Observational studyAnnals of clinical and translational neurology2025
HPDL Variant Type Correlates With Clinical Disease Onset and Severity.
Observational study in Annals of clinical and translational neurology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. It is linked to trial NCT05848271 (A Patient Registry and Natural History Study of Patients with Biallelic HPDL Mutations), which is not on this map. Cited by 2 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Patient Registry and Natural History Study of Patients with Biallelic HPDL Mutations
Who cites it
2 citing papers in PubMed.
- Article
- Article
Corrections and comments
- Erratum issued
Authors and funding
20 authors.
Funding
Abstract
objectiveRecently, 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.
methodsWe 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.
resultsPatients 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.
interpretationThis 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 registrationClinicaltrials.gov HPDL registry: https://clinicaltrials.gov/study/NCT05848271.
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