Catharina Whybra

Cumulative incidence rates of the mucopolysaccharidoses in Germany.

SummaryIn order to estimate the cumulative incidence rates of the mucopolysaccharidoses (MPS) in Germany, a retrospective epidemiological survey covering the period between 1980 and 1995 was implemented. Multiple ascertainment sources were used to identify affected patients. A prevalence of approximately 0.69 cases per 100 000 births was obtained for MPS I (Hurler phenotype). Within the study period, 4 patients with Hurler/Scheie phenotype and 7 cases with Scheie disease were detected. The cumulative incidence for MPS II (Hunter syndrome) was estimated as 0.64 cases per 100 000 births (1.3 cases per 100 000 male live births); that for MPS III (Sanfilippo syndrome types A, B and C) as 1.57 cases in 100 000 births; that for MPS IV A (Morquio syndrome) as 0.38 cases in 100 000; and that for MPS VI (Maroteaux–Lamy syndrome) as 0.23 cases per 100 000 births. Two cases of MPS IVB (β-galactosidase deficiency) have been identified, but no patients with MPS VII or MPS IX. A relatively high number of patients with MPS IIIB, MPS IVA and MPS VI were of Turkish origin. The crude rate for all types of mucopolysaccharidoses is approximately 3.53 cases in 100 000 live births. The cumulative incidence pattern of MPS in Germany was compared with the corresponding rates among other industrial nations obtained from recent literature: the crude cumulative rates for all types of mucopolysaccharidoses (3.4–4.5 in 100 000 live births) were similar among all published populations; however, different frequencies of the various forms of MPS were observed.

Anderson-Fabry disease: clinical manifestations of disease in female heterozygotes.

Anderson–Fabry disease is a rare, X-chromosomal lipid storage disorder caused by a deficiency of lysosomal α-galactosidase A. Clinical manifestations of Anderson–Fabry disease include excruciating pain in the extremities (acroparaesthesia), skin vessel ectasia (angiokeratoma), corneal and lenticular opacity, cardiovascular disease, stroke and renal failure, only renal failure being a frequent cause of death. Heterozygote female carriers have often been reported as being asymptomatic or having an attenuated form of the disease. To evaluate the spectrum of clinical signs in heterozygotes, a comprehensive clinical examination was performed on 20 carriers of Anderson–Fabry disease. This revealed that, in addition to the skin manifestation, various other clinical manifestations of the disease are present, including acroparaesthesia, kidney dysfunction, cerebrovascular disease, and gastrointestinal and heart problems. It therefore appears that Anderson–Fabry disease affects both hemizygotes and heterozyotes and therefore should be considered to be an X-linked dominant disease.

Clinical manifestations of Fabry disease in children: data from the Fabry Outcome Survey.

Background: Fabry disease is a rare X‐linked disorder caused by deficient activity of the enzyme α‐galactosidase A. This produces progressive lysosomal accumulation of globotriaosylceramide throughout the body, leading to organ failure and premature death. Aim: Here, we present the clinical manifestations of Fabry disease in children enrolled in FOS—the Fabry Outcome Survey—a European database of the natural history of Fabry disease and the effects of enzyme replacement therapy with agalsidase alfa (Replagal™). Methods: Currently, there are 545 patients in FOS, from 11 European countries. We analysed the baseline demographic and clinical characteristics of 82 of these patients (40 boys, 42 girls) who were below 18 y of age. The median age at evaluation (defined as the median age at entry into FOS) was 12.5 and 13.2 y for boys and girls, respectively. Results: The most frequent early clinical manifestations of Fabry disease were neurological (acroparaesthesiae, altered temperature sensitivity) and gastrointestinal symptoms (altered bowel habits and abdominal pain), which were documented in about 80% and 60% of patients, respectively, at the time of evaluation and subsequent entry into FOS. Tinnitus, vertigo, fatigue and angiokeratoma were present in over 40% of patients. Symptoms were noted in early childhood and occurred with similar frequency in boys and girls, although the onset of symptoms was 2–5 y later in girls than in boys. There was an approximately 3‐y delay from onset of symptoms to diagnosis, and patients were frequently misdiagnosed.

