Sly syndrome, also called

mucopolysaccharidosis Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosome, lysosomal enzymes needed to break down molecules called glycosaminoglycans (GAGs). These long chains of sugar carbohydrates occur within ...

type VII (MPS-VII), is an

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

lysosomal storage disease Lysosomal storage diseases (LSDs; ) are a group of over 70 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other ...

caused by a deficiency of the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

β-glucuronidase Beta-glucuronidases are members of the glycosidase family of enzymes that catalyze breakdown of complex carbohydrates. Human β-glucuronidase is a type of glucuronidase (a member of glycosidase Family 2) that catalyzes hydrolysis of β-D-glucur ...

. This enzyme is responsible for breaking down large sugar molecules called

glycosaminoglycan Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case ...

s (AKA GAGs, or mucopolysaccharides). The inability to break down GAGs leads to a buildup in many tissues and organs of the body. The severity of the disease can vary widely.

Signs and symptoms

The most severe cases of Sly syndrome can result in

hydrops fetalis Hydrops foetalis or hydrops fetalis is a condition in the fetus characterized by an accumulation of fluid, or edema, in at least two fetal compartments. By comparison, hydrops allantois or hydrops amnion is an accumulation of excessive fluid in ...

, which results in

fetal A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal develo ...

death or death soon after birth. Some people with Sly syndrome may begin to have symptoms in early childhood. Symptoms can include an enlarged head, fluid buildup in the brain, coarse facial features, enlarged tongue,

enlarged liver Hepatomegaly is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdomi ...

enlarged spleen Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulating ...

, problems with the

heart valve A heart valve is a one-way valve that allows blood to flow in one direction through the chambers of the heart. Four valves are usually present in a mammalian heart and together they determine the pathway of blood flow through the heart. A heart v ...

s, and abdominal

hernia A hernia is the abnormal exit of tissue or an organ (anatomy), organ, such as the bowel, through the wall of the cavity in which it normally resides. Various types of hernias can occur, most commonly involving the abdomen, and specifically the gr ...

s. People with Sly syndrome may also suffer from

sleep apnea Sleep apnea, also spelled sleep apnoea, is a sleep disorder in which pauses in breathing or periods of shallow breathing during sleep occur more often than normal. Each pause can last for a few seconds to a few minutes and they happen many times ...

, frequent lung infections, and problems with vision secondary to cloudy

cornea The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical power ...

s. Sly syndrome causes various musculoskeletal abnormalities that worsen with age. These can include short stature, joint deformities, dysostosis multiplex,

spinal stenosis Spinal stenosis is an abnormal narrowing of the spinal canal or neural foramen that results in pressure on the spinal cord or nerve roots. Symptoms may include pain, numbness, or weakness in the arms or legs. Symptoms are typically gradual in on ...

, and

carpal tunnel syndrome Carpal tunnel syndrome (CTS) is the collection of symptoms and signs associated with median neuropathy at the carpal tunnel. Most CTS is related to idiopathic compression of the median nerve as it travels through the wrist at the carpal tunn ...

. While some individuals have developmental delay, others may have normal intelligence. However, the accumulation of GAGs in the brain usually leads to the slowing of development from ages 1–3, and then a loss of previously learned skills until death.

Genetics

The defective gene responsible for Sly syndrome is located on

chromosome 7 Chromosome 7 is one of the 23 pairs of chromosomes in humans, who normally have two copies of this chromosome. Chromosome 7 spans about 159 million base pairs (the building material of DNA) and represents between 5 and 5.5 percent of the total DN ...

Diagnosis

Most people with Sly disease will have elevated levels of GAGs seen in the urine. A confirmatory test is necessary for diagnosis. Skin cells and

red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...

s of affected people will have low levels of β-glucuronidase activity. Sly syndrome can also be diagnosed through

prenatal testing Prenatal testing consists of prenatal screening and prenatal diagnosis, which are aspects of prenatal care that focus on detecting problems with the pregnancy as early as possible. These may be anatomic and physiologic problems with the health of ...

Treatment

Vestronidase alfa-vjbk Vestronidase alfa, sold under brand name Mepsevii, is a drug for the treatment of Sly syndrome. It is a recombinant form of the human enzyme beta-glucuronidase. It was approved in the United States in November 2017, to treat children and adul ...

(trade name Mepsevii), an enzyme replacement therapy which is a recombinant form of human β-glucuronidase, is approved by U.S. Food and Drug Administration for the treatment of Sly syndrome.

Hematopoietic stem cell transplant Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce ...

(HSCT) has been used to treat other types of MPS diseases, but this is not yet available for MPS-VII. Animal experiments suggest that HSCT may be an effective treatment for MPS-VII in humans.

Prognosis

The life expectancy of individuals with MPS VII varies depending on the symptoms. Some individuals are stillborn, while some may survive into adulthood.

Epidemiology

MPS-VII is one of the rarest forms of MPS. It occurs in less than 1 in 250,000 births. As a family, MPS diseases occur in 1 in 25,000 births, and the larger family of lysosomal storage diseases occur in 1 out of 7,000 to 8,000 births.

History

Sly syndrome was originally discovered in 1972. It was named after its discoverer William S. Sly, an American biochemist who has spent nearly his entire academic career at Saint Louis University.

References

External links

{{Mucopolysaccharidoses Proteoglycan metabolism disorders Autosomal recessive disorders Syndromes Rare diseases Skin conditions resulting from errors in metabolism