Thirty-year clinical outcomes after haematopoietic stem cell transplantation in neuronopathic Gaucher disease.

BACKGROUND: Neuronopathic Gaucher Disease (nGD) describes the condition of a subgroup of patients with the Lysosomal Storage Disorder (LSD), Gaucher disease with involvement of the central nervous system (CNS) which results from inherited deficiency of ß-glucosylceramidase. Although systemic manifestations of disease are now corrected by augmentation with macrophage-targeted therapeutic enzyme (enzyme replacement therapy, ERT), neurological disease progresses unpredictably as a result of failure of therapeutic enzyme to cross the blood-brain barrier (BBB). Without therapy, the systemic and neurological effects of the disease progress and shorten life: investigators, principally in Sweden and the UK, pioneered bone marrow transplantation (BMT; Haematopoietic Stem Cell Transplantation HSCT) to supply healthy marrow-derived macrophages and other cells, to correct the peripheral disease. Here we report the first long-term follow-up (over 20 years in all cases) of nine patients in the UK and Sweden who underwent HSCT in the 1970s and 1980s. This retrospective, multicentre observational study was undertaken to determine whether there are neurological features of Gaucher disease that can be corrected by HSCT and the extent to which deterioration continues after the procedure. Since intravenous administration of ERT is approved for patients with the neuronopathic disease and ameliorates many of the important systemic manifestations but fails to correct the neurological features, we also consider the current therapeutic positioning of HSCT in this disorder. RESULTS: In the nine patients here reported, neurological disease continued to progress after transplantation, manifesting as seizures, cerebellar disease and abnormalities of tone and reflexes. CONCLUSIONS: Although neurological disease progressed in this cohort of patients, there may be a future role for HSCT in the treatment of nGD. The procedure has the unique advantage of providing a life-long source of normally functioning macrophages in the bone marrow, and possibly other sites, after a single administration. HSCT moreover, clearly ameliorates systemic disease and this may be advantageous-especially where sustained provision of high-cost ERT cannot be guaranteed. Given the remaining unmet needs of patients with neuronopathic Gaucher disease and the greatly improved safety profile of the transplant procedure, HSCT could be considered to provide permanent correction of systemic disease, including bone disease not ameliorated by ERT, when combined with emerging therapies directed at the neurological manifestations of disease; this could include ex-vivo gene therapy approaches.

The definition of neuronopathic Gaucher disease.

Neuronopathic Gaucher disease (nGD) has a very wide clinical and genotypic spectrum. However, there is no consensus definition of nGD, including no description of how best to diagnostically separate the acute form-Gaucher type 2-from the subacute or chronic form-Gaucher type 3. In this article, we define the various forms of Gaucher disease with particular emphasis on the presence of gaze palsy in all patients with nGD. This consensus definition will help in both clinical diagnosis and appropriate patient recruitment to upcoming clinical trials.

Long-term hematological, visceral, and growth outcomes in children with Gaucher disease type 3 treated with imiglucerase in the International Collaborative Gaucher Group Gaucher Registry.

In Gaucher disease (GD), deficiency of lysosomal acid ß-glucosidase results in a broad phenotypic spectrum that is classified into three types based on the absence (type 1 [GD1]) or presence and severity of primary central nervous system involvement (type 2 [GD2], the fulminant neuronopathic form, and type 3 [GD3], the milder chronic neuronopathic form). Enzyme replacement therapy (ERT) with imiglucerase ameliorates and prevents hematological and visceral manifestations in GD1, but data in GD3 are limited to small, single-center series. The effects of imiglucerase ERT on hematological, visceral and growth outcomes (note: ERT is not expected to directly impact neurologic outcomes) were evaluated during the first 5years of treatment in 253 children and adolescents (<18years of age) with GD3 enrolled in the International Collaborative Gaucher Group (ICGG) Gaucher Registry. The vast majority of GBA mutations in this diverse global population consisted of only 2 mutations: L444P (77%) and D409H (7%). At baseline, GD3 patients exhibited early onset of severe hematological and visceral disease and growth failure. During the first year of imiglucerase treatment, hemoglobin levels and platelet counts increased and liver and spleen volumes decreased, leading to marked decreases in the number of patients with moderate or severe anemia, thrombocytopenia, and hepatosplenomegaly. These improvements were maintained through Year 5. There was also acceleration in linear growth as evidenced by increasing height Z-scores. Despite devastating disease at baseline, the probability of surviving for at least 5years after starting imiglucerase was 92%. In this large, multinational cohort of pediatric GD3 patients, imiglucerase ERT provided a life-saving and life-prolonging benefit for patients with GD3, suggesting that, with proper treatment, many such severely affected patients can lead productive lives and contribute to society.

