OOA (Old Order Amish)

DGM (Dutch-German Mennonite)

Inheritance: autosomal recessive
Genes: ATM

AT
AT1
Telangiectases
Ataxia
Louis-Bar syndrome

Unsteadiness
"Spider" type skin vessels
Cerebellar ataxia
Malignancies
Cancer

Ataxia-telangiectasia

Clinical Characteristics

General description (for patients): 

Children with this disorder often are noticeably unsteady as soon as they begin to walk.  Balance difficulties become so severe that most require a wheel chair by second decade of life.  The appearance of “spider” type blood vessels between the ages of 3 and 5 are diagnostic when combined with the unsteadiness.  These usually appear on the cheeks, eyelids, ears, and the forearms. Blood vessels over the whites of the eyes may appear especially prominent.  Other neurologic signs are slow, involuntary, writhing movements of the arms and fingers. Speech is often severely slurred, and muscle wasting in the hands and arms is prominent.  The immune system is compromised and reduced resistance to infection may be present.  Individuals are at risk for cancer, and there is an increased risk of the same in siblings, especially breast cancer.

Medical description: 

AT is a complex disorder involving multiple systems.  Truncal and then limb ataxia may be evident in childhood and progression is rapid. The immune system is compromised and chromosomal breakage is frequently observed.  Ionizing radiation such as X-rays is highly lethal to cells due to defective DNA repair.  Speech becomes dysarthric, and choreoathetoid movements can be pronounced.  Head-turning upon initiation of voluntary eye movements, especially lateral gaze, known as oculomotor apraxia, is common.  Muscle wasting in the extremities, especially the hands and feet, may be extreme.  The appearance of skin and conjunctival telangiectases by age 5 years is diagnostic, although not all patients have these.  They are usually seen on the pinnae, the forearms, the eyelids, and the butterfly areas of the face.  Affected individuals as well as their heterozygous sibs are vulnerable to the development of malignancies, especially leukemias, lymphomas, and breast cancer.

The risk of malignancies cannot be overemphasized.  Lymphomas and leukemia can precede the onset of ataxia and, while irradiation for these tumors can be ‘curative’, the treatment itself can incite new tumor formation.  It is recommended that young children with these malignancies undergo thorough neurological evaluations prior to treatment.

Genetics: 

Affected individuals have mutations in the ATM gene located on chromosome 11 (11q22.3) but the gene is large (66 exons) and over 400 mutations have been reported.  Offspring of consanguineous matings are usually homozygous while products of non-consanguineous unions usually are compound heterozygotes. The vast majority of mutations are truncating with a minority being missense.
This condition was first described among plain people in a single OOA family in Holmes County, OH.  The pedigree was subsequently extended to include six more cases with an AG (frameshift) deletion in three more nuclear families.  More recently, patients with an A>G substitution at nucleotide 5932 have been reported among Dutch-German Mennonites in Canada.
In some Canadian Mennonite famiies with confirmed mutations in ATM the disorder presents with signs of primary torsion dystonia and myoclonus-dystonia.  These signs may resemble an apparent autosomal dominant pattern with parent-child transmission.  It is unclear whether these families represent a variant of AT or a unique disorder.  The latter is suggested by an earlier onset of signs, the lack of cerebellar atrophy,  and the absence of ataxia and ocular telangiectases on initial presentation.  The risk of malignancies in these famiies is high.

Treatment: 

No treatment is known.

Prognosis: 

Many patients die in the first decades of life, possibly as a result of nasopharyngeal and pulmonary infections although cancer is a major risk.  There have also been reports of patients who lived into the 4th and 5th decades.
ANCILLARY TREATMENTS AND SUPPORT:  Radiation therapy must be avoided and both patients and their heterozygous sibs must avoid all ionizing radiation such as UV rays.  It is strongly suggested that mammograms be avoided.  Exposure to the common upper respiratory viral infections should be limited and childhood vaccinations are risky.

Specialists and specialty centers: 

Pediatrician, infectious disease, oncologist, neurologist.

References:

Gatti, R.A., Berkel, I., Boder, E., Braedt, G., Charmley, P., Concannon, P., Ersoy, F., Foroud, T., Jaspers, N.G., and Lange, K., et al:  Localizaiton of an ataxia-telangiectasia gene to chromosome 11q22-23. Nature 336: 577-580, 1988. PubMed ID: 3200306

Gatti, R.A., Boder, E., Vinters, H.V., Sparkes, R.S., Norman, A., and Lange, K.:  Ataxia-telangiectasia: an interdisciplinary approach to pathogenesis.  Medicine 70: 99-117, 1991. PubMed ID: 2005780

Woods, C.G., and Taylor, A.M.R.:  Ataxia telangiectasia in the British Isles: the clinical and laboratory features of 70 affected individuals.  Quart. J. Med. 82: 169-179, 1992. PubMed ID: 1377828

Telatar, M., Teraoka, S, Wang, Z., Chun, H.H., Liang, T., Castellvi-Bel, S., Udar, N., Borresen-Dale, A.L., Chessa, L., Bernatowska-Matuszkiewicz, E., Porras, O., Watanabe, M., Junker, A., Concannon, P,, Gatti, R.A..: Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am. J. Hum. Genet. 62:86-97, 1998. PubMed ID: 9443866

Ginter, D.N., and Tallapragada, R.:  Ataxia-telangiectasion.  In: Medical Genetic Studies of the Amish.  Johns Hopkins University Press, Baltimore, MD.  Pp. 144-145. 1978.

Orton, N.C., Innes, A.M., Chudley, A.E., and Bech-Hansen, N.T.:  Unique disease heritage of the Dutch-German Mennonite Population.  Am. J. Med. Genet. 146A: 1072-1087, 2008.  PubMed ID: 18348259

Yanofsky, R.A., Seshia, S.S, Dawson, A.J., Stobart, K., Greenberg, C.R., Booth, F.A., Prasad, C., Del Biqio, M.D., Wrogemann, J.J., Fike, F., and Gatti, R.A.:  Ataxia-telangiectasia: atypical presentation and toxicity of cancer treatment.  Can. J. Neurol. Sci. 36: 462-467.  PubMed ID: 19650357

Saunders-Pullman R, Raymond D, Stoessl AJ, Hobson D, Nakamura T, Pullman S, Lefton D, Okun MS, Uitti R, Sachdev R, Stanley K, San Luciano M, Hagenah J, Gatti R, Ozelius LJ, Bressman SB. Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites. Neurology. 2012 Feb 28;78(9):649-57. PubMed PMID: 22345219

Resources:

A-T Children's Project
NINDS Ataxia Telangiectasia Information

Associated Graphics