HPDL Variant Type Correlates With Clinical Disease Onset and Severity.

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.