Longitudinal analysis of endurance and respiratory function from a natural history study of Morquio A syndrome.

OBJECTIVES: Baseline data from the Morquio A Clinical Assessment Program (MorCAP) revealed that individuals with Morquio A syndrome show substantial impairment in multiple domains including endurance and respiratory function (Harmatz et al., Mol Genet Metab, 2013). Here, 1- and 2-year longitudinal endurance and respiratory function data are presented. METHODS: Endurance was assessed using the 6-minute walk test (6MWT) and the 3-minute stair climb test (3MSCT). Respiratory function was evaluated by measuring forced vital capacity (FVC) and maximum voluntary ventilation (MVV). Data were analyzed using repeated measures ANCOVA models. Annualized estimates of change were determined using model estimates and interpolation. RESULTS: 353, 184, and 78 subjects were assessed at Year 0 (baseline), Year 1, and Year 2, respectively. The overall annualized estimate of change (SE) in 6MWT distance was -4.86±3.25m; a larger decline of -6.84±5.38m was observed in the subset of subjects meeting the inclusion/exclusion criteria of the Phase 3 clinical trial of elosulfase alfa (≥5years of age with baseline 6MWT distance ≥30 and ≤325m). In contrast, little change (-0.14±0.60stairs/min) was observed in 3MSCT. Annualized changes (SE) in FVC and MVV were 2.44±0.68% and 1.01±2.38%, respectively. FVC and MVV increased in patients aged ≤14years, but decreased in older patients. CONCLUSIONS: The natural history of Morquio A syndrome is characterized by progressive impairment of endurance as measured by the 6MWT. Longitudinal trends in FVC and MVV showing increase in younger patients, but decrease in older patients, are likely to be influenced by growth. Changes in 6MWT may represent a sensitive measure of disease progression in ambulatory Morquio A patients.

Exome sequencing identifies CTSK mutations in patients originally diagnosed as intermediate osteopetrosis.

Autosomal Recessive Osteopetrosis is a genetic disorder characterized by increased bone density due to lack of resorption by the osteoclasts. Genetic studies have widely unraveled the molecular basis of the most severe forms, while cases of intermediate severity are more difficult to characterize, probably because of a large heterogeneity. Here, we describe the use of exome sequencing in the molecular diagnosis of 2 siblings initially thought to be affected by "intermediate osteopetrosis", which identified a homozygous mutation in the CTSK gene. Prompted by this finding, we tested by Sanger sequencing 25 additional patients addressed to us for recessive osteopetrosis and found CTSK mutations in 4 of them. In retrospect, their clinical and radiographic features were found to be compatible with, but not typical for, Pycnodysostosis. We sought to identify modifier genes that might have played a role in the clinical manifestation of the disease in these patients, but our results were not informative. In conclusion, we underline the difficulties of differential diagnosis in some patients whose clinical appearance does not fit the classical malignant or benign picture and recommend that CTSK gene be included in the molecular diagnosis of high bone density conditions.

The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects.

OBJECTIVES: The objectives of this study are to quantify endurance and respiratory function and better characterize spectrum of symptoms and biochemical abnormalities in mucopolysaccharidosis IVA subjects. METHODS: MorCAP was a multicenter, multinational, cross sectional study amended to be longitudinal in 2011. Each study visit required collection of medical history, clinical assessments, and keratan sulfate (KS) levels. RESULTS: Data from the first visit of 325 subjects (53% female) were available. Mean age was 14.5 years. Mean ± SD height z-scores were -5.6 ± 3.1 as determined by the CDC growth charts. Mean ± SD from the 6-minute-walk-test was 212.6 ± 152.2m, revealing limitations in functional endurance testing, and 30.0 ± 24.0 stairs/min for the 3-minute-stair-climb test. Respiratory function showed limitations comparable to MPS VI patients; mean ± SD was 1.2 ± 0.9l based on forced vital capacity and 34.8 ± 25.5l/min based on maximum voluntary ventilation. Mean urinary keratan sulfate (uKS) was elevated for all ages, and negatively correlated with age. Higher uKS correlated with greater clinical impairment based on height z-scores, endurance and respiratory function tests. The MPS Health Assessment Questionnaire reveals impairments in mobility and activities of daily living in comparison to an age-matched control population. CONCLUSIONS: MPS IVA is a multisystem disorder with a continuum of clinical presentation. All affected individuals experience significant functional limitations and reduced quality of life. Older patients have more severe exercise and respiratory capacity limitations, and more frequent cardiac pathology illustrating the progressive nature of disease.

SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity.

Human Autosomal Recessive Osteopetrosis (ARO) is a genetically heterogeneous disorder caused by reduced bone resorption by osteoclasts. In 2000, we found that mutations in the TCIRG1 gene encoding for a subunit of the proton pump (V-ATPase) are responsible for more than one-half of ARO cases. Since then, five additional genes have been demonstrated to be involved in the pathogenesis of the disease, leaving approximately 25% of cases that could not be associated with a genotype. Very recently, a mutation in the sorting nexin 10 (SNX10) gene, whose product is suggested to interact with the proton pump, has been found in 3 consanguineous families of Palestinian origin, thus adding a new candidate gene in patients not previously classified. Here we report the identification of 9 novel mutations in this gene in 14 ARO patients from 12 unrelated families of different geographic origin. Interestingly, we define the molecular defect in three cases of "Västerbottenian osteopetrosis," named for the Swedish Province where a higher incidence of the disease has been reported. In our cohort of more than 310 patients from all over the world, SNX10-dependent ARO constitutes 4% of the cases, with a frequency comparable to the receptor activator of NF-κB ligand (RANKL), receptor activator of NF-κB (RANK) and osteopetrosis-associated transmembrane protein 1 (OSTM1)-dependent subsets. Although the clinical presentation is relatively variable in severity, bone seems to be the only affected tissue and the defect can be almost completely rescued by hematopoietic stem cell transplantation (HSCT). These results confirm the involvement of the SNX10 gene in human ARO and identify a new subset with a relatively favorable prognosis as compared to TCIRG1-dependent cases. Further analyses will help to better understand the role of SNX10 in osteoclast physiology and verify whether this protein might be considered a new target for selective antiresorptive therapies.

Increased glucocerebrosidase (GBA) 2 activity in GBA1 deficient mice brains and in Gaucher leucocytes.

Lysosomal glucocerebrosidase (GBA1) deficiency is causative for Gaucher disease. Not all individuals with GBA1 mutations develop neurological involvement raising the possibility that other factors may provide compensatory protection. One factor may be the activity of the non-lysosomal ß-glucosidase (GBA2) which exhibits catalytic activity towards glucosylceramide and is reported to be highly expressed in brain tissue. Here, we assessed brain GBA2 enzymatic activity in wild type, heterozygote and GBA1 deficient mice. Additionally, we determined activity in leucocytes obtained from 13 patients with Gaucher disease, 10 patients with enzymology consistent with heterozygote status and 19 controls. For wild type animals, GBA2 accounted for over 85 % of total brain GBA activity and was significantly elevated in GBA1 deficient mice when compared to heterozygote and wild types (GBA1 deficient; 92.4 ± 5.6, heterozygote; 71.5 ± 2.4, wild type 76.8 ± 5.1 nmol/h/mg protein). For the patient samples, five Gaucher patients had GBA2 leucocyte activities markedly greater than controls. No difference in GBA2 activity was apparent between the control and carrier groups. Undetectable GBA2 activity was identified in four leucocyte preparations; one in the control group, two in the carrier group and one from the Gaucher disease group. Work is now required to ascertain whether GBA2 activity is a disease modifying factor in Gaucher disease and to identify the mechanism(s) responsible for triggering increased GBA2 activity in GBA1 deficiency states.

RANK-dependent autosomal recessive osteopetrosis: characterization of five new cases with novel mutations.

Autosomal recessive osteopetrosis (ARO) is a genetically heterogeneous disorder attributed to reduced bone resorption by osteoclasts. Most human AROs are classified as osteoclast rich, but recently two subsets of osteoclast-poor ARO have been recognized as caused by defects in either TNFSF11 or TNFRSF11A genes, coding the RANKL and RANK proteins, respectively. The RANKL/RANK axis drives osteoclast differentiation and also plays a role in the immune system. In fact, we have recently reported that mutations in the TNFRSF11A gene lead to osteoclast-poor osteopetrosis associated with hypogammaglobulinemia. Here we present the characterization of five additional unpublished patients from four unrelated families in which we found five novel mutations in the TNFRSF11A gene, including two missense and two nonsense mutations and a single-nucleotide insertion. Immunological investigation in three of them showed that the previously described defect in the B cell compartment was present only in some patients and that its severity seemed to increase with age and the progression of the disease. HSCT performed in all five patients almost completely cured the disease even when carried out in late infancy. Hypercalcemia was the most important posttransplant complication. Overall, our results further underline the heterogeneity of human ARO also deriving from the interplay between bone and the immune system, and highlight the prognostic and therapeutic implications of the molecular diagnosis.

