Largest Cohort Study of Gaucher Disease Type 3 from a Single Center in Egypt Spanning Two Decades

Background and objectives:Gaucher disease (GD) is renowned for genotype/phenotype studies and therapeutic innovation. However, the vast majority of the literature is focused on Type 1 GD related to the founder mutation, p.Asn409Ser in GBA gene although p.Leu483Pro GBA mutation associated GD may be far more prevalent across the world. In Egypt GD represents as high as 14.7% of all reported lysosomal disorders with the neuronopathic forms. Therefore, a large single center cohort study of a highly consanguineous GD population has the potential to inform genotype/phenotype, natural history studies and illuminate unmet needs.

Methods:At University of Cairo's Pediatric Hematology Clinic since 1998, we have managed a total of 156 patients with GD with longitudinal data captured under an approved IRB protocol. In the present study, we focused analysis on 85 patients in whom we had long-term outcome after 20 years of enzyme replacement therapy (ERT). GBA gene analysis was performed by whole exome sequencing of DNA isolated from dry blood spots.

Data on the clinical phenotype indicators at baseline and during ERT were collected including liver and spleen volumes, growth parameters, bone status, neurological assessment and eye movement. SPSS (Statistical Package for the Social Sciences) version 24 was used to compile data, assess significance and survival by Kaplan Meier analysis. Overall survival (OS) is defined as date of diagnosis till date of death, patients alive or lost during follow up was considered censored till the last date of follow up.

Results:The median age at diagnosis was 1 year (IQR: 0.08-15 years) with majority (64.7%) diagnosed in first 2 years of life (range 0.5-2 yrs). The patient population was highly consanguineous and 51% of the patients reported positive family history of GD. The most prevalent genotype (75% of patients) was p.Leu483Pro homozygous. Homozygosity for p.Asp448His was present in 11% of patients. Other GBA mutations included: p.Leu483Pro homozygous in 3 patients, one heteroallelic with p.Leu483Pro; pArg87Trp homozygous in 2 patients; p.Arg398Gln homozygous in one patient). Hematological features of patients at diagnosis revealed anemia in 76% and thrombocytopenia in 22%. Massive splenomegaly (˃15 Multiples of Normal by ultrasonography) was present in 49%, 4 patients were splenectomised, hepatomegaly (˃2.5 MN) in 11%, liver cirrhosis with hepatopulmonary syndrome in one patient. Skeletal findings included multiple fractures in 3 patients and kyphosis in 3 patients. The most common neurological findings were oculomotor apraxia, squint and bulbar symptoms (48%, 30.6% and 29.4% respectively). Bone marrow examination showed Gaucher cell infiltration in 76% of the patients.

Patients received Imiglucerase (Cerezyme) dose individualized by baseline disease severity. Debilitating and potentially life-threatening visceral and hematologic disease was reversed with ERT (table 1). One splenectomized patient with massive hepatomegaly and hepatopulmonary syndrome showed complete reversal on high dose ERT. Preliminary observer reported outcomes (by clinician and parent) with respect to neurological findings including oculomotor apraxia appeared to show mild improvement. Follow-up of 10 patients in whom ERT was initiated early had striking overall outcomes progressing through school and university. At 20 years, the overall survival was 71%; 20 patients died from disease complications mostly pulmonary and progressive neurological disease. Comparison of the OS in relation to gender, age at diagnosis, severity of hematological and visceral parameters showed that none of the studied variables affects OS (p˃0.05) (fig. 1).

Conclusion:This study represents the largest and most extensive single-center cohort of GD3 patients with predominant p.Leu483Pro homozygous GBA genotype, without presence of a complex allele. Patients had uniformly very early-onset disease before age 2 years with devastating hematological and visceral disease which was effectively reversed by ERT. During 20 year-follow up of the cohort, there was striking reversal of hematovisceral disease and about a third of the patients succumbed to complications of GD3. OS was not correlated with severity of baseline disease underscoring the potential role of modifier genes.

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