Maroteaux-Lamy Syndrome - A Hereditary Enzyme Deficiency Dwarfism

What Is Maroteaux-Lamy Syndrome?

Maroteaux-Lamy syndrome or mucopolysaccharidosis type VI (MPS VI), also known as an arylsulfatase-B deficiency or poly-diastrophic dwarfism, is a rare autosomal recessive hereditary genetic disorder that occurs due to a mutation in the ARSB gene that encodes the enzyme arylsulfatase B. The enzyme is involved in the breakdown of glycosaminoglycans molecules, the lack of which results in the accumulation of the molecules in the lysosomes, followed by cell and tissue injury, ultimately resulting in severe multi-organ failure.

Who Is Susceptible to Maroteaux-Lamy Syndrome?

MPS-VI has shown a prevalence of 1 in 65,000 births with no gender predilection, but a broader estimate marks the condition prevalence at 1 in 250,000 to 600,000 individuals. The incidence of MPS-VI is quite variable, with 0.0132 and 7.85 cases per 100,000 births in Poland and Saudi Arabia, respectively. In some small regions where consanguinity and endogamy are accepted norms, the prevalence is as high as 20 per 100,000 live births. Out of all MPS variants, MPS-VI is the most prevalent variant in Saudi Arabia, with 46 percent of all MPS cases, and Malaysia, with 40 percent of all MPS cases. MPS-VI has the lowest prevalence of all MPS variants in Poland and South Korea, with 1 percent and 1.4 percent of all MPS cases, respectively.

What Causes Maroteaux-Lamy Syndrome?

MPS-VI shows an autosomal recessive pattern of inheritance; hence the condition requires the accumulation of mutant ARSB gene from both parents. A pair of altered ARSB alleles leads to the reduction or complete elimination of the lysosomal enzyme-arylsulfatase B (also known as N-acetylgalactosamine-4-sulfatase). This enzyme catalyzes the degradation of the molecules-glycosaminoglycans, dermatan sulfate, and chondroitin 4-sulfate. The deficiency or lack thereof of the enzyme leads to abnormal accumulation of the said large molecules in the lysosomes and extracellular matrix that consecutively lead to large-scale cell and tissue damage. Left unchecked, this accumulation can lead to multi-system organ failure and ultimately prove fatal.

What Is the Pathophysiology of Maroteaux-Lamy Syndrome?

ARSB gene is present on the long arm of chromosome 5 (5q13-14) that contains 8 exons consisting of 4852 base pairs of nucleotides encoding the 533 amino acids of the mature arylsulfatase-B enzyme. More than 220 different types of mutations have been recognized in the ARSB gene accounting for the varying severity of the condition in patients. Due to various mutations in the ARSB gene, there is a deficiency or complete absence of the arylsulfatase-B enzyme. Due to the abnormality, glycosaminoglycans (a large sugar molecule- mucopolysaccharides) accumulate in the cell and extracellular matrix, especially in the lysosomes, which increases the size of the cells resulting in enlarged tissues and organs. Accumulated glycosaminoglycans levels are believed to be toxic to cells and may provoke the loss of function of various proteins within the lysosomes triggering inflammation and cell death. This leads to the atrophy of tissues, ultimately involving multiple organs and organ systems.

What Is the Histopathology of Maroteaux-Lamy Syndrome?

A histological study of peripheral blood smear reveals vacuolated lymphocytes and evident lysosomal engorgement in tissue biopsy.

What Are the Signs and Symptoms of Maroteaux-Lamy Syndrome?

1. Osteoarticular Manifestations:

• Short Stature.

• Dysostosis multiplex (multiple skeletal deformities throughout the body).

• Joint stiffness.

• Contractures.

• Kyphoscoliosis (abnormal spine curvature).

• Genu valgum (lower leg abnormality in toddlers and preschoolers).

• Hip dysplasia (ill-fitting hip joint).

