Mucopolysaccharidosis type VII

Other Names: MPS VII; Mucopolysaccharidosis type 7; MPS 7; Beta-glucuronidase deficiency; GUSB deficiency; Sly syndrome A rare, genetic lysosomal storage disease characterized by accumulation of glycosaminoglycans in connective tissue which results in progressive multisystem involvement with severity ranging from mild to severe. The most consistent features include musculoskeletal involvement (particularly dysostosis multiplex, joint restriction, thorax abnormalities, and short stature), limited vocabulary, intellectual disability, coarse facies with a short neck, pulmonary involvement (predominantly decreased pulmonary function), corneal clouding, and cardiac valve disease.

Cause

Mutations in the GUSB gene cause MPS VII. This gene provides instructions for producing the beta-glucuronidase (β-glucuronidase) enzyme, 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 GUSB gene reduce or completely eliminate the function of β-glucuronidase. The shortage (deficiency) of β-glucuronidase 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 VII that cause molecules to build up inside the lysosomes are called lysosomal storage disorders. The accumulation of GAGs increases the size of the lysosomes, which is why many tissues and organs are enlarged in this disorder. Researchers believe that the GAGs may also interfere with the functions of other proteins inside the lysosomes and disrupt many normal functions of cells.

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.

Signs and symptoms

Signs are extremely variable: there are prenatal forms with non-immune hydrops fetalis, and severe neonatal forms with dysmorphism, hernias, hepatosplenomegaly, club feet, dysostosis, small stature and severe hypotonia and neurological involvement that ultimately lead to profound intellectual deficit in patients who survive. At the other end of the spectrum, there are very mild cases that are discovered during adolescence or adulthood following presentation with thoracic kyphosis. 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

• Abnormal pleura morphology
• Anterior beaking of lower thoracic vertebrae
• Anterior beaking of lumbar vertebrae
• Ascites(Accumulation of fluid in the abdomen)
• Coarse facial features(Coarse facial appearance)
• Corneal opacity
• Diaphyseal thickening(Thickening of shaft or central part of long bones)
• Flat face(Flat facial shape)
• Inguinal hernia
• Intellectual disability(Mental deficiency)
• Lymphedema(Swelling caused by excess lymph fluid under skin)
• Recurrent respiratory infections(Frequent respiratory infections)
• Scoliosis
• Umbilical hernia

30%-79% of people have these symptoms

• Abnormality of the hip bone(Abnormality of the hips)
• Epiphyseal stippling(Speckled calcifications in end part of bone)
• Hepatitis(Liver inflammation)
• Hydrops fetalis
• Joint stiffness(Stiff joint)
• Metatarsus adductus(Front half of foot turns inward)
• Mucopolysacchariduria
• Muscular hypotonia(Low or weak muscle tone)
• Splenomegaly(Increased spleen size)

5%-29% of people have these symptoms

• Arteriovenous malformation
• Enlarged thorax(Wide rib cage)
• Short neck(Decreased length of neck)

Diagnosis

Diagnosis is supported by x-ray evidence of dysostosis multiplex and detection of increased levels of urinary glycosaminoglycan (either CS alone or CS+HS+DS) excretion, although this sign may be absent in adult forms. Diagnosis is confirmed by demonstration of beta-D-glucuronidase deficiency in cultured leucocytes or fibroblasts. Pseudodeficient alleles make mild forms more difficult to identify and prenatal diagnosis difficult.

Differential diagnosis

Differential diagnosis includes other types of mucopolysaccharidosis (MPS) and oligosaccharidosis. The determination of enzymatic activity in leucocytes allows heterozygous individuals to be detected for the severe forms. When the two mutations have been identified in the index patient, the detection of heterozygous relatives can be performed accurately.

Antenatal diagnosis

Diagnosis is possible in forms with in utero presentation and may prevent recurrence of pregnancies leading to in utero death or late termination of the pregnancy. Prenatal diagnosis (by molecular analysis or measurement of enzyme activity in trophoblasts or amniocytes) can be offered to parents with an affected child. Parents should be made aware of the availability of enzyme replacement therapy (ERT).

Treatment

ERT with recombinant human beta-glucuronidase has been approved in Europe and the USA for MPS type 7, and has shown improvement in walking, lung function and hepatosplenomegaly in clinical trials. Still, multidisciplinary management allows adapted symptomatic treatment, which is essential for improving the quality of life of the patients. In late-onset forms, treatment is mainly orthopedic. Bone marrow transplantation has been successful in three of five patients.

The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Vestronidase alfa-vjbk (Brand name: Mepsevii) Treatment of mucoploysaccharidosis type VII (MPS VII, Sly syndrome) in pediatric and adult patients.

Epidemiology

The prevalence at birth is reported to range between 1/345,000 -5,000,000. However, the frequency of the disease may be underestimated as the most frequent presentation is the antenatal form, which remains underdiagnosed.

Prognosis

Prognosis is typically poor for antenatal forms, often leading to death in utero. Neonatal and childhood forms typically have a very limited life expectancy, whereas milder forms have a prolonged survival. Whilst ERT is now available, long term outcome data are not yet available on the ERT treated patients.

NIH genetic and rare disease info

• NIH info on Mucopolysaccharidosis type VII

Mucopolysaccharidosis type VII is a rare disease.