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Mucolipidosis IV

Synonyms of Mucolipidosis IV

  • Berman Syndrome
  • Ganglioside Neuraminidase Deficiency
  • Ganglioside Sialidase Deficiency
  • ML Disorder IV
  • ML IV
  • Neuraminidase Deficiency
  • Sialolipidosis

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Mucolipidosis IV is a rare inherited metabolic disorder believed to be characterized by a deficiency of transport channel receptor protein, based upon the recent discovery of the Mucolipidosis IV gene. This deficiency may lead to the accumulation of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides) within the cells of many tissues of the body.

Mucolipidosis IV is characterized by mental retardation; severe impairment in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation); diminished muscle tone (hypotonia); clouding (opacity) of the clear portion of the eyes through which light passes (cornea); and/or degeneration of the nerve-rich membrane lining the eyes (retinal degeneration). Mucolipidosis IV is thought to be inherited as an autosomal recessive genetic trait.

Symptoms

The symptoms and physical findings associated with Mucolipidosis IV are usually apparent within three to eight months following birth. The first recognized symptom usually is clouding (opacity) of the clear portion of the eyes through which light passes (cornea). In some cases, this may not be apparent until three to five years of age.

Most affected infants exhibit diminished muscle tone (hypotonia); moderate to severe mental retardation; delays in reaching developmental milestones; and/or significant delays in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation).

In addition to opacities of the cornea, individuals with Mucolipidosis IV may have additional abnormalities affecting the eyes including crossed eyes (strabismus), puffy eyelids, degeneration of the nerve-rich membrane lining the eyes (retina), and/or visual impairment (amblyopia) in an eye that appears structurally normal. In some cases, such eye abnormalities may result in an abnormal sensitivity to light (photophobia) and/or nearsightedness (myopia).

Individuals with Mucolipidosis Type IV develop iron deficiency anemia because their stomachs do not secrete acid. They do not have enlarged livers or spleens, skeletal involvement, or mucopolysaccharides in the urine.

Causes

Mucolipidosis Type IV is inherited as an autosomal recessive genetic trait. Recently, the responsible gene was isolated and its protein-product, as well as its chromosomal location, determined. The gene has been tracked to 19p13.3-p13.2 where it encodes for the mucolipin-1 protein. It is designated as the MCOLN1 gene.

Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as p and a long arm identified by the letter q. Chromosomes are further subdivided into bands that are numbered. For example, chromosome 11p15.4 refers to band 15.4 on the short arm of chromosome 11.

Human traits including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother.

In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

Researchers suspect that the symptoms of Mucolipidosis Type IV develop due to deficiency of a transport protein. Cells take up metabolites from the environment. In the case of certain fatty substances (mucolipids) and certain complex carbohydrates (mucopolysaccharides), these products of metabolism must be transported within the cell to the lysosomes where these complex substances are further broken down into simpler components. If these complex substances are not transported within the cell to the factories in which they are further broken down, they accumulate within the cells with disastrous effects. It is the accumulation of the substances within the cell that is the cause of Mucolipidosis IV. These substances accumulate because of a lack, within the cells, of the protein necessary for the transportation process. Researchers believe that this cell-deficiency may lead to the symptoms of this disorder due to the abnormal accumulation of the complex chemical compounds within the cells of many tissues of the body.

Affected Populations

Mucolipidosis Type IV is a rare inherited metabolic disorder that affects males and females in equal numbers. The disorder was first identified in 1974. About one-half of the reported individuals with Mucolipidosis Type IV are of Ashkenazi Jewish parentage. The exact incidence is unknown with approximately 70 cases reported in the medical literature.

Related Disorders

N/A

Standard Therapies

Diagnosis
A carrier test is now available to screen for the Mucolipidosis IV gene. Mucolipidosis IV may be diagnosed before birth (prenatally) by means of a procedure known as amniocentesis. During amniocentesis, a small portion of the fluid that surrounds the fetus (amniotic fluid) is removed; cells from the fluid are then tested in the laboratory for the Mucolipidosis IV gene.

