Dados do Trabalho

Título

EARLY-ONSET EPILEPSY IN COMPLEX II MITOCHONDRIAL DISORDER RELATED TO THE SDHA GENE

Apresentação do caso

A 2-year-old girl with refractory epilepsy since 4 months of age and persistent daily seizures even with optimized therapy. At 15 months of age, she was presented with global delay in neuropsychomotor development, axial hypotonia, and no interaction. There was also hyperreflexia, clonus, and delayed dentition. Initial metabolic screening and MRI were standard. The electroencephalogram displayed slowed and disorganized baseline activity. She was born at term in good general condition, with early jaundice requiring phototherapy. When asked about other complaints, chronic diarrhea and difficulty gaining weight were raised. Her family members were healthy except for migraine in her mother and maternal half-siblings.
At 20 months she was hospitalized for epileptic status, requiring continuous sedation. MRI at the time exhibited diffuse atrophy and intensity signal changes in the basal ganglia. Exome sequencing test showed a compound heterozygous mutation in the SDHA gene confirming the diagnosis of complex II mitochondrial disease.

Discussão

So far, more than 400 mutations have been described in mitochondrial and nuclear DNA that lead to primary mitochondrial defects. Because they are present in all human cells, their dysfunction leads to multisystemic involvement in varying degrees. The complex II of the respiratory chain is the only one in which proteins are all encoded by nuclear DNA. It is known that mutations in the A subunit of the SDH gene lead to early epileptic encephalopathy with a phenotype similar to Leigh's syndrome. So far, just over 20 cases have been reported. Out of these, most patients have epilepsy, ataxia, hepatosplenomegaly, optic atrophy, cardiomyopathy, and lactic acidosis, with onset usually at preschool age. There is also a strong association with stromal tumors. Regarding the mutations found in the patient, one of them - paternal inheritance - has already been described in association with pheochromocytomas and heterozygosity in a patient with epilepsy. The second (of maternal inheritance) has not yet been reported.

Comentários finais

The present report indicates the phenotypic variability of the complex II mitochondrial disease related to the SDHA gene. Our patient showed early onset and predominant epileptic manifestation without multisystemic involvement, which differs from the case reports of this condition so far.

Referências (se houver)

Alston CL, Davison JE, Meloni F, et al. Recessive germline SDHA and SDHB mutations causing leukodystrophy and isolated mitochondrial complex II deficiency. J Med Genet. 2012;49(9):569-577. doi:10.1136/jmedgenet-2012-101146

Bourgeois M, Goutieres F, Chretien D, Rustin P, Munnich A, Aicardi J. Deficiency in complex II of the respiratory chain, presenting as a leukodystrophy in two sisters with leigh syndrome. Brain Dev. 1992;14(6):404-408. doi:10.1016/S0387-7604(12)80349-4

Birch-Machin MA, Taylor RW, Cochran B, Ackrell BA, Turnbull DM. Late-onset optic atrophy, ataxia, and myopathy associated with a mutation of a complex II gene. Ann Neurol. 2000;48(3):330-335.

Courage C, Jackson CB, Hahn D, et al. SDHA mutation with dominant transmission results in complex II deficiency with ocular, cardiac, and neurologic involvement. Am J Med Genet A. 2017;173(1):225-230. doi:10.1002/ajmg.a.37986

Gault MD, Mandelker D, Delair D, et al. Germline SDHA mutations in children and adults with cancer. Cold Spring Harb Mol Case Stud. 2018;4(4):1-11. doi:10.1101/mcs.a002584

Renkema GH, Wortmann SB, Smeets RJ, et al. SDHA mutations causing a multisystem mitochondrial disease: novel mutations and genetic overlap with hereditary tumors. Eur J Hum Genet. 2015;23(2):202-209. doi:10.1038/ejhg.2014.80

Fonte de Fomento (se houver)

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Área

Erros inatos do metabolismo