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To the Editor: Biallelic mutations in the HADH gene cause 3 alpha hydroxy acyl CoA dehydrogenase deficiency (HADH deficiency) [1]. We are reporting sibling pair presenting with refractory seizures.
A 13-y-old girl born to consanguineous parentage presented with seizures beginning from the age of 3 mo, delayed attainment of milestones, and ataxia. The seizures precipitated by fasting were refractory requiring multiple antiseizure medications (ASMs). Her younger sibling had seizures noted since the age of 3 d of life, progressed to clinical presentation as the elder sibling. On examination, weight: 29.4 kg (-2 to -3SD), height: 144 cm (-2 to -3SD) head circumference: 48.5 cm (<-3SD), spastic quadriparesis, and cerebellar signs were noted. Hypoglycaemia was documented in both siblings during episodes of seizures on few occasions. Tandem mass spectrometry showed elevated 3 hydroxy butyryl carnitine: 0.66 (Normal: 0-0.5). Urine for organic acids revealed mild elevation in lactate (24.58 mg/dl; 4.5–19.8 mg/dl), normal ammonia and blood gases with absence of urinary ketones. EEG revealed multifocal sharp waves; MRI of the brain was normal. Whole exome sequencing showed a novel homozygous frameshift deletion c.165_168delGGTA, p.Val56fs*41 in exon-2 of HADH gene. With diet modification of avoidance of fasting, having frequent meals as well as corn starch, there was significant decrease in frequency of seizures.
Mutations in the HADH gene present with hypoketotic hypoglycemia, failure to thrive, tone abnormalities, cardiac and hepatic involvement [2, 3]. Hypoglycemia in HADH deficiency is caused due to impaired beta oxidation and hyperinsulinism caused by loss of inhibitory effect of HADH on Glutamate dehydrogenase (GDH) [4]. Management involves avoiding episodes of fasting and stress. Treatment with diazoxide which reduces insulin secretion has shown variable response [4]. Awareness of this condition prevents antiseizures medications’ side-effects in addition to specific management of this condition and for genetic counselling.
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Gowda, V.K., Reddy, VS., Krishnanada, V. et al. Drug Resistant Epilepsy (DRE) Secondary to 3-Hydroxy Acyl-CoA Dehydrogenase Deficiency (HADH) in Siblings. Indian J Pediatr 91, 523 (2024). https://doi.org/10.1007/s12098-023-04978-y
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DOI: https://doi.org/10.1007/s12098-023-04978-y