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OVERVIEW 
Mucolipidosis type IV (ML4), first decribed in 1974, is the most recently recognized Jewish genetic disease.  To date, over 70 patients, most of Ashkenazic Jewish descent, have been reported.  Children with ML4 begin to exhibit developmental delay during the first year of life.  Many parents seek opthomalogic evaluations for pseudo-strabismus.  Motor and mental retardation ranges from mild to severe.  The earliest sign is corneal clouding; however, approximately 30% of patients develop clouding between three and five years of age.  Other eye findings may include pseudostrabismus (false appearance of crossed eyes) and/or retinal degeneration, which may lead to blindness in later years.  The is no gross involvement of the skeletal system nor urinary mucopolysaccharide excretion.  Patients currently range from one to 45 years of age.  Prognosis and life expectancy beyond the latter age is unknown.  Recently, a few very mildly affected children with ML4 have been diagnosed. This raises the possibility of other undiagnosed mildly involved patients. 

The name, ML4, derives from the presence of diagnostic storage bodies (cytoplasmic inclusions seen under electron microscope) in almost every cell of these patients.  The storage bodies are similar to those observed in the mucopolysaccharide and lipid storage diseases; thus the designation mucolipidosis.  The diagnosis should be considered in retarded Jewish children who have corneal clouding.  The electron microscopic demostration of characteristic storage bodies in a conjunctival biopsy supports the clinical diagnosis. 
The specific biochemical and genetic defects which cause ML4 are known to be associated with chromosome 19. This permits precise methods for diagnosis including identification of carriers of the gene which causes ML4 and prenatal diagnosis. Further research is required to isolate the disease gene.
The disease is inherited as an autosomal recessive trait.  Although both parents are normal, they carry the disease-causing gene.  Such carrier couples have a 25% risk for an affected fetus with each pregnancy.  The prenatal diagnosis of this disease has been successfully accomplished by electron microscopic demonstration of characterisic storage bodies in cultured amniotic cells obtained by amniocentesis.  The prenatal diagnosis is difficult and must be performed in centers with expertise in the specialized techniques required for this diagnosis. Carrier testing is available by blood test. 
At present, no specific therapy is available.  Optimal supportive care, including physical, occupational and speech therapy, can significantly improve the function and quality of life of affected children.  Families with affected children should seek genetic counseling  and be offered the option of prenatal diagnosis for future pregnancies. 
Contributions to sustain and expand this research are gratefully accepted.  All contributions are tax deductible.  Checks should be made payable to the ML4 Foundation, 719 East 17th Street, Brooklyn, New York 11230, USA; E-mail: ML4www@aol.com 
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SCIENTIFIC UPDATE by Jordan B. Glaser MD 

The ML4 Foundation is now accepting Grant Applications. Download the Grant Application in Word or Html formats.

The Foundation will be funding over $300,000 during the 2000 calendar year to researchers at Harvard University, the National Institutes of Health (NIH), and Hadassah Hospital. The NIH recently approved a three year grant of over one million dollars to Harvard University specifically for ML4 research. The ML4 Foundation has successfully lobbied the Congressional House Appropriations Committee to include ML4 as one of twenty neurological diseases as a NIH research priority. 

The supporters of the ML4 Foundation are, of course, very excited about the outcome of our current funding and the future prospects of the accomplished researchers that receive our support. 
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HARVARD MEDICAL CENTER RESEARCH 
Susan A. Slaugenhaupt Ph.D. & James Gusella, Ph.D, Harvard Medical Center/Massachusetts General Hospital 

The MGH Molecular Genetics Unit recently utilized an approach called linkage analysis to discover a region on chromosome 19 that harbors the ML4 gene. This will allow for carrier and prenatal testing for certain families already affected with ML4. These data were published in the September issue of the american Journal of Human Genetics. Future work will be concentrated on identifying and sequencing the ML4 gene. This will allow for carrier testing for the general population and potentially for specific treatment for those affected with ML4.
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HADASSAH MEDICAL CENTER RESEARCH 
Gideon Bach, Ph.D 

Dr. Bach collaborated with Dr. Gusella's group for the performance of linkage analysis on various samples from ML4 families. Hadassah and the Mayo Clinic elucidated an abnormal transport mechanism along the lysosomal pathway in ML4. These data were published in the Proceedings of the National Academy of Science. Dr. Bach collaborates with Dr. Asher Ornoy of the Hadassah Pathology Department to provide electron microscopic analysis of amniocenteses obtained for prenatal testing. Dr. Bach will also be coordinating linkage analysis based prenatal testing for Israeli families affected by ML4.

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NATIONAL INSTITUTES OF HEALTH RESEARCH 

October 9, 2001  The United States House Committee on Appropriations issued its Report on the budgets for various departments which included NIH.

"Mucolipidosis Type IV.--The Committee commends NINDS for sposoring research with the Mucolipidosis Type IV (ML4) Foundation. This research identified the gene whose mutation causes this debilitating genetic metabolic disease. The Committe urges NINDS and other Institutes to expand both intramural and extramural research on this disease."

The amount provided in the House bill for NINDS for Fiscal 2002 is $1,306,321,000, "which is $129,524,000 above the fiscal year 2001 comparable level and the same as the budget program request." (at p.71).  Howard Monderer

Raffi Schiffman, M.D. & Ehud Goldin Ph.D. 

Dr. Schiffman is directing the first prospective clinical trial on ML4. ML4 children are admitted yearly to the NIH for four days of testing, including MRI/MRS, EEG, blood tests, psychological testing, PT, OT, speech and opthamological evaluations.  The trial has yielded a variety of findings. The NIH discovered that those affected with ML4 have iron deficiency anemia related to low stomach acid secretion. These individuals were found to have high serum gastrin levels in response to the low acid secretion. These findings were published in the Proceedings of the National Academy of Science. The NIH also discovered pathopneumonic (specific) brain MRI findings for those affected with ML4. These data were published in Neurology. The NIH studied the EEGs of ML4 patients and found significant pathologic differences between ML4 and normal patients. These data were published in Electroencephalographic Clinical Neurophysiology.

Dr. Goldin continues to conduct basic scientific research. His group demonstrated that ML4 cells autoflouresce and are sensitive to chloroquine. The NIH ccollaborated with Harvard on the linkage analysis studies. The NIH discovered that the mutation is in the same gene for all ML4 patients. This discovery validated all chromosome and linkage studies and proves that ML4 is one disease. These data were published in the Proceeding of the National Academy of Science.
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THE BRIGHAM AND WOMEN'S HOSPITAL  Janice LaPlante,Ph.D., Boston, MA 

BWH has ongoing research in the area of Mucolipin-1 protein and its role in ML4. more...

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JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE  Craig Montell, Ph.D. Director of BCMB, Baltimore, MD 

One focus of the research is to characterize Mucolipin1 and related proteins using a combination of molecular, biochemical, cell biological and electrophysiological approaches. In particular, we are interested in addressing whether the Mucolipins are cation channels, whether they form heteromultimers and to determine the modes of regulation of this new class of putative ion channel. A second focus of the research is to further explore the functions of the mucolipins in vivo. There is one mucolipin gene in Drosophila. We plan to create a mutation in the Drosophila mucolipin and address its role in vivo. A long range goal of this research is to take advantage of the genetics in Drosophila to identify other proteins that function in concert with the fly mucolipin. Once this is accomplished, we will test whether related proteins interact functionally with the human mucolipins. more....