Developmental delay and non-phenylketonuria (PKU) hyperphenylalaninemia in DNAJC12 deficiency: Case and approach.

Autor: Wong RSH; Metabolic Genetics Service, The Sydney Children's Hospitals Network, Westmead, NSW, Australia; TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, NSW, Australia., Mohammad S; TY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia., Parayil Sankaran B; Discipline of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia., Junek R; NSW Newborn Screening (NBS) Programme, Sydney, NSW, Australia., Kim WT; NSW Newborn Screening (NBS) Programme, Sydney, NSW, Australia., Wotton T; NSW Newborn Screening (NBS) Programme, Sydney, NSW, Australia., Devanapalli B; NSW Biochemical Genetics Service, The Children's Hospital at Westmead, Westmead, NSW, Australia., Bandodkar S; Department of Biochemistry, The Sydney Children's Hospital Network, Westmead, NSW, Australia; University of Sydney Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, Sydney, NSW, Australia., Balasubramaniam S; Metabolic Genetics Service, The Sydney Children's Hospitals Network, Westmead, NSW, Australia; Discipline of Genomic Medicine, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. Electronic address: shanti.balasubramaniam@health.nsw.gov.au.
Jazyk: angličtina
Zdroj: Brain & development [Brain Dev] 2023 Oct; Vol. 45 (9), pp. 523-531. Date of Electronic Publication: 2023 May 06.
DOI: 10.1016/j.braindev.2023.04.004
Abstrakt: Background: Hyperphenylalaninemia is a biomarker for several monogenic neurotransmitter disorders where the body cannot metabolise phenylalanine to tyrosine. Biallelic pathogenic variants in DNAJC12, co-chaperone of phenylalanine, tyrosine, and tryptophan hydroxylases, leads to hyperphenylalaninemia and biogenic amines deficiency.
Methods and Results: A male firstborn to non-consanguineous Sudanese parents had hyperphenylalaninemia 247 µmol/L [reference interval (RI) < 200 µmol/L] at newborn screening. Dried blood spot dihydropteridine reductase (DHPR) assay and urine pterins were normal. He had severe developmental delay and autism spectrum disorder without a notable movement disorder. A low phenylalanine diet was introduced at two years without any clinical improvements. Cerebrospinal fluid (CSF) neurotransmitters at five years demonstrated low homovanillic acid (HVA) 0.259 µmol/L (reference interval (RI) 0.345-0.716) and 5-hydroxyindoleaetic acid (5HIAA) levels 0.024 µmol/L (reference interval (RI) 0.100-0.245). Targeted neurotransmitter gene panel analysis identified a homozygous c.78 + 1del variant in DNAJC12. At six years, he was commenced on 5-hydroxytryptophan 20 mg daily, and his protein-restricted diet was liberalised, with continued good control of phenylalanine levels. Sapropterin dihydrochloride 7.2 mg/kg/day was added the following year with no observable clinical benefits. He remains globally delayed with severe autistic traits.
Conclusions: Urine, CSF neurotransmitter studies, and genetic testing will differentiate between phenylketonuria, tetrahydrobiopterin or DNAJC12 deficiency, with the latter characterised by a clinical spectrum ranging from mild autistic features or hyperactivity to severe intellectual disability, dystonia, and movement disorder, normal DHPR, reduced CSF HIAA and HVA. DNAJC12 deficiency should be considered early in the differential workup of hyperphenylalaninemia identified from newborn screening, with its genotyping performed once deficiencies of phenylalanine hydroxylase (PAH) and tetrahydrobiopterin (BH4) have been biochemically or genetically excluded.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Crown Copyright © 2023. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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