Information on the following diseases can be found in the Related Disorders section of this report:

• Duane syndrome
• Moebius syndrome

Both populations studied (those related to Athabaskan Native Americans and the groups from the Middle East) showed "horizontal gaze palsy" or the inability to move the eyes easily from side to side. Both populations also shared deafness, developmental delays, and a spectrum of internal carotid artery malformations.

In contrast to the Middle Eastern groups, some of those in the Amerindian population had facial weakness and assumed developmental defects of the seventh cranial nerve. Some also had congenital heart defects. The Amerindian population, in contrast to the Saudi Arabian and Turkish population, also presented with central hypoventilation while asleep. Hypoventilation in the awake state, if present, was much milder (congenital central hypoventilation syndrome). Finally, both populations show signs of cognitive and behavioral impairments, as two Middle Eastern families were diagnosed with autism spectrum disorder (ASD) and all affected Athabaskan Indians exhibit mental retardation.

The malfunctioning gene responsible for human HOXA1 syndromes has been mapped to the short arm of chromosome 7 at band 15.2 (7p15.2). The mutated gene, known as HOXA1, plays a role in the development of the head, nervous system, inner ear, and vasculature system in mammals, and mutations in the recessive state result in BSAS and ABDS. Mutations in HOXA1 may also lead to increased susceptibility for autism spectrum disorder.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 7p15.2" refers to band 15.2 on the short arm of chromosome 7. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal 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 for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

About the only thing known about the distribution, incidence and/or prevalence of BSAS is that it has only been identified among three groups in North America, Saudi Arabia, and Turkey. Each group harbors its own founder mutation, suggesting that there is no epidemiological relationship between the disease in these different locations. Based on a study of languages among North American Indian populations, anthropologists and clinicians believe that the mutation found in the Native American population originated in a population that crossed the Bering Sea to Alaska and northern Canada about 4,000 years ago.

Duane syndrome (DS) is an eye movement disorder present at birth (congenital) characterized by a limited ability to move the eye inward toward the nose (adduction), outward toward the ear (abduction), or in both directions. In addition, when the affected eye(s) moves inward toward the nose, the eyeball retracts (pulls in) and the eye opening (palpebral fissure) narrows. In some cases, when the eye attempts to look inward, it moves upward (upshoot) or downward (downshoot). Duane syndrome falls under the larger heading of strabismus (misalignment of the eyes) under the subclassification of incomitant strabismus (misalignment of the eyes that varies with gaze directions) and subheading of extraocular fibrosis syndromes (conditions associated with fibrosis of the muscles that move the eyes).

Moebius syndrome is a rare developmental disorder present at birth (congenital) that is characterized by facial paralysis and horizontal gaze deficits. Affected individuals are not able to smile or frown. It is hypothesized that this results because two important nerves, the sixth (abducens) and seventh (facialis) cranial nerves, are absent or not fully developed. In some instances, this syndrome may also be associated with physical problems in other parts of the body. (For more information on this disorder, choose "Moebius syndrome" as your search term in the Rare Disease Database.)

Diagnosis
The diagnosis of human HOXA1 syndromes may be confirmed by a thorough clinical evaluation of members of the suspect populations and a variety of specialized tests, particularly advanced imaging techniques. For example magnetic resonance angiography (MRA) of the head and neck will reveal malformations of the carotid arteries as well as the inner ear. Other magnetic resonance studies will show whether parts of the brain are lacking or underdeveloped.

Treatment
The treatment of these syndromes is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, cardiologists, dental specialists, speech pathologists, specialists who assess and treat hearing problems (audiologists), eye specialists and others may need to systematically and comprehensively plan an affected child’s treatment.

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 web site.

For information about clinical trials being conducted at the NIH Clinical Center 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

Other information about current studies related to these syndromes may be available from the following individuals:

Dr. Steve A. Holve
Tuba City Regional Healthcare Corporation
P O Box 600
167 North Main St.
Tuba City, AZ 86045
Phone: 928-283-2406
Fax: 928-283-2408
e-mail: steve.holve@tcimc.ihs.gov

Elizabeth C. Engle, MD
Associate Professor of Neurology
Children’s Hospital Boston
Harvard Medical School
Program in Genomics & Neurology, Enders 560.2
300 Longwood Ave
Boston, MA 02115
Phone: 617-919-4030
e-mail: engle@enders.tch.harvard.edu

McKusick VA, ed. Online Mendelian Inheritance In Man (OMIM). The Johns Hopkins University. Athabaskan Brainstem Dysgenesis Syndrome; ABSD. Entry Number; 601536: Last Edit Date; 10/14/2005.

JOURNAL ARTICLES
Tischfield MA, Bosley TM, Salih MAM, et al. Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nat Genet. 2005;37:1035-37.

Holve S. Friedman B, Hoyme HE, et al. Athabaskan brainstem dysgenesis syndrome. Am J Med Genet. 2003;120A:169-73.

Friedman BD, Tarby TJ, Holve S, et al. Congenital horizontal gaze palsy, deafness, central hypoventilation, and developmental impairment: a brain stem syndrome prevalent in the Navaho population. Proc Greenwood Genet Ctr. 1997;16:160-61.

Erickson RP. Southwestern Athabaskan (Navajo and Apache) genetic diseases. Genet Med. 1999;1:151-57.

FROM THE INTERNET
Aaron Patnode. Rare Eye-Movement Disorder May Shed Light on Brain and Cardiovascular Development. Children’s Hospital Boston. September 11, 2005. 1p.
www.childrenshospital.org/newsroom/Site1339/mainpageS1339P1sublevel164.html

Medical Research News. HOXA1 is a gene that’s been looking for a disorder for a long tome. 12-Sep-2005. 1p.
www.news-medical.net/?id=13105

UA Researchers Clone Gene that Causes Athabaskan Brainstem Dysgenesis. UAHSC Advances. October 2005. 1p.
www.ahsc.arizona/ahsnews/oct05/clone.htm