Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease.

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when ≥75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account.

The associations between the changes in serum inflammatory markers and bone mineral accrual in boys with overweight and obesity during pubertal maturation: a 3-year longitudinal study in Estonian boys.

Adipose tissue produces different inflammatory cytokines which compromise bone mineral accrual during puberty. Vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), interleukin (IL)-8, and interferon-gamma (IFN-γ) are significantly related to bone mineral accrual during pubertal maturation in boys with different BMI values. INTRODUCTION: This longitudinal study aims to identify the inflammatory markers that most strongly associate with pubertal bone mineral density (BMD) increment in boys with overweight and obesity (OWB). METHODS: Twenty-six OWB and 29 normal-weight boys were followed yearly for 3 years to measure changes in 12 serum inflammatory markers, BMD (by DXA), and apparent volumetric BMD. The OWB group was further divided into two subgroups according to their BMI gain during the 3-year period. Data through time points presented as slopes were used to calculate correlation coefficients to explore the possible relationships between variables of interest. In the whole study group, linear mixed effects (LME) models were also used. RESULTS: Increment in serum VEGF concentration was inversely associated with an increase in total body (TB) BMD (r = - 0.82, P = 0.02) and TB bone mineral content (BMC)/height (r = - 0.82, P = 0.02) in those OWB whose BMI gain was higher during pubertal years. In the whole study group, the LME model confirmed the inverse association between VEGF and TB BMC/height (P < 0.05). EGF was inversely associated with LS BMD and LS BMAD (P < 0.05), whereas there was a positive association between IL-8 and TB BMAD and between IFN-γ and LS BMD (P < 0.05). CONCLUSIONS: Lower increment in BMD in OWB with higher BMI gain is associated with increasing serum VEGF concentration during pubertal maturation. VEGF, EGF, IL-8, and IFN-γ are significantly associated with BMD during pubertal maturation in boys with different BMI values.

Evaluation of treatment response to enzyme replacement therapy with Velaglucerase alfa in patients with Gaucher disease using whole-body magnetic resonance imaging.

OBJECTIVE: This was a retrospective data analysis to evaluate the treatment response to enzyme replacement therapy (ERT) with Velaglucerase alfa using whole-body magnetic resonance imaging (MRI). MATERIALS AND METHODS: A baseline and follow-up MRI were performed on 18 Gaucher Type 1 patients at an interval of 11.6 months. The MRI score systems determined the Bone-Marrow-Burden (BMB) score, the Düsseldorf-Gaucher score (DGS), and the Vertebra-Disc-Ratio (VDR). The Severity Score Index Type 1 (GD-DS3) was also assessed. RESULTS: The baseline MRI medians were: BMB, 7.00; DGS, 3.00; and VDR: 1.70; while, the follow-up MRI medians were: BMB, 7.00; DGS, 3.00; and VDR: 1.73. The baseline GD-DS3 median was 2.40 (BMB excl.: 0.50) and the follow-up median was 2.00 (BMB excl.: 0.50). There was weak statistical significance with the Wilcoxon signed-rank test for the DGS (p=0.034) and GD-DS3 (p=0.047) between both MRIs. CONCLUSION: Velaglucerase alfa therapy is a effective long-term treatment for Gaucher Type 1 patients who are newly diagnosed or switching therapies. Measurements with whole-body MRI and an objective scoring system were reliable tools for detecting early stage bone marrow activity. Further research is needed to evaluate the "Booster-Effect" of Velaglucerase alfa therapy in Gaucher skeletal disease.

Sleep-related symptoms and sleep-disordered breathing in adult Pompe disease.

