CRPPA – Walker–Warburg Syndrome

Walker–Warburg syndrome (WWS) is the most severe form of muscular dystrophy-dystroglycanopathy, type A, characterized by congenital muscular dystrophy with eye and brain malformations. CRPPA (HGNC:37276) encodes isoprenoid synthase domain containing (ISPD), a cytidyltransferase required for α-dystroglycan O-mannosylation. Recessive mutations in CRPPA disrupt the initial step of laminin-binding glycan synthesis, leading to defective dystroglycan processing and the Walker–Warburg phenotype.

Genetic evidence supports autosomal recessive inheritance with compound heterozygous and homozygous variants. To date, 15 probands have been reported in unrelated families with biallelic CRPPA variants, including loss-of-function, splice-site, and missense alleles (e.g., c.614G>T (p.Arg205Leu) in one patient) ([PMID:24120487];[PMID:23288328];[PMID:33199158];[PMID:26087224]).

Segregation analysis in seven families has demonstrated co-segregation of biallelic CRPPA variants with disease, confirming recessive transmission and supporting a definitive gene–disease relationship.

Functional complementation assays in patient fibroblasts showed restoration of dystroglycan O-mannosylation upon wild-type ISPD expression, and in vitro studies established cytidyltransferase activity toward ribitol 5-phosphate. Mass spectrometry mapping of α-dystroglycan glycans further confirmed loss of ribitol phosphate modification in ISPD-deficient cells ([PMID:22522420];[PMID:26687144];[PMID:27601598]).

Clinically, affected individuals present with Type II cobblestone lissencephaly, hydrocephalus, seizures, ocular malformations, and profound psychomotor arrest. Diagnosis is established by genetic testing of CRPPA and other dystroglycanopathy genes in infants with these hallmark features.

References

• European journal of medical genetics • 2013 • 160 kb deletion in ISPD unmasking a recessive mutation in a patient with Walker-Warburg syndrome. PMID:24120487
• Nature genetics • 2012 • ISPD loss-of-function mutations disrupt dystroglycan O-mannosylation and cause Walker-Warburg syndrome. PMID:22522420
• Brain : a journal of neurology • 2013 • ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies. PMID:23288328
• Chemistry & biology • 2015 • Human ISPD Is a Cytidyltransferase Required for Dystroglycan O-Mannosylation. PMID:26687144
• Molecular & cellular proteomics : MCP • 2016 • Direct Mapping of Additional Modifications on Phosphorylated O-glycans of α-Dystroglycan by Mass Spectrometry Analysis in Conjunction with Knocking Out of Causative Genes for Dystroglycanopathy. PMID:27601598
• Brain & development • 2021 • Neuroimaging manifestations and genetic heterogeneity of Walker-Warburg syndrome in Saudi patients. PMID:33199158
• European journal of medical genetics • 2015 • ISPD gene homozygous deletion identified by SNP array confirms prenatal manifestation of Walker-Warburg syndrome. PMID:26087224

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