Mutations in LRSAM1 Gene Tied to Rare CMT Subtype

Mutations in the LRSAM1 gene result in the rare, type 2P subtype of Charcot-Marie-Tooth disease, but the location of such mutations within the gene appears to influence the inheritance pattern and possibly the disease mechanism of CMT2P, according to a recent study.

The study, “Location matters – Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P,” was published in the journal Neuromuscular Disorders.

CMT2P is one of the rarer forms of Charcot-Marie-Tooth disease and is associated with a late onset and relatively mild symptoms. Published research lists roughly 150 patients from 30 independent families and describes fewer than 20 genetic mutations in the LRSAM1 gene, which causes the subtype.

A group of researchers from across Germany now identified seven new LRSAM1 variants, or mutations, from among 10 different variants carried by 14 CMT2P patients from 12 families. A mutation’s specific location within LRSAM1 appeared to influence its effect on CMT2P and how the disorder was inherited.

Of those seven, five were predicted to be likely pathogenic, or disease-causing, while two were classified as being of “uncertain significance.”

One likely pathogenic variant was inherited in an autosomal recessive fashion, meaning that two mutated gene copies — or alleles — would be needed for CMT2P to occur, while the others were all inherited in an autosomal dominant fashion, meaning that only one mutated allele might cause the disorder.

The mutation in the individual with both affected gene copies is predicted to render that gene nonfunctional, by changing how the instructions in the gene’s second-to-last exon are “read.”

Of note, genes are composed of different sequences of DNA called exons and introns. Proteins are made using only the instructions found on exons.

According to the American College of Medical Genetics and genomics (ACMG) guidelines, this so-called “frameshift” mutation is likely pathogenic.

The other likely pathogenic variants consisted of mutations found in the same exon. Two of these also were frameshift mutations ,while the remaining one was a “stop gain” mutation because it created a premature “stop” signal in the gene.

The two variants of uncertain significance involved changes of a single nucleotide — the building blocks of DNA — of the last exon. These cause a change in one of the resulting protein’s amino acids, which are the building blocks of proteins. Without further testing, it remains unknown exactly how these changes affect the LRSAM1 protein.

The newly-discovered variants suggest that the location of a mutation within the LRSAM1 gene influences the inheritance pattern and possibly the disease mechanism of CMT2P.

These variants also support the adult-onset and largely sensory characteristics of the disorder.

The average age at which symptoms began in this group was 41 and most patients could walk without assistance at age 50 and older.

Nine patients reported sensory symptoms at disease onset. Issues involving sensory input, such as losing one’s balance upon closing eyes, occurred regularly among the individuals involved in the study.

Nearly all patients showed both motor and sensory symptoms, with muscle weakness in the lower legs and no Achilles tendon reflex at their first neurological exam.

Weakness in the extremities and foot drop (difficulty lifting the front part of the foot) appeared in four patients. Five reported muscle cramps or nerve pain in their lower legs. Six patients reported foot deformities and all showed signs of reduced nerve conduction.

“CMT2P is a rare, but nevertheless relevant cause of adult-onset axonal and painful neuropathy,” the researchers concluded.

“ACMG criteria should be carefully applied in variant interpretation, with special attention to premature termination … variants and their location within the gene.”