2. Otorhinolaryngo Manifestations:

• Adenoid hypertrophy (increased size of adenoids).

• Tonsil hypertrophy (increased size of the tonsils).

• Hearing loss.

• Otitis media (inflammation in the middle ear).

• Chronic rhinosinusitis (inflammatory condition of paranasal sinuses).

3. Neurological Manifestations:

• Spinal cord compression.

• Spinal root compression.

• Myelopathy (injury to the spinal cord due to severe compression).

• Carpal tunnel syndrome (wrist problem due to compression of the median nerve).

• Abnormality in the ventricular system.

• Abnormality in the white matter space.

• Abnormality in the perivascular space.

4. Ocular Manifestations:

• Corneal clouding (clouding of the eye giving decreased vision).

• Refractive errors (eye problems requiring glasses).

• Optic disc swelling (swelling of the optic nerve).

• Optic atrophy (death of the retinal ganglion).

• Retinopathy (disease of the retina causing vision impairments).

• Glaucoma (increased fluid pressure build up in the eye).

5. Orodental Manifestations:

• Hypoplastic condyles (underdeveloped condyles of the mandible).

• Malposition of unerupted teeth (unerupted teeth within the jaw are at abnormal positions).

• Supernumerary teeth (more than a normal number of teeth).

• Dentigerous cysts (cyst formation around an unerupted tooth).

• Large dental follicles (large mesenchymal tissue around the developing tooth germ).

• Macroglossia (enlarged tongue).

• Gingival hyperplasia (overgrowth of gums).

• Anterior open bite (front teeth do not occlude).

• High-arched palate (palate is high and narrow).

6. Cardiac Manifestations:

• Valvular insufficiency (failure of one or more of the heart valves).

• Valvular stenosis (narrowing of the heart valves).

• Pulmonary hypertension (high blood pressure in the pulmonary artery).

• Cardiomyopathy (disease of the heart muscles).

• Fibroelastosis (thickening within the muscular lining of the heart chambers).

• Cardiac conduction disorders (problems with the electrical system of the heart).

• Heart failures.

7. Pulmonary Manifestations:

• Recurrent airway infections.

• Upper and lower airway obstruction.

• Sleep disorders.

8. Other Manifestations:

• Coarse facial features (abnormal proportions of facial features).

• Hepatosplenomegaly (increased size of liver and spleen).

• Umbilical hernia (intestine bulges into the abdominal muscles near the navel).

• Inguinal hernia (intestine bulges into the inguinal canal).

• Delayed puberty.

• Hirsutism (male pattern hair growth in females).

How to Diagnose Maroteaux-Lamy Syndrome?

Diagnosis of MPS-VI begins with recognizing specific clinical signs suggestive of a metabolic disorder that should be further investigated for specific etiology.

Laboratory studies can be ordered for urine glycosaminoglycan analysis using various qualitative or quantitative methods. Urinalysis may indicate the presence of mucopolysaccharide metabolic disorder (enzyme deficiency causing problems with the metabolism of long-chain carbohydrates), but enzymatic testing should be ordered to detect the MPS-VI variant.

A quantitative enzyme analysis by DMB-based assay, demonstrating an increase of total urinary glycosaminoglycans, or a qualitative analysis revealing an increase of dermatan sulfate is performed. This should be followed by an enzymatic assay evaluating enzymatic activity on leucocytes or fibroblasts.

Independent confirmation of MPS VI diagnosis is obtained by molecular genetic testing of ARSB, which may detect the mutation's level, type, and severity.

Skeletal survey studies reveal dysostosis multiplex.

• 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.

• Femoral head dysplasia.

• Severe hip dysplasia.

• Ovoid deformities of the vertebrae.

• Anterior hypoplasia lumbar vertebral bodies.

• Kyphoscoliosis.

Echocardiography to detect cardiac abnormalities, MRI (magnetic resonance imaging) of the brain and spine may demonstrate neurological manifestations, flexion-extension radiographs of the C-spine to detect atlantoaxial instability, and subluxation, and CT (computed tomography) can be ordered in case of poor radiographic interpretation.