Urine analysis of glucose tetrasaccharide by HPLC; a useful marker for the investigation of patients with Pompe and other glycogen storage diseases.

A high performance liquid chromatography method, adapted from an established urinary sugars method, has been developed for the analysis of a tetraglucose oligomer (Glc(4)) in urine. Pompe disease results from defects in the activity of lysosomal acid α-glucosidase (GAA) with patients typically excreting increased amounts of Glc(4). Rapid determination of GAA in dried blood spots is now possible. However, enzymatic analysis is unable to discriminate between patients with Pompe disease and those individuals harbouring pseudo deficiency mutations. This method was able to quantify Glc(4) levels in all patients analysed with an established diagnosis of Pompe disease, and all controls analysed had Glc(4) levels below the limit of detection for this method. Importantly the method was able to discriminate between an individual known to harbour a pseudo Pompe mutation and patients with Pompe disease, providing a useful supporting test to enzymatic analysis. Sequential measurement of urinary Glc(4) has been proposed to monitor the effects of enzyme replacement therapy (ERT). We observed a clear decrease in Glc(4) levels following commencement of treatment in three patients studied. Additionally, raised levels of Glc(4) were observed in patients with glycogen storage disease (GSD) type Ia and type III suggesting that this method may have applications in other GSDs.

Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure.

BACKGROUND: Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder that results in the accumulation of glycosaminoglycans causing progressive multi-organ dysfunction. Its clinical spectrum is very broad and varies from the severe Hurler phenotype (MPS I-H) which is characterized by early and progressive central nervous system (CNS) involvement to the attenuated Scheie phenotype (MPS I-S) with no CNS involvement. Indication, optimal timing, safety and efficacy of the two available treatment options for MPS I, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), are subject to continuing debate. A European consensus procedure was organized to reach consensus about the use of these two treatment strategies. METHODS: A panel of specialists, including 8 specialists for metabolic disorders and 7 bone marrow transplant physicians, all with acknowledged expertise in MPS I, participated in a modified Delphi process to develop consensus-based statements on MPS I treatment. Fifteen MPS I case histories were used to initiate the discussion and to anchor decisions around either treatment mode. Before and at the meeting all experts gave their opinion on the cases (YES/NO transplantation) and reasons for their decisions were collected. A set of draft statements on MPS I treatment options composed by a planning committee were discussed and revised during the meeting until full consensus. RESULTS: Full consensus was reached on several important issues, including the following: 1) The preferred treatment for patients with MPS I-H diagnosed before age 2.5 yrs is HSCT; 2) In individual patients with an intermediate phenotype HSCT may be considered if there is a suitable donor. However, there are no data on efficacy of HSCT in patients with this phenotype; 3) All MPS I patients including those who have not been transplanted or whose graft has failed may benefit significantly from ERT; 4) ERT should be started at diagnosis and may be of value in patients awaiting HSCT. CONCLUSIONS: This multidisciplinary consensus procedure yielded consensus on the main issues related to therapeutic choices and research for MPS I. This is an important step towards an international, collaborative approach, the only way to obtain useful evidence in rare diseases.

Four-year follow-up of chronic neuronopathic Gaucher disease in Europeans using a modified severity scoring tool.

In 2007, the European Task Force for neuronopathic Gaucher disease (NGD) published a review of 55 patients across four countries. Although some observations were possible, analysis was difficult due to the absence of a systematic way of assessing patients. In response to this, a Severity Scoring Tool (SST) was devised to offer a systematic means of assessing the neurological presentation seen. The SST has been modified (mSST) and is a valid tool for monitoring neurological progression. This review describes disease status and progression of neurological manifestations in a cohort of 39 chronic NGD patients across three European countries over a period of 4 years, using the mSST.

Treatment of mucopolysaccharidosis type II (Hunter syndrome) with idursulfase: the relevance of clinical trial end points.

