Maroteaux-Lamy Syndrome (Mucopolysaccharidosis Type VI) 

Updated: Mar 20, 2017
Author: Paul R Harmatz, MD; Chief Editor: Maria Descartes, MD 

Overview

Background

Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome and polydystrophic dwarfism, which is inherited as an autosomal-recessive trait, results from the deficiency of N- acetylgalactosamine 4-sulfatase (arylsulfatase B) activity and the lysosomal accumulation of dermatan sulfate. MPS VI is characterized by somatic features but not by mental retardation.

The mucopolysaccharidoses (MPSs) are a group of inherited disorders that result from the deficiency of 1 or more of the lysosomal enzymes required for glycosaminoglycan (GAG) catabolism. GAGs, which are a major constituent of connective tissues, are long-chain complex carbohydrates that are usually linked to proteins to form proteoglycans and include chondroitin 4-sulfate, chondroitin 6-sulfate, heparan sulfate, dermatan sulfate, keratan sulfate, and hyaluronic acid. Because GAGs are primarily found in connective tissue, the sites of pathology primarily include the skeleton, heart valves, and other areas with connective tissue stroma.

The clinical features of the MPSs result from lysosomal accumulation of partially degraded or undegraded GAGs and typically include coarse facies, corneal clouding, organomegaly, joint stiffness, dysostosis multiplex, hernias, short stature, and, in some disorders, mental retardation.[1, 2] The specific enzymatic deficiency and the resultant pattern of GAG degradation products determine the phenotype of each disorder. In general, dermatan, keratan, and chondroitin sulfate degradation products are associated with visceral manifestations, whereas the accumulation of heparan sulfate degradation products may be associated with mental deficiency.

Pathophysiology

MPS VI is characterized by progressive connective-tissue organ involvement that results from continuous storage of dermatan sulfate in the skeleton, heart valves, spleen, liver, lung, dura, and cornea. Pathological examination of affected tissues reveals the presence of engorged lysosomes. Patients appear healthy at birth and have accelerated growth in the first year, followed by deceleration and short stature later in childhood. The diagnosis is usually made in early childhood when organomegaly, corneal clouding, coarse features, enlarged tongue, frequent respiratory illness or otitis media, and joint stiffness are all apparent. Other complications include hearing loss, chronic respiratory tract infections, sleep apnea, pulmonary hypertension, hydrocephalus, rapid-onset blindness, and cardiac valve insufficiency or stenosis.

Epidemiology

Frequency

United States

The MPSs are rare disorders, and data concerning incidence are not widely available.

International

Several reports provide estimates of MPS VI incidence outside the United States. An Australian survey reported an incidence rate of 1 per 248,000 births from 1980-1996.[3] Reports from Germany, and northern Portugal noted birth incidences of 1 case per 432,610 births and 1 case per 238,095 births, respectively.[4, 5] A survey of MPS VI in the Asia-Pacific region illustrates the paucity of information and the need for improved communication and sharing of information.[6] A study in Brazil produced evidence in favor of community-based screening.[7]

Mortality/Morbidity

MPS VI is characterized by substantial morbidity because of progressive accumulation of GAGs.

Although mental development is normal, physical and visual defects can adversely affect psychomotor development.

Growth may be normal for the first few years of life but then stops, resulting in dwarfism.

Most patients have corneal clouding, which can interfere with vision. Sudden vision loss can occur and is related to increased intracranial pressure or possible compression of the optic nerve.

Restricted joint movement is a common feature, and patients develop claw-hand deformities due to contractures.

Cardiac involvement includes aortic and mitral valve dysfunction.

Skeletal changes are typified by dysostosis multiplex.

Cervical cord compression due to bony abnormality, atlanto-axial instability, and thickening of the dura can lead to extremity pain, loss of motor function and sensation in extremities, or both.

Patients may also have restrictive airway disease, obstructive airway disease, or both.

Age at death varies, and mild forms of the disease have been described with prolonged survival.

Race

MPS VI is panethnic, although increased birth frequency has been reported in certain populations (Turkish population living in Germany).[4]

Sex

MPS VI is inherited as an autosomal recessive trait and appears equally in males and females.

Age

MPS VI is an inherited disorder that typically manifests in early childhood with retarded growth, dysostosis multiplex, inguinal or umbilical hernias, recurrent respiratory illness, hepatosplenomegaly, and coarse facial features.

 

Presentation

History

Individuals with mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome, usually have a period of normal growth and development but later present when frequent respiratory infections or otitis media, inguinal or umbilical hernias, hepatosplenomegaly, coarse facial features, dysostosis multiplex, joint or spine abnormalities, and corneal clouding become evident.

