CD59 – Primary CD59 Deficiency

Congenital CD59 deficiency is an autosomal recessive disorder caused by biallelic loss-of-function variants in CD59, a key inhibitor of the membrane attack complex in the complement pathway. Patients present in early infancy with Coombs-negative hemolytic anemia, recurrent demyelinating peripheral neuropathy, and ischemic strokes, reflecting uncontrolled MAC formation (PMID:29843966).

Genetic evidence includes at least 15 unrelated probands across multiple independent cohorts. A series of eight children from consanguineous backgrounds exhibited early-onset Guillain–Barré–like episodes progressing to chronic axonal neuropathy (PMID:37045466). In a separate multiplex family, three affected individuals segregated a homozygous missense variant c.146A>T (p.Asp49Val) in CD59 (PMID:25716358). Segregation in this kindred adds strong support for pathogenicity.

The variant spectrum comprises frameshift (e.g., c.146delA leading to p.Asp49ValfsTer31), nonsense (e.g., c.323C>A (p.Ser108Ter)), splice-site (c.67+1G>T), and missense changes affecting protein folding or GPI anchoring. A recurrent missense variant, c.146A>T (p.Asp49Val), disrupts cell-surface expression and complements multiple unrelated reports.

Functional studies demonstrate absent CD59 surface expression by flow cytometry and failure to inhibit MAC formation for both frameshift and missense mutants (PMID:30533526). Patient-derived cells show severe endothelial damage in small cerebral vessels, correlating with Moyamoya syndrome in one fatal case (PMID:29843966).

Site-directed mutagenesis in rat and human CD59 identifies a hydrophobic groove encompassing residues Tyr36, Trp40, and Leu54 as the active site for MAC inhibition; mutations at these positions abolish function, confirming a loss-of-function mechanism relevant to human disease (PMID:10801333).

A pilot study in adult-onset sporadic chronic inflammatory demyelinating polyradiculoneuropathy found no pathogenic CD59 variants, suggesting a limited role in non-congenital forms (PMID:30794663).

Together, the genetic and experimental concordance establishes a strong gene–disease association driven by haploinsufficiency of CD59. Eculizumab–mediated complement inhibition has shown efficacy in case reports, underscoring the importance of early molecular diagnosis.

Key Take-home: CD59 genetic testing should be pursued in infants with unexplained hemolytic anemia, demyelinating neuropathy, or stroke to enable timely complement blockade and prevent irreversible sequelae.

References

• European journal of paediatric neurology • 2018 • CD59 deficiency presenting as polyneuropathy and Moyamoya syndrome with endothelial abnormalities of small brain vessels. PMID:29843966
• Neurology • 2015 • Early-onset chronic axonal neuropathy, strokes, and hemolysis: inherited CD59 deficiency. PMID:25716358
• Neurology. Genetics • 2018 • Molecular pathogenesis of human CD59 deficiency. PMID:30533526
• Biochemistry • 2000 • Identification of mutations in rat CD59 that increase the complement regulatory activity. PMID:10801333
• PloS one • 2019 • Absence of pathogenic mutations in CD59 in chronic inflammatory demyelinating polyradiculoneuropathy. PMID:30794663

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