Send to

Choose Destination
J Med Genet. 2017 Aug 9. pii: jmedgenet-2017-104875. doi: 10.1136/jmedgenet-2017-104875. [Epub ahead of print]

Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia: from attention deficit to severe dystonia and intellectual disability.

Author information

Beatrix Children's Hospital, University Medical Center, University of Groningen, Groningen, The Netherlands.
Dietmar-Hopp Metabolic Center, University Children's Hospital, Heidelberg, Germany.
Division of Metabolism, University Children's Hospital Zurich, Zurich, Switzerland.
Department of Rehabilitation Medicine, Xin Hua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Department of Pediatrics, Maternity and Children Hospital, Dammam, Saudi Arabia.
Department of Pediatric Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Department of Laboratory Medicine, University Medical Center Groningen, Groningen, The Netherlands.
Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland.
Children's Research Centre (CRC), University Children's Hospital Zürich, Zurich, Switzerland.
The Neuroscience Center Zurich (ZNZ), The Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland.



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.


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


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.


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.


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.


clinical research; metabolic disorders; molecular genetics; neurodegenerative disease

Conflict of interest statement

Competing interests: None declared.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center