The mainz severity Score index: a new instrument for quantifying the anderson-fabry disease phenotype, and the response of patients to enzyme replacement therapy

Anderson–Fabry disease (AFD) is an X‐linked disorder caused by deficient activity of the lysosomal enzyme α‐galactosidase A. The availability of enzyme replacement therapy (ERT) for this debilitating condition has led to the need for a convenient and sensitive instrument to monitor clinical effects in an individual patient. This study aimed to develop a scoring system – the Mainz Severity Score Index (MSSI) – to measure the severity of AFD and to monitor the clinical course of the disease in response to ERT. Thirty‐nine patients (24 males and 15 females) with AFD were assessed using the MSSI immediately before and 1 year after commencing agalsidase alfa ERT. Control data were obtained from 23 patients in whom AFD was excluded. The MSSI of patients with AFD was significantly higher than that of patients with other severe debilitating diseases. The MSSI indicated that, although more men than women had symptoms classified as severe, overall, the median total severity scores were not significantly different between male and female patients. One year of ERT with agalsidase alfa led, in all patients, to a significant (p < 0.001) reduction in MSSI score (by a median of nine points). This study has shown that the MSSI score may be a useful, specific measure for objectively assessing the severity of AFD and for monitoring ERT‐related treatment effects.

Enzyme-Replacement Therapy With Agalsidase Alfa in Children With Fabry Disease

CONTEXT. Fabry disease is an X-linked multisystem disorder. Enzyme-replacement therapy in adults has limited efficacy in treating major sequelae of advanced Fabry disease, such as kidney failure or stroke. This prompted a study of the safety and efficacy of enzyme replacement at an earlier stage of Fabry disease. OBJECTIVES. Our purpose with this work was to evaluate safety and to explore efficacy of enzyme treatment with agalsidase alfa in pediatric patients with Fabry disease. METHODS. We conducted a 6-month open-label study at 3 tertiary care centers with 24 children (19 boys and 5 girls) with a mean age of 11.8 (range: 6.5–18) years, to examine safety parameters, including infusion reactions and antiagalsidase alfa antibodies. RESULTS. Agalsidase alfa was well tolerated, and all of the patients completed the study. Six boys and 1 girl had mild-to-moderate infusion reactions. One boy developed transient immunoglobulin G antibodies against agalsidase alfa. The boys showed a significant reduction in plasma globotriaosylceramide on treatment. Mean estimated glomerular filtration rate, cardiac structure, and function were normal and did not change over 26 weeks. Heart rate variability, as determined by 2-hour ambulatory monitoring, was decreased in the boys compared with the girls at baseline. All indices of heart rate variability improved significantly in the boys. Three patients with anhidrosis, as determined by quantitative sudomotor axon reflex testing, developed sweating. Six of 11 patients could reduce or cease their use of antineuropathic analgesics. CONCLUSIONS. Enzyme replacement with agalsidase alfa was safe in this study. The exploratory efficacy analysis documented increased clearance of globotriaosylceramide and improvement of autonomic function. Prospective long-term studies are needed to assess whether enzyme replacement initiated early in patients with Fabry disease is able to prevent major organ failure in adulthood.

Cardiac manifestations of Anderson–Fabry disease in heterozygous females

OBJECTIVES We sought to define the prevalence of cardiac involvement in female patients with Anderson-Fabry disease (AFD). BACKGROUND Anderson-Fabry disease is a rare inborn X-linked lysosomal storage disorder. Globotriaosylceramide (Gb(3)), the major substrate of the deficient alpha-galactosidase A enzyme, accumulates progressively in vulnerable cells, including the cardiovascular system. It has been believed that heterozygous females have less cardiac involvement than hemizygous males with AFD. METHODS We performed two-dimensional echocardiographic examinations of female patients heterozygous for AFD. RESULTS Since 1997, a total of 55 female patients (mean age, 39.6 years; range, 6.1 to 70.8 years) with proven AFD have been investigated prospectively at our hospital. Of these, 13 (23.6%) had normal left ventricular (LV) geometry and LV mass (LVM). Seven patients (12.7%) had concentric remodeling, 29 patients (52.7%) concentric LV hypertrophy (LVH), and 6 patients (10.9%) eccentric LVH (2 with subaortic pressure gradients). There was a strong correlation between age and the severity of LVH (r(2) = 0.905; p < 0.0001), and all patients older than 45 years had LVH. With increasing LVM, there was a significant age-independent decrease in systolic and diastolic LV function. Mild thickening of the aortic valve leaflets was present in 25.5% of patients, with the same percentage demonstrating mild thickening of the mitral valve leaflets. Mild mitral valve prolapse was documented in 10.9% of patients. CONCLUSIONS Cardiac involvement, with LVH and structural valve abnormalities, is very common and worsens with age in females who are heterozygous for AFD, and they should therefore be considered candidates for enzyme replacement therapy.

