eP011: Diagnosis of DNAJC12-deficient hyperphenylalaninemia offers targeted therapeutic options to counteract neurotransmitter deficiency


      DNAJC12-related hyperphenylalaninemia is a recently described inborn error of metabolism (IEM) associated with hyperphenylalaninemia and neurotransmitter deficiency, caused by biallelic pathogenic variants in the DNAJC12 gene. Clinical features include global developmental delay, intellectual disability, autism spectrum disorder, and dystonia. DNAJC12-encoded protein functions as a chaperone facilitating the proper folding of the biopterin-dependent aromatic amino acid hydroxylases, including the phenylalanine, tyrosine, and tryptophan hydroxylases. Loss of the DNAJC12 chaperone causes destabilization of these hydroxylases, leading to hyperphenylalaninemia and deficiencies of the neurotransmitters dopamine, norepinephrine, epinephrine, and serotonin. Biopterin metabolism remains normal in affected individuals. We present the case of a patient who screened positive for hyperphenylalaninemia on newborn screening (NBS) and was discovered to be homozygous for a pathogenic variant in DNAJC12.

      Case presentation

      The patient was a twin birth, born premature at 25 weeks gestation via C-section. Neonatal course was prolonged and complicated, and included mechanical ventilation, surgical closure of a patent ductus arteriosus, and hyperalimentation. Newborn screen was positive for hyperphenylalaninemia, and results of confirmatory biochemical testing confirmed mild hyperphenylalaninemia. Phenylalanine and tyrosine levels were in the therapeutic range despite hyperalimentation and subsequently an unrestricted diet with formula was recommended. Genetic testing using a commercially available laboratory involved sequencing and deletion/duplication analysis of six genes related the hyperphenylalaninemia: PAH, GCH1, PCBD1, QDPR, PTS, and SPR. Genetic testing returned negative. Cofactor screening revealed findings consistent with PAH enzyme deficiency. Additional testing was limited as compliance with onsite clinical visits was limited especially during the pandemic.
      At 16 m.o., the patient had features inconsistent with a diagnosis of mild hyperphenylalaninemia and not explained by prematurity alone, including significant hypotonia, and developmental delay. She was beginning to sit up, but not pulling to stand. Fine motor skills were normal, but speech was delayed. No abnormal movements were noted. Exome sequencing was offered to exclude other genetic etiologies for her manifestations, which revealed that the patient was homozygous for a likely pathogenic variant in DNAJC12 (NM_021800.2:c. 235C>T, p.Arg79*).
      Neurotransmitter deficiency is measured by analyzing levels of neurotransmitter metabolites and precursors, including the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid (HVA), and the levodopa metabolite 3-O-Methyldopa (3-OMD). Levodopa is the precursor to dopamine, epinephrine, and norepinephrine. Neurotransmitter analysis revealed severe deficiencies in 5-HIAA (26 nmol/L, reference: 129-520 nmol/L), HVA (215 nmol/L, reference: 294-1115 nmol/L) and 3OMD (6 nmol/L, reference: <300 nmol/L). Prolactin levels were elevated (42.4 ng/mL, reference: 1.40-24.00 ng/mL), indicating dopamine deficiency.
      Therapy with sapropterin, levodopa/carbidopa and 5-hydroxytryptophan have been initiated. Patient continues on an unrestricted diet. Improvements in cognitive and motor functioning are evident and will be presented. Normal neurodevelopment has been reported when treatment was initiated within the first year of life. Treatment initiated early in life is integral to maintaining normal neurodevelopment and preventing neurologic defects in patients.


      Tabled 1
      1 m.o3 m.o*6 m.o9 m.o12 m.o16 m.o**19 m.o***24 m.o
      Phenylalanine (mg/dL)2.7 (H)3.7 (H)4.3 (H)3.6 (H)4.5 (H)3.9 (H)6.2 (H)2.7 (H)
      5-HIAA (nmol/L)------------------26 (L)---
      HVA (nmol/L)------------------215 (L)---
      3OMD (nmol/L)------------------6---
      Prolactin (nmol/L)------------------42.4 (H)---
      *Initial consultation with genetics.
      **reassessment by genetics.
      ***after diagnosis of DNAJC12-related hyperphenylalaninemia.