Because MPS VI is a recessive disorder, no family history is usually present.

Physical

Facial features associated with MPS VI include the following:

  • Coarse facial features (Compare the facial features with those of other family members to best appreciate the coarsening.)

  • Macrocephaly

  • Enlarged tongue

  • Prominent forehead

  • Possible coarse texture of hair

Hepatomegaly and splenomegaly are often present in patients with MPS VI.

Umbilical and inguinal hernias are common.

Growth may be normal for several years and may then stop, resulting in a final stature of 90-140 cm. A short trunk with lumbar lordosis is typically present.

Corneal opacities can be detected with slitlamp examination.

Restricted joint movement, including claw-hand deformities, appears in the first few years of life.

Examination of the skin frequently reveals hirsutism.

Causes

MPS VI results from the deficiency of N- acetylgalactosamine 4-sulfatase (arylsulfatase B) and the lysosomal accumulation of dermatan sulfate.

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Urine glycosaminoglycan analysis can be performed using various qualitative or quantitative methods. These studies are useful for establishing the likely diagnosis of mucopolysaccharidosis (MPS) but do not provide a specific diagnosis, which requires enzymatic testing.

Definitive diagnosis requires the determination of the specific lysosomal enzyme level in cultured fibroblasts or isolated leukocytes.

Normal levels of a second sulfatase should be documented to exclude multiple sulfatase deficiency.

Mutational analysis of the ARSB gene should be considered if the diagnosis is in question.[8, 9]

Imaging Studies

Perform skeletal survey studies to reveal dysostosis multiplex. Findings may include the following:

  • Macrocephaly with an enlarged j-shaped sella

  • Thickened, short metacarpal bones with proximal pointing and thin cortices

  • Paddle-shaped, widened ribs

  • Short, thick irregular clavicles

  • Dysplastic femoral head

  • Severe hip dysplasia

  • Ovoid deformities of the vertebrae

  • Anterior hypoplasia of the L1 and L2 vertebral bodies

  • Evidence of kyphoscoliosis

Echocardiography can reveal valvular heart disease, which is common. Acute infantile cardiomyopathy has also been reported in mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome.

MRI of the brain and spine may demonstrate hydrocephalus or provide evidence for spinal cord compression and spinal cord malacia, especially in the cervical region.

Flexion-extension radiography of the C-spine may demonstrate atlantoaxial instability and subluxation of C1 on C2; CT scanning may be necessary if radiograph images are not clearly interpretable.

Other Tests

Perform an audiological evaluation because deafness and hearing loss are common in MPS.

Perform an ophthalmologic examination to identify corneal opacities, vision change, and optic nerve abnormalities, suggesting increased intracranial pressure.

Perform pulmonary function tests to monitor restrictive and obstructive disease and perform a sleep study to evaluate for sleep apnea.

Histologic Findings

Lysosomal engorgement in tissue biopsies is evident, as are vacuolated lymphocytes on peripheral blood smear.

Staging

Urine glycosaminoglycan (GAG) level corrected for creatinine is a biochemical disease marker that can provide a crude estimate of disease severity and response to specific treatment (hematopoietic stem cell transplant [HSCT ] or enzyme replacement therapy).

 

Treatment

Medical Care

Patients with mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome, require ongoing medical care from numerous subspecialists. In addition, patients should receive routine pediatric care, including immunizations. The US Food and Drug Administration (FDA)–approved enzyme replacement therapy with galsulfase (Naglazyme) has been shown to improve walking and stair-climbing capacity and to decrease urine glycosaminoglycan (GAG) levels in patients with MPS VI.[10, 11]

Perform ongoing evaluations for the development of valvular cardiac disease. Such evaluations include annual echocardiograms.

Antibiotics (to prevent subacute bacterial endocarditis from medical and dental procedures) should be discussed with a cardiologist.

Many patients show evidence of restrictive airway disease, obstructive airway disease, or both. Conduct ongoing assessments for the development of clinically significant hypoventilation. Patients may benefit from oxygen or positive pressure therapy (continuous positive airway pressure [CPAP] or bilevel positive airway pressure [BIPAP]), especially when asleep if they have sleep apnea.

Patients typically have contractures and hand deformities. A program of physical therapy may be beneficial in maintaining optimal function. Carpal tunnel syndrome may be present and asymptomatic and should be evaluated with nerve conduction on a regular basis.

Patients who develop headache, vision change, or vomiting should be evaluated for increased intracranial pressure and hydrocephalus. Measuring intrathecal spinal fluid pressure to confirm increased intracranial pressure may be necessary.

Surgical Care

Patients who develop clinically significant valvular heart disease may require valve replacement.

