Case Report: Two Families With HPDL Related Neurodegeneration

There are recent reports of associations of variants in the HPDL gene with a hereditary neurological disease that presents with a wide spectrum of clinical severity, ranging from severe neonatal encephalopathy with no psychomotor development to adolescent-onset uncomplicated spastic paraplegia. Here, we report two probands from unrelated families presenting with severe and intermediate variations of the clinical course. A homozygous variant in the HPDL gene was detected in each proband; however, there was no known parental consanguinity. We also highlight reductions in citrate synthase and mitochondrial complex I activity detected in both probands in different tissues, reflecting the previously proposed mitochondrial nature of disease pathogenesis associated with HPDL mutations. Further, we speculate on the functional consequences of the detected variants, although the function and substrate of the HPDL enzyme are currently unknown.

Automated summary

Variants in the HPDL gene have been associated with a hereditary neurological disease with a wide range of clinical severities. Two probands from unrelated families with different clinical courses were found to have homozygous variants in the HPDL gene, despite no known parental consanguinity. Reductions in citrate synthase and mitochondrial complex I activity in different tissues of both probands suggest a mitochondrial nature in the pathogenesis associated with HPDL mutations.