The current treatment of mucopolysaccharidosis type II (MPS II, Hunter syndrome) is enzyme replacement therapy with recombinant idursulfase (Elaprase®). The efficacy of ERT was established based primarily on reduction in urine glycosaminoglycans:creatinine (GAG:Cr) ratio and improvement in a composite score of predicted forced vital capacity (FVC% predicted) and 6-min walk-test distance (6MWT). We retrospectively reviewed these parameters in 11 boys with MPS II treated with idursulfase between April 2007 (or the time of diagnosis) and February 2010. Some results were inconsistent with published trial data, and there was only a small number of analyzable results obtained for the FVC% predicted and 6MWT. A major drawback was the high prevalence of neurological involvement and young age of patients in the study cohort compared with the clinical trials. This study emphasizes the limitations of the current tools utilized to monitor ERT efficacy and MPS II disease burden in clinical practice.

Brain white matter abnormalities in paediatric Gaucher Type I and Type III using diffusion tensor imaging.

OBJECTIVE: Biomarkers to monitor neurological dysfunction in Neuronopathic Gaucher disease (NGD) are lacking. Diffusion tensor imaging (DTI) is a technique which allows us to probe the microstructure of the white-matter of the brain, in-vivo. The aim of this study was to investigate the value of DTI to visualise and quantify white matter integrity in children with NGD and Type I Gaucher. DESIGN: DTI was performed and fractional anisotropy (FA), mean diffusivity (MD), axial (λ(axial)) diffusivity and radial (λ(radial)) diffusivity maps calculated. Tract-based spatial statistics (TBSS) was used to perform a voxel-wise statistical analysis of the main white matter structures compared to age-sex matched control groups. SETTING: The study was performed at Great Ormond Street Children's Hospital NHS Trust PATIENTS: Four NGD and three Type I Gaucher paediatric patients were recruited RESULTS: The findings suggest the presence of microstructural white matter changes in NGD patients primarily in the middle cerebellar peduncles compared to an age-sex matched control group. This finding is relevant to the clinical manifestation of ataxia seen in NGD. Diffuse non-specific changes were seen in the Type I patients, but without a focal point. CONCLUSIONS: This study is the first to use DTI to examine the Gaucher brain. While the numbers studied are small, the results suggest that DTI may be an attractive surrogate marker of NGD, worthy of further exploration for use in clinical studies.

Idursulfase treatment of Hunter syndrome in children younger than 6 years: results from the Hunter Outcome Survey.

PURPOSE: To use the Hunter Outcome Survey, an international database, to assess the safety and effectiveness of enzyme replacement therapy with idursulfase in patients with Hunter syndrome who started treatment before 6 years of age. METHODS: The study population included all patients enrolled in the Hunter Outcome Survey who started idursulfase infusions (0.5 mg/kg every other week) before 6 years of age and who had at least one follow-up examination recorded. RESULTS: The study population included 124 patients, younger than 6 years, who had a mean age at start of idursulfase of 3.6 ± 1.6 years (mean ± SD). The mean duration of treatment was 22.9 ± 14.6 months. A total of 69 infusion-related reactions occurred in 33 (26.6%) patients, including three serious infusion-related reactions occurring in a single patient. After at least 6 months of idursulfase, urine glycosaminoglycan levels decreased from 592 ± 188 to 218 ± 115 µg/mg creatinine (P < 0.0001, n = 34). Liver size, estimated by palpation, was also significantly decreased (P = 0.005, n = 23). Similar safety and effectiveness results were seen in patients who were aged 6 years or older when initiating idursulfase. CONCLUSION: No new safety concerns were identified in patients younger than 6 years, and clinical benefit was suggested by the reduction in liver size.

Long-term, open-labeled extension study of idursulfase in the treatment of Hunter syndrome.

PURPOSE: This study evaluated the safety and effectiveness of long-term enzyme replacement therapy with idursulfase (recombinant human iduronate-2-sulfatase) in patients with Hunter syndrome. METHODS: All 94 patients who completed a 53-week double-blinded study of idursulfase enrolled in this open-labeled extension study and received intravenous idursulfase at a dose of 0.5 mg/kg weekly for 2 years, and clinical outcomes and safety were assessed. RESULTS: No change in percent predicted forced vital capacity was seen, but absolute forced vital capacity demonstrated sustained improvement and was increased 25.1% at the end of the study. Statistically significant increases in 6-minute walking test distance were observed at most time points. Mean liver and spleen volumes remained reduced throughout the 2-year extension study. Mean joint range of motion improved for the shoulder and remained stable in other joints. Both the parent- and child-assessed Child Health Assessment Questionnaire Disability Index Score demonstrated significant improvement. Infusion-related adverse events occurred in 53% of patients and peaked at Month 3 of treatment and declined thereafter. Neutralizing IgG antibodies were detected in 23% of patients and seemed to attenuate the improvement in pulmonary function. CONCLUSIONS: Weekly infusions of idursulfase result in sustained clinical improvement during 3 years of treatment.

