Somdattaa Ray1, Hansashree Padmanabha2, Vykuntaraju K Gowda3, Rohan Mahale1, Rita Christopher4, Shruthy Sreedharan5, Debjyoti Dhar1, Mahesh Kamate6, Madhu Nagappa1, Maya Bhat7, Rammurthy Anjanappa5, Gautham Arunachal5, M Pooja1, P S Mathuranath1, S R Chandra1. 1. Department of Neurology, Neuroscience Faculty Center, National Institute of Mental Health and Neurosciences, Near Diary Circle, Hosur Road, Bengaluru, Karnataka, 560029, India. 2. Department of Neurology, Neuroscience Faculty Center, National Institute of Mental Health and Neurosciences, Near Diary Circle, Hosur Road, Bengaluru, Karnataka, 560029, India. hansa777@gmail.com. 3. Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bengaluru, India. 4. Department of Neurochemistry, National Institute of Mental Health and Neurosciences, Bengaluru, 560029, India. 5. Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bengaluru, 560029, India. 6. Division of Pediatric Neurology, K.A.H.E.R's JN medical college, Belagavi, India. 7. Department of Neuro Imaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bengaluru, 560029, India.
Abstract
BACKGROUND: 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. METHODOLOGY: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: 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. METHODOLOGY: 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. RESULTS: 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. CONCLUSION: 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.
Authors: Y H Chien; S C Chiang; A Huang; J M Lin; Y N Chiu; S P Chou; S Y Chu; T R Wang; W L Hwu Journal: J Inherit Metab Dis Date: 2001-12 Impact factor: 4.982
Authors: Mark J Crabtree; Amy L Tatham; Yasir Al-Wakeel; Nicholas Warrick; Ashley B Hale; Shijie Cai; Keith M Channon; Nicholas J Alp Journal: J Biol Chem Date: 2008-11-14 Impact factor: 5.157