Dystonia and Hereditary Motor Sensory Neuropathy 6B Due to SLC25A46 Gene Mutations

Abstract

SLC25A46-related neuropathy or Hreditary motor or Hereditary motor and sensory neuropathy type VIB (HMSN 6B) is an autosomal recessive neurological disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. We report a Homozygous pathogenic mutation in SLC25A46 (c.1018C > T) in our index patient and his family members associated with characteristic imaging and clinical features. Eleven year old male presented with insidious onset, progressive vision loss & swaying since 8 years of age. He had no prior admissions or neurology consult, family history was not contributory. On examination (Video 1) gait ataxia, torticollis to left and tilt to right, head tremors and myoclonus with other findings of optic atrophy, hypotonia, impaired joint position & vibration up to ankle with absent ankle reflex were noted. Further findings of Pes cavus was present prompting for further investigation and diagnosis. On investigations routine blood and serology was normal, vitamin b12, serum cortisol and creatinine phosphokinase was normal. Thyroid profile showed markedly raised TSH of more than 100 mIU/L, TPO Antibodies of 971 IU/mL. Nerve conduction study had symmetrical sensory motor axonal neuropathy. MRI Brain (Fig. 1) T2 flair sequence shows hyperintensities in bilateral cerebellar hemispheres and T1shows cerebellar atrophy (Fig. 2). In view of his thyroid changes a Diagnosis of Hashimoto’s thyroiditis was made and started on adequate doses of thyroxine but with no response and due to progression of the symptoms further investigation was carried. Pyruvate0.99 mg/ dL (0.37–0.88) and Lactate9.70 mg/dL (4.5–14.4) levels were done to rule out any mitochondrial pathology including genetics for mitochondrial disorders which were normal. Mother was diagnosed to have hypothyroidism, clinical and neurological examination was unremarkable in her. In view of this varied presentation and a probable asymptomatic carrier state in the mother, whole exome sequencing(WES) was done which identified a Homozygous pathogenic mutation in SLC25A46 (c.1018C > T/p.Arg340Cys) gene, Mother and other unaffected family members were diagnosed as carriers for this pathogenic mutation (c.1018C > T). He was started on conservative management with beta blockers, vitamin E supplements, and gabapentin with limited response. Biallelic missense and loss of function variants in SLC25A46 have been reported to cause optic atrophy, axonal peripheral neuropathy and cerebellar atrophy. Slc25a46 is located in the outer mitochondrial membrane and plays an important role in maintaining the mitochondrial cristae and balancing mitochondrial