The mucopolysaccharidoses (MPSs) are inherited lysosomal storage disorders caused by the absence of functional enzymes that contribute to the degradation of glycosaminoglycans (GAGs). The progressive systemic deposition of GAGs results in multi-organ system dysfunction that varies with the particular GAG deposited and the specific enzyme mutation(s) present. Cardiac involvement has been reported in all MPS syndromes and is a common and early feature, particularly for those with MPS I, II, and VI. Cardiac valve thickening, dysfunction (more severe for left-sided than for right-sided valves), and hypertrophy are commonly present; conduction abnormalities, coronary artery and other vascular involvement may also occur. Cardiac disease emerges silently and contributes significantly to early mortality.The clinical examination of individuals with MPS is often difficult due to physical and, sometimes, intellectual patient limitations. The absence of precordial murmurs does not exclude the presence of cardiac disease. Echocardiography and electrocardiography are key diagnostic techniques for evaluation of valves, ventricular dimensions and function, which are recommended on a regular basis. The optimal technique for evaluation of coronary artery involvement remains unsettled.Standard medical and surgical techniques can be modified for MPS patients, and systemic therapies such as hematopoietic stem cell transplantation and enzyme replacement therapy (ERT) may alter overall disease progression with regression of ventricular hypertrophy and maintenance of ventricular function. Cardiac valve disease is usually unresponsive or, at best, stabilized, although ERT within the first few months of life may prevent valve involvement, a fact that emphasizes the importance of early diagnosis and treatment in MPS.

https://link.springer.com/content/pdf/10.1007%2Fs10545-011-9359-8.pdf

Cardiac disease in patients with mucopolysaccharidosis: presentation, diagnosis and management

Mucopolysaccharidosis IVA (MPS IVA), also known as Morquio A, is a rare, autosomal recessive disorder caused by a deficiency of the lysosomal enzyme N-acetylgalatosamine-6-sulfate-sulfatase (GALNS), which catalyzes a step in the catabolism of glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate (C6S). It leads to accumulation of the KS and C6S, mainly in bone and cornea, causing a systemic skeletal chondrodysplasia. MPS IVA has a variable age of onset and variable rate of progression. Common presenting features include elevation of urinary and blood KS, marked short stature, hypoplasia of the odontoid process, pectus carinatum, kyphoscoliosis, genu valgum, laxity of joints and corneal clouding; however there is no central nervous system impairment. Generally, MPS IVA patients with a severe form do not survive beyond the third decade of life whereas those patients with an attenuated form may survive over 70 years. There has been no effective therapy for MPS IVA, and care has been palliative. Enzyme replacement therapy (ERT) and hematopoietic stem cell therapy (HSCT) have emerged as a treatment for mucopolysaccharidoses disorders, including Morquio A disease. This review provides an overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS IVA and describes potential perspectives of ERT and HSCT. The issue of treating very young patients is also discussed.

Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment

To assess the efficacy and safety of enzyme replacement therapy (ERT) with BMN 110 (elosulfase alfa) in patients with Morquio A syndrome (mucopolysaccharidosis IVA). Patients with Morquio A aged ≥5 years (N = 176) were randomised (1:1:1) to receive elosulfase alfa 2.0 mg/kg/every other week (qow), elosulfase alfa 2.0 mg/kg/week (weekly) or placebo for 24 weeks in this phase 3, double-blind, randomised study. The primary efficacy measure was 6-min walk test (6MWT) distance. Secondary efficacy measures were 3-min stair climb test (3MSCT) followed by change in urine keratan sulfate (KS). Various exploratory measures included respiratory function tests. Patient safety was also evaluated. At week 24, the estimated mean effect on the 6MWT versus placebo was 22.5 m (95 % CI 4.0, 40.9; P = 0.017) for weekly and 0.5 m (95 % CI −17.8, 18.9; P = 0.954) for qow. The estimated mean effect on 3MSCT was 1.1 stairs/min (95 % CI −2.1, 4.4; P = 0.494) for weekly and −0.5 stairs/min (95 % CI −3.7, 2.8; P = 0.778) for qow. Normalised urine KS was reduced at 24 weeks in both regimens. In the weekly dose group, 22.4 % of patients had adverse events leading to an infusion interruption/discontinuation requiring medical intervention (only 1.3 % of all infusions in this group) over 6 months. No adverse events led to permanent treatment discontinuation. Elosulfase alfa improved endurance as measured by the 6MWT in the weekly but not qow dose group, did not improve endurance on the 3MSCT, reduced urine KS, and had an acceptable safety profile.

/pdf/efficacy-and-safety-of-enzyme-replacement-therapy-with-bmn-4nha1ugjth.pdf

Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study

Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA

The lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders that are caused for the most part by enzyme deficiencies within the lysosome resulting in accumulation of undegraded substrate. This storage process leads to a broad spectrum of clinical manifestations depending on the specific substrate and site of accumulation. Examples of LSDs include the mucopolysaccharidoses, mucolipidoses, oligosaccharidoses, Pompe disease, Gaucher disease, Fabry disease, the Niemann-Pick disorders, and neuronal ceroid lipofuscinoses. This review summarizes the main clinical features, diagnosis, and management of LSDs with an emphasis on those for which treatment is available.

