Mucopolysaccharidosis VI: cardiac involvement and the impact of enzyme replacement therapy.

OBJECTIVE: To describe cardiac abnormalities in patients with mucopolysaccharidosis (MPS) VI and to evaluate the impact of enzyme replacement therapy (ERT) on cardiac structure and function. METHODS: Data from electrocardiographic and echocardiographic evaluations were retrospectively collected from patients with MPS VI who are followed up at the Children's Hospital of Mainz. RESULTS: The study included 44 (16 male and 28 female) patients. At baseline, valvular regurgitation (mainly aortic and mitral) and left ventricular (LV) volume overload were present in over half of patients. Other common cardiac manifestations were sinus tachycardia, LV hypertrophy, concentric LV remodelling, and pulmonary hypertension. One patient had left atrial dilation and one had congestive heart failure. Interventricular septal wall thickness and LV posterior wall thickness were above normal in most patients. Twenty five patients had a pre-ERT and at least one follow-up visit after ERT start. Mean follow-up after ERT start was 5.6 (SD 2.3) years. Despite the late onset (mean age 14.6 years) of treatment, ERT appeared to improve or arrest the progression of LV remodelling and LV hypertrophy and suspend the progression of cardiac valve disease. CONCLUSIONS: MPS VI is associated with an array of cardiac manifestations. ERT appears to have some impact on cardiac structure and function when started late in life, but may have better long-term results when started during early infancy.

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.

Does enzyme replacement therapy influence the ocular changes in type VI mucopolysaccharidosis?

BACKGROUND: To describe the ocular changes noted in seven patients with type VI mucopolysaccharidosis (MPS VI) during 44 months of follow-up while on enzyme replacement therapy (ERT). METHODS: One male and six female patients with MPS VI were followed-up for a mean period of 44 months while undergoing enzyme replacement therapy (ERT) with recombinant arylsulfatase B (Naglazyme). They were examined annually for visual acuity, corneal clouding, intraocular pressure (IOP), optic nerve head and fundus morphology. Corneal clouding was documented by photography. We acknowledge that our methodology may not have been sensitive enough to detect extremely mild ocular changes, including minimal increases in corneal thickness or clouding. Nevertheless, this limitation has been considered in the interpretation of our findings. RESULTS: Ophthalmological findings remained stable in 5/7 patients. One patient experienced a modest improvement in visual acuity of more than 2 Snellen lines in one eye, while another patient suffered a deterioration in visual acuity of more than 2 Snellen lines in both eyes. Five out of seven patients showed optic nerve pathology: two of these exhibited optic nerve head swelling, while the other three showed variable degrees of optic nerve atrophy. All seven patients suffered from the typical corneal stromal opacities, however, to variable extents. CONCLUSION: Visual function and ocular findings did not deteriorate in six out of seven MPS VI patients during a mean follow-up period of 3 and a half years on ERT.

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.