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Mucolipidosis Type II, Genetic Testing

Mucolipidosis type II (ML II), also known as I-cell disease, is a rare inherited lysosomal storage disorder. It is characterized by the abnormal accumulation of substances within cellular structures called lysosomes, leading to various physical and developmental abnormalities. Mucolipidoses are classified into 4 types according to the affected lysosomal enzyme. Type II mucolipidosis is caused by a deficiency of the enzyme N-acetylglucosamine-1-phosphotransferase caused by pathogenic variants in the GNPTAB gene. The prevalence of type II mucolipidosis is approximately 1 case per 1.000.000 people and may be higher in certain geographic areas such as the Saguenay-Lac-Saint-Jean region of Quebec.

Mucolipidosis type II genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).

Critical features of mucolipidosis type II include:

  • Skeletal Abnormalities: Individuals with mucolipidosis type II often exhibit skeletal abnormalities, including dysostosis multiplex, which involves malformation and deformities of multiple bones.
  • Facial Dysmorphism: Individuals with mucolipidosis type II may have coarse facial features, a flat nasal bridge, a prominent forehead, and an enlarged tongue.
  • Organomegaly: Enlargement of organs, such as the liver and spleen (organomegaly), may occur.
  • Developmental Delay: Children with mucolipidosis type II typically experience significant developmental delays, including motor and cognitive skills.
  • Hypotonia: Low muscle tone (hypotonia) is typical, contributing to difficulties with motor skills and coordination.
  • Joint Stiffness: Stiffness and limitation of joint mobility may be present.
  • Cardiac Involvement: Mucolipidosis type II can affect the heart, leading to cardiomyopathy and other cardiac abnormalities.
  • Respiratory Complications: Respiratory issues may arise, and affected individuals may be prone to respiratory infections.
  • Corneal Clouding: Clouding of the corneas may occur, affecting vision.
  • Intellectual Disability: Intellectual disability is a standard feature, and affected individuals may have limited cognitive abilities.

Mucolipidosis type II is inherited in an autosomal recessive manner, meaning that affected individuals inherit mutations in the GNPTAB gene from both parents.

There is no cure for mucolipidosis type II, and management involves supportive care to address the specific symptoms and complications. This may include physical and occupational therapy, respiratory support, and interventions to address cardiac and musculoskeletal issues.

Due to the severity of mucolipidosis type II and its impact on various systems, affected individuals often require multidisciplinary care involving pediatricians, geneticists, orthopedic specialists, and other healthcare professionals.

Genetic counseling is essential for families affected by mucolipidosis type II to understand the risk of having affected children and to discuss family planning options. Due to the complexity of ML II and its challenges, ongoing medical supervision and supportive care are essential for optimizing the quality of life for affected individuals.

More Information

Mucolipidosis type II is a lysosomal depot disease with an autosomal recessive mode of inheritance. The disease's origin lies in mutations in the GNPTAB gene encoding the alpha and beta subunits of the N-acetylglucosamine phosphotransferase complex. These mutations lead to mannose-6-phosphate deficiency, failing lysosomal function.

The c.3503_3504TC mutation (p.Leu1168fs) is the most frequent worldwide and is associated with a severe phenotype. It is a two-nucleotide deletion observed in both homozygosis and compound heterozygosis, along with other milder GNPTAB mutations. This deletion causes an alteration of the reading pattern, generating a non-functional truncated protein. Functional studies indicate that this truncated protein is retained in the endoplasmic reticulum and is not transported to the Golgi apparatus. The c.3503_3504TC variant is especially prevalent in the Saguenay-Lac-Saint-Jean region of Quebec, which has the highest rate of carriers globally (1/39) due to a founder effect.

The second most prevalent mutation, c.3565C > T (p.Arg1189Ter), was identified in Asia but is also present in patients in Australia, Germany, Ireland, Israel, and the United States.

Mucolipidosis type II genetic testing analyzes the 10 most frequent pathogenic mutations of the GNPTAB gene.

The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).

Additional information
Results Time4 - 5 Weeks
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