Comprehensive and long-term outcomes of enzyme replacement therapy followed by stem cell transplantation in children with Gaucher disease type 1 and 3

Background

Gaucher disease (GD) is a lysosomal storage disorder, characterized by hepatosplenomegaly, pancytopenia, bone diseases, with or without neurological symptoms. Plasma glucosylsphingosine (lyso-Gb1), a highly sensitive and specific biomarker for GD, has been used for diagnosis and monitoring the response to treatment. Enzyme replacement therapy (ERT) is an effective treatment for the non-neurologic symptoms of GD. Neuronopathic GD (type 2 and 3) accounts for 60%–70% of the Asian affected population.

Methods

We explored combination therapy of ERT followed by hematopoietic stem cell transplantation (HSCT) and its long-term outcomes in patients with GD type 3 (GD3).

Results

Four patients with GD3 and one with GD type 1 (GD1) underwent HSCT. The types of donor were one matched-related, one matched-unrelated, and three haploidentical. The age at disease onset was 6–18 months and the age at HSCT was 3.8–15 years in the patients with GD3. The latest age at follow-up was 8–22 years, with a post-HSCT duration of 3–14 years. All patients had successful HSCT. Chronic graft-versus-host disease occurred in one patient. The enzyme activities were normalized at 2 weeks post HSCT. Lyso-Gb1 concentrations became lower than the pathological value. All of the patients are still alive and physically independent. Most of them (4/5) returned to school. None of the patients with GD3 had seizures or additional neurological symptoms after HSCT, but showed varying degrees of cognitive impairment.

Conclusions

ERT followed by HSCT could be considered as an alternative treatment for patients with GD3 who have a high risk of fatal neurological progression.     

Molecular characterization of type 3 (neuronopathic) Gaucher disease in Thai patients

Gaucher disease is an autosomal recessive lysosomal storage disorder due to deficiency of the lysosomal enzyme glucocerebrosidase. Three clinical phenotypes, type 1, nonneuronopathic; and types 2 and 3, acute and subacute neuronopathic are recognized. The incidence of Gaucher disease in the Thai population is unknown, but likely under-diagnosed. We performed molecular analysis in four patients, from three sibships, with type 3 Gaucher disease. Four mutant glucocerebrosidase (GBA) alleles were identified including two novel splice site mutations, IVS6-1G>C and IVS9-3C>G; both are predicted to result in truncated protein products, p.F255fsX256, and p.K464fsX487 and p.S463fsX480, respectively. One patient, homozygous for the L444P point mutation, had a "Norbottnian-like" phenotype, with more severe visceral involvement, kyphosis, barreled chest, and no neurological involvement other than supranuclear gaze palsy. These molecular studies of neuronopathic Gaucher disease will provide additional genotype-phenotype correlation particularly in non-Caucasian population.     

The molecular basis of mucopolysaccharidosis type I in two Thai patients

Two Thai patients diagnosed with Hurler syndrome (mucopolysaccharidosis type 1, MPS I) were found to have no detectable alpha-iduronidase (E.C. 3.2.1.76) activity in leukocytes, while normal Thai children all had significant activity, with a mean of 135 +/- 30 nmol/mg/18h. One patient was heterozygous for A75T (311G>A) and S633L (1986C>T) mutation, previously reported to cause MPS I, together with 9 other heterozygous polymorphisms also found in normal controls. The other patient had the previously described frameshift mutation 252insert C and a new nonsense mutation E299X (983G>T).     

Hb Kurosaki [alpha7(A5)Lys -->Glu (AAG --> GAG)]: an alpha2-globin gene mutation found in Thailand

Hb Kurosaki [alpha 7(A5)Lys --> Glu (AAG --> GAG)], has been found for the first time in Thailand. The 30-year-old Thai male had a normal hematological profile at the steady state, but showed an abnormal hemoglobin (Hb) present at a level of 28%. Protein characterization was performed by automated sequencer analysis of the abnormal alpha-globin chain and amino acid analysis of the abnormal alphaT-1,2 peptide. Direct DNA sequence analysis of selectively amplified segments of the alpha1 and alpha2 genes showed that codon 7 of the alpha2-globin gene was heterozygous for AAG (Lys) and GAG (Glu). This was confirmed by restriction endonuclease digestion with Eco31I.     

Two cases of compound heterozygosity for Hb Hekinan [alpha27(B8)Glu-->Asp (alpha1)] and alpha-thalassemia in Thailand

Two unrelated cases of compound heterozygosity for Hb Hekinan [alpha27(B8)Glu-->Asp (alpha1) and alpha-thalassemia have been found in Thailand. Mutations were established at protein level by peptide mapping and at the DNA level by direct sequence analysis. Proband S.S. had genotype - -SEA/alpha2(A)alpha1Hekinan, betaA/betaE, while an unrelated proband, S.J., is the first case described with the genotype - -SEA/alpha2(A)alpha1Hekinan, betaA/betaA. Both alpha1Hekinan mutations were located in the alpha1 locus. Hb Hekinan could not be accurately estimated by HPLC, since it was poorly separated from Hb A. However IEF gave good separation of Hb Hekinan and Hb A, leading to estimates of Hb Hekinan (alpha Hekinan 2/beta A 2 and alpha Hekinan 2/beta E 2) level as 40-43% of total Hb.     

Dietary Intake and Physical Activity of Thai Children and Adolescents with Type 1 Diabetes Mellitus

Appropriate dietary intake and physical activity (PA) are essential for glycemic control and optimal growth in youth with type 1 diabetes (T1D). Thus, this study aimed to compare dietary intake and PA between youth with T1D and healthy controls. One hundred Thai youth with T1D and 100 age-matched healthy participants were recruited. A 3-day food record was completed and converted into nutrient intake data. PA data were collected via interview. Participants with T1D had a significantly higher mean ± SD carbohydrate (50.8 ± 6.8% vs. 46.2 ± 7.5%, p < 0.01), lower fat (32.4 ± 5.9% vs. 35.9 ± 6.4%, p < 0.01), and lower protein (16.8 ± 2.6% vs. 17.9 ± 3.5%, p = 0.01) intake compared to controls. Fifty percent of T1D participants and 41% of control participants consumed saturated fat more than recommendations (p = 0.20). Participants with T1D had a higher median (IQR) calcium intake compared to controls (474 (297–700) vs. 328 (167–447) mg/day, p < 0.01). Both groups consumed less fiber and more sodium compared to recommendations. Both groups had inadequate PA. Participants with T1D had significantly less PA compared to controls (25 (13–48) vs. 34 (14–77) minutes/day, p = 0.04). In addition to the need for counseling that promotes consumption of more dietary fiber and calcium and less saturated fat and sodium, the benefits of performing regular exercise need to be emphasized among youth with T1D.