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DDHD1 encodes a phospholipase A1 implicated in the SPG28 subtype of hereditary spastic paraplegia. Biallelic loss-of-function variants in DDHD1 have been reported in multiple families presenting with spastic paraparesis, urinary incontinence and motor axonal neuropathy. The mode of inheritance is autosomal recessive, with homozygous or compound heterozygous variants disrupting enzymatic activity and leading to neurodegeneration in long corticospinal tracts.
Genetic studies identified four probands from two unrelated families harboring recessive truncating or frameshift variants, including the novel nonsense mutation c.1429C>T (p.Arg477Ter) in homozygosity in two siblings (PMID:26944165). A separate family with two affected members carried compound heterozygous frameshift variants (e.g., c.702_708del (p.Cys235fs)) and displayed distal sensory impairment and peripheral axonal neuropathy (PMID:24989667). All variants predict loss of phospholipase function and segregate with disease in both families.
Functional assays in patient-derived muscle and fibroblasts revealed mitochondrial abnormalities, including multiple mtDNA deletions, reduced respiratory chain enzyme activities, and fragmented mitochondrial networks (PMID:26944165). MR spectroscopy in a second family demonstrated impaired brain and muscle energy metabolism, consistent with OXPHOS dysfunction in SPG28 (PMID:24989667).
A Ddhd1–/– mouse model corroborates these findings, showing decreased polyunsaturated lysophosphatidylinositol and altered phosphatidylinositol phosphate homeostasis in brain tissue, confirming DDHD1 as a principal regulator of neuronal lipid metabolism (PMID:30221923). Phosphorylation studies in HEK293 cells indicate Ser11/Ser727 modifications alter subcellular localization but have minimal impact on catalytic activity, suggesting post-translational regulation without major loss of function (PMID:34089703).
Collectively, genetic and functional data support that autosomal recessive loss of DDHD1 causes SPG28 through impaired phospholipase activity and mitochondrial compromise. No conflicting reports have been published to date, and the evidence satisfies ClinGen criteria for a Moderate gene–disease association. Further studies could expand variant spectrum and refine phenotype–genotype correlations.
Key Take-home: Biallelic DDHD1 loss-of-function variants underlie SPG28 by disrupting lipid metabolism and mitochondrial integrity, informing diagnostic testing and potential therapeutic targeting.
Gene–Disease AssociationModerate4 probands across 2 unrelated families; consistent autosomal recessive loss-of-function Genetic EvidenceModerate4 recessive probands with biallelic truncating/frameshift variants in two families Functional EvidenceModeratePatient cell assays and Ddhd1–/– mouse model demonstrate mitochondrial and lipid metabolism defects |