Gaucher disease type I results from biallelic pathogenic variants in GBA1, which encodes glucocerebrosidase, a lysosomal hydrolase responsible for cleaving glucocerebroside into glucose and ceramide. When both alleles carry loss-of-function variants, residual enzyme activity is insufficient to prevent substrate accumulation in macrophage lysosomes. Inheritance follows an autosomal recessive pattern, requiring pathogenic variants in both copies of GBA1 for disease expression; heterozygous carriers of a single pathogenic variant are generally unaffected. Measured glucocerebrosidase enzyme activity in vitro does not reliably predict clinical severity, a finding attributed to the limitations of cell-based assays and the influence of additional biological factors in vivo. Certain GBA1 variants—notably p.Asn409Ser (formerly N370S)—are associated with the non-neuronopathic type I phenotype and are enriched in the Ashkenazi Jewish population due to a founder effect; however, genotype-phenotype correlations remain imprecise. The relationship between heterozygous GBA1 variants and increased risk of Parkinson disease has also been established and represents a distinct biological consideration.

Diagnosis is established through biochemical and molecular testing. Measurement of glucocerebrosidase enzyme activity in leukocytes or on dried blood spots below established cutoffs confirms enzyme deficiency. Molecular genetic testing identifies the specific GBA1 pathogenic variants, confirms the diagnosis, differentiates Gaucher disease from other lysosomal storage disorders, and enables family studies. Plasma biomarkers—including chitotriosidase and glucosylsphingosine—serve as supplementary diagnostic and longitudinal monitoring tools; glucosylsphingosine in particular has utility as an activity-sensitive marker. In some regions, newborn screening programs measure glucocerebrosidase activity on dried blood spots, with values below cutoffs prompting confirmatory evaluation. The GeneReviews chapter describes evaluations following initial diagnosis, which typically include abdominal imaging to quantify spleen and liver volumes, skeletal MRI to assess bone marrow infiltration, complete blood count, and additional organ-specific assessments based on clinical presentation and age at ascertainment.

Targeted therapies for Gaucher disease type I are available and constitute the primary treatment modality for symptomatic individuals, per published clinical management guidelines. Enzyme replacement therapy (ERT) supplies exogenous glucocerebrosidase intravenously; velaglucerase alfa (VPRIV) and alglucerase (Ceredase) are agents with approved status for Gaucher disease. Substrate reduction therapy (SRT) reduces the rate of glucocerebroside biosynthesis as an alternative or complementary approach; eliglustat (Cerdelga) and miglustat (Zavesca) are FDA-approved SRT agents. Eliglustat is a substrate of CYP2D6, and prescribing is informed by CYP2D6 metabolizer status. Treatment selection is individualized according to disease manifestations, age, reproductive status, organ involvement, and therapeutic response. Per clinical management guidelines described in the GeneReviews chapter, multidisciplinary care through Gaucher disease Comprehensive Treatment Centers is a framework for ongoing management. Supportive measures address skeletal complications, hematologic parameters, and quality of life. Published guidance notes heightened risk with nonsteroidal anti-inflammatory drug use in the setting of significant thrombocytopenia.

Gaucher disease type I is a condition for which effective targeted therapies exist. Published clinical series have demonstrated improvement in organomegaly, hematologic parameters, and skeletal markers following initiation of ERT or SRT. Outcomes are generally more favorable when treatment begins before irreversible skeletal complications—such as established osteonecrosis—have developed. The clinical course is highly variable: some individuals experience a mild, stable disease course requiring minimal intervention, while others develop progressive multisystem complications. Pulmonary arterial hypertension, when present, may represent a more refractory manifestation. Because Gaucher disease type I does not involve primary neurological disease, cognitive function is generally preserved. Long-term clinical and biochemical monitoring is a standard component of care to assess treatment response, guide therapeutic adjustments, and detect emerging complications.

The research landscape for Gaucher disease type I includes 184 classified publications, with a substantial proportion of reviews reflecting the accumulated evidence base for this well-characterized condition. Gene therapy is an active area of investigation: a recruiting clinical trial (NCT07223944) is evaluating FLT201, a gene therapy candidate for Gaucher disease, and a further recruiting study (NCT05487599) is evaluating PR001 (LY3884961) for peripheral Gaucher disease manifestations. The investigational SRT agent venglustat—a brain-penetrant glucosylceramide synthase inhibitor—is under study in combination with enzyme replacement therapy; early-phase data from an active trial (NCT02843035) in adults demonstrated acceptable safety and preliminary clinical stability, with applications under continued evaluation. Biomarker research, including plasma glucosylsphingosine as an activity-sensitive marker, has been productive. The established association between heterozygous GBA1 variants and elevated Parkinson disease risk continues to generate substantial basic science and translational investigation, with relevance to the broader understanding of GBA1 biology and potential neuroprotective therapeutic strategies.