Treatment of infantile Pompe disease with alglucosidase alpha: the UK experience.

Treatment of infantile Pompe disease with recombinant human acid α-glucosidase has shown substantial improvement in survival, and in cardiac, motor and respiratory functions. We analyzed the outcome of all patients with infantile Pompe disease treated in the United Kingdom since the availability of the enzyme, using a questionnaire-based survey circulated to all treating centres. A total of 20 infants were treated from 2000 to 2009. Median ages at diagnosis and treatment were 5.75 months (range 0.25-31 months) and 6.5 months (0.5-32 months), respectively. Median duration of treatment was 31 months (1-102 months). Overall ventilator-free survival was 35% (7/20 infants), while 35% (7/20) died at a median age of 10 months (5.75-15 months) and 30% (6/20) were alive but ventilator-dependent. Endotracheal intubation for acute deterioration carried a high risk of failure of extubation and progression to long-term ventilation (LTV), but elective general anaesthesia, in contrast, was well tolerated. Overall outcome was worse than in the pivotal clinical trials; possible causes include later diagnosis and treatment in our patients and a higher incidence of infants at the severe end of the clinical spectrum. Careful consideration must be given to all possible outcomes, including LTV, before commencing enzyme replacement therapy in newly diagnosed infants.

Pulmonary hemorrhage in type 3 Gaucher disease: a case report.

A 2-year-old boy with type 3 Gaucher disease (GD) on treatment with enzyme replacement therapy (ERT) was found dead in bed having been apparently well the night before. At the time of diagnosis, he had significant respiratory symptoms (severe and persistent bouts of coughing) that had been attributed to Gaucher lung infiltration and that were controlled by inhaled and orally administered steroids. These symptoms had begun to reappear just prior to death. Postmortem revealed extensive pulmonary hemorrhage and intra-alveolar collections of Gaucher cells. There was very little evidence of GD elsewhere. Death was ascribed to pulmonary hemorrhage secondary to GD. The pathogenesis was unclear. To the best of our knowledge, this is the first case of isolated pulmonary hemorrhage secondary to GD and may represent a hitherto unrecognized complication of this condition. Given the apparent temporal relationship, we propose that it represented a severe, terminal event in the course of Gaucher lung disease.

Neuronopathic Gaucher disease: demographic and clinical features of 131 patients enrolled in the International Collaborative Gaucher Group Neurological Outcomes Subregistry.

OBJECTIVE: To describe demographic, genetic, and clinical characteristics of patients with neuronopathic Gaucher disease (NGD). METHODS: All patients enrolled in the Neurological Outcomes Subregistry of the International Collaborative Gaucher Group (ICGG) Gaucher Registry as of June 2007 were identified. RESULTS: The study cohort comprised 131 patients from 17 countries who were enrolled in the Neurological Outcomes Subregistry. The onset of neurological manifestations had occurred before 2 years of age in 47% (61 out of 131 patients), 2 years of age or older in 41% (54 out of 131), and could not be ascertained in the remaining 12% (16 out of 131). The most common manifestations were inability to look to the extreme up or down (45%, 55 out of 123), abnormally slow object tracking (43%, 53 out of 123), convergent squint (36%, 44 out of 121), and ataxia (15 to 20%, 18-27 out of 117). Seizures were reported in 19 out of 122 patients (16%), and myoclonic seizures were reported in 3 out of 121 patients (2%). The most common genotypes were L444P/L444P (76 out of 108, 70%), L444P/D409H (9 out of 108, 8%), D409H/D409H (8 out of 108, 7%), and L444P/rare allele (6 out of 108, 6%); full sequencing was not performed in all patients. CONCLUSIONS: Neurological manifestations of GD often begin to appear before the age of 2 years. The most common neurological signs and manifestations are brainstem abnormalities and fine motor dysfunction. The most common genotype is L444P/L444P.