Researchers Share Case of Family with Rare CMT4J Subtype

José Lopes, PhD avatar

by José Lopes, PhD |

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NfL as disease biomarker

Researchers described the case of a family with Charcot-Marie-Tooth (CMT) disease type 4J that has two mutations in the FIG4 gene, leading to the classic features of CMT disease in addition to parkinsonism and speech abormalities.

The study “Charcot Marie Tooth disease type 4J with complex central nervous system features,” was published in the journal Annals of Clinical and Translational Neurology.

CMT4 is a disease type characterized by damage in the myelin sheath, the insulating layer of the long projections of neurons called axons, which result in the patients’ progressive inability to walk.

CMT4J is a specific subtype caused by mutations in the FIG4 gene. It affects only 0.24 percent of people with CMT.

Prior isolated case reports described the occurrence of CMT4J along with central nervous system (CNS) CNS features, such as parkinsonism, which refers to Parkinson’s disease-like motor complications. The rare, genetic, multi-organ Yunis-Varon syndrome and familial epilepsy, both causing severe alterations in CNS development, also have been observed in CMT4J patients.

In this report researchers describe the case of a 52-year-old right-handed woman diagnosed with CMT at age 12. The patient developed slowly progressive leg weakness, which accelerated in her late 40s.

She also exhibited multiple CNS abnormalities, including slow, hesitant speech consistent with aphemia (a disorder of articulation due to lesions in the brain’s frontal lobe), resting hand tremor, slow finger tapping, and bilateral upper muscle rigidity. The patient further exhibited absent tendon reflexes and reduced perception of knee vibration on sensory testing.

Nerve conduction exams at age 51 revealed slowed motor conduction velocities, which are indicative of myelin damage. The patient’s CMT Neuropathy Score was consistent with moderate impairment. Brain imaging revealed loss of cerebral cortex volume and atrophy in the left temporal lobe.

The patient’s IQ at age 52 was only 78, which was associated with impairments in hearing attention, expressive language, and executive functioning, which involves goal-directed actions and adaptation to new situations. Overall, the patient met the criteria for mild cognitive impairment.

The patient’s younger brother, aged 48, also had CMT with speech abnormalities, parkinsonism, and behavioral difficulties.

Genetic results showed that the patient had three mutations, two in the FIG4 gene and one in the LITAF gene. Her brother had only the FIG4 variants.

“The Parkinsonism and cognitive language impairment with a moderate CMT phenotype are unique to our family,” the researchers wrote. “Thus, our case study expands the phenotypic [observable symptoms] spectrum of patients with FIG4 deficiency.”

Work in mice showed that FIG4 is found often both in the CNS and the peripheral nervous system. Therefore, “variable clinical phenotypes with different degrees of CNS involvement are not unexpected, and new clinical phenotypes may continue to emerge in the future studies,” the scientists concluded.