I-cell disease. The Queen of Storage Disease

I-cell disease (mucolipidosis II, inclusion cell disease) is a rare hereditary metabolic disorder with coarse facial features, skeletal abnormalities, and mental retardation. This disease belongs to a group of mucolipidoses caused by lysosomal storage diseases.

These symptoms appear in infancy and may include multiple skull and facial abnormalities and growth retardation.

The lysosome is an organelle that breaks down fats and carbohydrates. Lysosome enzyme deficiencies associated with I-cell disease lead to accumulations of mucolipids and complex carbohydrates (mucopolysaccharides).

I-cell disease affects both men and women equally. The disease is more common in Japan than in other countries. Autosomal recessive inheritance is the mode of inheritance.

The etiology and pathogenesis

The study of I-cell disease revealed that all hydrolases are absent from fibroblast lysosomes, yet they are found in the blood. Therefore, the structural genes encoding these enzymes are not damaged. The anomaly, in this case, is caused by a breakdown of the sorting process within the Golgi apparatus, which results in hydrolases being secreted into the surrounding area instead of entering the lysosomes. A missorting process is caused by damage or absence of GlcNAc phosphotransferase (N-acetylglucosamine phosphotransferase). Lysosomal enzymes in these cells cannot be phosphorylated and mannose phosphate receptors cannot assemble their bordered vesicles in the Golgi apparatus. Rather, they are delivered to the cell membrane and secreted. Uncleaved substrates accumulate as large inclusions in fibroblasts, hence the name of the disorder, inclusion cell disease.

The disease is caused by a recessive mutation of a single gene, the GNPTAB gene, which is located on the 12th chromosome.

The clinical picture

The physical characteristics of I-cell disease may be congenital, while others may appear between 6 and 10 months of age.

I-cell disease symptoms:

• Craniofacial anomalies: coarse facial features, depressed nasal bridge, long and narrow head, unusually high or narrow forehead, or epicanthal fold. A person’s skin may appear unusually thick and tight in certain places on the body (such as the face, arms, and legs). Corneas may look cloudy;
• Skeletal malformations: scoliosis and/or kyphosis, low neck, congenital dislocation of the hip, swelling of the upper spine, reduced shoulder mobility. A displacement of bones in the spine, wide spaces between the ribs, and a placement of the fingers (metacarpal pointing). Sometimes, children with I-cell disease’s fingers fuse together (ectrodactyly);

• Slow development of gross and fine motor skills, hearing loss, hypotension, mental retardation, dwarfism

• Hepatomegaly, inguinal hernia, umbilical hernia;

• There may be frequent respiratory infections, constipation and/or diarrhea, gingival hyperplasia, and cardiac abnormalities (valvular defects, cardiomegaly, congestive heart failure, heart murmurs).

Diagnosis

I-cell disease can be diagnosed in utero with amniocentesis or chorionic villus sampling. The presence of abnormally low levels of UDP-N-acetylglucosamine-1-phosphotransferase activity in amniotic fluid or chorionic villus cells suggests I-cell disease.

A diagnosis can be confirmed in an infant based on careful clinical evaluation, medical history, and specialized laboratory testing. A measure of UDP-N-acetylglucosamine-1-phosphotransferase activity can be detected in white blood cells or cultured fibroblasts. Typical lysosomal enzyme levels increase in serum and decrease in cultured fibroblasts.

The differential diagnosis

• Hurler syndrome, also known as mucopolysaccharidosis type I,
• Sialidosis (mucolipidosis I, type I and type II),
• Mucolipidosis III (pseudogerling polydystrophy),
• The Galactosialidosis,
• The Sly syndrome (Mucopolysaccharidosis VII),
• Hunter syndrome (mutopolysaccharidoses II),
• A Moroto-Lami syndrome (mupolysaccharidosis VI).

Therapy

The treatment of I-cell disease is symptomatic and supportive. Antibiotics are typically prescribed for respiratory infections, and flu shots are recommended each year. Physical therapy can help maintain joint function and mobility for as long as possible. Total hip replacements are most effective after puberty. Other orthopedic complications can be treated as they occur. A hearing aid may be used. The severity of obstructive sleep apnea and the need for treatment are determined by sleep studies. Heart problems can sometimes be treated with surgery.

A genetic counseling session is recommended for families who have already had a child with this condition.

Prognosis

Those with I-cell disease typically die in childhood, although some may survive into adolescence.