Abstract
In addition to tetrahydrobiopterin deficiencies and phenylalanine hydroxylase deficiency (phenylketonuria) due to PAH variants, the deficiency of the co-chaperone protein DNAJC12 was identified in 2017 as a novel cause of inherited hyperphenylalaninemia, revealing the genetic etiology in previously unresolved cases. In this study, we aimed to investigate DNAJC12 deficiency in non-tetrahydrobiopterin-deficient persistent hyperphenylalaninemia cases without biallelic PAH variants in a single pediatric metabolic center. It was determined retrospectively that 471 patients with non-tetrahydrobiopterin deficiency-hyperphenylalaninemia had undergone PAH gene sequencing and 451 patients had biallelic variants in PAH. DNAJC12 sequencing was performed in the remaining 20 patients, identifying a previously reported homozygous splice-site variant (c.158-2A > T) in one patient with axial hypotonia and developmental delay, and a novel, homozygous c.404del (p.Arg135Lysfs*21) frameshift variant in an asymptomatic patient. In segregation analysis, the asymptomatic patient’s both parents were also found to be homozygous for this variant and hyperphenylalaninemic. The parents may have had academic difficulties but intellectual disability could not be confirmed due to lack of cooperation. The symptomatic patient significantly benefited from treatment with sapropterin dihydrochloride and neurotransmitter precursors. DNAJC12 deficiency might be responsible for approximately 10% or more of cases with unexplained hyperphenylalaninemia. The phenotypic spectrum is broad, ranging from early infantile hypotonia to incidental diagnosis in adulthood. Similar to tetrahydrobiopterin deficiencies, early diagnosis and treatment with sapropterin dihydrochloride and neurotransmitter precursors can be beneficial, supporting the analysis of DNACJ12 gene in patients with unexplained hyperphenylalaninemia.
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Data availability
Study data are available from the corresponding author upon reasonable request.
Change history
09 June 2021
A Correction to this paper has been published: https://doi.org/10.1007/s11011-021-00759-8
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Kısmet Çıkı: Conceptualization, methodology, investigation, writing–original draft; Yılmaz Yıldız: Conceptualization, methodology, investigation, writing, review and editing; Didem Yücel Yılmaz: Genetic analysis, writing, editing; Emine Pektaş: Investigation, review; Ayşegül Tokatlı: Methodology, review and editing, supervision; R. Köksal Özgül: Genetic analysis, editing; H. Serap Sivri: Methodology, review and editing, supervision; Ali Dursun: Methodology, review and editing, supervision. All authors approved the final manuscript as submitted.
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Approval was obtained from the ethics committee of Hacettepe University (Date: August 25, 2020; Approval no: 2020/16–21). The procedures used in this study adhere to the tenets of the Declaration of Helsinki.
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Çıkı, K., Yıldız, Y., Yücel Yılmaz, D. et al. DNACJ12 deficiency in patients with unexplained hyperphenylalaninemia: two new patients and a novel variant. Metab Brain Dis 36, 1405–1410 (2021). https://doi.org/10.1007/s11011-021-00753-0
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DOI: https://doi.org/10.1007/s11011-021-00753-0