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Mucolipidosis type IV is an inherited lysosomal storage disorder characterized by severe developmental delay and progressive vision problems. The delay in development occurs within the first year, while vision slowly diminishes until patients are blind by adolescence.
What are the Symptoms of Mucolipidosis Type IV?
There are two distinct forms of mucolipidosis type IV. The severe form (known as typical mucolipidosis type IV) occurs in 95% of cases. Most patients have intellectual disabilities and very limited speech ability. They will have difficulty chewing and swallowing, and controlling hand movements, weak muscle tone leading to abnormal muscle stiffness and a delay in learning to crawl, sit, stand, walk and grasp objects. Most people will not develop beyond the intellectual skills of a 1-2 year old, even though most live into adulthood. Generally affected people are never able to walk unaided and in some cases any limited psychometer skills that they are able to achieve slowly worsen again over time.
Vision is normal at birth but will diminish during the first decade of life due to retinal degeneration and retinal pigment changes. Individuals with typical mucolipidosis type IV will develop clouding of cornea and progressive breakdown of the retina. They experience severe vision loss or blindness by their early teen years.
Progressive renal failure is another feature of typical mucolipidosis type IV. Renal failure occurs in the third decade of life. Iron deficiency is seen in 50% of affected people, as well as iron deficiency anemia, which occurs in about 10% of the cases. People with typical mucolipidosis type IV also have defective production of stomach acid (achlorhydria). While it does not cause symptoms in these individuals it causes high blood levels of gastrin, a hormone that regulates the production of stomach acids.
People with the rare atypical form of mucolipidosis type IV will usually experience mild psychomotor delay and may be able to walk unaided. They have milder eye abnormalities and achlorhydria may be present. Some cases present with a muscle disorder (congenital myopathy) with significant hypotonia and elevated muscle creatine kinase levels.
What Causes Mucolipidosis Type IV?
Mucolipidosis type IV is caused by mutations in the MCOLN1 gene that encodes the mucolipin-1 protein. Mucolipin-1 is found in the membranes of lysosomes and endosomes, compartments within the cell that digest and recycle material. It is thought to play a role in transport of fats and proteins between the lysosomes and endosomes and also appears to be essential for the development and the maintenance of the brain and retina. Mucolipin-1 is also likely critical for normal functioning of cells in the stomach that produce digestive acids.
Two mutations in MCOLN1, delta 6.4kb and IVS3-2A>G, have been linked to over 95% of the cases of mucolipidosis type IV in Ashkenazi Jewish patients. Both mutations result in the production of abnormally short, non-functional mucolipin-1. Without functional mucolipin-1, fats and proteins accumulate in the lysosomes, which is why mucolipidosis type IV is known as a lysosomal storage disease. Approximately 60% of the Ashkenazi Jewish patients in the United States carry two copies of the IVS3-2A>G mutation (also known as c.406-2A>G). The delta 6.4kb mutation can also be referred to as g.511_6943del and results in the deletion of exons 1-5 and part of exon 6.
How is Mucolipidosis Type IV Diagnosed?
Anyone showing the clinical signs of mucolipidosis (developmental delay and vision problems) should be analyzed for the disease. This diagnosis is based upon laboratory analysis of the patient’s plasma to detect high gastrin levels and molecular genetic testing to identify mutations in the MCOLN1 gene. Individuals with mucolipidosis type IV normally have elevated plasma gastrin levels, ranging from 400-4100 pg/mL, compared to the normal range of 0-200 pg/mL.
This Jewish disease panel will determine if an individual has one or more copies of a disease-causing mutation in the MCOLN1 gene. This panel analyzes two mutations, delta 4.6kb and IVS3-2A>G, that have been linked to over 95% of the cases of mucolipidosis type IV occurring in Ashkenazi Jewish individuals. Genetic analyses are able to diagnose affected individuals, who have two defective copies of MCOLN1, as well as identify unaffected carriers, who have one defective copy and one normal copy of MCOLN1. The identification of carriers is important to allow couples to understand their risks of having affected children.
How is Mucolipidosis Type IV Treated?
There is no cure for mucolipidosis type IV and the disease is managed by treating symptoms and through providing supportive care. Speech and physical therapy help to enable patients to achieve some speaking and movement ability, and anti-epileptic drugs are used to prevent seizures. Several treatments are required for the eye problems associated with this disease, including topical lubrication eye drops, artificial tears, gels or ointments to manage eye irritation, surgical correction of strabismus (the abnormal alignment of the eyes) and high contrast black and white material for those with visual impairments. Iron preparations, such as oral ferrous sulfate, are recommended when iron deficiency anemia is detected.
Recommended Links: Ferreira JC, Schreiber-Agus N, Carter SM, Klugman S, Gregg AR, Gross SJ. (2014) Carrier testing for Ashkenazi Jewish disorders in the prenatal setting: navigating the genetic maze. Am J Obstet Gynecol. 211(3): 197-204.
Schiffmann R, Grishchuk Y, Goldin E. (2005) [Updated 2015 Jul 30]. Mucolipidosis IV. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.