Sly syndrome

Overview

Sly syndrome, also known as Mucopolysaccharidosis type VII (MPS VII), is a rare inherited lysosomal storage disorder characterized by a deficiency of the enzyme beta-glucuronidase. This enzyme is essential for breaking down glycosaminoglycans (GAGs), complex sugar molecules found in connective tissue. In the absence or deficiency of beta-glucuronidase, GAGs accumulate in various tissues and organs, leading to progressive cellular damage and multi-system complications.

The severity and age of onset of Sly syndrome can vary widely, ranging from a severe neonatal form to a milder, later-onset presentation. It is part of a broader group of disorders known as mucopolysaccharidoses, each of which involves specific enzyme deficiencies leading to similar pathological outcomes.

Causes

Sly syndrome is caused by mutations in the GUSB gene, which encodes the beta-glucuronidase enzyme. These genetic mutations impair the enzyme's ability to break down glycosaminoglycans such as dermatan sulfate, heparan sulfate, and chondroitin sulfate. The accumulation of these substances disrupts normal cellular function and contributes to the characteristic symptoms of the disease.

The condition follows an autosomal recessive inheritance pattern. This means that a child must inherit two copies of the mutated gene — one from each parent — to be affected by the disorder. Carriers, who have one normal and one mutated gene, typically do not show symptoms but can pass the mutation to their offspring.

Symptoms

The clinical presentation of Sly syndrome can vary based on the level of residual enzyme activity, but common symptoms include:

• Coarse facial features

• Enlarged liver and spleen (hepatosplenomegaly)

• Short stature and skeletal abnormalities (dysostosis multiplex)

• Delayed cognitive development or intellectual disability

• Joint stiffness and restricted movement

• Hernias (umbilical or inguinal)

• Respiratory complications and frequent infections

• Heart valve abnormalities

• Clouding of the cornea and vision problems

• Hearing loss

Severe forms of the disease may be evident at birth, including hydrops fetalis (severe fluid buildup in the fetus), which can be life-threatening. Milder forms may present later in childhood or adolescence with fewer systemic complications.

Diagnosis

Diagnosing Sly syndrome involves a combination of clinical examination, biochemical tests, and genetic analysis. Key diagnostic steps include:

• Urine tests: Elevated levels of glycosaminoglycans (GAGs) in the urine may suggest a mucopolysaccharidosis disorder.

• Enzyme assay: Measuring the activity of beta-glucuronidase in white blood cells or cultured skin fibroblasts confirms the enzymatic deficiency.

• Genetic testing: Molecular analysis of the GUSB gene can identify causative mutations and confirm the diagnosis.

• Imaging studies: X-rays or MRI scans may reveal characteristic skeletal abnormalities.

• Prenatal testing: Available for families with a known mutation through chorionic villus sampling or amniocentesis.

Treatment

There is no cure for Sly syndrome, but various therapies are available to manage symptoms and improve quality of life. Treatment strategies include:

• Enzyme replacement therapy (ERT): Vestronidase alfa is an FDA-approved recombinant form of human beta-glucuronidase that can reduce GAG accumulation in tissues and alleviate symptoms.

• Supportive care: Physical therapy, occupational therapy, and speech therapy can assist with mobility, communication, and daily functioning.

• Surgical interventions: May be required for hernias, joint contractures, or spinal decompression in severe skeletal involvement.

• Cardiac and respiratory monitoring: Regular follow-up with specialists to manage complications like heart valve dysfunction or obstructive sleep apnea.

• Hematopoietic stem cell transplantation (HSCT): Has been attempted in some cases but remains controversial due to variable outcomes and associated risks.

Prognosis

The prognosis for individuals with Sly syndrome varies widely depending on the severity of the condition and the effectiveness of treatment. In severe neonatal-onset cases, life expectancy may be significantly shortened due to complications such as hydrops fetalis or organ failure. In milder forms, individuals may live into adolescence or adulthood, although ongoing medical care is usually necessary to manage complications and maintain function.

Early diagnosis and initiation of enzyme replacement therapy can improve clinical outcomes and help delay the progression of the disease. Genetic counseling is recommended for affected families to understand recurrence risks and explore prenatal diagnosis options in future pregnancies.