BACKGROUND AND PURPOSE: Respiratory muscle weakness is the major cause of early death in patients with adult Pompe disease. It first manifests as nocturnal hypercapnia, eventually leading to sleep disruption. Sleep-related symptoms along with motor performance, forced vital capacity (FVC) and respiratory symptoms were investigated in 65 adult patients with Pompe disease. METHODS: Patients answered the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale, the Fatigue Severity Scale, the Rotterdam Nine-item Handicap Scale, the SF-36 health-related quality of life questionnaire, and a respiratory symptom questionnaire. In all patients, the 6-min walk test was performed and FVC was obtained. Polysomnography and oxycapnometry results were available in 31 patients. RESULTS: Sixty patients received enzyme replacement therapy, and 32 individuals were on home ventilatory support. Reduced sleep quality was highly prevalent (PSQI > 5; 43.1%) and correlated with both excessive daytime sleepiness (Epworth Sleepiness Scale > 10; 24.6%) and fatigue (Fatigue Severity Scale > 4; 72.3%). The SF-36 health-related quality of life questionnaire was reduced in the physical domains, and was inversely correlated with sleep quality, FVC and motor performance. In 11 out of 17 non-ventilated patients with polysomnography records, sleep-disordered breathing was present, and duration of nocturnal oxygen desaturation (SaO2 < 90%) was significantly correlated to the PSQI global score. CONCLUSIONS: In adult Pompe disease, sleep disturbances are a common cause of excessive daytime sleepiness and fatigue. Sleep-related symptoms may be indicative of respiratory muscle weakness and should give rise to further work-up of sleep-disordered breathing.

[Diagnosis and therapy of late onset Pompe disease]. / Diagnose und Therapie des Late-onset-Morbus-Pompe.

As Pompe disease glycogen storage disease type 2 with a severely reduced life expectancy is now a treatable disorder, accurate diagnostic procedures and evidence-based indications for therapy are mandatory. We screened the literature for consensus reports and published trial data of late-onset Pompe disease. These data were summarized in a Delphi consensus method approach. The clinical suspicion of late-onset Pompe disease should be substantiated by the validated dry blood spot test measurement for acid α-glucosidase activity. Alternatively, enzyme activity analysis in lymphocytes is also feasible. Glucosidase α gene sequencing for verifying the diagnosis is recommended. A muscle biopsy including measurements of acid α-glucosidase activity and glycogen concentration is warranted for differential diagnosis in selected cases. The confirmed diagnosis should lead to a multidisciplinary treatment approach, possibly including enzyme replacement therapy.

Miglustat in patients with Niemann-Pick disease Type C (NP-C): a multicenter observational retrospective cohort study.

Miglustat has been shown to stabilize disease progression in children, juveniles and adults with Niemann-Pick disease type C (NP-C), a rare genetic disorder characterized by progressive neurological deterioration. We report findings from a retrospective observational cohort study assessing the effects of miglustat on neurological disease progression in patients treated in the clinical practice setting. Data from all NP-C patients prescribed miglustat at 25 expert centers were evaluated using a disease disability scale. The scale analyzed four key parameters of neurological disease progression in NP-C (ambulation, manipulation, language, swallowing). Mean individual parameter scores and a composite score were calculated at baseline (time of diagnosis) and up to 4 follow-up visits. Overall, 66 patients were included (mean [SD] age at diagnosis, 9.7 [7.6] years, and at treatment start, 12.8 [9.5] years). The median (range) miglustat exposure was 1.46 (0.05-4.51) years. Mean annual progression was +0.11 score units/year from diagnosis to treatment start, indicating disease progression prior to therapy, and decreasing to -0.01 score units/year from treatment start to last clinic visit, indicating stabilization. Stabilization of neurological disease on miglustat was observed in all age groups, but the magnitude of the effect was greater in patients diagnosed in late childhood and in juveniles and adults. Stabilization of neurological disease was also observed in a subset of 19 patients with extended pre-treatment information. Overall, these data support previous clinical trial findings indicating clinically relevant beneficial effects of miglustat on neurological disease progression in patients with NP-C.

Scheie syndrome: enzyme replacement therapy does not prevent progression of cervical myelopathy due to spinal cord compression.