Other tests include audiological evaluation, ophthalmologic examination, pulmonary function tests, and abdominal ultrasounds to detect hernias.

How to Treat or Manage Maroteaux-Lamy Syndrome?

1. Medical Care:

The treatment of MPS-VI is symptomatic and tailored specifically to each patient. In the case of neonatal diagnosis, pediatric care with a standard immunization regimen is followed. An enzyme replacement therapy with galsulfase (naglazyme) is implemented, which has shown a marked decline of glycosaminoglycans in urine output.

2. Pharmacotherapy and Oxygen Therapy:

Antibiotic therapy with cardiologist consultation is required to prevent bacterial endocarditis, especially prior to dental appointments. Patients with pulmonary manifestations may benefit from oxygen or positive pressure therapy or bilevel positive airway pressure, especially when asleep if they have sleep apnea. A physical therapy protocol can be included in cases of skeletal deformity, carpal tunnel syndrome, and joint stiffness. The use of anti-inflammatory medications like Infliximab and Pentosan polysulfate is indicated to reduce inflammation.

3. Surgical Care:

• Valvular replacement surgeries in patients with valvular heart disease.

• Tonsillectomy and adenoidectomy in patients with repeated airway obstruction may also require tracheostomy in situations like severe airway obstruction and hypoventilation.

• Corneal transplants may be required in case of corneal clouding.

• Surgical decompression of the carpal tunnel to preserve median nerve function.

• Ventriculoperitoneal decompression shunts may be required against hydrocephalus or increased intracranial pressure.

• Decompression of the spinal cord or stabilization of the atlantoaxial junction may be required.

• Hip replacement surgeries are indicated in patients with hip dysplasia.

4. Other Treatment Options:

• Bone Marrow Transplantation (BMT) and Hematopoietic Stem Cells Transplantation (HSCT): Transplantation of multipotent hematopoietic stem cells derived from bone marrow, peripheral blood, or umbilical cord blood of a healthy donor

• Intra-Articular Enzyme Replacement Therapy: Intra-articular injection of the enzyme directly into the joint.

• Gene Therapy: ARSB gene transfer by retroviral vectors.

• Substrate Reduction Therapy: Reduce GAG accumulation by interfering with their biosynthetic pathway by oral administration of Odiparcil.

• Pharmacological Stop Codon Read-through: Gentamicin and PTC124 are used to suppress the effect of premature stop codon termination and restore the production of the full-length protein.

What Is the Differential Diagnosis of Maroteaux-Lamy Syndrome?

• Hunter syndrome (mucopolysaccharidosis type II).

• Sly syndrome (mucopolysaccharidosis type VII).

• Mucopolysaccharidosis type VII.

• Mucopolysaccharidosis type I.

• Mucopolysaccharidosis type IH.

• Mucopolysaccharidosis type IS.

• Mucopolysaccharidosis type IV.

• Multiple sulfatase deficiency (enzyme deficiency causing some sugar metabolism problems).

What Is the Prognosis of Maroteaux-Lamy Syndrome?

MPS-VI is a progressive disorder with early fatality and significant morbidity. So, the prognosis of the condition is dependent on the severity of symptoms as dictated by the degree and variation of mutation in the gene.

What Are the Complications of Maroteaux-Lamy Syndrome?

• Blindness.

• Deafness.

• Carpal tunnel syndrome.

• Respiratory failure.

• Cardiac failure.

• Valvular failure.

• Paralysis.

Conclusion

Maroteaux-Lamy syndrome is a complex disease that needs continuous multi-disciplinary care to be managed efficiently. Although significant improvement has been observed in newer treatment therapies like enzyme replacement and bone marrow transplant, the availability of such treatment is in a nascent stage. Extensive research in the field is required to make the diagnosis and treatment options available to the general public in an affordable and easily accessible way.