HPDL – Neurodevelopmental Disorder with Progressive Spasticity and Brain White Matter Abnormalities

Autosomal recessive biallelic variants in HPDL (HGNC:28242) have been associated with a severe infantile neurodevelopmental disorder characterized by global developmental delay, progressive spasticity, seizures, and characteristic white matter changes on MRI ([PMID:35985664]).

Inheritance is autosomal recessive with segregation observed in three independent families. To date, three unrelated probands harbor compound heterozygous or homozygous HPDL variants across three pedigrees, with segregation confirmed in affected relatives in both branches of a large kindred ([PMID:33634263]; [PMID:35222531]).

The variant spectrum includes loss-of-function alleles (c.995delC (p.Thr332MetfsTer9)[PMID:35985664], c.1051C>T (p.Gln351Ter)[PMID:35985664]) and a pathogenic missense change (c.527T>C (p.Leu176Pro)[PMID:33634263]). No recurrent or founder alleles have been reported thus far.

Functional studies support a mitochondrial mechanism: affected individuals exhibit reduced citrate synthase and complex I activity in patient tissues, and HPDL localizes to mitochondria with proposed enzyme dysfunction mirroring clinical spasticity and white matter loss ([PMID:35222531]; [PMID:33634263]).

No conflicting evidence disputing HPDL’s role has been reported. The combined genetic and biochemical data fulfill ClinGen criteria for a Moderate level of clinical validity, with consistent genotype–phenotype correlation and supportive functional assays.

Key Take-home: HPDL testing should be included in diagnostic panels for early-onset spastic paraplegia and neurodevelopmental delay, as identification of biallelic variants directly informs prognosis and potential mitochondrial-targeted therapies.

References

• Molecular genetics & genomic medicine • 2022 • HPDL mutations identified by exome sequencing are associated with infant neurodevelopmental disorders. PMID:35985664
• Brain communications • 2021 • Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in HPDL. PMID:33634263
• Frontiers in genetics • 2022 • Case Report: Two Families With HPDL Related Neurodegeneration. PMID:35222531

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