means "to phosphorylate." Put these together and hexokinase is an enzyme that converts into other substances sugars that contain six carbon atoms, and this is accomplished by adding a group of phosphates to the sugars. Glucose just happens to be a six-carbon sugar—a hexose. Adding a phosphate group to glucose converts it to a different sugar, and further down the complicated hexokinase pathway, after several additional biochemical conversions, the end result is fructose, which is then used by the cell for energy (Chaudhry & Varacallo, 2021).

Another pathway in which glucose is converted to energy is the polyol pathway. The polyol pathway is a two-step biochemical conversion that converts monosaccharides to their corresponding polyol in the first step and then converts the polyol to fructose in the second step. Fructose is then used for energy by the cell. The polyol pathway is the important one for SORD-CMT. What does all this mean and why is this pathway important?

A polyol is an alcohol sugar, of which there are many (poly- = many, -ol = alcohol sugar). The term, "alcohol sugar," is misleading though. Alcohol sugars are neither alcohol nor sugar. They are, however, a compound chemically similar to sugars (BiologyOnline, 2022). A monosaccharide (mono-sack-ah-ride) is any sugar that cannot be further reduced into a simpler sugar. A monosaccharide (mono- = one, -saccharide = sugar) is a sugar in its simplest form. The polyol pathway converts these simple sugars into their corresponding polyol sugar. Hence, polyol pathway. The first step in the two-step polyol pathway is aldose reductase.

Aldose reductase is an enzyme that reduces aldoses to their corresponding polyol. Aldoses are a large family of monosaccharides. Biochemically, an aldose is a simple sugar that contains an aldehyde group (ald- = aldehyde, -ose = simple sugar) (BiologyOnline, 2022). Reductase (re-duck-tace) is any enzyme that reduces a substance to another substance. In biochemistry, metabolism (substance conversion) occurs in terms of electrons: if electrons are lost during the chemical conversion, the process is called oxidation—something is oxidized; and if electrons are gained, it’s a reduction—something is reduced. (The University of Hawaiʻi, 2022).

Glucose, as you might have guessed, just so happens to be a member of the aldose family of simple sugars. The corresponding polyol for glucose is glucitol (gluc- = glucose derivative, -ol = alcohol sugar). Glucitol (gloose-eh-tall) is more commonly known as sorbitol. In the first step of the polyol pathway, aldose reductase converts glucose to sorbitol. Sorbitol cannot cross the cell wall and becomes trapped within the cell. To manage sorbitol levels within the cell, sorbitol must be converted to another substance.

The second step of the polyol pathway, sorbitol dehydrogenase, converts sorbitol to fructose. Fructose is then used by the cell for energy. This solves the issue of sorbitol being trapped within the cell and reaching toxic levels as more glucose is converted by aldose reductase. It’s a simple, quick, and easy two-step (two-enzyme) process for managing glucose levels and acute (short-term) cell energy demands, especially when compared to the more complex hexokinase pathway.

The hexokinase pathway handles the bulk of metabolizing glucose to energy. Under normal conditions, the polyol pathway is barely used, if at all. The polyol pathway, however, becomes activated when hyperglycemic conditions are present within the cell (elevated levels of glucose) or when the cell needs extra energy.

Under normal conditions, sorbitol levels are very low. As sorbitol is produced by the polyol pathway, it’s converted to fructose and sorbitol levels are kept in check. If this pathway is inactive, glucose isn’t being converted to sorbitol within the cell. When the polyol pathway is active, the amount of glucose being converted is minimal compared to the hexokinase pathway, and the sorbitol that is produced is converted to fructose by sorbitol dehydrogenase (Shendelman, 2022). Normally low sorbitol levels are maintained by sorbitol dehydrogenase. So, what happens if sorbitol dehydrogenase can’t perform its job?

Enter SORD-Deficiency CMT

SORD-deficiency CMT is caused by autosomal recessive mutations in the SORD gene (autosomal = gene lives on a numbered chromosome (the SORD gene lives on chromosome 15), recessive = gene must have two mutations in order to cause the disease). Researchers have identified many different CMT-causing mutations within this gene since the initial discovery. Each of these can either cause the SORD enzyme to not be produced at all or they can cause the enzyme to completely shut off and stop working. Because the SORD enzyme no longer functions in this CMT subtype, SORD is deficient - the biochemical conversion performed by the SORD enzyme is deficient. Hence, SORD-deficiency as this CMT subtype name. The subtype name describes the biochemical impairment that causes CMT.

When everything is running well, the polyol pathway, also called the aldose reductase pathway, runs smoothly. When activated in times of need, aldose reductase converts glucose to sorbitol and the SORD enzyme converts sorbitol to fructose. The cellular machinery is happy, and everything moves along nicely. However, the mutations that shut off the SORD enzyme throw a big boulder into this finely tuned machine, as you can imagine.

All the sorbitol created by aldose reductase in the polyol pathway stays trapped within the cell from the very outset. This is normal with sorbitol. Sorbitol is unable to cross the cell wall. Essentially, all sorbitol created by the polyol pathway remains within the cell until SORD converts it to fructose. Since the mutations in the SORD gene that cause SORD-CMT cause the sorbitol dehydrogenase enzyme to completely stop working, sorbitol is not converted. The sorbitol, instead, remains within the cell, trapped. The more glucose that’s converted to sorbitol by aldose reductase, the higher the sorbitol levels climb, and they keep climbing, over time, until they reach levels that become toxic to peripheral nerves and their neurons, leading to neuronal and peripheral nerve impairment, or as we like to call it, CMT. And then, they keep climbing, unabated, as aldose reductase continues to do its job.

The body does process sorbitol in other ways, albeit minimally. Certain enzymes called, “scavenger enzymes,” whose job it is to basically perform cellular housekeeping duties, is one way sorbitol is processed. The kidney’s also play a role in managing sorbitol. In the absence of a functioning SORD enzyme, while these methods do remove some sorbitol, they are quite inefficient and pale in comparison to the amount of sorbitol the SORD enzyme can handle (Shendelman, 2022). For the amount of sorbitol the body is able to process in the absence of a functioning SORD enzyme, aldose reductase keeps adding sorbitol back into the mix, and at a rate greater than what non-SORD sorbitol processing can handle. The result is chronically high sorbitol levels that become toxic to especially motor neurons thereby causing CMT symptom onset, and these things only worsen over time.

The Toxicity of Our [Sorbitol]

When SORD is deficient, the sorbitol created by the polyol pathway cannot be converted to fructose. This sorbitol ends up just sitting there, in the cells, trapped, accumulating over time because sorbitol cannot exit the cell. Eventually, sorbitol accumulates to levels high enough, toxic enough, to cause CMT symptoms to start. As sorbitol levels continue to accumulate, symptoms worsen. These elevated levels of sorbitol are quite toxic especially for motor neurons. Hence, SORD-CMT symptoms. Research has shown that overall symptom severity in SORD-CMT correlates with sorbitol levels in the blood (Shendelman, 2022). The higher the sorbitol levels, the worse the CMT. Because sorbitol continues to accumulate and causes damage over time, the older the CMTer who has SORD-CMT gets, the more severe their CMT becomes.

It's well understood that high sorbitol levels via the polyol pathway in diabetes are a contributing factor to diabetes-induced peripheral neuropathy, or what is referred to as diabetic neuropathy. When glucose is high, such as what is commonly seen in diabetes, there’s more to convert. Elevated glucose activates the polyol pathway causing sorbitol levels to become higher as aldose reductase is converting more glucose. The higher sorbitol levels contribute to the acquired neuropathy often seen in diabetes. Because this is well described and understood in medical scienc