A diagnosis of Mucolipidosis Type IV may also be confirmed based upon a thorough clinical examination, a detailed patient history, and a variety of specialized tests. In most cases, an electron microscope is used to visualize characteristic lysosomal storage bodies in certain connective tissue cells (fibroblasts). Fibroblasts are usually obtained from biopsied tissue of the skin and/or the delicate membrane that lines the eyes (conjunctiva). As noted above, genetic testing has recently become available for diagnostic purposes. Individuals with ML-IV present with iron deficiency anemia, high serum gastrin levels and characteristic findings on brain MRI examinations.

Treatment
Treatment of Mucolipidosis Type IV is symptomatic and supportive. Symptoms associated with clouding of the corneas may be treated by the use of contact lenses and/or artificial tears. Genetic counseling will be of benefit for affected individuals and their families. Intense physical, occupational and speech therapy are also of benefit. Iron replacement is utilized for those with anemia.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Since prenatal diagnosis is now possible through amniocentesis, new treatments aimed at checking mucolipidosis IV are now under investigation. One method might involve replacing defective transport protein. Scientific study of gene replacement in animal models raises the hope that gene replacement therapy may someday be made available to people with genetic disorders such as mucolipidosis IV.

In a study sponsored by the National Institute of Neurological Disorders and Stroke (NINDS), scientists are investigating the natural history and causes of mucolipidosis IV. This study seeks to better understand the disease, identify the medical difficulties for patients, and discover improved methods of diagnosing mucolipidosis IV. Information on this clinical trial is available from the NIH sources listed above.

Organizations related to Mucolipidosis IV

References

TEXTBOOKS
Scriver CR, et al., eds. The Metabolic and Molecular Basis of Inherited Disease. 7th Ed. New York, NY; McGraw-Hill Companies, Inc; 1995:36, 374.

Menkes JH, au, Pine JW, et al., eds. Textbook of Child Neurology, 5th ed. Baltimore, MD: Williams & Wilkins; 1995: 86-87.

REVIEW ARTICLES
Bach G. Mucolipidosis type IV. Mol Genet Metab. 2001;73:197-203.

Pshezetsky AV, Ashmarina M. Lysosomal multienzyme complex: biochemistry, genetics, and molecular pathophysiology. Prog Nucleic Acid res Mol Biol. 2001;69:81-114.

Mancini GM, Havelaar AC, Verheijen FW. Lysosomal transport disorders. J inherit Metab Dis. 2000;23:278-92.

JOURNAL ARTICLES
Bargal R, Bach G. Mucolipidosis type IV: abnormal transport of lipids to lysosomes. J inherit Metab Dis. 1997;20:625-32.

Chen C-S, Bach G, Pagano RE. Abnormal transport along the lysosomal pathway in mucolipidosis, type IV disease. Proc Nat Acad Sci. 1998;95:6373-78.

Raas-Rothschild A, Bargal R, Dellapergola S, et al. Mucolipidosis type IV: the origin of the disease in the Ashkenazi-Jewish population. Europ J Hum Henet. 1999;7:496-498.

Slaugenhaupt SA, et al., Mapping of the mucolipidosis type IV gene to chromosome 19p and definition of founder haplotypes. Am J Med Genet. 1999;65:773-8.

Bargal R, Avidan N, Ben-Asher E, et al. Identification of the gene causing mucolipidosis type IV. Nature Genet. 2000,26:120-123.

Sun M, Goldin E, Stahl S, et al. Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel. Hum Mol Genet. 2000;9:2471-78.

Wang ZH, Zeng B, Pastores GM, et al. Rapid detection of two common mutations in Ashkenazi Jewish patients with mucolipidosis type IV. Genet Test. 2001;5:87-92.

Acierno JS Jr, Kennedy JC, Falardeau JL, et al. A physical and transcript map of the MCOLN1 hene region on human chromosome 19p13.3-p13.2. Genomic. 2001;73:203-10.

Bargal R, Avidan N, Olender T, et al. Mucolipidosis type IV: novel MCOLN1 mutations in Jewish and non-Jewish patients and the frequency of the disease in the Ashkenazi Jewish population. Hum Mutat. 2001;17:397-402.

Altarescu G, et al., The neurogenetics of mucolipidosis type IV. Neurology. 2002;59:306-13.

FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 252650; Last Update: 12/6/2000.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2008/05/08 00:00:00 GMT+0

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