engleski

Fumaric aciduria: Mild phenotype in a 8-year-old girl with novel mutations

Fumaric aciduria is a rare, autosomal recessive disorder caused by deficient acitivity of fumarate hydratase (FH), one of the constituent enzymes of the Krebs’ s cycle. The most common clinical features are hypotonia, failure to thrive, severe developmental retardation and seizures. Facial dysmorphy and brain malformations are frequent. We report a patient with relatively mild phenotype and previously not reported genotype.The patient is the only child of unrelated parents. Mother and grandmother had uterine myomas. The pregnancy was complicated by bleeding and intrauterine growth retardation. Delivery was spontaneous after 35 weeks, with normal Apgar ascore. The girl was hypotonic since birth. At age 2 months parents noticed short apnoic crises. Psychomotor delay became evident at age 6 months. At that time brain ultrasound revealed normotensive ventricular enlargement. She could sit at age 1.5 years, walk with assistance at 4 years. Diagnosis was established at age 8 years when highly increased excretion of fumaric acid was found twice (217 and 445 mmol/mol creatinine). Shortly before that the girl started to have leg and arm spasms, induced by various stimuli. She had grand mal seizures twice. Facial dysmorphy included depressed nasal bridge, otapostasis, hypertelorism and microcephaly. Speech was limited to few disyllable words. She was atactic with spastic paraparesis. Blood lactate was normal. Brain MRI showed slight ventriculomegaly, white matter atrophy and hypoplasia of corpus callosum. Acivity of FH in cultured skin fibroblasts was decreased to about 5% of the lowest value of 5 controls, i.e. to 1.9 nmol/min/mg protein (controls 40-80). The amount of FH was severely decreased, as well. Gene analysis revealed two mutations of the FH gene, the maternally derived [c. 1029_1031delAGT], resulting in Val deletion and amino acid substitution of Gln into His, and paternally derived [c. 976C>T], resulting in substitution of Pro into Ser.

Fumaric aciduria; fumarate hydratase; hypotonia; developmental retardation; facial dysmorphy; brain malformations

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