Sanfilippo syndrome

Overview

Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is a rare inherited metabolic disorder characterized by the body’s inability to break down heparan sulfate, a complex sugar molecule found in various tissues. It falls under the broader category of lysosomal storage disorders, where a deficiency in specific enzymes leads to the accumulation of substances that damage cells and tissues over time.

Sanfilippo syndrome primarily affects the central nervous system, leading to severe neurological deterioration. It typically begins in early childhood and progressively worsens, causing developmental delays, behavioral issues, and ultimately severe cognitive and physical decline. The syndrome is devastating in its course, often resulting in early death during adolescence or early adulthood.

The condition is subdivided into four types—Types A, B, C, and D—based on the specific enzyme that is deficient. Although the clinical progression is similar across all types, Type A is generally considered the most severe and rapidly progressing form. Because of its rarity and overlapping symptoms with other developmental disorders, early diagnosis is often challenging but essential for care planning and potential inclusion in clinical trials.

Causes

Sanfilippo syndrome is caused by mutations in genes responsible for producing enzymes that degrade heparan sulfate in lysosomes. The specific genes and corresponding enzyme deficiencies are:

• Type A: Mutation in the SGSH gene, leading to deficiency of heparan N-sulfatase

• Type B: Mutation in the NAGLU gene, causing deficiency of alpha-N-acetylglucosaminidase

• Type C: Mutation in the HGSNAT gene, resulting in deficiency of acetyl-CoA:alpha-glucosaminide N-acetyltransferase

• Type D: Mutation in the GNS gene, leading to deficiency of N-acetylglucosamine-6-sulfatase

These mutations are inherited in an autosomal recessive pattern, meaning a child must receive one defective copy of the gene from each parent to develop the disease. Carriers (with only one defective gene) typically do not show symptoms but can pass the mutation to their offspring.

Symptoms

Symptoms of Sanfilippo syndrome typically appear between the ages of 2 and 6. The early signs may be subtle and mistaken for other developmental conditions. As the disease progresses, neurological symptoms become more pronounced. Common symptoms include:

• Developmental delays: Especially in speech and language

• Behavioral problems: Hyperactivity, aggression, temper tantrums, and sleep disturbances

• Intellectual decline: Gradual loss of learned skills and severe cognitive regression

• Mobility issues: Difficulty walking, poor coordination, and eventual loss of motor functions

• Hearing loss: Progressive sensorineural hearing loss is common

• Recurrent infections: Frequent ear and respiratory infections

• Coarse facial features: Such as thick eyebrows, broad nose, and full lips (more subtle compared to other mucopolysaccharidoses)

• Seizures: Often develop in later stages of the disease

While physical manifestations such as organ enlargement (hepatosplenomegaly) and skeletal abnormalities are less severe than in other MPS disorders, the neurological deterioration is the defining feature of Sanfilippo syndrome.

Diagnosis

Diagnosis of Sanfilippo syndrome is often delayed due to the nonspecific nature of early symptoms. A combination of clinical evaluation, laboratory tests, and genetic studies is required for confirmation:

• Urine test: Elevated levels of heparan sulfate in the urine suggest a mucopolysaccharidosis disorder

• Enzyme assay: Blood or skin samples are tested to determine the activity of specific lysosomal enzymes

• Genetic testing: DNA analysis to identify mutations in the SGSH, NAGLU, HGSNAT, or GNS genes

• MRI of the brain: May show signs of brain atrophy or white matter abnormalities in advanced cases

Early diagnosis is critical for initiating supportive therapies and considering enrollment in clinical trials for emerging treatments.

Treatment

Currently, there is no cure for Sanfilippo syndrome. Treatment is primarily supportive and focused on managing symptoms, improving quality of life, and slowing disease progression where possible. Common treatment strategies include:

• Behavioral and educational support: Tailored educational programs and behavioral therapy for managing hyperactivity and aggression

• Physical and occupational therapy: To maintain mobility and functional skills for as long as possible

• Speech therapy: To support communication as language skills decline

• Anti-seizure medications: For patients who develop epilepsy

• Hearing aids: To manage progressive hearing loss

• Sleep management: Use of melatonin or other medications for sleep disturbances

Experimental treatments are under investigation, including:

• Gene therapy: Aims to replace or repair defective genes

• Enzyme replacement therapy (ERT): Though challenging due to difficulty in crossing the blood-brain barrier

• Substrate reduction therapy: Reduces the production of heparan sulfate to slow disease progression

Families should also receive genetic counseling to understand inheritance risks and family planning options.

Prognosis

The prognosis for Sanfilippo syndrome is poor. The condition is progressive and ultimately fatal. Most children experience a steady decline in cognitive and physical abilities. By their teenage years, many patients become non-verbal, wheelchair-dependent, and require full-time care. Death usually occurs in the second or third decade of life, often due to respiratory complications or infections.

However, the rate of progression can vary depending on the subtype and individual differences. While current treatments cannot halt the disease, supportive care and symptomatic management can significantly enhance comfort and quality of life. Advances in gene therapy and ongoing clinical trials offer hope for future treatment breakthroughs.