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FRAXA syndrome

Fragile X Syndrome is the most common inherited cause of mental retardation, and is associated with autism. more...

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Causes

The fragile X syndrome is a genetic disorder caused by mutation of the FMR1 gene on the X chromosome. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 4000 females.

Normally, the FMR1 gene contains between 6 and 53 repeats of the CGG codon (trinucleotide repeats). In people with the fragile X syndrome, the FMR1 allele has over 230 repeats of this codon.

Expansion of the CGG repeating codon to such a degree results in a methylation of that portion of the DNA, effectively silencing the expression of the FMR1 protein.

This methylation of the FMR1 locus in chromosome band Xq27.3 is believed to result in constriction and fragility of the X chromosome at that point, a phenomenon that gave the syndrome its name.

The mutation and methylation of the FMR1 gene lead to the transcriptional silencing of the fragile X-mental retardation protein, FMRP. In normal individuals, FMRP binds and facilitates the translation of a number of essential neuronal RNAs. In fragile X patients, however, these RNAs are not translated into proteins. The various sequelae of fragile X syndrome result.

Transmission of the Fragile X

The diagram (above) of X-linked recessive inheritance is not entirely inappropriate but it markedly oversimplifies the situation and does not provide a sufficient foundation for genetic counseling with the fragile X syndrome.

Because males normally have only one copy of the X chromosome, those males with significant trinucleotide expansion at the FMR1 locus are symptomatic. They are mentally retarded and may show various physical features of the fragile X syndrome.

Females have two X chromosomes and thus have double the chance of having a working FMR1 allele. Females carrying one X chromosome with an expanded FMR1 gene can have some signs and symptoms of the disorder or be normal.

Males with the fragile X cannot transmit it to any of their sons (since males contribute a Y chromosome, not an X, to their male offspring.)

Females carrying one copy of the fragile X can transmit it to their sons or daughters. Sons who receive the fragile X are at high risk for mental retardation. Daughters who receive the fragile X may appear normal or they may be mentally retarded, usually to a lesser degree than boys with the syndrome.

Symptoms

Aside from mental retardation, prominent characteristics of the syndrome include an elongated face, large or protruding ears, large testicles (macroorchidism), and low muscle tone. Behavioral characteristics may include stereotypic movements (e.g., hand-flapping) and atypical social development, particularly shyness and limited eye contact. Some individuals with the fragile X syndrome also meet the diagnostic criteria for autism.

Read more at Wikipedia.org

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Sention to Develop Novel Merck Compounds for Mental Retardation, Sention Secures Access to Potential New Product
From Business Wire, 1/19/05

PROVIDENCE, R.I. -- Sention Inc. today announced that it has entered into an exclusive licensing and research collaboration agreement with Merck & Co., Inc. (NYSE: MRK) to develop a family of Merck compounds known as mGluR5 antagonists as potential treatments for Fragile X mental retardation. Fragile X is the most commonly inherited form of mental retardation.

The use of metabotropic glutamate receptor (mGluR) antagonists for the treatment of mental retardation was first suggested by Mark Bear, Ph.D., one of Sention's founders. The agreement provides Sention with access to preclinical drug candidates discovered by Merck, the development of which Sention is pursuing at its own expense with the intention of moving a candidate into clinical trials. The agreement also allows Sention to develop the drug for Down Syndrome and includes an option to develop the drug for Huntington's Disease.

"Abnormal mGluR signaling offers a clear molecular logic behind a diverse constellation of symptoms associated with Fragile X syndrome. An exciting prospect is that some or all of these symptoms could be improved by drug therapies that specifically target signaling by mGluRs," said Dr. Bear, Professor of Neuroscience at the Picower Center for Learning and Memory at MIT.

Since licensing the use of mGluR antagonists for Fragile X from Dr. Bear's laboratory, Sention has worked closely with FRAXA, the Fragile X Research Foundation, which funds some of Dr. Bear's work. "We are thrilled that these companies are collaborating to work toward providing a therapeutic option for our children. We're excited to see Dr. Bear's work move closer to the clinic and look forward to working with Sention and Merck in the hopes of seeing this happen," said Michael Tranfaglia, M.D., Medical Director and Co-Founder of FRAXA.

"Merck is pleased to enter into this collaboration," said Dennis W. Choi, M.D., Ph.D., Executive Vice President, Neuroscience at Merck. "Dr. Bear's work represents a potential scientific breakthrough, and this agreement with Sention offers the opportunity to work toward translating this science into clinical practice."

"This collaboration with one of the world's premier pharmaceutical companies represents a significant milestone for Sention," added Randall Carpenter, M.D., President and CEO of Sention. "The agreement exemplifies an ideal synthesis of academic research, non-profit foundation support, small biotech innovation and large pharmaceutical company resources and know-how. Most importantly, we hope to advance an mGluR5 antagonist into clinical development for Fragile X, a syndrome that currently has no therapeutic options."

About Sention Inc.

Sention Inc. is a pharmaceutical development company focused on the discovery and development of drugs to treat cognitive impairment and other central nervous disorders. Sention has a pipeline of proprietary compounds in preclinical development that have shown efficacy in a variety of animal models of memory, cognition, and other central nervous system conditions. Sention has two compounds in clinical trials, C105 in Phase II for cognitive impairment and SN522 in Phase I for the enhancement of learning and memory.

Sention is a privately held company located in Providence, RI. For more information, please visit www.sentionpharma.com.

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