Their study, “A very mild phenotype of Charcot-Marie-Tooth disease type 4H caused by two novel mutations in FGD4,” was published in the Journal of the Neurological Sciences.
Charcot-Marie-Tooth (CMT) is the most common heritable disease that affects the peripheral nervous system — the network of nerves responsible for controlling movement and sensation in the limbs. The disease can be caused by different genetic mutations and manifest at different ages, depending on the particular type and sub-type.
CMT4H is normally associated with genetic mutations in the frabin (FGD4) gene, which provides instructions to make a protein involved in the control of cell shape and architecture.
Since the discovery that mutations in FGD4 cause CMT4H, 31 cases of patients affected by the disorder have been reported in the literature, most of whom started showing symptoms during their childhood (before age 3), including delayed walking.
In this study, a group of Spanish researchers described the clinical cases of two siblings who carried new genetic mutations in FGD4 and ended up developing a milder form of CMT4H.
Both siblings — a 20-year-old woman and a 17-year-old man — were born from healthy parents and had mild foot deformities that did not affect muscle strength or lower limb sensitivity, and moderate walking impairments. No major alterations in their feet composition (i.e., muscle replacement by fatty tissue) was found through magnetic resonance imaging.
The older sibling did not experience any symptoms of the disorder during her childhood and was diagnosed at 19 with a mild case of cavovarus foot (the most common foot deformity in CMT) and retraction of the Achilles tendon.
Genetic screenings were performed in both siblings to pinpoint the exact cause of their condition. Analyses revealed the siblings carried two genetic mutations in FGD4 (c.514delG and c.2211dupA), one in each copy of the gene, which had never been described in the literature.
Further analysis measuring the expression levels of FGD4 in the siblings’ blood suggested none of the mutations affected gene splicing (the process of creating different proteins from the same gene), or led to the premature degradation of FGD4 messenger RNA (mRNA, the template sequence that encodes for a functional protein).
Both genetic variants led to the production of an abnormally short FGD4 protein that nevertheless contained most, if not all, the important functional domains of the normal FGD4 protein, according to the researchers.
“The conservation of functional domains in the proteins produced from the FGD4 gene of two patients with CMT4H, could explain both the milder phenotype [visible symptoms] and the later disease onset in these patients. These results expand the clinical and mutational spectrum of FGD4-related peripheral neuropathies,” the scientists wrote.