Objective: to expand the phenotypic characterization of this rare disorder, clinical presentation and outcome of a cohort of patients affected DNAJC12 defect are reported.

Background: autosomal recessive DNAJC12 deficiency is the most recently identified disorder of biogenic amine synthesis, presenting with neurodevelopmental disorders in early childhood, and parkinsonism-dystonia later in adulthood.  Diagnostic biomarkers include hyperphenylalaninemia (HPA), CSF serotonin, and dopamine depletion.

Method: psychiatric, and neuropsychological assessments (BRIEF, VABS-II, and IQ) were performed in 8 Italian patients with DNAJC12 defect (2M/6F; range 5.8-61 years) from 4 kindreds. Biochemical data included blood Phe, CSF homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) in 4 subjects. In the others, the diagnosis was performed by NGS.

Results: six patients from 3 kindreds presented with neurodevelopmental disorders (global developmental delay and intellectual disability (DI) mild to severe in 3, autism spectrum disorder and DI in 1, motor delay in 1) progressing during adolescence/adulthood to limb dystonia (1) ataxia (1) non-degenerative parkinsonism-dystonia (3). Two patients presented in adulthood with L-DOPA-responsive non-degenerative parkinsonism. A patient, now five years old, was diagnosed and treated pre-symptomatically thanks to neonatal screening for PKU and showed a mild language disorder. Clinically relevant psychiatric disorders affected five subjects (psychosis and anxiety in 2, anxiety in 3). Clinical follow-up confirms DNAJC12 defect as a stable non-degenerative condition. Blood Phe level at diagnosis was 348±127 µmol/L (range 204-529; r.v. 60-120 µmol/L). In patients who underwent CSF examination, HVA and 5-HIAA were low, with an increased ratio of HVA/5-HIAA. Prolactin levels were mildly increased in 5 out of 8 patients.

Conclusion: DNAJC12 defect has been reported so far in about 30 cases. On the clinical ground, present longitudinal data confirm this as a new neurodevelopmental disorder superimposed by a severe MD, including ataxia or parkinsonism–dystonia, from the second decade of life on. However, this condition should also be considered for early-onset parkinsonism in adulthood. The preventing effect on the clinical course of an early restoration of brain neurotransmitters by early supplementation of their precursors needs further study.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dnajc12-defect-a-new-neurodevelopmental-disorder-associated-with-parkinsonism-dystonia/