Maroteaux–Lamy syndrome

Other Names: MPS VI; Mucopolysaccharidosis type 6; MPS 6; Arylsulfatase B deficiency; ARSB deficiency; N-acetylgalactosamine-4-sulfatase deficiency; Mucopoly-saccharidosis type VI; Maroteaux Lamy syndrome

Mucopolysaccharidosis type 6 (MPS 6) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B (ASB) leading to the accumulation of dermatan sulfate.

Corneal clouding visible in the eye of a 30-year-old male with MPS VI

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A slowly-progressing female patient in her 20s, showing few physical abnormalities

Clinical description

The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease.

Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (GAG, generally >100 microgram/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades.

A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally <100 microgram/mg creatinine), mild dysostosis multiplex, with death in the 4th or 5th decades. Other clinical findings may include cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Although intellectual deficit is generally absent in MPS 6, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness.

Cause

Mutations in the ARSB gene cause MPS VI. The ARSB gene provides instructions for producing an enzyme called arylsulfatase B, which is involved in the breakdown of large sugar molecules called glycosaminoglycans (GAGs). GAGs were originally called mucopolysaccharides, which is where this condition gets its name. Mutations in the ARSB gene reduce or completely eliminate the function of arylsulfatase B. The lack of arylsulfatase B activity leads to the accumulation of GAGs within cells, specifically inside the lysosomes. Lysosomes are compartments in the cell that digest and recycle different types of molecules. Conditions such as MPS VI that cause molecules to build up inside the lysosomes are called lysosomal storage disorders. The accumulation of GAGs within lysosomes increases the size of the cells, which is why many tissues and organs are enlarged in this disorder. Researchers believe that the buildup of GAGs may also interfere with the functions of other proteins inside lysosomes, triggering inflammation and cell death.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Symptoms

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormality of the metaphysis(Abnormality of the wide portion of a long bone)
• Chronic otitis media(Chronic infections of the middle ear)
• Coarse facial features(Coarse facial appearance)
• Disproportionate short-trunk short stature(Disproportionate short-trunked dwarfism)
• Epiphyseal dysplasia(Abnormal development of the ends of long bones in arms and legs)
• Failure to thrive(Faltering weight)
• Joint stiffness(Stiff joint)
• Mucopolysacchariduria
• Opacification of the corneal stroma
• Recurrent upper respiratory tract infections(Recurrent colds)
• Sinusitis(Sinus inflammation)
• Thick lower lip vermilion(Increased volume of lower lip)
• Thick nasal alae

30%-79% of people have these symptoms

• Broad ribs(Wide ribs)
• Genu valgum(Knock knees)
• Hearing impairment(Deafness)
• Hernia
• Kyphosis(Hunched back)
• Ovoid vertebral bodies
• Short neck(Decreased length of neck)
• Splenomegaly(Increased spleen size)

5%-29% of people have these symptoms

• Abnormal heart valve morphology
• Cognitive impairment(Abnormality of cognition)
• Macroglossia(Abnormally large tongue)
• Visual impairment(Impaired vision)

Diagnostic methods Diagnosis generally requires evidence of clinical picture, ASB activity of less than 10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes, and demonstration of a normal activity of a different sulfatase enzyme (to exclude mucosulfatidosis, see this term). The finding of elevated urinary dermatan sulfate with the absence of heparan sulfate is supportive.

Differential diagnosis

In addition to multiple sulfatase deficiency, the differential diagnosis should also include other forms of MPS (MPS 1, 2, 4A, 7), sialidosis and mucolipidosis.

Treatment

Before enzyme replacement therapy (ERT) with galsulfase (Naglazyme®), clinical management was limited to supportive care and hematopoietic stem cell transplantation. Galsulfase is now widely available and is a specific therapy providing improved endurance with an acceptable safety profile. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• N-acetylgalactosamine-4-sulfatase, recombinant human (Brand name: Naglazyme) For patients with mucopolysaccharidosis VI. Galsulfase has been shown to improve walking and stair-climbing capacity.

Epidemiology

Birth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births.

Prognosis

Prognosis is variable depending on the age of onset, rate of disease progression, age at initiation of ERT and on the quality of the medical care provided.