NORD gratefully acknowledges Elizabeth C. Engle, MD, Professor of Neurology and Ophthalmology, Children's Hospital Boston and Harvard Medical School, and Max A. Tischfield, PhD, Johns Hopkins Medical School, for assistance in the preparation of this report.
Human HOXA1 syndromes are rare disorders with complex neurological and systemic symptoms. These syndromes are found among a few American Indian tribes such as the Navajo and Apaches, who are related to Athabaskan Indians of northern Canada.
It is also found in consanguineous Saudi Arabian and Turkish families. Various names have been applied (see the synonyms above), but the name human HOXA1 syndromes is generally used because it is not linked to a specific geographic location.
The identity of the disorder was determined by genetic studies of the parents and affected children. To date, each affected child acquires a copy of the same mutated gene from each of the parents (homozygosity) who share ancestral relationships. The abnormal gene has been identified and its location on chromosome 7 has been determined. Human HOXA1 syndromes are inherited as autosomal recessive genetic conditions.
Both populations studied (those related to Athabaskan Native Americans and the groups from the Middle East) presented with Duane syndrome and/or “horizontal gaze palsy”, both of which are characterized by restrictions in horizontal eye movements. Both populations also shared deafness, developmental delays, and a spectrum of internal carotid artery and conotruncal heart malformations. Facial asymmetries and mild external ear malformations were also sometimes present.
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. The Amerindian population also presented with central hypoventilation while asleep, a phenotype not yet identified in Middle Eastern families. Hypoventilation in the awake state, if present, is much milder (congenital central hypoventilation syndrome). Finally, both populations show signs of cognitive and behavioral impairments, as two Middle Eastern children from separate families were diagnosed with autism spectrum disorder (ASD) and most affected Athabaskan Indians exhibit intellectual disabilities; however, it is still unclear if the intellectual disabilities are secondary to brain hypoxia in Athabaskan patients.
The range and types of clinical findings in affected patients can vary significantly. Patients who have horizontal gaze restrictions and sensorineural deafness, and are thus candidates for HOXA1 mutations, should undergo magnetic resonance angiography (MRA) to determine the extent of vascular malformations. Furthermore, some patients can also display normal eye movements and hearing, but may still have arterial and/or conotruncal heart malformations that could cause significant medical problems. Thus, siblings of affected children should undergo genetic testing to determine if they have the disease despite lack of obvious clinical symptoms.
Human HOXA1 syndromes are inherited as autosomal recessive genetic conditions.
HOXA1, the mutated gene responsible for the human HOXA1 syndromes, has been mapped to the short arm of chromosome 7 at band 15.2 (7p15.2). HOXA1 regulates the development of the head, nervous system, inner ear, and vasculature system in mammals, and homozygous mutations result in human HOXA1 syndromes. All of the mutations identified to date cause premature stop codons that severely truncate the protein and presumably result in loss of function. Notably, heterozygous carriers are phenotypically normal and do not display clinical symptoms.
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 two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person is a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
All individuals carry several abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than non-consanguineous parents to carry the same abnormal gene, which increases the risk to have children with a rare recessive genetic disorder.
About the only thing known about the distribution, incidence and/or prevalence of the Human HOXA1 Syndromes is that they have 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 diseases 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.
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 and outflow tracts of the heart. Other magnetic resonance studies will show whether parts of the brain are lacking or underdeveloped.
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.
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Contact for additional information about congenital fibrosis of the extraocular muscles:
Elizabeth C. Engle, MD
Professor of Neurology and Ophthalmology
Children’s Hospital Boston, CLS14075
300 Longwood Ave
Boston, MA 02115
e-mail: [email protected]
Bosley TM, Alorainy IA, Salih MA, Aldhalaan HM, Abu-Amero KK, Oystreck DT, Tischfield MA, Engle EC, Erickson RP. The clinical spectrum of homozygous HOXA1 mutations. Am J Med Genet A. 2008;146A(10):1235-40. doi: 10.1002/ajmg.a.32262. PMID: 18412118
Bosley TM, Salih MA, Alorainy IA, Oystreck DT, Nester M, Abu-Amero KK, Tischfield MA, Engle EC. Clinical characterization of the HOXA1 syndrome BSAS variant. Neurology. 2007;18;69(12):1245-53. PMID: 17875913
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.
Erickson RP. Southwestern Athabaskan (Navajo and Apache) genetic diseases. Genet Med. 1999;1:151-57.
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.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No: 601536; Last Update: 1/27/12. Available at: http://omim.org/entry/601536 Accessed January 14, 2013.
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