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HPDL Variant Type Correlates With Clinical Disease Onset and Severity
Eun Hye Lee1,2, Olivia Kim-Mcmanus3, Jennifer H Yang3
1Rady Children's Institute for Genomic Medicine, San Diego, California, USA.
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.
Insights
Genetic variants in HPDL cause mitochondrial encephalopathy. Truncating variants and specific missense variants are linked to severe, early-onset disease, while other missense variants correlate with milder presentations.
Area of Science:
- Biochemistry
- Genetics
- Neuroscience
Background:
- Mitochondrial encephalopathy linked to biallelic HPDL variants presents with diverse clinical manifestations, from severe infantile neurodegeneration to adolescent hereditary spastic paraplegia.
- HPDL is crucial for synthesizing 4-hydroxymandelate (4-HMA), a precursor for the mitochondrial electron transporter CoQ10.
- Genotype-phenotype correlations for HPDL variants remain largely uncharacterized.
Purpose of the Study:
- To establish genotype-phenotype correlations in HPDL-related mitochondrial encephalopathy.
- To classify clinical presentations and correlate them with specific HPDL genotypes.
- To lay the groundwork for a potential clinical trial by establishing an HPDL Patient Registry.
Main Methods:
- Established an HPDL Patient Registry and analyzed data from 13 enrolled participants and 86 previously reported patients.
- Classified patients into severe, intermediate, and mild clinical groups based on age of onset (infancy, childhood, adolescence).
- Categorized biallelic HPDL genotypes (truncating/truncating, truncating/missense, missense/missense) and mapped variants onto the 3D protein structure to correlate with disease severity.
Main Results:
- Patients with biallelic truncating HPDL variants exhibited severe phenotypes and earlier onset.
- Missense variants generally correlated with milder phenotypes, with exceptions for those near the VOC2 domain or C-terminus, which showed more severe presentations.
- HPDL variants at the p.Met1? position were also associated with more severe disease phenotypes.
Conclusions:
- Age of onset and disease severity in HPDL-related conditions are significantly correlated with specific genotypes.
- Truncating variants and certain missense variants predict severe, early-onset disease.
- The presence of at least one missense variant outside critical iron-binding sites suggests a milder disease course.
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