Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia

Am J Hum Genet. 2020 Aug 6;107(2):364-373. doi: 10.1016/j.ajhg.2020.06.015. Epub 2020 Jul 23.


We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.

Keywords: HPDL; Leigh-like syndrome; developmental delay; encephalopathy; exome sequencing; hereditary spastic paraplegia; mitochondrial metabolism; movement disorder.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Amino Acid Sequence
  • Brain Diseases / genetics*
  • Child
  • Female
  • Humans
  • Male
  • Mitochondria / genetics
  • Mitochondrial Proteins / genetics*
  • Neurodegenerative Diseases / genetics*
  • Pedigree
  • Phenotype
  • Spastic Paraplegia, Hereditary / genetics*
  • Young Adult


  • Mitochondrial Proteins