Abstract
OBJECTIVE: Recently, a mitochondrial encephalopathy due to biallelic HPDL variants was described, associated with a broad range of clinical manifestations ranging from severe, infantile-onset neurodegeneration to adolescence-onset hereditary spastic paraplegia. HPDL converts 4-hydroxyphenylpyruvate acid (4-HPPA) into 4-hydroxymandelate (4-HMA), necessary for the synthesis of the mitochondrial electron transporter CoQ10. This suggests a possible bypass of the metabolic block by 4-HMA treatment; however, genotype-phenotype correlations are lacking. METHODS: We established an HPDL Patient Registry to prepare for a future clinical trial. Here we report the clinical features of 13 enrolled participants and compare them with 86 previously reported patients. We establish three major clinical classes: severe, intermediate, and mild, presenting onset in early infancy, childhood, and adolescence, respectively. The biallelic genotypes were classified into truncating/truncating, truncating/missense, and missense/missense variants, mapped onto the predicted 3D protein structure, and correlated with severity. RESULTS: Patients with biallelic truncating variants presented with severe phenotypes and earlier ages of onset. Missense variants were often associated with milder phenotypes, except those with variants predominantly located in or near the VOC2 domain containing iron-binding sites or the C-terminus, which had more severe phenotypes. In addition, p.Met1? variants were also correlated with more severe phenotypes. INTERPRETATION: This study demonstrates the correlation of age of onset and disease severity with genotype for HPDL-related conditions. Patients with truncating variants and specific missense variants correlated with severe, early-onset features, whereas the presence of at least one missense variant located outside of the iron-binding sites correlated with milder presentations. TRIAL REGISTRATION: Clinicaltrials.gov HPDL registry: https://clinicaltrials.gov/study/NCT05848271.