Congenital/Inherited CD59 Deficiency: A Systematic Review.

Background

Inherited CD59 deficiency is a rare autosomal recessive complement-mediated disorder caused by biallelic loss-of-function variants in the CD59 gene. It typically presents in infancy with Coombs-negative hemolytic anemia, relapsing demyelinating polyneuropathy, and recurrent ischemic strokes. Diagnosis is often delayed due to overlapping with more common neurological and hematological disorders. The present study was carried out to systematically review the literature on congenital CD59 deficiency, focusing on genotype-phenotype correlations, geographic distribution, clinical presentation, diagnostic approaches, and treatment outcomes.

Methods

Eligible studies included case reports and case series of genetically or functionally confirmed inherited CD59 deficiency. Demographic, molecular, clinical, and therapeutic data were extracted and analyzed descriptively.

Results

20 reports included. Evidence remains mainly limited to case reports and small case series. The disorder demonstrates a severe and heterogeneous phenotype with predominant neuromuscular involvement, frequently associated with hematologic and cerebrovascular manifestations. Most reported cases originate from regions with high consanguinity, particularly the Middle East and Asia, suggesting possible founder effects and underrecognized prevalence. Exploratory analysis suggested a possible relationship between predicted variant functional impact and clinical severity. However, given the small and heterogeneous evidence base, this finding should be considered hypothesis-generating. Responses to conventional immunomodulatory therapies are variable and often transient. Eculizumab has shown clinical benefit in some patients, although treatment responses remain inconsistent.

Conclusions

Congenital CD59 deficiency is a severe and underrecognized complement-mediated disorder with major diagnostic and therapeutic challenges. Current evidence remains insufficient to establish definitive genotype-phenotype correlations or standardized management strategies. Increased clinical awareness, early integration of functional and genetic testing, and further studies are needed to improve diagnosis and optimize treatment outcomes.