Hurler-Scheie syndrome is caused by alpha-l-iduronidase deficiency. Enzyme replacement therapy (ERT) can improve physical capacity and reduces organomegaly. However, the effect on bradytrophic connective tissue is limited. As intravenously administered enzyme cannot cross the blood-brain barrier, the therapy of choice for the more severe Hurler syndrome is haematopoietic stem cell transplantation (HCT). In the more attenuated Scheie syndrome, neurological impairment is less severe; therefore, ERT may be appropriate to treat these patients. Information on long-term outcome in Scheie patients undergoing ERT is scarce. We report a 38-year-old female Scheie patient who has been on ERT for 8 years. While non-neurological symptoms improved, she developed paresthesias in her hands and feet and progressive pain in her legs. Somatosensory evoked potentials were abnormal, suggesting dysfunction of the dorsal funiculus and lemniscus medialis. After 6 years of ERT, a spinal MRI showed dural thickening at the upper cervical spine. These soft-tissue deposits are presumably due to the accumulation of mucopolysaccharides. Intramedullary hyperintensities at the level of C1/2 revealed cervical myelopathy. An MRI before the start of ERT had shown milder spinal lesions. Cystic lesions in the white matter of the centrum semiovale due to dilated Virchow-Robin spaces were essentially unchanged compared with the MRI scan before ERT. Decompression of the spinal cord resulted in clinical improvement. In an adult patient with Scheie syndrome, ERT failed to prevent progression of cervical myelopathy. Clinical significance of cerebral changes is unclear. Whether early HCT or intrathecal ERT could have prevented these lesions remains speculative.

Management of neuronopathic Gaucher disease: revised recommendations.

The original guidelines drawn up for the management of the neuronopathic forms of Gaucher disease were felt to be in need of revision; in particular, the role of high-dose enzyme replacement therapy (120 IU/kg of body weight every 2 weeks) in stabilizing neurological disease. The existing published evidence was analysed; it was concluded that it did not support the role of high-dose ERT, although this might be required to treat severe visceral disease.

Methods for a prompt and reliable laboratory diagnosis of Pompe disease: report from an international consensus meeting.

Pompe disease is an autosomal recessive disorder of glycogen metabolism caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). It presents at any age, with variable rates of progression ranging from a rapidly progressive course, often fatal by one-year of age, to a more slowly, but nevertheless relentlessly progressive course, resulting in significant morbidity and premature mortality. In infants, early initiation of enzyme replacement therapy is needed to gain the maximum therapeutic benefit, underscoring the need for early diagnosis. Several new methods for measuring GAA activity have been developed. The Pompe Disease Diagnostic Working Group met to review data generated using the new methods, and to establish a consensus regarding the application of the methods for the laboratory diagnosis of Pompe disease. Skin fibroblasts and muscle biopsy have traditionally been the samples of choice for measuring GAA activity. However, new methods using blood samples are rapidly becoming adopted because of their speed and convenience. Measuring GAA activity in blood samples should be performed under acidic conditions (pH 3.8-4.0), using up to 2 mM of the synthetic substrate 4-methylumbelliferyl-alpha-D-glucoside or glycogen (50 mg/mL), in the presence of acarbose (3-9 microM) to inhibit the isoenzyme maltase-glucoamylase. The activity of a reference enzyme should also be measured to confirm the quality of the sample. A second test should be done to support the diagnosis of Pompe disease until a program for external quality assurance and proficiency testing of the enzymatic diagnosis in blood is established.

Direct comparison of enzyme measurements from dried blood and leukocytes from male and female Fabry disease patients.

