Abstract
Disorders of tetrahydrobiopterin metabolism represent a rare group of inherited neurotransmitter disorders that manifests mainly in infancy or childhood with developmental delay, neuroregression, epilepsy, movement disorders, and autonomic symptoms. A retrospective review of genetically confirmed cases of disorders of tetrahydrobiopterin metabolism over a period of three years (Jan 2018 to Jan 2021) was performed across two paediatric neurology centres from South India. A total of nine patients(M:F=4:5) fulfilled the eligibility criteria. The genetic variants detected include homozygous mutations in the QDPR(n=6), GCH1(n=2), and PTS(n=1) genes. The median age at onset of symptoms was 6-months(range 3-78 months), while that at diagnosis was 15-months (8-120 months), resulting in a median delay in diagnosis of 9-months. The main clinical manifestations included neuroregression (89%), developmental delay(78%), dystonia(78%) and seizures(55%). Management strategies included a phenylalanine restricted diet, levodopa/carbidopa, 5-Hydroxytryphtophan, and folinic acid. Only, Patient-2 afforded and received BH4 supplementation at a sub-optimal dose later in the disease course. We had a median duration of follow up of 15 months (range 2-48 months). Though the biochemical response has been marked; except for patients with GTPCH deficiency, only mild clinical improvement was noted with regards to developmental milestones, seizures, or dystonia in others. Tetrahydrobiopterin deficiencies represent a rare yet potentially treatable cause for non-phenylketonuria hyperphenylalaninemia with better outcomes when treated early in life. Screening for disorders of biopterin metabolism in patients with hyperphenylalaninemia prevents delayed diagnosis. This study expands the genotype-phenotype spectrum of patients with disorders of tetrahydrobiopterin metabolism from South India.
Highlights
Disorders of tetrahydrobiopterin (BH4) metabolism were initially described in the late 19th century as ‘atypical’ or ‘malignant Phenylketonuria’ (PKU) in a subset of patients diagnosed to have hyperphenylalaninemia (HPA) who were not responding to dietary intervention [1,2]
Biosynthesis of BH4 occurs from guanosine triphosphate (GTP) through a threestep reaction catalysed by the enzymes guanosine triphosphate cyclohydrolase (GTPCH), 6- pyruvoyl tetrahydropterin synthase (PTPS), and sepiapterin reductase (SR)
We have described the clinical features, investigations, treatment and outcome of 9 genetically confirmed patients with BH4 deficiency from South India
Summary
Disorders of tetrahydrobiopterin (BH4) metabolism were initially described in the late 19th century as ‘atypical’ or ‘malignant Phenylketonuria’ (PKU) in a subset of patients diagnosed to have hyperphenylalaninemia (HPA) who were not responding to dietary intervention [1,2]. BH4 is an essential cofactor for the enzymatic hydroxylation of three aromatic amino acids, namely phenylalanine, tryptophan and tyrosine; three isoforms of nitric-oxide (NO) synthase and alkylglycerol mono oxygenase [3,4]. Enzymatic hydroxylation of aromatic amino acids results in synthesis of monoamine neurotransmitters serotonin, dopamine and its metabolites[3,4]. Biosynthesis of BH4 occurs from guanosine triphosphate (GTP) through a threestep reaction catalysed by the enzymes guanosine triphosphate cyclohydrolase (GTPCH), 6- pyruvoyl tetrahydropterin synthase (PTPS), and sepiapterin reductase (SR). BH4 reacts with aromatic amino acid hydroxylase as an active cofactor and is converted into pterin-4α-carbinolamine. Disorders of tetrahydrobiopterin metabolism represent a rare group of inherited neurotransmitter disorders which manifest mainly in infancy or childhood with developmental delay, neuroregression, epilepsy, movement disorders and autonomic symptoms
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