The study was approved by the Institutional Ethics Committee of our institute. Records of patients with confirmed diagnosis of Gaucher disease (by estimation of b-glucocerebrosidase activity and/or identification of pathogenic mutations and/or histopathological evidence of Gaucher cells) were retrospectively reviewed from January 1995 through December 2011 (n = 31, 83.8 %) and six patients (16.2%) were prospectively enrolled from January 2012 through June 2013. Of these, 35 cases constituted a subset of lysosomal storage disorders analyzed previously for diagnostic time frame and genotype [3].

TABLE I	Clinical Characteristics and Severity Score with GauSSI for Hematologic and Biomarker 
Domains in Study Subjects (N=37) 

ERT was initiated in 12 cases. Before commencing ERT, all 12 cases had splenomegaly and hepatomegaly whereas stunting (height <3rd centile, NCHS chart) was noted in 10 (83.3 %) and osteopenia (DEXA Z score -1 to -2.5) in 9 (75%). Three (25%) had undergone splenectomy. Baseline liver volume in one patient was <1.25 times normal, four each had moderate hepatomegaly (1.25-2.5 times normal) and severe hepatomegaly (>2.5 times normal) and in three individuals baseline liver volume was not available. The average liver volume was 2.27 times normal (range of 1.06-4). Nine individuals with an intact spleen had severe splenomegaly (volume > 15 times normal, average 40.2 times normal, range: 20.7-67). The average (range) age at initiation and duration of ERT was 85 (17-140) months and 55 (1-144) months, respectively. Average annual dose ranged from 23-53Units/kg and varied every year. Response to enzyme replacement was prospectively analyzed in 11 out of 12 cases (7 males; 7 with type 1 disease and 4 with type 3). One 10 year old with advanced disease died due to intracranial hemorrhage after the first infusion of ERT. The response to ERT is presented in Table II.

TABLE II	Response to Enzyme Replacement Therapy in Terms of Achievement of Therapeutic Goals 
within the recommended Time-frame

The broad phenotypic spectrum of Gaucher disease and wide variation in severity makes treatment with ERT a challenge. Acknowledging these aspects has resulted in adoption of individualized dose regimen [6,7].

A key determinant of the initial treatment dose is disease severity, rate of progress, nature of organ involvement and impact of disease manifestation on quality of life [6,7]. This stratifies patients to high or low risk groups [7]. Children are categorized as high-risk on the basis of various clinical and laboratory parameters [6,7]. A dose of 60 Units/kg every two weeks has been recommended to treat high-risk children and as a minimum dose for children with type 3 phenotype [7,8].

We found that Indian children have severe disease based on the following observations: early age of onset (average of 28 months), objectively graded moderate to severe manifestations of splenomegaly, hepatomegaly, anemia and thrombocytopenia corroborated by extremely elevated plasma chitotriosidase levels (indicating a high disease burden) [9], and high proportion of the severe genotype (p.Leu483Pro) (representing severe manifestations and neuronopathic disease) [8]. The severe manifestations could partly be attributed to the diagnostic lag (average of 30 months) in our study.

Thus majority of our cohort would be candidates for receiving a dose of 60 Units/kg every two weeks as they have multiple high risk criteria. Due to supply constraints, our children received low doses that varied every year. Despite receiving dose of <60 Units/kg, early response with hematological reconstitution by the first year of therapy was adequate. However, the visceral and skeletal response digressed from the recommended targets. Only 50% and 25% of ERT recipients achieved the target reduction in liver and spleen volume, respectively by the first year of therapy. Skeletal response was likewise suboptimal with only 22% showing improvement in BMD and 30% achieving normal height by 3 years. As visceral and skeletal response is dose-dependent and determined by age at initiation of ERT; late initiation, high disease burden and low doses was the most likely cause for sub-optimum visceral and skeletal response [10-12].

A publication describing collective results of five Indian centers has shown significant hematological and visceral response and improved weight and height [2]. However, parameters that were not addressed in this early publication were dose of ERT, objective severity of disease and response in terms of prescribed therapeutic goals. Additionally, as skeletal and growth response are only observed after the third year of treatment [5,8], the relatively shorter duration of therapy (average of 2.5 years in eight out of 22 patients completing more than one year therapy) did not permit effective conclusions. Thus our study contributes to the experience of treating Gaucher disease in India by documenting long-term data against established therapeutic goals.

A limitation of our study was reliance on retrospective data due to which clinical information was incompletely captured, evaluations were partial and patients were lost to follow-up. The other limitation was lack of complete systemic assessment of solid organs, lungs, heart and skeleton by imaging due to financial constraints as all expenses were out-of-pocket. In conclusion, severe disease phenotype and higher proportion of type 3 disease in Indian children necessitates ERT in higher doses along with cautious dose tapering for long term management if optimum response in all disease domains is to be a reality. As ethnic/geographic background of a Gaucher disease population may be a consideration for optimum dosing [7], our study has important therapeutic ramifications. Such phenotype and risk categorization of Indian children along with comprehensive pre-treatment evaluation of organ involvement and disease burden would determine whether the therapeutic promise of ERT in India is realized in its entirety.