GUSB – Mucopolysaccharidosis type VII

Mucopolysaccharidosis type VII (MPS VII, Sly syndrome) is a rare autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in GUSB, encoding β-glucuronidase. Clinical presentations range from severe nonimmune hydrops fetalis to attenuated adult‐onset forms, often with hepatosplenomegaly, coarse facies, skeletal dysplasia, corneal clouding, and progressive pulmonary and cardiac involvement. Early prenatal signs such as increased nuchal translucency and foamy Hofbauer cells in the placenta can prompt enzymatic and molecular diagnosis in utero.

Genetic evidence encompasses at least 20 unrelated probands: a single pediatric case with homozygous p.Ala619Val ([PMID:2115490]), two Japanese patients homozygous for p.Ala619Val or p.Arg382Cys ([PMID:1702266]), and 17 severely affected individuals with diverse GUSB mutations including missense, nonsense, small deletions, and splice alterations ([PMID:8644704]). Segregation in consanguineous families and recurrence in siblings confirm autosomal recessive inheritance, with at least 3 additional affected relatives in documented pedigrees.

The variant spectrum includes over 40 distinct alleles: missense changes (e.g., p.Ala619Val, p.Arg382Cys), nonsense (e.g., p.Trp507Ter), frameshift (e.g., p.Arg625fs), splice‐site (e.g., IVS8+0.6kbdelTC), and synonymous mutations causing exon skipping (e.g., p.Ser539=). A common founder mutation p.Leu176Phe has been identified in certain populations, while pseudodeficiency alleles such as p.Asp152Asn can complicate interpretation without molecular and enzymatic correlation.

Functional assays demonstrate that pathogenic GUSB variants uniformly reduce enzyme activity. Patient fibroblast and lymphocyte lysates show near‐absent β-glucuronidase activity despite normal mRNA levels, and COS‐cell expression of mutant cDNAs yields accelerated turnover or impaired secretion ([PMID:2115490], [PMID:1702266]). In a murine MPS VII model, short‐term enzyme replacement therapy corrects many but not all transcriptional abnormalities in liver, highlighting residual disease mechanisms ([PMID:14705966]).

Therapeutic interventions include early enzyme replacement therapy (ERT) with vestronidase alfa and hematopoietic stem cell transplantation (HSCT). Allogeneic bone marrow transplantation in a 12-year-old homozygous p.Ala619Val patient restored enzyme activity and dramatically improved motor function, respiratory infections, and quality of life over 31 months ([PMID:9543069]).

Overall, the evidence supports a Strong gene–disease association. Genetic testing for GUSB variants, combined with β-glucuronidase activity assays, enables definitive diagnosis, informs recurrence risk, and facilitates timely initiation of ERT or HSCT. Key take-home: GUSB sequencing and enzyme assays are clinically actionable for early detection and management of MPS VII.

References

• Gene • 1990 • Molecular basis of mucopolysaccharidosis type VII: replacement of Ala619 in beta-glucuronidase with Val. PMID:2115490
• American Journal of Human Genetics • 1991 • Mucopolysaccharidosis type VII: characterization of mutations and molecular heterogeneity. PMID:1702266
• American Journal of Human Genetics • 1996 • Molecular analysis of patients with beta-glucuronidase deficiency presenting as hydrops fetalis or as early mucopolysaccharidosis VII. PMID:8644704
• Biochemical Journal • 2004 • Numerous transcriptional alterations in liver persist after short-term enzyme-replacement therapy in a murine model of mucopolysaccharidosis type VII. PMID:14705966
• Bone Marrow Transplantation • 1998 • Treatment of MPS VII (Sly disease) by allogeneic BMT in a female with homozygous A619V mutation. PMID:9543069

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