/pdf/lysosomal-storage-disease-overview-2w74gajzy9.pdf

Lysosomal storage disease overview

Mucopolysaccharidosis IVA (MPS IVA; Morquio A disease) is a lysosomal storage disorder caused by deficiency of N-acetylgalactosamine-6-sulfate sulfatase. The natural history of this disease is incompletely understood. To study which variables influence the clinical outcome, we conducted a study in which MPS IVA patients were asked to fill out a questionnaire with inquiries regarding family history, diagnosis, signs and symptoms, height, weight, surgical history, physical activity, and general complaints. A total of 326 patients (172 male, 154 female) from 42 countries enrolled in the Morquio A Registry programme. The mean age of patients enrolled was 14.9 years for males and 19.1 years for females, with a wide range of 1–73 years. Sixty-four per cent of the patients were under 18 years. Initial symptoms were recognized between 1 and 3 years of age (mean age 2.1 years) and mean age at diagnosis for the patients was 4.7 years. A progressive skeletal dysplasia was commonly observed among the MPS IVA patients. Fifty per cent of patients underwent surgical operations to improve their quality of life. The most frequent surgical sites include neck (51%), ear (33%), leg (26%) and hip (25%). The birth length for affected males and females was 52.2 ± 4.7 cm and 52.2 ± 4.5 cm, respectively. The final adult height for affected males and females was 122.5 ± 22.5 cm and 116.5 ± 20.5 cm, respectively. The results of this study provide a reference for assessment of efficacy for studies of novel therapies.

International Morquio A Registry: Clinical manifestation and natural course of Morquio A disease

Children with Morquio A disease grow poorly and become physically handicapped because of systemic bone disease. The purpose of this study was to describe observed growth patterns and their relationship with the physical condition of patients with Morquio A. In a one-center study, questionnaire-based longitudinal and cross sectional data were used to develop growth curves, to assess physical activity and to determine the incidence of surgical procedures in 354 patients with Morquio A. Mean birth lengths of boys and girls were 52.6 and 52.1 cm, respectively. The mean final heights for males and females at 18 years and older were 122.4 +/- 21.5 and 113.1 +/- 22.6 cm, respectively. These results corresponded to -7.4 SD for males and -7.7 SD for females compared to the normal healthy controls. Mean birth weights for boys and girls were 3.59 +/- 0.58 and 3.5 +/- 0.7 kg, respectively. The mean body mass index for males and females at over 18 years of age was 24.7 +/- 6.1 and 25.6 +/- 5.4 kg/m(2), respectively. The growth pattern in Morquio A patients was characterized by impaired growth velocity after 1 year of age. This is the first report providing growth charts for patients with Morquio A, which can help with monitoring the disease and assessing the clinical efficacy of treatments.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/ajmg.a.32281

Growth charts for patients affected with Morquio A disease

Children with mucopolysaccharidoses (MPS) grow poorly and become physically handicapped because of systemic bone disease. For children with skeletal dysplasias, such as MPS, it is important to know the natural history of growth. Understanding of the growth pattern provides assessment of current growth and data on efficacy of individualized medicine in growth-promoting treatments. The purpose of this chapter is to review natural history of growth patterns for MPS II, IVA, and VI patients. The cross-sectional and/or longitudinal data were collected to develop growth curves for the following types of MPS. Interestingly, accelerated growth has been observed in the first years of life in any type of MPS reviewed here, followed by slowing growth rate and growth failure. (1) MPS II: We obtained height and weight measurements from 46 Japanese male patients with MPS II. Mean birth length of boys was 50.9 ± 2.1 cm. The mean height for MPS II at 18 years of age or older was 127.2 ± 8.5 cm. These values corresponded to 0.9 SD and −7.5 SD of the height for normal Japanese males. The mean height was kept higher until 5 years and the mean weight was heavier until 8 years of age. After 7 years of age, short stature was commonly observed in spite of clinical severity by CNS involvement. (2) MPS IVA: Height and weight measurements from 193 girls and 195 boys with MPS IVA were collected. Mean birth lengths of boys and girls were 52.4 ± 3.9 and 52.1 ± 2.9 cm, respectively. Mean heights for males and females at 18 years of age were 119.3 ± 22.6 and 113.5 ± 23.1 cm, respectively. These values correspond to −8.0 SD and −7.7 SD of the mean height for normal males and females. Mean birth weights for boys and girls were 3.56 ± 0.5 and 3.5 ± 0.7 kg, respectively. (3) MPS VI: Growth is severely impacted on this type of MPS. In an observational study in 121 untreated MPS VI patients, a mean height was 115.2 cm ± 26.1 cm and median height was 103.7 cm with a range of 80–169 cm. An inverted correlation of height with the excretion of urinary GAGs and an influence of the genotype on the pattern of this excretion were also demonstrated. Thus, the growth pattern in MPS II patients was characterized by impaired growth velocity after 4 years of age, while the growth patterns in MPS IVA and VI patients were characterized by impaired growth velocity after 1 and 2 years of age.

Mary Smith

Papers

International Morquio A Registry: Clinical manifestation and natural course of Morquio A disease

Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment

Growth charts for patients affected with Morquio A disease

Impairment of Body Growth in Mucopolysaccharidoses