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Short Report
Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia: from attention deficit to severe dystonia and intellectual disability
  1. Francjan J van Spronsen1,
  2. Nastassja Himmelreich2,3,
  3. Véronique Rüfenacht3,
  4. Nan Shen2,4,
  5. Danique van Vliet1,
  6. Mohammed Al-Owain5,6,
  7. Khushnooda Ramzan7,
  8. Salwa M Alkhalifi8,
  9. Roelineke J Lunsing9,
  10. Rebecca M Heiner-Fokkema10,
  11. Anahita Rassi11,
  12. Corinne Gemperle-Britschgi3,
  13. Georg F Hoffmann2,
  14. Nenad Blau2,
  15. Beat Thöny3,11,12,13
  1. 1 Beatrix Children’s Hospital, University Medical Center, University of Groningen, Groningen, The Netherlands
  2. 2 Dietmar-Hopp Metabolic Center, University Children’s Hospital, Heidelberg, Germany
  3. 3 Division of Metabolism, University Children’s Hospital Zurich, Zurich, Switzerland
  4. 4 Department of Rehabilitation Medicine, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  5. 5 Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
  6. 6 Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
  7. 7 Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
  8. 8 Department of Pediatrics, Maternity and Children Hospital, Dammam, Saudi Arabia
  9. 9 Department of Pediatric Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  10. 10 Department of Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands
  11. 11 Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, Zurich, Switzerland
  12. 12 Children’s Research Centre (CRC), University Children’s Hospital Zürich, Zurich, Switzerland
  13. 13 The Neuroscience Center Zurich (ZNZ), The Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland
  1. Correspondence to Nenad Blau, Dietmar-Hopp-Metabolic Center, University Children’s Hospital, Heidelberg, Germany; Nenad.Blau{at} and Beat Thöny, Division of Metabolism and Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, Zürich CH-8032, Switzerland; beat.thony{at}


Background Autosomal recessive mutations in DNAJC12, encoding a cochaperone of HSP70 with hitherto unknown function, were recently described to lead to hyperphenylalaninemia, central monoamine neurotransmitter (dopamine and serotonin) deficiency, dystonia and intellectual disability in six subjects affected by homozygous variants.

Objective Patients exhibiting hyperphenylalaninemia in whom deficiencies in hepatic phenylalanine hydroxylase and tetrahydrobiopterin cofactor metabolism had been excluded were subsequently analysed for DNAJC12 variants.

Methods To analyse DNAJC12, genomic DNA from peripheral blood (Sanger sequencing), as well as quantitative messenger RNA (Real Time Quantitative Polymerase Chain Reaction (RT-qPCR)) and protein expression (Western blot) from primary skin fibroblasts were performed.

Results We describe five additional patients from three unrelated families with homozygosity/compound heterozygosity in DNAJC12 with three novel variants: c.85delC/p.Gln29Lysfs*38, c.596G>T/p.*199Leuext*42 and c.214C>T/p.(Arg72*). In contrast to previously reported DNAJC12-deficient patients, all five cases showed a very mild neurological phenotype. In two subjects, cerebrospinal fluid and primary skin fibroblasts were analysed showing similarly low 5-hydroxyindolacetic acid and homovanillic acid concentrations but more reduced expressions of mRNA and DNAJC12 compared with previously described patients. All patients responded to tetrahydrobiopterin challenge by lowering blood phenylalanine levels.

Conclusions DNAJC12 deficiency appears to result in a more heterogeneous neurological phenotype than originally described. While early identification and institution of treatment with tetrahydrobiopterin and neurotransmitter precursors is crucial to ensure optimal neurological outcome in DNAJC12-deficient patients with a severe phenotype, optimal treatment for patients with a milder phenotype remains to be defined.

  • metabolic disorders
  • molecular genetics
  • neurodegenerative disease
  • clinical research

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  • FJS and NH contributed equally.

  • Contributors FJvS, NB and BT contributed equally in writing and preparing of the manuscript, including table 1. NH and NS assisted in developing figures and description of methods. FJvS, DvV, MA-O, KR, SMA, RJL and RMH-F provided patients’ data and performed clinical assessments. NS, VR, NH, AR and CG-B performed biochemical, metabolic and genetic analyses. FJvS, GFH, NB and BT supervised the study.

  • Funding This work is part of the RD-CONNECT initiative and was supported by the FP7-HEALTH-2012-INNOVATION-1 EU Grant No. 305444 (to NB) and funding from the Dietmar-Hopp Foundation (to GFH and NB).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Declaration of Helsinki and approved by the Ethical Committees of the centres participating in this study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Additional unpublished data.