MPS6 can be considered as a spectrum of the disease since the clinical picture can range from mild to severe. Patients with the rapidly progressive form develop symptoms between ages 2 and 3 years. This is typically characterized by limitations in joint motion during infancy, walking disabilities in childhood as well as delayed puberty, cervical spine compression, respiratory failure, and heart failure (second or third decade). The slowly progressive variant occurs at a later onset with a diagnosis often during the second or third decade although they may experience symptoms sooner.

Numerous organs systems are involved in MPS6:

Musculoskeletal

Patients very commonly exhibit a disproportionately short stature. Major skeletal abnormalities include hypoplastic bones, hip dysplasia, pectus carinatum, genu valgum, and kyphoscoliosis. Major sequelae include spinal cord compression, degenerative joint disease [9] [10], contractures, and arthritis. The affected individuals often suffer from pain, gait difficulties, and restriction of joint movement.

Face

In severe cases, patients display prominent facial characteristics. Examples include low and flat nasal bridge, frontal bossing, gingival hypertrophy, macroglossia, and hirsutism [9] [10].

Eyes and ears

Patients may have corneal opacification which causes glaucoma and papilledema [9] [10]. Hearing loss is common and can occur due to conductive or sensorineural etiologies.

Neurologic

Carpal tunnel syndrome is a frequent complication in individuals with MPS6. Furthermore, hydrocephalus is a more severe neurologic manifestation that occurs in some patients.

Gastrointestinal

Common findings on physical exam are hepatosplenomegaly and umbilical and inguinal hernias. The latter two develop as a result of weakened abdominal muscles.

Cardiac

Patients frequently have aortic, mitral, and tricuspid valvular disease. Also, structural pathologies such as cardiomyopathy and endocardial fibroelastosis are notable defects. As a result of cardiac involvement, patients exhibit failure to thrive and experience difficulty with feeding.

Pulmonary

Storage of mucopolysaccharides causes swelling of tissues, which leads to obstruction of the airways. Patients are typically susceptible to developing obstructive and restrictive lung disease which are accompanied by complications such as recurrent pneumonia and obstructive sleep apnea (OSA).

Cognitive

Intelligence is normal in these patients.

Patients suspected to have this disease should be assessed thoroughly through a full personal and family history, a complete physical exam, and the appropriate key tests.

Laboratory testing

The initial diagnostic study is the qualitative and quantitative analysis of urinary GAGs, which establishes the general diagnosis of MPS6. While quantitative assessment yields the measurement of the amount of GAGs, qualitative methods identify the specific GAG that is increased. To obtain the latter, techniques such as thin-layer chromatography (TLC) and/or electrophoresis (ELP) are utilized [11]. It is important that both qualitative and quantitative methods should be performed to avoid false conclusions.

Further studies include the evaluation of the enzymatic activity of ASB using dried blood spots, cultured fibroblasts or leukocytes, of which last two are the gold standard samples [11]. With regards to the level of enzymatic activity, it is not predictive of the clinical course.

If possible the ARSB gene can be assessed for detection of the mutation(s) [11].

Other

Imaging tools should be performed to identify skeletal defects. Furthermore, echocardiography is used to evaluate valvular abnormalities, wall thickness, and other findings. Also, magnetic resonance imaging (MRI) of the brain and spine is important to determine the presence of spinal cord compression, hydrocephalus, and other findings.

Further testing depends on the clinical picture. Hence, additional tests include:

• Audiogram
• Ophthalmology assessment
• Pulmonary function tests

Management of patients with MPS6 is best provided by a team of pediatricians, orthopedic surgeons, cardiologists, pulmonologists, dentists, ophthalmologists, audiologists, geneticists, and other specialists as needed.

The two standard treatments currently used are enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT).

ERT

One orphan drug, galsulfase, has been approved by the Food and Drug Association (FDA) since 2005. As a recombinant form of arylsulphatase B, galsulfase provides the patient with an exogenous supply of the deficient enzyme. According to a long-term follow-up study, patients receiving weekly infusions demonstrated a significant decline in urinary GAGs [12]. It is also associated with improvement in walking and stair climbing capacity, and in the range of motion of joints as well [13]. Side effects were deemed acceptable [12].

