Researchers identified a novel genetic mutation affecting the FGD4 gene in a patient with Charcot-Marie-Tooth disease type 4H (CMT4H).
With an early onset, CMT4 is a slow progressive neurological disease caused by genetic variations in genes involved in nerve cells function or structure. In the CMT4H subtype, several mutations on the FGD4 gene are pointed as the trigger.
The frabin protein encoded by FGD4 is known to be involved in mechanisms that are essential for normal activity of myelin-producing cells, the Schwann cells. These cells are specialized in the production of myelin, which protect the nerve cells and allow electrical signals to pass through them.
When genetic mutations disrupt frabin levels or its activity, the Schwann cells cannot maintain the normal myelin production, impairing the nerve cells activity response and survival.
In the study titled “A novel mutation in FGD4 causes Charcot-Marie-Tooth disease type 4H with cranial nerve involvement,” published in the journal Neuromuscular Disorders, researchers from Kyushu University in Japan reported the case of a patient with CMT4H with a new FGD4 genetic mutation.
The patient was 15 years old when he started presenting unsteadiness and numbness in both lower limbs. By the age of 20, he developed double vision, erectile dysfunction, clumsiness, and sensory impairment in the upper limbs. At age 35, he started to notice finger deformities. All symptoms progressed very slowly and culminated by the age of 65, with lower limb and hand deformities, eye misalignment with movement limitation, facial muscle weakness, hearing loss, muscle weakness with loss of reflexes, and generalized loss of sensitivity to pain.
Genetic analysis revealed that the patient’s two copies – one inherited from the mother and other from the father – of the FGD4 gene had a substitution of a single genetic base at the 724 position of the gene sequence, which the researchers identified as p.Arg242X. No other mutations were found in any of the 64 CMT-related genes that could be accounted as responsible for CMT diagnosis.
With the observation that this new mutation in the FGD4 gene was found to lead to a smaller form of the fabrin protein, the authors believe that the p.Arg242X mutation was responsible for the patient’s symptoms. However, further functional studies are warranted to confirm the impact of the mutation in fabrin’s activity.
Evaluation by magnetic resonance images (MRI) confirmed that the ophthalmic, the maxillary, and the mandibular nerves were enlarged. This finding showed for the first time that CMT4H can also implicate involvement of such nerves, which are more commonly associated with other subtypes of CMT.
Overall the research team considered that “the present atypical case of CMT4H, with a novel [p.Arg242X] mutation, further expands the clinical spectrum of CMT4H.”