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

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 mmol/L [reference interval (RI) < 200 mu mol/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 mu mol/L (reference interval (RI) 0.345-0.716) and 5-hydroxyindoleaetic acid (5HIAA) levels 0.024 mu mol/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. (c) 2023 Published by Elsevier B.V. on behalf of The Japanese Society of Child Neurology. All rights reserved.

Automated summary

This study reports the clinical manifestations and genetic variants of hyperphenylalaninemia and biogenic amines deficiency caused by DNAJC12 deficiency. Urine, cerebrospinal fluid neurotransmitter studies, and genetic testing can differentiate between different related diseases.