HSCT

The goal of stem cell transplantation is to endogenously supply the enzyme through the production of a new stem cell population. This treatment is associated with high morbidity and mortality as one study reported a one-year survival rate of 67% [14].

Surgical intervention

Orthopedic surgical procedures may be needed for patients with spinal cord compression, atlantoaxial imbalance, hip dysplasia, carpal tunnel syndrome, and other defects. Additionally, neurosurgery is required for ventriculoperitoneal shunt placement in patients with hydrocephalus. Very importantly, cardiac surgery may be indicated in cases with valvular abnormalities.

Other

Physical rehabilitation including physical and occupational therapy should be instituted early. Additionally, psychosocial support should be provided to the children and their parents. There are resources such as support groups and community programs to assist the families.

The prognosis is influenced by numerous factors, which are the age of onset, the rate of progression, and the age at which therapy was initiated. Additionally, the quality of care received by the patient plays a role in the overall outcome. With regards to biochemical manifestations, a urinary GAG level greater than 100 μg/mg creatinine is indicative of a poor prognosis.

Early recognition and treatment is very important in improving the prognosis since both forms, rapid and slowly progressive, can cause irreversible damage. Therefore, treatment should not be delayed.

In a long-term study, ERT prolonged survival. It was also observed to improve growth, endurance, and pulmonary function [8]. However, ERT did not impact variables measuring the quality of life such as pain or disability [8].

The etiology of this autosomal recessive disorder is a mutation in the ARSB gene, which codes for the lysosomal enzyme known as ASB. The latter plays a key role in the breakdown of GAGs such as dermatan sulfate and chondroitin sulfate. Hence, a deficiency in this lysosomal enzyme leads to an accumulation of dermatan sulfate in the various organs and tissues of the body.

The estimated incidence of MPS6 ranges from 1 in 248,000 to 1 in 300,000 live births [3]. With regards to patient demographics, there is no gender preference.

One community observed to have a higher frequency is the city of Monte Santo located in the northeastern region of Brazil. The prevalence in this population is greater than that noted in the literature [4]. Furthermore, there were numerous patients diagnosed with Maroteaux Lamy syndrome in Colombia [5].

MPS6 develops secondary to mutations on chromosome 5 [5], of which missense mutations account for most of the genetic defects [6].

The disease manifests when there is a profound deficiency in enzymatic activity [7], in which the absent or severely low levels of ASB enzyme are incapable of performing a complete degradation of GAGs. The latter are major components of connective tissues and are constituted of unbranched chains of polysaccharides composed of repetitive disaccharides.

As a result, dermatan sulfate, a type of GAG, builds up in sites that are prominently composed of connective tissue such as the skeleton, joints, heart valves, vessels, ears, eyes, and/or teeth. This disease is characterized by progressive damage to these sites.

There is often multisystem involvement of the skeletal, cardiovascular, respiratory, gastrointestinal, and central nervous systems. Hence, the clinical picture may include bone dysplasia, short stature, joint stiffness, coarse facies, organomegaly, corneal clouding, cardiac and pulmonary abnormalities, etc. Patients commonly have a decreased life expectancy and exhibit decreased exercise capacity, reduced endurance, and a restricted range of motion in the joints [3].

While there are no preventative measures, parents with known personal and/or family genetic defects can be offered biochemical prenatal testing. Samples can be obtained from amniocytes [15].

Additionally, patients and family members should seek genetic counseling to receive education about what the disease entails, its mode of inheritance, the prognosis, and other relevant information.

Mucopolysaccharidosis (MPS) type 6 is also referred to as Maroteaux Lamy syndrome. The MPSs encompass a group of inherited lysosomal disorders that result from mutations in arylsulfatase B (ARSB) gene. The genetic defects lead to a deficiency in the activity of the lysosomal enzyme, ASB, which is necessary for the catabolism of mucopolysaccharides or glycosaminoglycans (GAGs). This culminates in the buildup of GAGS in various organs and tissues.

The clinical manifestations reflect the accumulation of GAGs in the involved connective tissues such as the skeleton, heart valves, eyes, ears, etc. The symptomology varies and includes skeletal dysplasia, dwarfism, joint restriction, abnormal facies, and other features as well [1] [2]. There are two variants which are characterized by the rate of disease progression and age of onset: rapidly progressive and slowly progressive.

