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MAROTEAUX LAMY SYNDROME

Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI; MPS VI) is a rare genetic disorder characterized by complete or partial lack of activity of the enzyme arylsulphatase B (also called N-acetylgalactosamine-4-sulfatase). Deficiency or absence of this enzyme activity leads to the accumulation of complex carbohydrates called glycosaminoglycans (previously known as mucopolysaccharides) in the body. Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome,is a progressive condition that causes many tissues and organs to enlarge and become inflamed or scarred. Skeletal abnormalities are also common in this condition. The rate at which symptoms worsen varies among affected individuals.

Arylsulfatase B

Introduction

The mucopolysaccharidoses (MPS) are a group of inherited lysosomal storage disorders. More than 50 lysosomal storage disorders have been identified so far. Lysosomes function as the primary digestive units within cells. Enzymes within lysosomes break down or digest particular metabolites, such as certain carbohydrates and fats. In individuals with MPS disorders, deficiency or malfunction of specific lysosomal enzymes leads to an abnormal accumulation of certain complex carbohydrates known as mucopolysaccharides or glycosaminoglycans in the arteries, skeleton, eyes, joints, ears, skin, and/or teeth. These accumulations may also be found in the respiratory system, liver, spleen, central nervous system, blood, and bone marrow. This accumulation eventually causes progressive damage to cells, tissues, and various organ systems of the body. There are several different types and subtypes of MPS. These disorders, with one exception (MPS type II), are inherited in an autosomal recessive manner. Maroteaux-Lamy syndrome was named from the two French physicians who first described this disorder in the medical literature in 1963.

Synonyms of Maroteaux Lamy Syndrome

• arylsulfatase-B Deficiency
• MPS 6
• MPS type VI
• MPS VI
• mucopolysaccharidosis type VI
• polydystrophic dwarfism

Inheritance Pattern

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.Maroteaux-Lamy syndrome is caused by mutations in the ARSB gene. Genes provide instructions for making proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

Investigators have determined that the ARSB gene is located on the long arm (q) of chromosome 5 (5q13-q14). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 5q13-q14” refers to bands 13-14 on the long arm of chromosome 5. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The ARSB gene is related to (encodes) the lysosomal enzyme arylsulfatase B. Deficiency of this enzyme results in the accumulation of dermatan sulfate, a type of mucopolysaccharide, in the cells of various tissues of the body. More than 140 different mutations in the ARSB gene have been identified. Certain mutations are more likely to be associated with specific symptoms and/or severity (genotype-phenotype correlation).

The ARSB mutation is inherited as an autosomal recessive disorder. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal copy of the gene and one mutation that causes the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% in each pregnancy. The risk to have a child who is a carrier like the parents is 50% in each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

Frequency

The exact incidence of MPS VI is unknown, although it is estimated to occur in 1 in 250,000 to 600,000 newborns. Maroteaux-Lamy syndrome affects males and females in equal proportion. The exact incidence and prevalence of the disorder is unknown. The prevalence of all forms of MPS is estimated to be from one in 43,261 to one in 1,505,160 births. However, because MPS disorders, especially milder forms, often go unrecognized, these disorders are underdiagnosed or misdiagnosed, making it difficult to determine their true frequency in the general population.

Clinical Features

Although mental development proceeds normally in Maroteaux-Lamy patients, the progression of physical and visual impairments ultimately impedes psychomotor abilities. The clinical features and severity in Maroteaux-Lamy patients is variable, but usually include short stature, hepatosplenomegaly, stiff joints, corneal clouding, cardiac abnormalities, facial dysmorphism and dystosis multiplex. Dystosis multiplex refers to a constellation of skeletal abnormalities that are characterized by an enlarged skull, thickened calvarium, premature closure of lamboid and sagittal sutures, shallow orbits, enlarged J-shaped sella turcica (a saddle-shaped skull structure into which sits the bottom of the pituitary gland), and abnormal spacing of the teeth with dentigerous cysts. There is anterior hypoplasia of the lumbar vertebrae, the long bone diaphyses are enlarged and an irregular appearance of the metaphyses. The epiphyseal centers not well developed, the pelvis is poorly formed with small femoral heads and coxa valga. The clavicles are short, thick and irregular and the ribs are oar shaped. Phalanges are shortened and trapezoidal in shape. Hepatosplenomegaly is always present in Maroteaux-Lamy patients after the age of 6. In patients with the most severe forms of the disease there is a shortened trunk, protuberant abdomen and prominent lumbar lordosis (excessive inward curvature of the lower spine). Because of the cardiac involvement, most patients with the severe forms of the disease will die of heart failure by the second or third decade.

Signs & Symptoms

The symptoms, onset and rate of progression of Maroteaux-Lamy syndrome vary greatly from one person to another. The disorder can be thought of as a spectrum or continuum of disease. Some individuals may only have a few symptoms and others may have serious symptoms affecting several different organ systems simultaneously. Maroteaux-Lamy syndrome can potentially cause life-threatening complications. Some individuals will have severe symptoms during infancy, while others have slowly progressive symptoms that develop over the course of multiple decades.