Enzyme replacement therapy in heterozygous females with Fabry disease: Results of a phase IIIB study

Summary: Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency of α-galactosidase A. Affected patients experience debilitating neuropathic pain and have premature mortality due to renal failure, cardiovascular disease or cerebrovascular complications. The disease may be X-linked dominant, since most females heterozygous for Fabry disease are affected clinically. We evaluated the safety, efficacy and pharmacokinetics of agalsidase alfa (Replagal) administered intravenously to female patients with Fabry disease in an open-label, single-centre study. Fifteen severely affected patients received agalsidase alfa at 0.2 mg/kg every other week for up to 55 weeks. Agalsidase alfa was safe and well-tolerated in female patients. None of the patients developed antibodies or experienced an infusion reaction to agalsidase alfa. The pharmacokinetic profile of agalsidase alfa in female patients is comparable to the pharmacokinetics of agalsidase alfa in male patients. Mean urine sediment and plasma Gb3 levels decreased from baseline at 13, 27 and 41 weeks. A significant decrease in left ventricular mass from baseline was seen at weeks 27 (p = 0.003) and 41 (p = 0.039), and a significant reduction in QRS durations was seen at week 27 (p = 0.007). Furthermore, there was a significant improvement in quality of life. Renal function did not deteriorate in these 15 female patients over the 13- to 41-week period of observation. We conclude that enzyme replacement therapy with agalsidase alfa was safe and effective in female patients heterozygous for Fabry disease.

Onset and progression of the Anderson–Fabry disease related cardiomyopathy

BACKGROUND Cardiac involvement is responsible for substantial morbidity and mortality in Anderson-Fabry disease (AFD). We sought to document its onset and progression in a population of male and female AFD patients. METHODS We performed a cross sectional echocardiographic study of a cohort of 177 male and female AFD patients with subsequent longitudinal follow-up of 76 patients (38 males and 38 females; mean follow-up 4.5 years) who did not receive enzyme replacement therapy. RESULTS In this population, aged 3.3 to 70.8 years, a strong correlation between age and left ventricular mass indexed (LVMi, g/m(2.7)) was found in both males and females (P<0.0001 for both). At the initial examination 48.6% of the male patients and 36.4% of the female patients were classified as having left ventricular hypertrophy (LVH). The cumulative prevalence of LVH peaked at age 40 years in males and 60 years in females. In patients with longitudinal follow-up, LVMi increased by 4.07+/-1.03 g/m(2.7) per year in males and by 2.31+/-0.81 g/m(2.7) in females (P<0.01, Wilcoxon rank sum). In patients with LVH at baseline, the median progression rate was 5.52 g/m(2.7) per year in males and by 1.80 g/m(2.7) in females (P=0.12). CONCLUSION AFD is associated with high prevalence of LVH in both genders. However, the age of onset is delayed in females and progression rate slower.

Enzyme replacement therapy with agalsidase alfa in children with Fabry disease.

Aim: To assess the effects of enzyme replacement therapy (ERT) in children with Fabry disease.

Disease manifestations and X inactivation in heterozygous females with Fabry disease

Aim: Fabry disease is an X-linked lysosomal storage disorder characterized by an accumulation of neutral glycosphingolipids in multiple organ systems caused by α-galactosidase A deficiency due to mutations in the GLA gene. The majority of heterozygous females show the characteristic signs and symptoms of the disease, and some of them are severely affected. The current hypothesis for the occurrence of disease manifestations in females is skewed X inactivation favouring the mutant GLA allele. Method: We analyzed the patterns of X inactivation in the leukocytes of 28 biochemically and genetically characterized symptomatic Fabry disease heterozygotes and their correlation with clinical and biochemical disease expression. Results: X inactivation patterns in symptomatic females who are heterozygous for Fabry disease did not differ from those of female controls of the same age (p = 0.669). Thirteen (46%) of the 28 females with Fabry disease showed random X inactivation, ten (36%) moderate skewing, and five (18%) highly skewed X inactivation. Segregation analysis was performed in the families of six females who had highly or moderately skewed X inactivation. In four of these females, skewing favoured the wild-type GLA allele and in the other two skewing favoured the mutant allele. Patterns of X inactivation or the extent of skewing were not related to the severity of clinical manifestations or to residual enzyme activity. Conclusion: In this study we provide evidence that heterozygous females with Fabry disease show random X inactivation. Our data do not support the hypothesis that the occurrence and severity of disease manifestations in the majority of Fabry heterozygotes are related to skewed X inactivation.