Carla E. M. Hollak

The Dutch Fabry cohort: Diversity of clinical manifestations and Gb3 levels

SummaryBackground: Fabry disease (OMIM 301500) is an X-linked lysosomal storage disorder with characteristic vascular, renal, cardiac and cerebral complications. Globotriaosylceramide (Gb3) accumulates in Fabry patients as a result of α-galactosidase A deficiency. The phenotypic variability is high, but the relationship between clinical symptoms in individual Fabry patients has not been uniformly documented. Also, the relation between the most prominent biochemical abnormalities, elevated Gb3 levels in plasma and urine, and clinical symptoms is not firmly established. Methods: Clinical and biochemical characteristics of 96 (25 deceased) Dutch Fabry patients were collected retrospectively and before the initiation of enzyme therapy. Results: Clinical assessment revealed that median life expectancy was 57 years for male and 72 years for female patients. Cerebral complications, acroparaesthesias and gastrointestinal complications, but not cardiac and auditory complications, were all seen more frequently in male than female patients. Glomerular filtration rate (GFR) was highly variable in male patients, including 2 patients with GFR < 30 ml/min, but median GFR did not differ between males and females (103 and 101 ml/min, respectively). Hyperfiltration was more frequently observed in the female patient group. Microalbuminuria was present in 60% of males and 45% of females. No specific pattern of combined symptoms existed except for a relationship between left ventricular hypertrophy (LVH) and cerebral complications (males 36%, females 32%), or proteinuria (males 35%, females 31%). Gb3 was found to be more elevated in plasma samples from male (n = 26; median 6.27 μmol/L (1.39–9.74)) than female Fabry patients (n = 37; median 2.16 (0.77–4.18)). This was also observed for urinary Gb3: males (n = 22) median 1851 nmol/24 h (40–3724); females (n = 29) median 672 (86–2052). Plasma and urinary Gb3 levels correlated with each other in both males (r = 0.4, p = 0.05) and females (r = 0.4, p = 0.03), but no correlation between elevated Gb3 levels and clinical symptoms could be detected. Conclusion: Analysis of the characteristics of the Dutch Fabry cohort has revealed that a limited relationship between various disease manifestations exists and that individual symptoms do not correlate with elevated urinary or plasma Gb3 levels, limiting their value as surrogate disease markers.

Long term enzyme replacement therapy for Fabry disease: effectiveness on kidney, heart and brain

BackgroundFabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency leading to renal, cardiac, cerebrovascular disease and premature death. Treatment with α-galactosidase A (enzyme replacement therapy, ERT) stabilises disease in some patients, but long term effectiveness is unclear.MethodsRenal, cardiac, and cerebral outcomes were prospectively studied in males and females with Fabry disease treated with ERT. Additionally, the occurrence of major cardiac events, stroke, end-stage renal disease and death was compared to a natural history (NH) cohort meeting treatment criteria.ResultsOf 75 patients on ERT (median treatment duration 5.2 years, range 0.05-11.0), prospective follow-up was available for 57 adult patients (30 males) and 6 adolescents. Renal function declined in males (-3.4 ml/min/1.73 m2 per year, SE 0.2; pu2009<u20090.001) despite ERT, but followed the normal course in females (-0.8 ml/min/1.73 m2 per year, SE 0.3; pu2009=u20090.001). Cardiac mass increased during ERT in males (+ 1.2 gram/m2.7, SE 0.3; pu2009<u20090.001), but remained stable in females (-0.3 gram/m2.7 per year, SE 0.4; pu2009=u20090.52). ERT did not prevent the occurrence of cerebral white matter lesions. Comparison of ERT treated to untreated patients revealed that the odds to develop a first complication increased with age (OR 1.05 (95% CI: 1.0-1.1) per year, pu2009=u20090.012). For development of a first or second complication the odds declined with longer treatment duration (OR 0.81 (95% CI: 0.68-0.96) per year of ERT, pu2009=u20090.015;OR 0.52 (0.31-0.88), pu2009=u20090.014 respectively).ConclusionsLong term ERT does not prevent disease progression, but the risk of developing a first or second complication declines with increasing treatment duration. ERT in advanced Fabry disease seems of doubtful benefit.

Recommendations for the management of the haematological and onco-haematological aspects of Gaucher disease

Current knowledge of the haematological and onco‐haematological complications of type 1 Gaucher disease has been reviewed with the aim of identifying best clinical practice for treatment and disease management. It was concluded that: (i) Awareness of typical patterns of cytopenia can help clinicians distinguish haematological co‐morbidities. (ii) Red blood cell studies and complete iron metabolism evaluation at baseline are recommended. (iii) Haemoglobin levels defining anaemia should be raised and used in Gaucher disease treatment and monitoring. (iv) Surgeons should be aware of potential bleeding complications during surgery in Gaucher patients.

