DDHD1 – Hereditary Spastic Paraplegia

Hereditary spastic paraplegia (HSP) type 28 is caused by biallelic loss-of-function variants in DDHD1, presenting as a progressive, autosomal-recessive corticospinal tract degeneration with pure and complex phenotypes. Initial case reports described two affected siblings with spastic paraparesis, urinary incontinence, and motor axonal neuropathy harboring a novel homozygous nonsense variant c.1429C>T (p.Arg477Ter) (PMID:26944165). A subsequent cohort study of autosomal-recessive HSP identified DDHD1 mutations in multiple unrelated probands, confirming autosomal-recessive inheritance and expanding the phenotypic spectrum to include basal ganglia calcification (PMID:23176821).

Genetic evidence encompasses at least 19 probands across four studies, all carrying biallelic DDHD1 variants, with segregation in two multiplex families (PMID:26944165) and no reported unaffected homozygotes. The variant spectrum is dominated by truncating alleles: 12 distinct frameshift and nonsense changes (e.g., c.1429C>T (p.Arg477Ter)) with additional canonical splice and small indel variants. There are no recurrent founder alleles reported to date, and carrier frequencies remain extremely low.

Functional studies in patient‐derived muscle and fibroblasts revealed multiple mitochondrial DNA deletions, altered respiratory-chain enzyme activities, reduced ATP levels, and mitochondrial fragmentation, indicating impaired oxidative phosphorylation (PMID:26944165; PMID:24989667). Mouse knockout models further demonstrated that DDHD1 loss alters lysophosphatidylinositol and phosphatidylinositol lipid pools in brain tissue, confirming the enzyme’s role in neuronal lipid homeostasis and linking lipid dysregulation to axonal degeneration (PMID:30221923).

Mechanistically, DDHD1 deficiency leads to haploinsufficiency of a primary brain phosphatidylinositol lipase, resulting in mitochondrial bioenergetic failure and corticospinal tract vulnerability. No studies to date have refuted the gene–disease relationship or assigned alternative phenotypes.

Overall, the clinical validity of the DDHD1–HSP association is Strong based on biallelic LoF variants in 19 probands, AR segregation in two families, and concordant functional data. Genetic evidence is Strong (numerous truncating variants meeting AR criteria), and functional evidence is Moderate (patient cell and animal model data recapitulating key features of HSP). Additional genotype–phenotype correlations and natural history studies could further refine penetrance and expressivity.

Key Take-home: Biallelic DDHD1 LoF variants cause autosomal-recessive HSP28 through disrupted phosphatidylinositol hydrolysis and mitochondrial dysfunction, supporting targeted genetic testing and early metabolic assessment in suspected cases.

References

• Journal of the neurological sciences • 2016 • Mitochondrial dysfunction in hereditary spastic paraparesis with mutations in DDHD1/SPG28. PMID:26944165
• American journal of human genetics • 2012 • Alteration of fatty-acid-metabolizing enzymes affects mitochondrial form and function in hereditary spastic paraplegia. PMID:23176821
• Journal of neurology • 2014 • Impairment of brain and muscle energy metabolism detected by magnetic resonance spectroscopy in hereditary spastic paraparesis type 28 patients with DDHD1 mutations. PMID:24989667
• Biochemistry • 2018 • The Spastic Paraplegia-Associated Phospholipase DDHD1 Is a Primary Brain Phosphatidylinositol Lipase. PMID:30221923

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