A new genetic mutation in the MCM3AP gene was identified and associated with three cases of Charcot-Marie-Tooth (CMT) disease in one family, who also showed symptoms of multiple sclerosis (MS), according to a case study.
This is the first report of a recessive form of CMT — meaning it requires two copies of the disease-related genetic variant— coexisting with changes to the central nervous system consistent with MS.
The study, “Charcot-Marie-Tooth and multiple sclerosis associated with a variant in MCM3AP,” was published in the journal Brain Communications.
CMT is a group of hereditary disorders characterized by progressive damage to peripheral nerves (commonly known as neuropathies). More than 70 genes have been identified as the cause of CMT, including MCM3AP variants.
MCM3AP mutations have been linked to severe cases of childhood-onset CMT with mild to moderate intellectual disability. Impaired function of the MCM3AP coded protein has also been associated to immunodeficiency, genomic instability, skin changes, and blood cancer in a child.
An international research team reported the cases of three individuals from an Iranian family who had CMT and also developed MS. No cases of isolated CMT or MS were reported within the family.
All three individuals started experiencing hand tremors in early childhood, followed by progressive muscle weakness mainly affecting the upper and lower extremities. As they reached adolescence, a detailed analysis of the response of motor nerve cells confirmed they had severe motor neuropathy with preserved sensory responses.
They also started to develop muscle atrophy affecting not only their hands but also their feet, which are hallmark features of CMT.
Upon adulthood, they started to experience different neurological symptoms, including blurred vision, gait difficulties, seizures, and slurred speech.
To further explore the cause of these neurological symptoms, their brains were evaluated by magnetic resonance imaging (MRI). The scans revealed several structural alterations and white matter lesions in each one of them, consistent with an MS diagnosis.
Genetic analysis revealed they were all carriers of the same missense mutation in MCM3AP gene that resulted in the change of a single amino acid in the encoded protein — identified as Ile954Thr.
This MCM3AP variant had not previously been reported or linked to CMT. When explored using computer modeling analysis methods, the mutation was found to have the potential to prevent the normal activity of MCM3AP coded protein and induce disease.
“Although segregation of CMT with MCM3AP variants has previously been reported, the clinical features varies between the individuals in the present study and the previously reports,” the researchers wrote.
These cases suggest that MCM3AP may be involved in cellular mechanisms that are shared by CMT and MS. Still, the team highlights that incidental coexistence of CMT and MS in this family “could not be excluded.” More studies are warranted to further explore a potential association between the two diseases.