Natural course of Fabry disease and the effectiveness of enzyme replacement therapy: a systematic review and meta-analysis: effectiveness of ERT in different disease stages.

ObjectiveCurrent available evidence on long-term effectiveness of enzyme replacement therapy (ERT) for Fabry disease is limited. More insight is needed whether ERT effectiveness differs in patients with and without baseline end-organ damage.DesignThrough a systematic review, untreated and ERT treated males and females with Fabry disease were compared for main clinical outcomes: renal function, left ventricular mass (LVmass), cerebral white matter lesions (WMLs) and end-organ complications. Through a meta-analysis ERT effectiveness was estimated in different disease stages.Data extractionTwo reviewers assessed quality of the included studies according to guidelines for prognosis research. Data were synthesized using a random effects meta-analysis.ResultsThirty-one studies were systematically reviewed while six studies were included in the meta-analysis. In patients with a GFRu2009>u200960xa0ml/min/1.73xa0m2, decline of renal function was similar for treated and untreated patients. Only ERT treated males with a GFRu2009<u200960xa0ml/min/1.73xa0m2 had a slower rate of decline in renal function, possibly attributable to anti-proteinuric therapy. Regardless of left ventricular hypertrophy (LVH) at baseline, LVmass remained stable or increased in males despite ERT, however at a slower rate compared to untreated male patients. In ERT treated females with LVH LVmass decreased, and remained stable in females without LVH. WMLs can not be prevented by ERT. Stroke, cardiac and end-stage renal complications develop, though the incidence of new complications seems to be reduced during ERT.ConclusionERT is effective in reducing LVH, but has a limited effect on renal function. Improved treatment options are needed for Fabry disease.

Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III

SummaryWe report three siblings with Gaucher disease type III, born between 1992 and 2004. During this period, new developments resulted in different potential therapies, changing clinical practice. The two eldest siblings received enzyme replacement therapy (ERT) from the age of 24 and 5 months respectively, later followed by an increase in dosage. ERT was combined with substrate reduction therapy (SRT) from the ages of 12 and 8 years, respectively. In the youngest sibling the combination of high-dose ERT and SRT was given from the age of 5 months. The two eldest siblings showed significant neurological impairment from the age of 1.5 years, starting with a convergent strabismus and partial oculomotor apraxia, followed by cognitive decline and an abnormal EEG and BAER. In contrast, the neurological development in the youngest sibling is almost completely normal. At the age of 3 years, cognitive development, EEG and BAER are all normal. Disturbed saccadic eye movements, which were already present at the start of therapy, remained stable. In addition to the clinical efficacy, we report on the biochemical response to therapy. Based on our results, the combination of high-dose ERT and SRT should be considered as a possible therapeutic approach for GD III, especially if started at a young age. Further follow-up studies are necessary to explore the long-term therapeutic effects.

Quality of life in patients with Fabry disease: a systematic review of the literature

Fabry disease (FD), caused by deficiency of the lysosomal enzyme α-galactosidase-A, is a progressive multisystem disease. The disease is X-linked with generally more severe manifestations in males, but can impact on quality of life (QoL) of both male and female patients. The purpose of this literature review is to analyse the currently available data concerning QoL measurement, specifically which questionnaires have been used to measure QoL, how patients with FD score compared to the general population, and the effects of enzyme replacement therapy (ERT) on QoL. Fifty-four articles were relevant for this literature review. Patients with FD had a lower QoL compared to the general population. No definite conclusions could be drawn from the studies on the effect of ERT on QoL; natural history data is scarce, changes observed were limited and the cohorts were of small size. We propose that a FD specific questionnaire be made to accurately assess QoL in patients with FD.

Social-cognitive functioning and social skills in patients with early treated phenylketonuria: a PKU-COBESO study

ObjectiveEarly treatment of phenylketonuria (ET-PKU) prevents mental retardation, but many patients still show cognitive and mood problems. In this study, it was investigated whether ET-PKU-patients have specific phenylalanine (Phe-)related problems with respect to social-cognitive functioning and social skills.MethodsNinety five PKU-patients (mean age 21.6u2009±u200910.2xa0years) and 95 healthy controls (mean age 19.6u2009±u20098.7xa0years) were compared on performance of computerized and paper-and-pencil tasks measuring social-cognitive abilities and on parent- and self-reported social skills, using multivariate analyses of variance, and controlling for general cognitive ability (IQ-estimate). Further comparisons were made between patients using tetrahydrobiopterin (BH4, Nu2009=u200930) and patients not using BH4. Associations with Phe-levels on the day of testing, during childhood, during adolescence and throughout life were examined.ResultsPKU-patients showed poorer social-cognitive functioning and reportedly had poorer social skills than controls (regardless of general cognitive abilities). Quality of social-cognitive functioning was negatively related to recent Phe-levels and Phe-levels between 8 and 12xa0years for adolescents with PKU. Quality of social skills was negatively related to lifetime phenylalanine levels in adult patients, and specifically to Phe-levels between 0 and 7, and between 8 and 12xa0years. There were no differences with respect to social outcome measures between the BH4 and non-BH4 groups.ConclusionPKU-patients have Phe-related difficulties with social-cognitive functioning and social skills. Problems seem to be more evident among adolescents and adults with PKU. High Phe-levels during childhood and early adolescence seem to be of greater influence than current and recent Phe-levels for these patients.

