Lecture Notes

Co-chaperone deficiencies, resulting from mutations or reduced expression of co-chaperone proteins, can lead to a variety of diseases due to disrupted protein folding and cellular homeostasis. These deficiencies impact the ability of cells to properly fold, refold, and degrade proteins, particularly under stress

• Gene Involved: DNAJC12
  • Encodes a heat shock co-chaperone protein of the HSP40 family
  • Interacts with:
    • Phenylalanine hydroxylase (PAH)
    • Tyrosine hydroxylase (TH)
    • Possibly tyrosine hydroxylase phosphorylase (THPs), based on in silico data
• Clinical and Genetic Findings:
  • Biallelic mutations in DNAJC12 identified in patients with:
    • Hyperphenylalaninemia (HPA)
    • Dopamine and serotonin deficiency
    • No mutations in known neurotransmitter synthesis or pterin metabolism genes
  • Approximately 20 patients described to date
  • Symptoms may range from mild or absent to significant neurological involvement
• Clinical Features:
  • Dystonia
  • Speech delay
  • Axial and limb hypertonia
  • Parkinsonism
  • Psychiatric features
  • A milder phenotype may include:
    • Mild intellectual disability
    • Slowly progressive parkinsonism
    • No dystonia at disease onset (noted during adolescence)
• Diagnostic Clues:
  • HPA detected via newborn screening (NBS)
  • Standard testing fails to confirm known primary neurotransmitter or BH4 metabolism defects
  • CSF analysis shows:
    • Low 5-HIAA (5-hydroxyindoleacetic acid)
    • Low HVA (homovanillic acid)
    • Normal or elevated biopterin levels
• Treatment Strategy:
  • Should be started early
  • Consists of:
    • L-Dopa/carbidopa
    • 5-hydroxytryptophan (5-HTP)
    • BH4 (sapropterin) supplementation