Mutations in SACS Gene Linked to CMT-Like Symptoms in Two Patients

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by Alice Melao |

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Mutations on the sequence of the SACS gene can lead to sensorimotor impairment similar to that observed in patients with Charcot-Marie-Tooth disease (CMT), researchers contend in a case report study published at Muscular Disorders.

More than 20 genes have been associated with the development of different forms of CMT. The several genetic subtypes of CMT share some clinical and biological features, but they are characterized by specific neurological and systemic involvement that can overlap with other neurodegenerative diseases, such as mitochondrial disorders and distal hereditary motor neuropathies.

CMT usually is characterized by a progressive degradation of the axonal section of nerve cells. This neuropathy leads to abnormal communication between nerve cells and impaired communication of peripheral nerves with the central nervous system, and consequently sensory and motor (sensorimotor) symptoms.

In the study “Early-onset axonal Charcot-Marie-Tooth disease due to SACS mutation,” a Brazilian research team reported two cases of unrelated men with CMT-like disease due to genetic mutations affecting the SACS gene.

Results from the initial clinical and physical evaluation of both patients were consistent with a CMT diagnosis. However, neuroimaging data did not confirm the typical characteristics of nerve cell degeneration associated with CMT.

To identify the genetic basis of the patients’ disease, the team performed whole-exome sequencing (WES), a technique used to sequence all the parts of our DNA that actually code for proteins. They found that both patients were carriers of two copies (one inherited from the mother and the other from the father) of mutated variant of the SACS gene. The identified mutations already had been reported to cause a disease called autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS).

ARSACS is characterized by childhood-onset cerebellar ataxia associated with brisk tendon reflexes, abnormal muscle contraction, nerve cells degeneration, “pes cavus” (foot deformity), and accumulation of myelin on the retina (light-sensitive tissue at the back of the eye). Patients with this disease can present a broad spectrum of neurological features, including intellectual disability, uncontrolled movement, and progressive myoclonic epilepsy.

Interestingly, evaluation of the two patients revealed they did not present any of the classical features of ARSACS. In addition, the axonal sensorimotor CMT-like neuropathy they had has never been associated with ARSACS or other diseases caused by SACS gene mutations (sacsinopathies).

Overall, these findings suggest that “SACS gene mutations can be associated with pure axonal sensorimotor neuropathy without other neurological features, but with typical neuroimaging features of other sacsinopathies, disclosing the importance of performing neuroimaging studies in patients with suspected axonal CMT,” the authors stated.