Mutation Causing Lesch-Nyhan Syndrome Linked to Other Neurological Disorders

Scientists have shown that gene expression errors impair the ability of stem cells to produce normal neurons, resulting instead in neurological disease. They indicate that at least some distinctly different neurodevelopmental and neurodegenerative disorders share basic, causative defects.

A gene mutation that causes a rare but destructive neurological disorder known as Lesch-Nyhan syndrome could help explain the developmental and neuronal defects found in other, diverse neurological disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. Lesch-Nyhan syndrome is caused by defects in the hypoxanthine guanine phosphoribosyltransferacgene (HPRT1), a gene that helps generate purine nucleotides, needed for DNA and RNA.

The findings, published in the October 9, 2013, issue of the journal PLOS ONE provide the first experimental picture of how gene expression errors impair the ability of stem cells to produce normal neurons, resulting instead in neurological disease. They indicate that at least some distinctly different neurodevelopmental and neurodegenerative disorders share basic, causative defects.

Mutations in the HPRT gene result in deficiencies in the HPRT enzyme, leading to defective expression of the neurotransmitter dopamine and subsequent abnormal neuron function. HPRT mutation is the specific cause of Lesch-Nyhan, an inherited neurodevelopmental disorder characterized by uncontrollable repetitive body movements, cognitive defects and compulsive self-mutilating behaviors.

They discovered that the cells do not develop normally. Instead, they differentiate from full-fledged neurons into cells that resemble and partially function as neurons, but also perform functions more typical of glial cells, a kind of supporting cell in the central nervous system. In addition, they noted that HPRT deficiency causes abnormal regulation of many cellular functions controlling important operational and reproduction mechanisms, DNA replication and repair and many metabolic processes.

The scientific team, headed by Theodore Friedmann, MD, professor of pediatrics at the University of California, San Diego School of Medicine (USA), says a gene mutation that causes a rare but destructive neurological disorder known as Lesch-Nyhan syndrome appears to explain the developmental and neuronal defects found in other, diverse neurological disorders like Alzheimer’s, Parkinson’s and Huntington’s diseases.

The scientists say that understanding defects in Lesch-Nyhan could help identify errant processes in other, more common neurological disorders, perhaps pointing the way to new kinds of therapies. Lesch-Nyhan syndrome is caused by defects in the hypoxanthine guanine phosphoribosyltransferacgene (HPRT1), a gene that is well-known for its essential tasks among them helping generate purine nucleotides–the building blocks of DNA and RNA.

“We believe that the neural aberrations of HPRT deficiency are the consequence of these combined, multisystem metabolic errors,” said Prof. Friedmann. “And since some of these aberrations are also found in other neurological disorders, we think they almost certainly play some role in causing the neurological abnormalities in diseases like Alzheimer’s, Parkinson’s, Huntington’s and possibly others. That makes them potential therapeutic targets for conditions that currently have limited or no treatments, let alone cures.”

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University of California, San Diego School of Medicine