Anderson-Fabry disease is an X-linked disorder that is caused by deficiency of the lysosomal enzyme alpha-galactosidase A. Symptoms include chronic progressive painful small-fibre neuropathy, cornea verticillata, renal failure and heart disease. Interestingly, female heterozygous patients may also show severe symptoms. After clinical suspicion, usually the determination of alpha-galactosidase activity in leukocytes is requested first. Alternatively, an enzymatic assay using dried blood specimens has been described. Dried blood samples require less material and are substantially more stable (several months at room temperature) than whole-blood specimens. To validate the new method and to asses its usefulness for diagnosis of female patients, enzyme activities of alpha-galactosidase, beta-galactosidase and beta-glucuronidase from 78 known Fabry patients were compared (29 males, 47 females) between both materials. In summary, the determination of alpha-galactosidase activity using dried blood and leukocytes as well as the ratio of alpha-galactosidase to beta-glucuronidase in dried blood can improve the diagnostic specificity in cases of female patients who are difficult to identify when only leukocyte enzyme activities are considered.

Outcome of type III Gaucher disease on enzyme replacement therapy: review of 55 cases.

The European Task Force for Neuronopathic Gaucher Disease (NGD) met in 2006 to review its 2001 guidelines. Fifty-five patients from five European countries were reviewed; 29 were male and 26 female. The majority of the patients were homozygous for the L444P mutation. All had been on enzyme replacement therapy (ERT). However, there was considerable variation in the dose of ERT, as well as an uneven distribution of risk factors. Thus, the oldest patients were on the lowest doses, and several had had a total splenectomy, while the youngest patients had a high proportion of compound heterozygosity and were on the highest doses, and very few had had a splenectomy. This heterogeneity rendered analysis very difficult. However, some observations were possible. The older patients appeared to remain relatively stable despite a low dose of ERT. In the younger patients, there was no clear effect of high-dose ERT. However, the period of follow-up was too short in many patients to draw valid conclusions. These data will be used to draw up revised guidelines.

Childhood Pompe disease: clinical spectrum and genotype in 31 patients.

BACKGROUND: As little information is available on children with non-classic presentations of Pompe disease, we wished to gain knowledge of specific clinical characteristics and genotypes. We included all patients younger than 18 years, who had been evaluated at the Pompe Center in Rotterdam, the Netherlands, between 1975 and 2012, excluding those with the classic-infantile form. None were treated with enzyme replacement therapy at the time of evaluation. We collected information on first symptoms, diagnosis, use of a wheelchair and/or respirator, and enzyme and mutation analysis and assessed muscle strength, pulmonary function, and cardiac parameters. RESULTS: Thirty-one patients participated. Median age at symptom onset was 2.6 years (range 0.5-13y) and at diagnosis 4.0 years. Most first problems were delayed motor development and problems related to limb-girdle weakness. Fatigue, persistent diarrhea and problems in raising the head in supine position were other first complaints. Ten patients were asymptomatic at time of diagnosis. Five of them developed symptoms before inclusion in this study. Over 50 % of all patients had low or absent reflexes, a myopathic face, and scoliosis; 29 % were underweight. Muscle strength of the neck flexors, hip extensors, hip flexors, and shoulder abductors were most frequently reduced. Pulmonary function was decreased in over 48 % of the patients; 2 patients had cardiac hypertrophy. Patients with mutations other than the c.-32-13T > G were overall more severely affected, while 18 out of the 21 patients (86 %) with the c.-32-13T > G/'null' genotype were male. CONCLUSIONS: Our study shows that Pompe disease can present with severe mobility and respiratory problems during childhood. Pompe disease should be considered in the differential diagnosis of children with less familiar signs such as disproportional weakness of the neck flexors, unexplained fatigue, persistent diarrhea and unexplained high CK/ASAT/ALAT. Disease presentation appears to be different from adult patients. The majority of affected children with GAA genotype c.-32-13T > G/'null' appeared to be male.

Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3ß,5α,6ß-Triol and Further Insight into the Clinical Phenotype.

