Patients with variant ataxia-telangiectasia (A-T) — an autosomal recessive multisystem disease that causes neurodegeneration, primarily cerebellar, with oculocutaneous telangiectasia — may go undiagnosed for decades because they don't necessarily have the same symptoms as people with the classic version of the disease.
A-T is marked by immune deficiency, endocrinopathy, respiratory failure, increased risk for malignancy, elevated serum alpha-fetoprotein levels, and chromosomal instability. The endocrinopathy includes some or all of the following: pernicious anemia, hypothyroidism, hypoadrenocorticism, gonadal failure, and diabetes mellitus.
Investigators in the Netherlands, led by MM Verhagen, MD, of the Radboud University Nijmegen Medical Center, characterized the differences between classic and variant A-T by reviewing the medical records of six unrelated adults with classic disease and 13 patients from nine families with the variant form. The patients with variant A-T had been given various diagnoses over the years, from “resting tremor of unknown cause,” to “dystonic cerebral palsy.” One patient developed symptoms at age 6, but was not correctly diagnosed until age 44.
They reported that people with variant A-T often have extrapyramidal symptoms in childhood and don't develop cerebellar ataxia and other telltale signs until they are adults, if at all. The paper was published online in advance of the Aug. 11 print edition of Neurology.
The investigators looked at gene mutations as well as other clinical features. The ataxia telangiectasia mutated (ATM) gene, located on chromosome 11, encodes a protein that is a “key player in the cellular response to DNA damage,” according to the investigators. “It has been suggested that variant A-T is associated with mutations that leave some residual ATM kinase activity, whereas ATM kinase activity is fully absent in patients with classic A-T.”
In the classic group, “mutation analysis revealed mutations in 9/12 alleles,” all of which “would be predicted to result in loss of the function of the ATM gene,” the paper said. In the variant group, different mutations correlated with severity of disease.
Table. CLINICAL FEAT...Image Tools
The researchers said that the mildest variant A-T phenotype was associated with missense mutations in the ATM gene, which resulted in expression of some residual ATM protein with kinase activity.” On the other hand, “two splicing mutations….caused a more severe variant A-T phenotype” and “resulted in less ATM protein and kinase activity than the missense mutations.”
Patients with classic A-T usually have an ataxic gait by the time they begin to walk, use a wheelchair by age 10, and die between ages 20 and 40 from cancer or respiratory failure, the investigators wrote. Patients with variant A-T have milder symptoms and live longer.
“In this paper we demonstrate that variant A-T patients, like classical patients, have an increased risk for malignancies,” Michel A. Willemsen, MD, PhD, an associate professor in pediatric neurology at Radboud University Nijmegen Medical Centre, told Neurology Today. He said clinicians need to be on the lookout for “malignancies and the higher risk for side effects of subsequent cancer treatment, including radiation therapy.”
The Dutch researchers found distinct differences in the neurologic features of the two groups. The classic A-T patients' first symptom was ataxic gait, starting between ages 1 and 5, and all were using a wheelchair between the ages of 8 and 11. They had cerebellar dysarthria and oculomotor apraxia and most had chorea-athetosis, among other symptoms.
In contrast, the variant A-T patients tended to have extrapyramidal symptoms. Most had slowly worsening chorea-athetosis starting in early childhood and five had a resting tremor as a child or young adult. Twelve patients had slowly progressing cerebellar ataxia, beginning on average at age 27, and five required a wheelchair between ages of 15 and 43.
All of the patients in both the classic and variant A-T groups had elevated alpha-fetoprotein levels, though immunodeficiency was more common in the classic patients. Rearrangements of chromosome 7 and 14 and radiation sensitivity were less an issue in the variant group. (For more comparisons, see “Clinical Features: Classic and Variant A-T.”)
The researchers said that patients with unexplained extrapyramidal or cerebellar-related symptoms should be tested for alpha-fetoprotein. “Additionally, routine chromosomal analysis can be helpful in diagnosing variant A-T,” they wrote. “Subsequent ATM protein studies and ATM gene mutation analysis should finally prove the diagnosis.”
Susan L. Perlman, MD, clinical professor of neurology and director of the Ataxia Center and HD Center for Excellence at the University of California, Los Angeles, told Neurology Today that she was pleased to see a paper that so systematically described the spectrum of A-T. She said the findings may allow “doctors to look back on patients who were not well explained,” and make a correct diagnosis.
“We're on the threshold of disease-modifying therapy for A-T, it's going to become a treatable disease, and it's important that we can identify the disease in an early or atypical form,” said Dr. Perlman, who is medical director for the National Ataxia Foundation. Drugs in the class of aminoglycoside antibiotics are one of the potential therapies that will soon be tested in clinical trials, she said.
Stefan M. Pulst, MD, professor and chair of the department of neurology at the University of Utah, told Neurology Today that “it is important for patients to have a name for their disease,” noting that patients will sometimes spend a lot of time and energy going from doctor to doctor looking for an explanation for their baffling symptoms. Having a correct diagnosis is also important for parents who are making decisions about future pregnancies, he said. “You need to sit them down and say, ‘Your next child will have a 1 in 4 chance of having A-T,’” he said.
Dr. Pulst said there are some suggestions in the literature that A-T carriers may have a slightly increased risk for breast cancer, though that isn't proven. He suggested that physicians refer to this NIH Web site to review options for genetic testing for A-T: www.ncbi.nlm.nih.gov/sites/GeneTests/lab/clinical_disease_id/2802?db=genetests
• Verhagen MM, Abdo WF, van Deuren M, et al. Clinical spectrum of ataxia-telangiectasia in adulthood. Neurology 2009; 73:430–437.
©2009 American Academy of Neurology