Patients with obstructive airway disease sometimes benefit from tonsillectomy and adenoidectomy. Severe airway obstruction and hypoventilation may eventually require tracheostomy.

Corneal transplants have been successful in restoring vision to patients with corneal clouding, although storage in the transplanted cornea may recur over time.

Surgical decompression of the carpal tunnel to preserve median nerve function may be necessary.

Neurosurgery may be required to place ventriculoperitoneal decompression shunts for hydrocephalus or increased intracranial pressure.

Orthopedic surgery may be necessary to decompress the spinal cord or to stabilize the atlantoaxial junction.

Patients often develop hip dysplasia and require hip replacement surgery

Consultations

Geneticist: Refer all patients suspected of having an MPS to a medical geneticist. The geneticist is needed to provide definitive diagnosis and appropriate counseling of the family about recurrence risks.

Cardiologist: Refer affected patients to a cardiologist because of the risk for valvular heart disease.

Audiologist: Refer affected patients to an audiologist for periodic hearing evaluations because both conductive and sensorineural hearing loss can occur.

Ophthalmologist: Obtain slitlamp and funduscopic examinations during the initial evaluation and then periodically thereafter. Corneal clouding can lead to significant visual impairment.

Neurosurgeon or orthopedist: Spinal cord compression secondary to boney narrowing of the canal and thickening of the dura in the cervical canal has been described. Spinal cord compression results in myelopathy, which may require surgical intervention.

Pulmonologist: A pulmonologist should evaluate the patient regularly to identify airway obstruction, hypoventilation, or sleep apnea.

Rehabilitation medicine: This specialist can prescribe appropriate occupational and physical therapy, identify medical devices such as the wheel chair that will improve quality of life, and often provide nerve conduction studies to follow median nerve function and diagnose carpal tunnel and need for surgery.

Diet

No special dietary requirements are noted.

Activity

Patients with MPS VI usually have some limitations on their level of activity because of contractures and joint stiffness.

Patients with cardiac manifestations or pulmonary insufficiency may be limited in their activity level.

 

Medication

Medication Summary

Specific therapy for mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome, is just beginning to emerge, with recent clinical trials showing benefit from a recombinant DNA glycoprotein enzyme replacement therapy.

Enzyme replacement therapy

Class Summary

Recombinant DNA variant of N -acetylgalactosamine 4-sulfatase has been shown to improve endurance of individuals with MPS VI.[12]

Galsulfase (Naglazyme)

Indicated for MPS VI, which is characterized by the absence or marked reduction of N -acetylgalactosamine 4-sulfatase; provides exogenous enzyme as treatment. Recombinant DNA glycoprotein (Chinese hamster ovary cell line) variant form of polymorphic human enzyme N -acetylgalactosamine 4-sulfatase. Clinical trials showed improvement in walking and stair-climbing capacity. Most patients in the clinical trials were pediatric patients; however, children < 5 y were not included.

 

Follow-up

Further Outpatient Care

Physical therapy to maximize joint mobility is beneficial.

Further Inpatient Care

Obstructive airway disease can result from narrowing of the trachea, enlarged tongue, and redundant tissue in patients with mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome. Tracheostomy has been performed in some patients. Tonsillectomy and adenoidectomy are also frequently performed to relieve obstruction.

Many patients develop carpal tunnel syndrome, which may require nerve decompression.

Inpatient & Outpatient Medications

Patients with cardiac disease may require pharmacological therapy to manage cardiac failure. Monitor these patients closely with a pediatric cardiologist.

Transfer

Transfer patients with MPS VI who require general anesthesia for any procedure to a facility equipped to handle the substantial anesthetic risks.

Deterrence/Prevention

In most cases, a history of MPS VI is not present, and the affected child is the first affected individual in the family.

In future pregnancies, prenatal diagnosis is possible.

Complications

Vision loss due to corneal clouding is common. Rapid vision loss may occur related to increased intracranial pressure or compression of optic nerve.

Hearing loss is common and may require hearing aids.

Carpal tunnel syndrome is a common complication.

Obstructive airway disease can result in hypoventilation and pulmonary hypertension.

Valvular heart disease is common and may lead to congestive heart failure.

Spinal cord compression with damage and paralysis may occur.

Prognosis

MPS VI is a progressive disorder with significant morbidity and early mortality. As with many genetic inborn errors of metabolism, considerable variation exists among individual patients. Therefore, the prognosis for a particular patient must be determined after consideration of the presentation and complications.

Patient Education

Counsel patients and their families about the autosomal recessive inheritance pattern of MPS VI, the risk for occurrence in future pregnancies, and the availability of prenatal diagnosis.