A Novel Myelin Protein Zero variant in Charcot-Marie-Tooth Disease Type 2I (P3.4-038)

Objective: To describe the clinical presentation and a novel myelin protein zero (MPZ) pathogenic variant causing Charcot-Marie-Tooth disease type 2I (CMT2I) in an index patient and his father.

Background: Myelin protein zero is the major myelin structural protein made by schwann cells. MPZ mutations are known to cause autosomal dominant CMT2B, congenital hypomyelinating neuropathy, Distal Intermediate CMT (DI-CMT), and CMT2I/J.

Design/Methods: A 45-year-old man with a past medical history of hyperlipidemia and hypertension, presented with a four-year history of progressive bilateral foot numbness. The numbness is up to ankles and is associated with intermittent sharp shooting pain in feet. The patient’s father (77 years of age), who has a well-controlled diabetes, had symptoms of neuropathy since his mid-sixties. Mother and a 3-year-old son have no symptoms of neuropathy but paternal grandmother had neuropathy. Examination of the index patient revealed high arched feet, stocking distribution sensory loss to pinprick, light touch, and vibration up to ankles. Muscle strength and reflexes were normal as was sensory examination in arms, gait, pupillary reflexes and cerebellar exam.

Results: Vitamin B12, HbA1c, TSH, and serum protein electrophoresis/immunofixation were normal. Electrodiagnostic testing revealed mild sensory neuropathy and right chronic and mild S1 radiculopathy. MRI of the lumbar spine showed no significant central canal or foraminal narrowing. Genetic sequencing of 72 genes known to cause CMT identified a heterozygous (p.Tyr181Cys) variant in MPZ in the index patient. MPZ sequencing in parents revealed a similar heterozygous variant in MPZ in the patient’s father only.

Conclusions: We presented a novel MPZ variant causing autosomal dominant CMT2I. The pathogenicity of this mutation is supported by its consistency with the clinical phenotype, segregation with disease in the patient’s family, and the male-to-male transmission. In addition, in silico analysis of the variant using SIFT and Polyphen algorithms identify the variant as deleterious and probably damaging respectively.

Disclosure: Dr. Kushlaf has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, PTC therapeutics, Genzyme, and Strongbridge Biopharma.