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BACKGROUND: The axonal subtype of Charcot-Marie-Tooth (CMT2A) is commonly caused by dominant mutations in MFN2, which encodes a protein involved in mitochondrial dynamics and axonal transport. Over 100 variants in MFN2 are reportedly pathogenic. MFN2 dysfunction yields heterogenous neuropathies which can include optic atrophy, dysautonomia and diaphragmatic/airway dysfunction.

CASE REPORT: A 52-year-old man presented with a 10-year history of burning forefoot dysthesias and orthostasis. His examination revealed reduced sensation to light touch and pinprick distally with preserved strength and reflexes. NCS/EMG demonstrated mild, symmetric axonal polyneuropathy. Autonomic testing revealed orthostatic tachycardia and postganglionic sudomotor dysfunction. Laboratory evaluation for common causes of neuropathy was negative. He represented at age 55 with increasing pain and numbness, worsening orthostasis and syncope. Examination and NCS/EMG confirmed progression of axonal sensorimotor polyneuropathy. Family history revealed similar symptoms in his mother and sister. All 3 reported subacute visual disturbances. Targeted gene sequencing of the proband returned heterozygous variants of uncertain significance (VUS) in 3 genes: KIF1A (c.3584G>A; p.Arg1195His), MFN2 (c.1979C>A; pAla660Asp), and PLEKHG5 (c.823G>A; pGly275Ser). Confirmatory familial testing revealed identical variants in his mother, and both MFN2 and PLEKHG5 variants in his sister. Recessively-inherited PLEKHG5 is inconsistent with this pedigree. Functional protein modeling indicated that this MFN2 variant would likely alter protein function, making it the most likely punitive mutation.

CONCLUSIONS: This case illustrates a utility of targeted multigene panels and VUS resolution programs in the molecular diagnosis of inherited neuropathies. Family studies can help establish genotype-phenotype correlations in MFN2-related disease. This polymorphism is being considered for reclassification as pathogenic.

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