Inherited Neurologic Disorders Traced to Chromosome 15

Researchers have identified mutations in four genes on chromosome 15 that give rise to several related inherited neurologic syndromes. The disorders include Prader-Willi syndrome, Angelman syndrome, and hereditary spastic paraplegia (HSP).

HSP is a group of clinically and genetically diverse disorders that share the primary feature of progressive, generally severe, lower extremity spasticity. HSP is classified as "uncomplicated” (symptoms confined to lower extremity weakness, bladder disturbance, and to a lesser extent impaired position sense in the legs) or "complicated,” when additional neurologic deficits are present. Prader-Willi occurs when the defective chromosome is inherited from the father, and it features mild cognitive impairment and morbid obesity. Angelman is inherited from the mother and is characterized by seizures, movement disorders, and severe mental retardation. Prader-Willi and Angelman syndromes occur in one in every 12,000 to 15,000 births.

Investigators at the University of Pennsylvania School of Medicine (Philadelphia, USA; www.upenn.edu) reported in two papers in the October 2003 issue of the American Journal of Human Genetics that breakpoint regions on chromosome 15 contribute to chromosome rearrangements in evolution but in individuals may cause Prader-Willi and Angelman syndromes. They identified four genes, NIPA1, NIPA2, CYFIPI, and GCP5, in the unstable area of chromosome 15. A mutation in NIPA1 was found in families where members suffered from hereditary spastic paraplegia.

"Genes located in this part of chromosome 15 sit among a lot of genetic flotsam and duplicated regions we refer to as breakpoint regions. In the grand scheme of things, this is an evolutionary plus for humans, as these regions are prone to genetic recombination, duplication, and other forms of gene shuffling that can add diversity to the human genome in the process of passing down chromosomes,” explained senior author Dr. Robert D. Nicholls, professor of psychiatry and genetics at the University of Pennsylvania. "In individuals, however, it can cause disease.”