Talk:Sly syndrome

August, 2018: Mepsevii

Mucopolysaccharidosis type VII (Sly syndrome)

MPS VII, Beta-glucuronidase deficiency, Mucopolysaccharidosis type 7, MPS 7, Sly syndrome, Mucopolysaccharidosis type VII, GUSB deficiency

Overview

Mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome, is a rare, progressive lysosomal storage disease was first described in 1973 by Dr. William Sly.

It is caused by the inherited deficiency of the β-glucuronidase enzyme due to mutations in the beta-glucuronidase (GUSB) gene. Deficient β-glucuronidase activity leads to the accumulation of glycosaminoglycans (GAGs) in the lysosomes of many tissues, causing multi-organ dysfunction, cognitive impairment and reduced life expectancy. The GUSB gene encoding for the β-glucuronidase enzyme is located on chromosome 7q11.22-7q11.22, containing 12 exons and spanning 20 kb of genomic deoxyribonucleic acid (DNA). Over 60 unique disease-causing mutations have been identified in MPS VII patients. At present, genotype/phenotype correlations have not been defined for MPS VII, and patients cannot be classified according to genotype.

MPS VII has an overall prevalence of 1:300,000-1:2,000,000. It is estimated that there are 200 patients living with MPS VII worldwide. The actual incidence and prevalence of MPS VII may be underestimated due to lack of diagnosis or early death in infancy. MPS VII is inherited in an autosomal recessive manner.

MPS VII is a chronic, progressive disease with marked variability in phenotypic expression. Symptoms of MPS VII can present in the prenatal or postnatal period.

Some cases of MPS VII are characterized by hydrops fetalis, a condition in which excess fluid builds up in the fetus before birth. While most babies with hydrops fetalis are stillborn or die soon after birth, the condition is not always fatal. MPS VII is the most commonly diagnosed lysosomal storage disorder in NIHF. A survey-based natural history study of 56 patients with MPS VII found that approximately 40% (23 patients) had a history of NIHF. The presence of hydrops fetalis does not predict the eventual severity of the disease.

Features/Characteristics The features of MPS VII include a large head (macrocephaly), a buildup of fluid in the brain (hydrocephalus), distinctive-looking facial features that are described as "coarse," and a large tongue (macroglossia). Affected individuals also frequently develop an enlarged liver and spleen (hepatosplenomegaly), heart valve abnormalities, and a soft out-pouching around the belly-button (umbilical hernia) or lower abdomen (inguinal hernia). The airway may become narrow in some people with MPS VII, leading to frequent upper respiratory infections and short pauses in breathing during sleep (sleep apnea). The clear covering of the eye (cornea) becomes cloudy, which can cause significant vision loss. People with MPS VII may also have recurrent ear infections and hearing loss. Affected individuals may have developmental delay and progressive intellectual disability, although intelligence is unaffected in some people with this condition. MPS VII causes various skeletal abnormalities that become more pronounced with age, including short stature and joint deformities (contractures) that affect mobility. Individuals with this condition may also have dysostosis multiplex, which refers to multiple skeletal abnormalities seen on x-ray. Carpal tunnel syndrome develops in many children with MPS VII and is characterized by numbness, tingling, and weakness in the hands and fingers. People with MPS VII may develop a narrowing of the spinal canal (spinal stenosis) in the neck, which can compress and damage the spinal cord. Clinical presentations include: • Head, eyes, ear-nose-throat: course facial features, hearing loss, corneal clouding • Lung and heart: decreased pulmonary function, obstructive airway disease, cardiac valve disease, cardiomyopathies • Thoracolumbar and abdominal: large liver and spleen, hernias • Musculoskeletal: joint stiffness and pain, skeletal abnormalities • Neurological: cognitive impairment • Some patients may have non-immune hydrops fetalis (NIHF), a severe neonatal condition of collection of fluid in at least two body areas, such as lungs, heart, and abdomen

Diagnosis Variable time between symptom onset and diagnosis is observed in MPS VII. Diagnosis of MPS VII is often suggested through clinical examination and urine tests for excess glycosaminoglycan (GAG) excretion. Urinary GAG testing is a screening test for MPS VII, and usually the first step in the diagnostic pathway. Enzyme activity assay is considered the gold standard for a definitive diagnosis of MPS. GUSB gene sequencing is available to confirm diagnosis and identify the disease-causing mutation for carrier testing in family members.

Prognosis

MPS VII negatively impacts function, independence, and quality of life. The multi-organ clinical manifestations of MPS disorders can lead to poor endurance, restricted mobility, pain, and fatigue. Patients with MPS VII have a shortened life expectancy.

Treatment

Management goals for MPS VII include early diagnosis and supportive care to manage symptoms such as lung and heart complications, loss of hearing and vision, joint and bone symptoms. Bone marrow transplantation is rarely used in MPS VII as there is little experience, and high morbidity and mortality risk due to other complications

Vestronidase alfa-vjbk is currently the only FDA-approved enzyme replacement therapy for MPS VII. The effect of this drug on the central nervous system manifestations of MPS VII has not been determined.

Gary at Ultragenyx (talk) 20:23, 2 August 2018 (UTC)Gary at Ultragenyx