Maroteaux–Lamy syndrome

Overview

Maroteaux–Lamy syndrome, also known as Mucopolysaccharidosis type VI (MPS VI), is a rare, inherited lysosomal storage disorder characterized by the accumulation of glycosaminoglycans (GAGs) in the body's tissues and organs. It was first described by French doctors Pierre Maroteaux and Maurice Lamy in 1963. This disorder is progressive and primarily affects connective tissue, leading to skeletal abnormalities, organ enlargement, and reduced physical function.

Unlike some other mucopolysaccharidoses, individuals with Maroteaux–Lamy syndrome typically have normal intellectual development. However, the physical manifestations can be severe and debilitating, impacting the quality of life and life expectancy if not managed appropriately. The disease presents with a wide range of symptoms and severity, from slowly progressing forms to rapidly deteriorating cases.

Causes

Maroteaux–Lamy syndrome is caused by mutations in the ARSB gene, which provides instructions for producing an enzyme called arylsulfatase B. This enzyme is responsible for breaking down dermatan sulfate, a type of glycosaminoglycan (GAG).

When the ARSB gene is mutated, arylsulfatase B is either absent or deficient, leading to the accumulation of dermatan sulfate in lysosomes—the recycling centers of cells. This buildup interferes with normal cellular function, particularly in connective tissues, bones, heart valves, and organs.

The disorder is inherited in an autosomal recessive manner, meaning a child must receive one defective gene from each parent to be affected. Carriers (those with only one copy of the mutated gene) typically do not show symptoms.

Symptoms

The symptoms of Maroteaux–Lamy syndrome usually appear in early childhood and progress over time. The severity of symptoms varies among individuals but commonly includes:

• Skeletal abnormalities (dysostosis multiplex):

  • Short stature

  • Joint stiffness and contractures

  • Abnormal curvature of the spine (kyphosis or scoliosis)

  • Abnormal gait or walking difficulties

• Facial features:

  • Coarse facial appearance

  • Enlarged head (macrocephaly)

  • Thick lips and enlarged tongue

• Cardiac involvement:

  • Thickening of heart valves

  • Heart murmurs or valve dysfunction (especially mitral and aortic valves)

• Respiratory problems:

  • Chronic nasal congestion and sinus infections

  • Sleep apnea due to airway obstruction

• Organomegaly: Enlargement of the liver (hepatomegaly) and spleen (splenomegaly)

• Hearing loss: Due to frequent ear infections or conductive hearing problems

• Vision issues: Corneal clouding, glaucoma, or retinal degeneration

• Hernias: Umbilical or inguinal hernias are common

• Normal intelligence: Unlike other MPS types, cognitive function is typically unaffected

In severe cases, these symptoms can significantly affect daily activities, mobility, and overall health.

Diagnosis

Diagnosis of Maroteaux–Lamy syndrome involves a combination of clinical evaluation, biochemical tests, and genetic analysis. Key steps include:

• Clinical examination: Recognition of characteristic physical features and medical history, including growth delays and joint stiffness.

• Urine test: Elevated levels of dermatan sulfate in urine suggest a mucopolysaccharidosis disorder.

• Enzyme activity testing: Measuring arylsulfatase B activity in blood or skin fibroblasts confirms the deficiency.

• Genetic testing: Identification of mutations in the ARSB gene confirms the diagnosis and allows for carrier testing and prenatal diagnosis in future pregnancies.

• Imaging studies:

  • X-rays to identify skeletal changes (dysostosis multiplex)

  • Echocardiography to evaluate heart valve involvement

  • MRI for spinal cord compression or brain anomalies

Early diagnosis is crucial for initiating treatment and managing complications effectively.

Treatment

While there is no cure for Maroteaux–Lamy syndrome, treatment focuses on slowing disease progression, alleviating symptoms, and improving quality of life. Treatment options include:

• Enzyme Replacement Therapy (ERT):

  • Galsulfase (Naglazyme): A recombinant form of arylsulfatase B given via intravenous infusion weekly

  • ERT has been shown to improve endurance, reduce liver and spleen size, and slow progression of some symptoms

• Surgical interventions:

  • Cataract removal or corneal transplantation for vision problems

  • Orthopedic surgery for joint deformities or spinal issues

  • Heart valve replacement in cases of severe cardiac involvement

  • Adenoid and tonsil removal to relieve airway obstruction

• Physical and occupational therapy:

  • Maintains joint mobility and assists with daily functioning

• Assistive devices: Braces, wheelchairs, and communication aids may be needed as disease progresses

• Supportive care: Audiological, ophthalmologic, cardiac, and pulmonary evaluations at regular intervals

• Bone marrow transplantation: Has been attempted in some cases, though it is not standard treatment and carries significant risks

Multidisciplinary care involving geneticists, cardiologists, orthopedic surgeons, pulmonologists, and other specialists is essential.

Prognosis

The prognosis for individuals with Maroteaux–Lamy syndrome varies depending on the severity of symptoms and the age at which treatment begins. With early diagnosis and proper management, especially through enzyme replacement therapy, many patients can experience improved physical function and slowed progression of the disease.

Without treatment, individuals may develop serious complications including heart failure, respiratory distress, and reduced mobility. Life expectancy in untreated severe cases may be shortened, often due to cardiorespiratory complications. In milder cases, patients may live into adulthood with fewer complications.

Ongoing research into gene therapy and improved enzyme formulations offers hope for more effective treatments in the future. Genetic counseling is recommended for affected families to understand inheritance patterns and future reproductive options.