Natural History Study of Patients with HPDL Mutations

This natural history study collects long-term data on individuals with mutations in the HPDL gene — a rare genetic condition that can cause a range of neurological problems including hereditary spastic paraplegia (progressive muscle stiffness and weakness in the legs), neonatal mitochondrial encephalopathy (a severe brain energy disorder in newborns), and related conditions affecting the white matter of the brain and spinal cord. Because HPDL-related disease is newly described and very rare, very little is known about how it progresses over time, what complications arise, and which treatments might help. A natural history study addresses this critical gap. Eligible participants must have a confirmed pathogenic or likely pathogenic variant in the HPDL gene, regardless of age. The clinical diagnosis can include hereditary spastic paraplegia, neonatal mitochondrial encephalopathy, SPG83, or related neurodevelopmental disorders. Individuals with other known genetic abnormalities (beyond HPDL) or conditions that would prevent safe study completion are excluded. Participants will undergo clinical evaluations and have detailed medical history data collected at intervals over time, without experimental treatments being administered. This research is profoundly important for families affected by this rare disease — because without understanding the natural history, clinical trials cannot be designed, biomarkers cannot be validated, and children and adults with HPDL mutations cannot be given accurate prognoses. Building this database is the essential first step toward developing therapies.