MPS VI

MPS VI
Name	MPS VI
Synonyms	Maroteaux–Lamy syndrome
Inheritance	Autosomal recessive
Gene	ARSB
Enzyme	N-acetylgalactosamine-4-sulfatase
OMIM	253200
Orphanet	583
MedlinePlus	001206
EMedicineSubj	ped
EMedicineTopic	1376
DiseasesDB	7226

MPS VI. MPS VI, also known as Maroteaux–Lamy syndrome, is a rare lysosomal storage disease caused by a deficiency of the enzyme N-acetylgalactosamine-4-sulfatase. This deficiency leads to the accumulation of complex carbohydrates called glycosaminoglycans within lysosomes of cells throughout the body. The progressive buildup of these substances results in widespread cellular and tissue dysfunction, manifesting in a multisystemic disorder primarily affecting the skeleton, heart valves, cornea, and other connective tissues.

Signs and symptoms

The clinical presentation is highly variable but typically involves severe skeletal dysplasia, often described as dysostosis multiplex. This includes characteristic facial features, short stature, kyphoscoliosis, and joint contractures. Patients frequently develop hepatomegaly and splenomegaly due to glycosaminoglycan storage. Corneal clouding is common and can impair vision, while hearing loss may occur from recurrent otitis media or nerve involvement. Cardiovascular complications are a major concern, with progressive thickening of the heart valves, particularly the mitral valve and aortic valve, leading to valvular heart disease. Obstructive sleep apnea and restrictive lung disease can arise from upper airway abnormalities and reduced chest wall mobility.

Genetics

MPS VI is inherited in an autosomal recessive pattern, meaning an affected individual must inherit two defective copies of the responsible gene, one from each parent. The disease is caused by mutations in the ARSB gene located on chromosome 5q14.1. This gene provides instructions for producing the enzyme N-acetylgalactosamine-4-sulfatase, also known as arylsulfatase B. Over 130 different mutations in ARSB have been identified, including missense mutations, nonsense mutations, and small deletions. The specific mutations influence the residual enzyme activity, which correlates with the wide spectrum of disease severity observed, ranging from rapidly progressive, severe forms to slower, attenuated variants.

Diagnosis

Diagnosis is suspected based on clinical findings and confirmed through laboratory testing. Initial screening often involves detecting elevated levels of dermatan sulfate in the urine via tests like the Berry spot test or quantitative glycosaminoglycan analysis. Definitive diagnosis requires demonstration of deficient N-acetylgalactosamine-4-sulfatase activity in leukocytes or cultured skin fibroblasts. Molecular genetic testing of the ARSB gene can identify the causative mutations, which is valuable for confirming the diagnosis, predicting disease severity, and facilitating genetic counseling. Prenatal diagnosis is available for at-risk pregnancies through enzyme assay of cultured amniocytes or chorionic villus sampling.

Treatment

The standard of care is enzyme replacement therapy with galsulfase, a recombinant form of N-acetylgalactosamine-4-sulfatase approved by the Food and Drug Administration and the European Medicines Agency. Administered by weekly intravenous infusion, it helps reduce glycosaminoglycan accumulation, improving endurance and mobility while stabilizing or slowing progression of organ involvement. Hematopoietic stem cell transplantation has been used historically, particularly in severe, early-onset cases, to provide a source of enzyme-producing cells. Management is multidisciplinary, often involving orthopedic surgery for carpal tunnel syndrome and spinal cord compression, cardiac surgery for valve replacement, and interventions for hydrocephalus and hearing loss.

Prognosis

The prognosis varies significantly with the severity of the disease and the age at which symptoms begin. Without treatment, the severe classical form leads to progressive physical decline, with survival rarely extending beyond the second or third decade, often due to cardiorespiratory failure. The attenuated form allows for longer survival into adulthood, though with significant morbidity. The advent of enzyme replacement therapy has substantially altered the natural history, improving survival and quality of life by stabilizing many disease manifestations. However, therapy does not reverse established skeletal or corneal changes, and patients require lifelong, comprehensive monitoring and supportive care.

Epidemiology

MPS VI is considered an ultra-rare disorder with an estimated incidence between 1 in 43,000 and 1 in 1.5 million live births globally. The prevalence shows significant geographic and ethnic variation. Higher incidence rates have been reported in specific populations, such as in Turkey, Portugal, and Brazil, likely due to founder effects and a higher degree of consanguinity. In the United States, the estimated prevalence is approximately 0.36 per 100,000 live births. The disease affects males and females equally, consistent with its autosomal recessive inheritance.

Category:Lysosomal storage diseases Category:Autosomal recessive disorders