Clinical characteristics of adults with slowly progressing mucopolysaccharidosis VI: a case series.

OBJECTIVE: To assess clinical features and general health status of adult patients with mucopolysaccharidosis (MPS) VI. METHODS: This report includes the clinical history of patients older than 18 years with slowly progressing MPS VI and the retrospective analysis of the outcomes of available data collected between September 2003 and October 2008 at the Center of Pediatric and Adolescent Medicine, University Medical Center, Johannes Gutenberg-University of Mainz, Germany. Variables included were urinary glycosaminoglycan (uGAG) level, mutation analysis, body height, forced vital capacity (FVC), 6-minute walk test, echocardiographic findings, the need for craniocervical decompression surgery, orthopaedic findings and ophthalmological assessments. RESULTS: The analysis included nine patients with MPS VI aged 19-29 years. The median age at diagnosis was 12 (range 6-20) years. At the time of the assessment (median age 25 years), median uGAG was 29 (range 15-149) µg/mg creatinine and median height 152 (range 136-161) cm. All patients had a FVC below standard values, seven showed reduced endurance in the 6-minute-walk test, all had valve changes with valve replacement in three, two underwent craniocervical decompression surgery, two underwent carpal tunnel surgery, five had ear/nose/throat (ENT) interventions, seven had hip pain/dysplasia, seven had corneal clouding and two were visually impaired. CONCLUSIONS: Although patients with slowly progressing MPS VI are a heterogeneous group showing disease manifestations in several organs, they seem to have some typical characteristics in common. Despite the attenuated clinical course, many of these patients show severe morbidity. Therefore, early diagnosis and proper follow-up and treatment are essential.

The craniocervical junction following successful haematopoietic stem cell transplantation for mucopolysaccharidosis type I H (Hurler syndrome).

Mucopolysaccharidosis I Hurler (MPS IH) is a progressive multisystemic disorder caused by alpha-L-iduronidase deficiency. First choice of treatment in MPS IH children is haematopoietic stem cell transplantation (HSCT). The effect of HSCT has been shown to have limited influence on skeletal manifestations by poor penetration of musculoskeletal tissues by the enzyme derived from donor leucocytes. Aim of this study was to investigate the effect of HSCT on the craniocervical junction (CCJ) in Hurler patients. We analysed retrospectively sequential magnetic resonance imaging (MRI) scans of 30 patients with Hurler disease treated by HSCT since 1982 at the Royal Manchester Children's Hospital, UK, in order to determine whether the patients suffer from dens hypoplasia. Results were compared with biochemical and clinical characteristics: Enzyme activity (EA), chimerism, urinary glycosaminoglycan (GAG) excretion and neurological status. Investigations were part of standard clinical procedures. Results are descriptive in presentation. In 26/30 patients a determination of odontoid hypoplasia was feasible. The majority showed a normal dens length and an increase with age. Only 3/26 revealed a dens hypoplasia. One of them had only partial donor engraftment (DE) with reduced EA, one of them suffered from chronic graft versus host disease (GVHD). One patient with only partial DE and reduced EA presented with initial dens hypoplasia until preadolescence but normalized later on. There may be a trend towards lower EA and the occurrence of DH in transplanted MPS patients - perhaps the dosage of enzyme plays a role in the correction of skeletal complications in this patient group. HSCT patients with incomplete DE and therefore lower EAs may require special attention and care.

A 4-year study of the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa in 36 women with Fabry disease.

PURPOSE: Although Fabry disease is X linked and considered to affect primarily male hemizygotes, female heterozygotes may experience all the signs and symptoms of this metabolic disorder. This prospective, single-center, open-label, clinical trial was performed to evaluate the long-term response of female patients with Fabry disease to enzyme replacement therapy. METHODS: Symptomatic women (average age = 47 years) enrolled in this 4-year study were treated with agalsidase alfa (Replagal, Shire HGT, Inc.) at a dose of 0.2 mg/kg, every other week for 4 years (N = 36). Clinical and biochemical assessments were conducted at 12-month intervals. RESULTS: The Mainz Severity Score Index, a measure of total disease burden, was significantly reduced after 12 months (P < 0.01) of treatment and continuously improved over 4 years. Brief Pain Inventory "pain at its worst" score was reduced from 4.6 +/- 2.9 at baseline to 3.3 +/- 2.9 after 12 months (P = 0.001) and remained reduced through 4 years. Mean left-ventricular mass decreased from 89.4 +/- 29.3(2.7) g/m at baseline to 66.5 +/- 29.3(2.7) g/m after 12 months (P < 0.001) and remained reduced through 4 years. Average kidney function (estimated glomerular filtration rate and proteinuria) remained constant during the study. No safety issues were identified. CONCLUSIONS: Long-term agalsidase alfa is effective and was well tolerated in women with 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.