Abstract
Hypoglycemia, neutropenia, enterocolitis and recurrent infections are common manifestations of glycogen storage disease 1b (GSD1b). GSD1b is a rare genetic disorder caused by mutations in G6PT1, the gene for the glucose 6 phosphate transporter principally responsible for the transport of glucose into the endoplasmic reticulum in neutrophils and other cells. In myeloid cells, mutant G6PT1 causes abnormalities in both neutrophil deployment and function.
We recently formed a cooperative GSD1b study group to investigate the diagnosis, manifestations and treatment of GSD1b associated neutropenia. This report summarizes data for 68 patients with GSD1b followed prospectively in North America by the Severe Chronic Neutropenia International Registry-Seattle (SCNIR-Seattle), Duke University and University of Florida. It is the largest cohort of patients yet assembled for the study of this form of glycogen storage disease. We enrolled a total 29 males, 39 females, including 41 currently adult patients (mean age 17.5; range 2.3-41.1). All patients were recognized in very early childhood, most commonly because of hypoglycemia, hepatomegaly, seizures or because of clinical features similar to those of older sibling with GSD1b. Diagnostic DNA sequencing results were available for 30 patients. Before the availability of genetic testing, liver biopsy was commonly done to secure the diagnosis. G-CSF has been widely used in management of these patients since the early 1990’s. The earliest treatment of a patient in the cohort began G-CSF in 1989.
Neutrophil counts were available for 54/68 patients prior to treatment. Median neutrophil count prior to treatment with G-CSF was 0.45 x 109/L, mean 0.59 +/- 0.09 x 109/L (range 0-3.5 x 109/L) and elevations of blood neutrophils were common with infections. Bone marrow examination and neutrophil function tests were not usually performed. Two-thirds of these patients (42/68) reported symptoms of enterocolitis, a dominant problem for most of these patients. Other common problems were: recurrent fevers, mouth ulcers, gingivitis, periodontitis, cellulitis, abscesses, sinusitis, otitis and pneumonia. Bacteremia, sepsis and deep tissue abscesses were relatively rare. The specific G6PT1 mutations in these patients could not be correlated with the severity of symptoms or neutropenia, similar to previous reports. (Melis et al, Eur J Pediatr 2005;164:501-8)
Sixty-six of the 68 patients were treated with G-CSF, starting at a median age 3.9 years (range 0.04-30.4 years) with a median dose of 3.1 mcg/kg/day (range 0.4-13.8 mcg/kg/day), for a median of 9.3 years (range 0.9-23.8 mcg/kg/day). Neutrophils increased in all patients, with median values on treatment 1.28 x 109/L, mean 1.54 +/- 0.14 x 109/L (range 0-5.7 x 109/L). G-CSF doses and blood neutrophil levels were kept relatively low because splenic enlargement is a recognized manifestation of GSD1b. (pre G-CSF 16/68 had splenomegaly, on G-CSF 49/68 patients had splenomegaly), based on spleen size by physical examination.
Longitudinal observations indicate that G-CSF consistently increases neutrophil counts, reducing enterocolitis and decreasing the occurrence and severity of infections. The high proportion of adult patients enrolled (60%) suggests that many GSD1b patients are now surviving to adulthood with improvements in overall management. Data from annual follow-up, however, indicate that fever and recurrent infections remain a significant problem for many patients, perhaps because G-CSF dosing to achieve a normal ANC is limited by the risk of massive splenomegaly and neutrophil dysfunction may not be corrected with G-CSF. In our study population, five patients have had splenectomies, four had liver transplants, two had hematopoietic transplants, and two developed AML. Three patients have died, one from AML and two from sepsis; one 18 months post splenectomy and off G-CSF. There are now a total of 4 reported cases of AML in GSD1b, 1 before G-CSF and three in patients treated with G-CSF.
We conclude that despite great progress with understanding the genetic and molecular basis for GSD1b and improvement in its treatment, the natural history and long term treatment outcomes are yet poorly understood. Important issues are the risk of bacterial infections despite normalization of the ANC, the risk of massive splenomegaly and the risk of AML. We believe that a cooperative group approach can clarify many of these issues.
Disclosures:
Dale: Amgen: Consultancy, Research Funding. Boxer:Amgen: Equity Ownership.
Quality of Life in Adult Patients with Glycogen Storage Disease Type I: Results of a Multicenter Italian Study
