Paige Kaplan

Almost half of patients with Gaucher disease are diagnosed by the age of 10 years, and approximately two thirds are diagnosed by the age of 20 years. Besides symptomatic children, some presymptomatic children are being diagnosed through community screening programs and because of affected siblings. In addition, it is anticipated that in the near future, newborn screening for lysosomal diseases such as Gaucher disease will be introduced in the USA, identifying additional pre/nonsymptomatic children. Currently, there is no severity scoring system for children. A validated disease severity scoring system in the pediatric Gaucher population will be essential for classifying disease severity in these children, monitoring their disease progression, making decisions about when to treat them, and monitoring disease improvement with therapy. A severity scoring system will also be helpful in comparing therapeutic options as new therapies are designed. Therefore, a Pediatric Gaucher Severity Scoring System (PGS3) was devised using expert opinion and validated in 26 patients with type 1 Gaucher disease. The PGS3 correlates well with disease severity in patients at diagnosis and over time. Conclusion: A practical system that will help clinical management, based on signs and symptoms in children with type 1 Gaucher disease, is presented.

Gaucher disease is an inherited pan-ethnic disorder that commonly begins in childhood and is caused by deficient activity of the lysosomal enzyme glucocerebrosidase. Two major phenotypes are recognized: non-neuropathic (type 1) and neuropathic (types 2 and 3). Symptomatic children are severely affected and manifest growth retardation, delayed puberty, early-onset osteopenia, significant splenomegaly, hepatomegaly, thrombocytopenia, anemia, severe bone pain, acute bone crises, and fractures. Symptomatic children with types 1 or 3 should receive enzyme replacement therapy, which will prevent debilitating and often irreversible disease progression and allow those with non-neuropathic disease to lead normal healthy lives. Children should be monitored every 6 months (physical exam including growth, spleen and liver volume, neurologic exam, hematologic indices) and have one to two yearly skeletal assessments (bone density and imaging, preferably with magnetic resonance, of lumbar vertebrae and lower limbs), with specialized cardiovascular monitoring for some type 3 patients. Response to treatment will determine the frequency of monitoring and optimal dose of enzyme replacement. Treatment of children with type 2 (most severe) neuropathic Gaucher disease is supportive. Pre-symptomatic children, usually with type 1 Gaucher, increasingly are being detected because of affected siblings and screening in high-prevalence communities. In this group, annual examinations (including bone density) are recommended. However, monitoring of asymptomatic children with affected siblings should be guided by the age and severity of manifestations in the first affected sibling. Treatment is necessary only if signs and symptoms develop. Conclusion: Early detection and treatment of symptomatic types 1 and 3 Gaucher disease with regular monitoring will optimize outcome. Pre-symptomatic children require regular monitoring. Genetic counseling is important.

Cystinuria, an inherited defect of dibasic amino acid transport, causes accumulation of urinary cystine and cystine urolithiasis. In adults penicillamine reduces stone formation but has a high incidence of dose limiting toxicity. We evaluated the effects of penicillamine in preventing stone formation and with respect to toxicity in our cystinuria cohort at a pediatric biochemical genetics clinic. We reviewed the charts of all 11 children with cystinuria treated at our clinic using a gradual dose escalation of penicillamine. Mean +/- SD patient age at diagnosis was 5.8 +/- 4.3 years (range 1.2 to 12). We tracked urinary cystine concentration before and after initiation of treatment, penicillamine side effects and incidence of new stones during maintenance therapy. During the gradual escalation of penicillamine to the target dose none of the 11 patients experienced toxicity and all had improved urinary cystine concentration (mean +/- SD percent reduction 54% +/- 25%, range 5% to 81%). We followed the patients for a total of 1,203 months (mean +/- SD 109 +/- 73 months, range 41 to 221), periodically assessing urinary cystine concentration, urine protein content, complete blood count, blood urea nitrogen, creatinine and liver function. During this time only 2 patients experienced significant side effects and no patient had stones or stone crises while compliant with treatment. In our cohort penicillamine was well tolerated after gradual initiation and it reduced urinary cystine concentration. Long-term compliance with the medication appeared to protect patients from acute stone crises.

Objective To describe the clinical and demographic characteristics of nonneuronopathic Gaucher disease (GD) in children at the time of diagnosis. Design Longitudinal observational database of the International Collaborative Gaucher Group Gaucher Registry. Setting Data reported to the Registry from January 1, 1989, to June 3, 2005, were included in this report. Patients/Participants All 887 patients were diagnosed as having nonneuronopathic GD from birth to younger than 18 years and did not receive enzyme replacement therapy. Main Outcome Measures Eight measures of the clinical manifestations and demographics of nonneuronopathic GD. Results The most common signs and symptoms noted were splenomegaly (95%), hepatomegaly (87%), radiologic bone disease (81%), thrombocytopenia (50%), anemia (40%), growth retardation (34%), bone pain (27%), and bone crisis (9%). Anemia and more severe splenomegaly and hepatomegaly were observed more frequently in younger patients. Skeletal manifestations were found more often in older children. Only 23% were identified as Ashkenazi Jews. Conclusions Nonneuronopathic GD commonly manifests in childhood and affects many ethnic groups. The high prevalence of rare mutations may be associated with earlier onset and/or more severe disease. Increased awareness of the clinical and demographic characteristics of nonneuronopathic GD in children may improve early recognition of this treatable lysosomal storage disorder, decrease morbidity, and prevent irreversible sequelae.