Maroteaux-Lamy syndrome

ALSO KNOWN AS: Mucopolysaccharidosis type VI; MPS VI; arylsulfatase B deficiency; ASRB deficiency; N-acetylgalactosamine 4-sulfatase deficiency

DEFINITION Maroteaux-Lamy syndrome, an autosomal recessive condition caused by deficiency of the N-acetylgalactosamine 4-sulfatase, or arylsulfatase B (ARSB) enzyme, results in accumulation of dermatan sulfate throughout the body. Excess dermatan sulfate damages underlying tissue structure, resulting in significant, progressive functional impairment.

Risk Factors

Individuals with mutations in both copies of the ARSB gene develop Maroteaux-Lamy syndrome. Full siblings of affected individuals have a 25 percent risk of being affected. According to the National Organization for Rare Disorders, males and females are affected with equal frequency. The organization reported the incidence in 2022 as varying from 1 in 250,000 to 600,000 cases, which were reported among many different ethnic groups. There appears to be a higher incidence among individuals of Brazilian and Portuguese descent—18.5 percent of all national mucopolysaccharidosis (MPS) cases and 16 percent, respectively (as reported by Valayannopoulos et al.)—suggestive of a possible founder effect.

Etiology and Genetics

Glycosaminoglycans (GAGs), or mucopolysaccharides, are complex sugar molecules that are significant components of connective tissue. GAGs are continuously broken down and reconstructed within the body, a process necessary for proper formation and maintenance of tissue structure. The ARSB gene, located at chromosome 5q14.1, produces arylsulfatase B, one of the enzymes needed to break down dermatan sulfate, a type of GAG. Without sufficient ARSB activity, partially degraded dermatan sulfate accumulates within the lysosomes of the cell, ultimately resulting in cellular destruction. Animal models suggest that excess dermatan sulfate may trigger an anti-inflammatory response, leading to increased cell death among affected tissues.

The of Maroteaux-Lamy syndrome varies, ranging from rapidly to slowly progressive disease. Disease severity is difficult to predict, though some prognostic factors have been proposed. In general, the level of ARSB activity is not correlative to disease severity. As reported in Genetic Cardiomyopathies (2012), individuals with urinary GAG levels lower than 100 micrograms per milligram of creatinine are thought to have a more attenuated phenotype, while those with higher levels are thought to be more severe, though this generalization is not always applicable.

The presence of certain types of mutations is thought to be predictive of phenotype. Mutations in the of the gene, as well as mutations that result in a prematurely shortened protein, are thought to result in more severe disease. Specific missense mutations resulting in substitutions have been reported in both the severe and attenuated forms of the disease. The combination of mutations among individual patients also contributes to the wide phenotypic variability.

Symptoms

Symptoms of Maroteaux-Lamy syndrome may not be evident at birth but become more pronounced as GAG accumulates over time. Young children may present with relatively nonspecific findings, such as frequent infections, hernias, or short stature. Short stature may be one of the most noticeable features of Maroteaux-Lamy syndrome; most affected individuals achieve a final height between three and four feet. Coarsened facial features may be seen in more severely affected individuals. There are increased risks for cardiac valvular disease, progressive hearing loss, and corneal clouding. Progressive joint contractures and bone structure changes may cause loss of mobility and dexterity. Changes in the structure of vertebral bodies can result in spinal cord or nerve root injury. Significant curvature of the spine may affect respiratory status. Narrowing of the airway and obstructive sleep apnea are common. In general, intelligence is not affected.

Screening and Diagnosis

If mucopolysaccharidosis (MPS) is suspected, quantitative and qualitative evaluation of urinary GAGs is a useful screening test. In most cases, the presence of excessive amounts of GAG will suggest a diagnosis of mucopolysaccharidosis, and the types of GAG present will suggest specific types of MPS to consider further. If excess dermatan sulfate is present, Maroteaux-Lamy syndrome should be considered. The diagnosis can be confirmed by documenting deficient ARSB activity (typically less than 10 percent of normal, according to Valayannopoulos et al.) on leukocytes or fibroblasts, and/or the presence of mutations in the ARSB gene.

Treatment and Therapy

Hematopoietic stem cell transplantation is available for those with suitable matched donors. If successful, it results in donor cells providing sufficient amounts of ARSB to the patient. This procedure, however, is associated with significant morbidity and mortality and with variable clinical results. An alternative therapy became available in 2005, when the Food and Drug Administration (FDA) approved Naglazyme (galsulfase), the first enzyme replacement therapy for Maroteaux-Lamy syndrome. In clinical trials, Naglazyme was shown to improve endurance of patients, as measured by a twelve-minute walk test and a three-minute stair climb test, as well as to reduce levels of urinary GAGs, with an acceptable safety profile. Naglazyme is administered once weekly via intravenous infusion over a minimum of four hours. As neither therapy is able to address all the issues present in Maroteaux-Lamy syndrome, supportive treatment is still necessary.

Prevention and Outcomes

There is no effective means of prevention for Maroteaux-Lamy syndrome. Historically, untreated individuals had a shortened life expectancy, though this varied based on individual clinical presentation. Treatment, either via hematopoietic stem cell transplantation or Naglazyme, is thought to prolong the life span by slowing the progression of the disease, though this has not been definitively proven. In the case of Naglazyme, the FDA reported that, as of 2013, long-term effects of treatment, especially on young children under age five and on pregnant and lactating mothers, were still under investigation. Prenatal diagnosis is available for Maroteaux-Lamy syndrome, and individuals with a personal or family history of this condition should be offered for a personalized discussion of risks and options.

Bibliography

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Giugliani, Roberto. "Maroteaux-Lamy Syndrome." RareDiseases.org. National Organization for Rare Disorders, 2014. Web. 4 Aug. 2014.

Harmatz, P., et al. “Long-Term Follow-Up of Endurance and Safety Outcomes during Enzyme Replacement Therapy for Mucopolysaccharidosis VI: Final Results of Three Clinical Studies of Recombinant Human N-Acetylgalactosamine 4-Sulfatase.” Molecular Genetics and Metabolism 94 (2008): 469–75. Print.

Karageorgos, L., et al. “Mutational Analysis of 105 Mucopolysaccharidosis Type VI Patients.” Human Mutation 28.9 (2007): 897–903. Print.

"Maroteaux Lamy Syndrome." National Organization for Rare Disorders, 16 July 2020, rarediseases.org/rare-diseases/maroteaux-lamy-syndrome/. Accessed 10 Sept. 2024.

McKusick, Victor A., et al. "#253200 Mucopolysaccharidosis Type VI; MPS6." OMIM.org. Johns Hopkins U, 4 Oct. 2012. Web. 4 Aug. 2014.

"Mucopolysaccharidoses Fact Sheet." National Institute of Neurological Disorders and Stroke. Natl. Institutes of Health, US Dept. of Health and Human Services, 16 Apr. 2014. Web. 4 Aug. 2014.

"Mucopolysaccharidosis type VI." Medline Plus, 28 June 2021, medlineplus.gov/genetics/condition/mucopolysaccharidosis-type-vi/. Accessed 10 Sept. 2024.

Sinagra, Gianfranco, Fulvio Camerini, and Luisa Mestroni, eds. Genetic Cardiomyopathies: A Clinical Approach. New York: Springer-Verlag Italia, 2012. Print.

Valayannopoulos, Vassili, Helen Nicely, Paul Harmatz, and Sean Turbeville. "Mucopolysaccharidoses VI." Orphanet Journal of Rare Diseases 5.5 (2010): n. pag. Web. 4 Aug. 2014.