Rapidly progressive Maroteaux-Lamy syndrome is associated with an onset before three years of age. Affected individuals may develop walking problems (impaired mobility) by the age of 10 and experience delayed or absence of puberty. These individuals may be at risk of heart failure by second or third decades of life.

Slowly progressive disease is characterized by later onset. A diagnosis is usually obtained after five years of age, most often during the second or third decade. Despite a slower progression, individuals may still develop a decrease in overall function and ability by their late teen-aged years. Most individuals with Maroteaux-Lamy syndrome will develop serious complications at some point such as joint degeneration, cardiovascular disease, reduced pulmonary function or sleep apnea.

Intelligence is usually not affected in Maroteaux-Lamy syndrome. However, learning difficulties may be present as a consequence of other problems associated with the disorder (e.g., hearing loss).

Affected individuals often exhibit short stature due to growth restrictions. Short stature is described as disproportionate because the trunk may be shorter than the legs. In severe cases, final height may be less than 4 feet (120 centimeters). Degenerative joint disease is also common and can lead to the development of multiple joint contractures. A contracture occurs when thickening or shortening of tissue such as muscle fibers cause deformity and restrict the movement of an affected joint.

Affected individuals may experience chronic watery, mucous discharge from nose (rhinorrhea), frequent sinus infections, and middle ear infections (otitis media). Hearing loss is common. Hearing loss may be due to failure of sound to be conducted from the outer ear trough the eardrum and tiny bones of the middle ear (conductive hearing loss) or may be due to damage to the inner ear or the nerves that transmit sound from the inner ear to the brain (sensorineural). In rare cases, hearing loss may be due to a combination of both problems (mixed hearing loss).

Abnormalities of the heart are common in children with Maroteaux-Lamy syndrome. Symptoms associated with heart disease can include breathlessness, cough, wheezing, excessive sweating and recurrent chest infections.

Diagnosis

A diagnosis of Maroteaux-Lamy syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests.

Clinical Testing and Workup In individuals suspected of Maroteaux-Lamy syndrome the urine will be examined to assess the levels of the mucopolysaccharides. Elevated levels of dermatan sulfate are indicative of Maroteaux-Lamy syndrome. In addition, a blood sample may be taken to measure the enzyme activity of arylsulfatase B because deficient or absent activity of this enzyme is also indicative of the disorder. Certain types of skin cells (skin fibroblasts) can also be examined to determine arylsulfatase B enzyme activity.

Molecular genetic testing can confirm a diagnosis of Maroteaux-Lamy syndrome. Molecular genetic testing can detect mutations in the gene ARSB, but is available only at specialized laboratories.

Standard Therapies

Treatment

The treatment of Maroteaux-Lamy syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, orthopedists, cardiologists, dental specialists, ear-nose-throat specialists (otorhinolaryngologists), specialists who deal with diseases of the lungs and respiratory tract (pulmonologists), specialists who asses and treat hearing problems (audiologists), specialists who asses and treat vision problems (ophthalmologists), and other healthcare professionals may need to systematically and comprehensively plan the treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.

Additional treatment is symptomatic and supportive. For example, surgery may be necessary to treat various abnormalities associated with Maroteaux-Lamy syndrome including carpal tunnel syndrome, skeletal malformations, spinal cord compression, degeneration of the hip, and hernias. Heart valve replacement may be necessary in some cases. Surgical removal of the tonsils and/or adenoids may be recommended. Tracheomalacia is usually treated by noninvasive measures, but in rare cases can require surgical intervention.

Hydrocephalus may be treated by the insertion of a tube (shunt) to drain excess of cerebrospinal fluid (CSF) away from the brain and into another part of the body where the CSF can be absorbed. A corneal transplantation can be performed for individuals with severe corneal clouding. Individuals with conductive hearing loss may experience the accumulation of a sticky fluid within the middle ear (glue ear). This is treated with a procedure called a myringotomy, in which a thin incision is made in the eardrum to release the fluid. There is no specific treatment for sensorineural hearing loss. Hearing aids may help to maximize remaining hearing.

Certain medications can be used to treat heart abnormalities, asthma-like episodes, and chronic infections. Anti-inflammatory medications may be of benefit. Respiratory insufficiency may require treatment with supplemental oxygen. Aggressive management of airway secretions is necessary as well.

Some affected individuals may undergo a sleep study, in which people are evaluated on how well they sleep and how well their body responds to sleep problems. Sleep apnea may be treated with continuous positive airway pressure (CPAP), which involves the use of a mask or similar device to deliver mild air pressure to keep airways open. In some cases, a similar treatment method known as bilevel positive airway pressure (BPAP) may be used. BPAP devices provide more pressure when you breathe in and less pressure when you breathe out.

Physical therapy and exercise may improve joint stiffness. Speech therapy may help children with hearing loss communicate effectively. Nutritional counseling and occupational therapy may also beneficial.