Restricted upper extremity range of motion in mucopolysaccharidosis type I: no response to one year of enzyme replacement therapy

SummaryBackground: Mucopolysaccharidosis type I (MPS I) results from deficiency of the lysosomal enzyme α-L-iduronidase (IDUA). Glycosaminoglycans (GAGs) accumulate in multiple organs and the storage in connective tissues results in restricted mobility. Previous studies provided evidence of an improvement in range of motion (ROM), as measured by goniometry, after supplementation of recombinant enzyme (ERT). Aim: The aim of the study was to evaluate the efficacy of ERT in improving ROM in patients with MPS I, using a blinded three-dimensional (3D) video analysis of unrestricted movements of the upper extremities. Methods: In 6 patients with the attenuated phenotype of MPS I, the longitudinal changes in the upper extremity ROM were analysed by 3D video analysis during one year of ERT. Results: At baseline, all studied movements except for elbow flexion were restricted. No significant improvement of the restricted upper extremity ROM was observed after one year of ERT. Conclusion: Long-standing restrictions in ROM probably cannot be reversed by ERT. Early initiation of treatment might be essential to prevent irreversible functional defects.

Home treatment with enzyme replacement therapy for mucopolysaccharidosis type I is feasible and safe

SummaryObjective:Intravenous enzyme replacement therapy (ERT) with recombinant α-l-iduronidase may ameliorate the non-neurological symptoms in patients with mucopolysaccharidosis type I (MPS I). Since home-based ERT for Gaucher and Fabry diseases has been reported to be safe and successful, we investigated the feasibility and safety of home therapy in patients with MPS I.Setting:This two-centre study included 17 ERT-treated MPS I patients between 1 and 35 years of age. A patient was allowed to transfer to home treatment after a minimum period of 6 months of in-hospital administration of ERT and after a self- or home nurse-supported home setting was arranged.Results:Thirteen out of 17 patients transferred to home treatment with a median time to transfer of 13 months (range 7–40 months). Two patients preferred to continue ERT in the hospital, whereas for two other patients the transfer to home was hampered for practical reasons. All patients who received ERT at home were assisted by either a relative or a nurse. In total over 1000 home infusions were performed and no serious complications were observed. Two infusion-associated reactions were observed, both within the first 3 months of in-hospital administration of ERT. All patients except one developed antibodies against the recombinant enzyme, but this was not associated with the development of hypersensitivity reactions.Conclusion:ERT for MPS I applied at home is safe and might alleviate the burden of life-long intravenous treatment in these patients.

Hypermetabolism in Gaucher disease type I is not associated with altered thyroid hormone levels

SummaryType I Gaucher disease (OMIM 231000) is an inherited storage disorder in which deficiency of the enzyme glucocerebrosidase (EC 32145) leads to accumulation of glucocerebroside in lysosomes of macrophages. These storage cells are present in liver, spleen and bone marrow resulting in hepatosplenomegaly, cytopenia and bone complications. Metabolic abnormalities in Gaucher patients include hypermetabolism, possibly caused by elevated levels of pro-inflammatory cytokines. Nonthyroidal illness (NTI) is a combination of changes in circulating thyroid hormone levels (decreased T3, elevated rT3, normal or mildly depressed TSH) present in different illnesses and might be an adaptation to protect the organism from harmful catabolic effects of hypermetabolism. The hypermetabolism and the elevated cytokine levels in Gaucher disease led us to hypothesize that the alterations in thyroid hormone levels as seen in NTI might also occur in Gaucher patients. We studied thyroid hormone levels before and during treatment in 22 adult type I Gaucher patients and resting energy expenditure (REE) and correlations with thyroid hormone levels in 12 patients. Baseline thyroid hormone levels were normal in the majority (17) of patients. No cases of nonthyroidal illness were detected. Baseline REE (kcal/kg per 24xa0h) was not correlated with circulating levels of T3, rT3 or fT4. Treatment of Gaucher disease with enzyme replacement therapy for several years resulted in a decrease in circulating fT4 levels. After several months of treatment most patients showed a decrease in REE. There was no correlation between the changes in REE and changes in fT4 and T3.