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. Pyruvate- 0.99 mg/dL (0.37–0.88) and Lactate- 9.70 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 fission and fusion, probably acting in a pro-fission manner. Slc25a46 deficiency has been suggested to be included in the spectrum of optic atrophy ‘plus’ that are related to defective mitochondrial dynamics.1-4 SLC25A46 loss of-function mutations have also been identified with lethal congenital pontocerebellar hypoplasia. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they may show abnormal movements, such as ataxia, dysmetria, and myoclonus. The most severely affected patients are hypotonic at birth and die in infancy.5, 6 The MRI findings of our case and from charlesworth et al, with cerebellar hyperintensities can add as an early diagnostic clue for identifying this rare disorder. It needs further confirmation of this entity but these two cases add more to our clinical knowledge to this complex disorder.7 In conclusion this case highlights the complex heterogeneity and rarity of the presentation with unique features of cervical dystonia and a probable association of Hashimoto's thyroiditis which needs further validation with characteristic association of optic atrophy and axonal neuropathy supporting a clinical diagnosis of SLC25A46-related neuropathy, confirmed by WES with a Homozygous pathogenic mutation in SLC25A46 (c.1018C > T/p.Arg340Cys) gene. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of final draft, B. Review and Critique. S.R.: 1A, 1B, 1C, 2A, 2B S.M.: 1A, 1B, 1C, 2B N.B.: 1A, 1B, 2B The authors confirm that the Ethics board clearance was not required for this work. The subject has provided written video consent. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. No specific funding was received for this work and the authors declare that there are no conflicts of interest relevant to this work. Authors have no financial disclosures.
Search from 250 M+ research papersSearch from 250 M+ research papers
Open Access
Jan 4, 2024
Jiacheng Li + 5