INTRODUCTION: Niemann-Pick type C disease is a rare disorder caused by impaired intracellular lipid transport due to mutations in either the NPC1 or the NPC2 gene. Ninety-five % of NPC patients show mutations in the NPC1 gene. A much smaller number of patients suffer from NPC2 disease and present respiratory failure as one of the most frequent symptoms. Several plasma oxysterols are highly elevated in NPC1 and can be used as a biomarker in the diagnosis of NPC1. METHODS: Plasma cholestane-3ß,5α,6ß-triol was evaluated as biomarker for NPC2 by GC/MS and LC-MS/MS analysis. The diagnosis was confirmed by Sanger sequencing and filipin staining. RESULTS: We report three NPC2 patients with typical respiratory problems and a detailed description of the nature of the lung disease in one of them. All patients had elevated levels of plasma cholestane-3ß,5α,6ß-triol. In two of these patients, the positive oxysterol result led to a rapid diagnosis of NPC2 by genetic analysis. The phenotype of the third patient has been described previously. In this patient a cholestane-3ß,5α,6ß-triol concentration markedly above the reference range was found. CONCLUSIONS: Measurement of plasma cholestane-3ß,5α,6ß-triol enables to discriminate between controls and NPC1 and NPC2 patients, making it a valuable biomarker for the rapid diagnosis not only for NPC1 but also for NPC2 disease.The measurement of oxysterols should be well kept in mind in the differential diagnosis of lysosomal diseases, as the elevation of oxysterols in plasma may speed up the diagnosis of NPC1 and NPC2.

Bone complications in children with Gaucher disease.

For paediatric patients with Gaucher disease, enzyme replacement therapy (ERT) has the potential to prevent the development of serious, irreversible skeletal complications. Analysis of skeletal data for paediatric patients receiving ERT must take into account the pubertal growth spurt and developmental changes in bone marrow composition. In a study conducted at the Burlo Garofolo Institute in Trieste, Italy, 10 paediatric patients have received ERT, and data are available for 3-9 years of follow-up. ERT was associated with a significant increase in the mean lumbar bone mineral density (BMD) Z score after 2 years of treatment (p=0.003). Skeletal growth rates increased among patients exhibiting growth delays. At the Gaucher Disease Treatment Center in Cincinnati, OH, USA, a total of 11 paediatric patients have been followed for 2 years or more of ERT. Of these 11 patients, 6 have demonstrated significant increases in lumbar BMD after 2 years of ERT; these patients tended to have lower BMD Z scores at the start of ERT. At the Children's Hospital of the Johannes-Gutenberg University in Mainz, Germany, 7 children with type 1 Gaucher disease presented with reduced BMD in the distal ulna, and after 18-24 months of ERT, these patients demonstrated increases in BMD at this site. The patients exhibiting growth retardation experienced growth acceleration during treatment. These studies suggest that ERT improves BMD and growth rates in paediatric patients with Gaucher disease. ERT in paediatric patients may have the potential to prevent serious skeletal complications such as fractures and vertebral compression later in life.

[Enzyme replacement therapy: a new treatment concept in Gaucher disease]. / Enzym-Ersatz-Therapie: Ein neues Behandlungsprinzip bei M. Gaucher.

Until recently the treatment of lysosomal storage disorders was entirely supportive. A new enzyme replacement therapy has become available in Gaucher's disease, a lipid storage disorder that is due to a genetic defect of beta-glucocerebrosidase. Intravenous infusions of modified beta-glucocerebrosidase has produced clinical improvement in Gaucher patients, with regression of organomegaly and increase in blood counts. At the Children's Hospital of Mainz 13 patients (6 children and 7 adults) were treated with alglucerase on a high-dosage regimen (60 units per kilogram every two weeks). A decrease in liver and spleen size was observed 4 to 6 months after commencement of therapy. Hemoglobin and the number of platelets increased. In some cases, a reduction of the dosage was possible after a year of enzyme replacement-therapy. A growth spurt was observed in the children. The availability of enzyme replacement therapy is limited by its high cost; however, in the future gene transfer may become the treatment of choice.

[Diagnosis and therapy of Gaucher disease. Current recommendations of German therapy centers in the year 2000]. / Diagnose und Therapie des Morbus Gaucher. Aktuelle Empfehlungen der deutschen Therapiezentren im Jahr 2000.

