Case Report: Two Families With HPDL Related Neurodegeneration

Abstract

There are recent reports of associations of variants in the <i>HPDL</i> 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 <i>HPDL</i> 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 <i>HPDL</i> mutations. Further, we speculate on the functional consequences of the detected variants, although the function and substrate of the HPDL enzyme are currently unknown.