FUCA1 – Fucosidosis

Fucosidosis (MONDO:0009254) is a rare autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in FUCA1 (HGNC:4006). The phenotype encompasses progressive psychomotor deterioration, coarse facial features, growth delay, and recurrent infections (HP:0007272; HP:0000280; HP:0001510; HP:0002719) with variable onset and severity (PMID:2012122).

Genetic evidence includes segregation of homozygous and compound heterozygous FUCA1 variants with disease in multiple unrelated families. A canonical splice site mutation c.969+1G>A segregated in three affected siblings of consanguineous parents (PMID:8097260). Additional LoF alleles such as c.1216G>T (p.Gly406Ter) and other nonsense and frameshift mutations have been reported in diverse populations (PMID:8401503; PMID:9039984).

Over 36 unique FUCA1 pathogenic variants (nonsense, splice site, small and large deletions) have been characterized in at least 77 affected individuals, confirming a broad allelic spectrum without clear genotype–phenotype correlation (PMID:10094192; PMID:2012122). Founder and recurrent variants have been identified in Italian, Japanese, Tunisian, and other cohorts, underscoring the need for comprehensive variant screening (PMID:34425818).

Functional assays consistently demonstrate absent or severely reduced alpha-L-fucosidase activity and protein in patient cells. SSCP and enzyme activity studies in fibroblasts and lymphoblasts confirm LoF for multiple mutations (PMID:9039984). Homology-based modeling of missense and truncating variants reveals disruption of active-site conformation and overall protein stability (PMID:34425818).

No studies have refuted the FUCA1–fucosidosis association. Clinical heterogeneity spans from infantile fatal forms to attenuated adult phenotypes including dystonia and psychosis, reflecting a continuous spectrum rather than discrete subtypes (PMID:38053939).

In summary, definitive genetic and experimental evidence establishes FUCA1 as the causative gene for autosomal recessive fucosidosis. Early molecular diagnosis via FUCA1 sequencing and enzyme assays enables prompt genetic counseling and consideration of hematopoietic stem cell transplantation to prevent irreversible neurological damage.

Key Take-home: FUCA1 testing and enzymatic confirmation are essential for accurate diagnosis and timely intervention in fucosidosis.

References

• American journal of medical genetics • 1991 • Fucosidosis revisited: a review of 77 patients. PMID:2012122
• Journal of medical genetics • 1993 • A 5' splice site mutation in fucosidosis. PMID:8097260
• Human molecular genetics • 1993 • Six additional mutations in fucosidosis: three nonsense mutations and three frameshift mutations. PMID:8401503
• Journal of medical genetics • 1997 • Fucosidosis: genetic and biochemical analysis of eight cases. PMID:9039984
• European journal of human genetics : EJHG • 1999 • Spectrum of mutations in fucosidosis. PMID:10094192
• BMC medical genomics • 2021 • Fucosidosis in Tunisian patients: mutational analysis and homology-based modeling of FUCA1 enzyme. PMID:34425818

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