The clinical assessment includes the personal and family history, a full physical examination, and appropriate testing. The diagnostic tools consist of the quantitative and qualitative analysis of urinary GAGs followed by the measurement of the enzyme's activity. Additional studies such as a skeletal survey and echocardiogram should be performed in accordance with the clinical picture.

The patients should receive comprehensive care by a multidisciplinary team of specialists. The medical management of Maroteaux Lamy syndrome consists of enzyme replacement therapy (ERT) or hematopoietic stem cell transplantation (HSCT). ERT is associated with significant improvement in multiple aspects of the disease including survival.

Prompt diagnosis and early treatment with ERT can profoundly impact the outcome. Sometimes Maroteaux Lamy syndrome can be detected prenatally. Genetic counseling is available to affected individuals and their family members.

What is mucopolysaccharidosis (MPS) type 6?

The mucopolysaccharidoses (MPS) is a group of inherited diseases that develop due to a deficiency of a specific type of lysosomal enzyme called arylsulfatase B. Normally, this enzyme breaks down complex carbohydrates called mucopolysaccharides. Therefore, if this enzyme is absent, mucopolysaccharides will accumulate in various organs and tissues such as the skeleton, joints, ears, eyes, skin, heart, liver, and/or teeth.

What causes this disease?

This disease develops as a result of mutations in the ARSB gene, which provides instructions to produce the arylsulfatase B enzyme. Mucopolysaccharidosis type 6 is inherited in an autosomal recessive pattern. In other words, the affected child received two bad copies of the gene, one from each parent.

What are the signs and symptoms?

Some patients will have a rapidly progressive form, in which they develop symptoms between ages 2 and 3 years. Others will have the slowly progressive type which develops at a later onset with a diagnosis often during the second or third decade although they may experience symptoms sooner. Many organs are affected. Signs and symptoms include:

• Musculoskeletal: Short stature, underdeveloped bones, hip deformities, and chest deformities
• Neurology: Spinal cord compression, carpal tunnel syndrome
• Joint disease: Arthritis, contractures, restricted movement of joints
• Facial features: Flat nasal bridge, prominent forehead, overgrowth of the gums, large tongue, and hair growth on face
• Eyes: Clouding of the corneas
• Ears: Hearing loss, ear infections
• Abdomen: Enlargement of the liver and spleen
• Heart: Diseases of the heart valves, high blood pressure, weakening of the heart wall
• Head: Hydrocephalus (accumulation of a large amount of cerebrospinal fluid in the skull)
• Pulmonary: Recurrent pneumonia and obstructive sleep apnea
• Other: Difficult to feed and thrive, delayed puberty, difficulty walking

How is it diagnosed?

In children suspected to have mucopolysaccharidosis (MPS) type 6, the clinician will obtain a thorough history of the patient and the family, perform a physical exam, and order the appropriate tests such as:

• Patient's urine will be assessed for the levels of mucopolysaccharides
• Blood and skin cells can be evaluated to determine the activity of the enzyme
• Genetic testing can be done to detect the mutation

Other tests should look for clinical manifestations:

• X-rays of the skeleton
• Echocardiography
• MRI of the brain and spine
• Audiogram
• Ophthalmology assessment
• Pulmonary function tests

How is it treated?

The treatment is best provided by a multidisciplinary team consisting of pediatricians, orthopedic surgeons, cardiologists, pulmonologists, dentists, ophthalmologists, audiologists, geneticists, and other specialists as needed.

The two standard treatments currently used are enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT). With ERT, patients are treated with an intravenous medication called Naglazyme (galsulfase), which is a recombinant form of the enzyme. Therefore, the patient receives the missing enzyme through the treatment.

Stem cell transplantation is associated with severe side effects and high risk of death.

What is the prognosis?

It is important to diagnose and treat the disease as soon as possible. Treatment with enzyme replacement therapy has shown to improve survival, walking, endurance, and joint movement.

Can this be prevented?

Since this disease is inherited, it cannot be prevented. Patients and affected family members are encouraged to receive genetic counseling to learn about the disease, what it entails, how it is inherited, and other important information.

The family should be provided with numerous community and state resources.

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