BACKGROUND: Gaucher's disease is the autosomally recessively inherited deficiency of the lysosomal enzyme glucocerebrosidase. Increasing storage of glucocerebrosides leads to a multisystem disease, the prevalence of which is about 1:40,000 in central Europe and up to 1:2,000 in some other countries (e.g. Israel). The acute and chronic neuronopathic forms of the disease (formerly defined as Gaucher types 2 and 3) account for only 5 to 10% of all Gaucher patients in Central Europe and Germany and are thus less frequent than the non-neuronopathic disease (formerly defined as Gaucher type 1). Gaucher's disease is usually associated with spleno- and hepatomegaly, fatigue, skeletal complications, and several corresponding hematological and laboratory abnormalities. In 5 to 10% of the patients there are also central nervous symptoms such as myoclonic seizures, oculomotoric apraxia and a slight mental retardation. METHODS: Four specialized centers care for more than 2/3 of all German Gaucher patients today. These centers present their consensus recommendations for state-of-the-art diagnosis and treatment of Gaucher's disease. RESULTS: Recent epidemiological data indicate that only 10 to 20% of all Gaucher patients are correctly diagnosed (and treated) in Germany. The diagnosis today can be done in all patients by noninvasive methods, i.e. determination of the glucocerebrosidase activity in peripheral leukocytes and of the genetic defect. The current enzyme replacement therapy with glucocerebrosidase has proven effective to improve and often normalize hematological abnormalities, hepatosplenomegaly, skeletal complications and quality of life, provided that the therapy is started early and is given at adequate dosages. CONCLUSION: In view of the availability of an effective therapy, efforts should be made to increase the awareness of Gaucher's disease in differential diagnosis, to help to diagnose the disease with noninvasive techniques at early stages, and to provide practical guidelines for adequate treatment.

Enzyme replacement therapy with alglucosidase alfa in 44 patients with late-onset glycogen storage disease type 2: 12-month results of an observational clinical trial.

Late-onset glycogen storage disease type 2 (GSD2)/Pompe disease is a progressive multi-system disease evoked by a deficiency of lysosomal acid alpha-glucosidase (GAA) activity. GSD2 is characterized by respiratory and skeletal muscle weakness and atrophy, resulting in functional disability and reduced life span. Since 2006 alglucosidase alfa has been licensed as a treatment in all types of GSD2/Pompe disease. We here present an open-label, investigator-initiated observational study of alglucosidase alfa enzyme replacement therapy (ERT) in 44 late-onset GSD2 patients with various stages of disease severity. Alglucosidase alfa was given i.v. at the standard dose of 20 mg/kg every other week. Assessments included serial arm function tests (AFT), Walton Gardner Medwin scale (WGMS), timed 10-m walk tests, four-stair climb tests, modified Gowers' maneuvers, 6-min walk tests, MRC sum score, forced vital capacities (FVC), creatine kinase (CK) levels and SF-36 self-reporting questionnaires. All tests were performed at baseline and every 3 months for 12 months of ERT. We found significant changes from baseline in the modified Gowers' test, the CK levels and the 6-min walk test (341 +/- 149.49 m, median 342.25 m at baseline; 393 +/- 156.98 m; median 411.50 m at endpoint; p = 0.026), while all other tests were unchanged. ERT over 12 months revealed minor allergic reactions in 10% of the patients. No serious adverse events occurred. None of the patients died or required de novo ventilation. Our clinical outcome data imply stabilization of neuromuscular deficits over 1 year with mild functional improvement.

The ratio of alpha-galactosidase to beta-glucuronidase activities in dried blood for the identification of female Fabry disease patients.

Female heterozygous patients with Fabry disease are difficult to identify because of the relatively high residual activity of alpha-galactosidase. We systematically evaluated the activities of various lysosomal enzymes in dried blood samples from Fabry patients and found that the beta-glucuronidase activity was frequently elevated. The ratio of alpha-galactosidase to beta-glucuronidase proved to be a helpful tool for the diagnosis of female Fabry disease patients.