Inclusion-Cell (I-Cell) Disease

Inclusion-cell disease is a genetic disorder characterized by developmental delays, skeletal abnormalities, and coarse facial features.

Inclusion-cell (I-cell) disease, also known as mucolipidosis II, is a rare inherited disorder that affects multiple organ systems in the body. It is a lysosomal storage disorder that primarily affects lysosomes—membrane-bound organelles found in the cytoplasm of most eukaryotic cells.

• Lysosomes are organelles in the cells responsible for breaking down and recycling molecules such as proteins, carbohydrates, and lipids.
• They lose their ability to break down specific complex molecules in I-cell disease, resulting in the accumulation of complex molecules within the cell.
• This buildup can lead to several health issues, including developmental delays, skeletal abnormalities, and organ dysfunction.

The incidence of the I-cell disease is 1 in 100,000 to 400,000 people. Such people have severe skeletal dysplasia and profound short stature from birth.

Inclusion-cell (I-cell) disease is a genetic disease inherited in an autosomal recessive manner. A person must inherit two copies of the defective gene (one from each parent) to develop the disease. If both parents are carriers of a GNPTAB (protein-coding gene) gene mutation, their children have a 25 percent chance of inheriting two copies of the mutated gene and developing I-cell disease.

The defective gene responsible for I-cell disease is the GNPTAB gene, which provides instructions for making an enzyme involved in the proper functioning of lysosomes.

The symptoms of inclusion-cell (I-cell) disease can vary in severity and affect multiple organ systems in the body.

Some common symptoms of I-cell disease include:

• Developmental delays in children, such as sitting up, crawling, and walking
• Facial dysmorphism
  • Prominent forehead
  • Flat nasal bridge
  • Large tongue
• Skeletal abnormalities
  • Abnormal curvature of the spine such as scoliosis or kyphosis
  • Joint deformities or stiffness
  • Wide spacing between the ribs
  • Short stature
• Organ dysfunction or enlargement
• Congestive heart failure
• Sleep-disordered breathing
• Recurrent infections, especially respiratory infections
• Hernia
• Vision issues
• Hearing loss
• Intellectual disability
• Seizures

Inclusion-cell (I-cell) disease is a genetic disorder caused by mutations in the GNPTAB gene. The GNPTAB gene provides instructions for making an enzyme called N-acetylglucosamine-1-phosphotransferase which is responsible for adding a specific chemical tag to certain proteins that are broken down and recycled by lysosomes.

Mutations in the GNPTAB gene cause I-cell disease by preventing the proper function of N-acetylglucosamine-1-phosphotransferase. This results in the accumulation of various molecules within the lysosome. This accumulation can interfere with normal cellular processes and cause the characteristic symptoms of the disease.

Although mutations in the GNPTAB gene are the primary cause of I-cell disease, other factors may also play a role in the severity and progression of the disease, including: 

• Additional genetic variations
• Environmental factors
• Lifestyle factors

However, further research is needed to fully understand the complex interactions between these factors and I-cell disease.

Inclusion-cell (I-cell) disease is a rare genetic disorder that can be challenging to diagnose due to its wide range of symptoms and rarity. However, healthcare professionals may use several methods to diagnose I-cell disease.

A doctor performs a thorough physical examination to identify characteristic facial features, skeletal abnormalities, and organ enlargement that are common in individuals with I-cell disease. Noting down the detailed medical history can help the doctor to identify symptoms that are consistent with I-cell disease.

Other tests that are done to determine the diagnosis of I-cell disease include:

• Blood tests to detect abnormalities in lysosomal enzymes, which can be indicative of I-cell disease
• Urine tests to detect the presence of specific molecules that accumulate in individuals with this condition
• Genetic testing to identify mutations in the GNPTAB gene responsible for causing the disease
• Imaging studies, such as X-rays or MRIs, to reveal skeletal abnormalities and organ enlargement that are common in individuals with I-cell disease
• Enzyme analysis of samples from chorionic villus or the amniotic fluid to make a prenatal diagnosis of the condition

A definitive diagnosis of I-cell disease may require multiple diagnostic tests and a comprehensive evaluation by a team of healthcare professionals, including geneticists, neurologists, and other specialists.

Currently, there is no cure for inclusion-cell (I-cell) disease, and treatment is primarily focused on managing symptoms and improving quality of life.

Various supportive treatments may be given to address specific symptoms, which include:

• Pain management
• Assisted oxygen therapy for ventilation during breathing difficulties
• Enzyme replacement therapy with a synthetic version of the enzyme
• Physical therapy to improve mobility
• Emotional support from both doctors and family and friends
• Surgical corrections of skeletal abnormalities and rectifying complications caused by enlarged organs

Research is constantly producing new findings that can contribute to developing other effective treatment options for lysosomal disorders, such as gene therapy and stem cell transplantation.

The life expectancy of individuals with inclusion-cell (I-cell) disease can vary widely depending on the severity of the disease and specific symptoms present. In general, individuals with severe forms of I-cell disease may have a significantly shortened life span and death occurs between the fifth and seventh year, whereas those with milder forms of the disease may live into adulthood.

Individuals with I-cell disease frequently experience significant developmental delays and intellectual disabilities, which can hurt their quality of life and necessitate ongoing support and care. Furthermore, disease-related complications, such as organ enlargement and skeletal abnormalities, can increase the risk of medical complications and shorten the life span.

It is difficult to provide a specific life expectancy for individuals with I-cell disease due to its rarity and the significant variability in disease severity. Early diagnosis, comprehensive medical management, and ongoing support and care can help improve outcomes and quality of life for people with the disease.