MME Mutation Newly Identified in Iranian Family With CMT2
A new MME gene mutation was discovered in three members of a large Iranian family diagnosed with Charcot-Marie-Tooth disease type 2 (CMT2), according to a recent case report.
The report, “A nonsense mutation in MME gene associates with autosomal recessive late-onset Charcot-Marie-Tooth disease,” was published in the journal Molecular Genetics & Genomic Medicine.
CMT2 is characterized by damage to axons, the nerve cell projections that send signals to other nerves or muscle cells.
Mutations in MME are associated with the CMT2 T subtype (CMT2T), a rare CMT type marked by axonal neuropathy (nerve damage) emerging in adulthood. Since CMT symptoms develop gradually and often overlap with other types of neuropathies, diagnosing the disorder without genetic testing can be difficult.
A team of researchers used genetic testing to identify a previously unknown MME mutation in the three members of a large and consanguineous (related by blood, a common ancestor) family, leading to a diagnosis of CMT2.
A 52-year-old man first complained of weakness in his feet and hands, and difficulty walking that began when he was 45. He reported frequent falls, sensory disturbances in his hands and feet, and foot abnormalities.
Two of the man’s cousins, brothers ages 51 and 52, also experienced muscle weakness, walking difficulties, and foot abnormalities, with the first symptoms emerging at ages similar to their cousin.
One brother also had a severe stutter when speaking, and MRI abnormalities suggesting axonal demyelination — a loss of the fatty, protective substance surrounding nerve cells, called myelin.
All three patients underwent electromyography and nerve conduction tests to determine the health of their muscles and nerves. Test results were consistent with damage to both motor and sensory nerves, with characteristics of a late-onset axonal form of nerve damage.
Chronic inflammatory demyelinating polyneuropathy (CIDP) — marked by progressive weakness and impaired sensory function — was considered as a diagnosis. However, the patients’ cerebrospinal fluid (the liquid surrounding the brain and spinal cord) lacked the high protein levels that are a characteristic CIDP sign. Due to their similarities, CMT can be confused with CIDP when making a diagnosis.
Genetic testing was performed on one of the brothers, leading to discovery of the new MME mutation (c.1564C>T). The same mutation was subsequently identified in the other two patients, further supporting this mutation as the cause of the disease.
The mutation was recessive, meaning that each of the three men inherited two mutated gene copies, one from each parent, in order to show CMT symptoms. Parents of the affected siblings, as well as the unaffected brother of their cousin, had the mutation in one MME copy.
Due to the late age at which symptoms emerge in this CMT type, as in these patients, younger family members who have not undergone genetic testing may also have the disease, the researchers noted.
They determined that the mutation causes a loss of function in MME, which results in a short, non-working version of its protein product, NEP.
While the mechanisms by which NEP loss causes CMT are unclear, it is likely that the function of Schwann cells, which form myelin in nerves outside the brain and spinal cord, is disrupted and causes axonal damage, the researchers suggested.
“In conclusion, we identified a [loss-of-function] mutation in MME gene … which caused late-onset axonal form of CMT,” they wrote.
“Further research would be required to unravel the mechanistic function of MME mutations in the development of late-onset sensorimotor polyneuropathies [i.e., CMT]. Establishment of genetic tests for screening mutations in MME gene could be considered as a primary option for the diagnosis of late-onset axonal form of CMT or CMT2,” the team added.