Contents
Rare inhertited progressive, degenerative disease characterized by cerebellar degeneration, immunodeficiency, radiosensitivity, and a predisposition to cancer.
- Also known as Louis-Bar Syndrome
- Type of genome instability syndrome, DNA repair disorder and DNA damage response (DDR) syndrome
- Type of primary immunodeficiencies (PID)
History:
The term ataxia-telangiectasia (A-T) was initially proposed by Boder and Sedgwick in 1957, however this clinical entity received other designations that include Louis-Bar syndrome, suggested by Centerwall and Miller in 1958, and Boder-Sedgwick syndrome, suggested by Sagarra (1959), Jablonsky (1969) and François (1972). The first eponym relates to Madame Louis-Bar, a Belgian neurologist who published a case report in 1941 describing a nine-year-old boy with progressive cerebellar ataxia and extensive cutaneous telangiectasia. She included this new disease in the group of phakomatoses. For the next couple of decades, A-T was referred to worldwide as Louis-Bar syndrome, until 1964, when Martin published the manuscript Aspect choréoathétosique du syndrome d’ataxie-télangiectasie, stating that there was a previous description of A-T in the literature, published in French by Syllaba and Henner (1926) fifteen years before the classical description by Louis-Bar. In fact, Syllaba and Henner described three adolescent Czech siblings with progressive chorea and dystonia in association with ocular telangiectasia. Subsequently, in 1968, Henner confirmed that the disease described previously was in fact A-T. Two other important studies were published in 1957, one by Boder and Sedgwick and another by Biemond. Boder and Sedgwick described eight patients with classical A-T, suggesting the name “ataxia-telangiectasia”. They also reported the absence of the thymus and ovaries in their cases. Biemond published another case series with neuropathological findings in which he described the familial nature of this disorder and the presence of extrapyramidal manifestations. later, several groups published case series of A-T patients, including Wells and Shy (1957), Centerwall and Miller (1958), Boder and Sedgwick (1958, 1960, 1963) and Dunn et al. (1964). The 1963 publication of Boder and Sedgwick evaluated the clinical features of 101 cases of A-T and found cerebellar ataxia (100% cases), oculocutaneous telangiectasia (100% of cases), characteristic facies (98%), choreoathetosis (91 %), progeric changes of the skin and hair (88%), eye movement apraxia (84%), sinopulmonary infections (83%), familial occurrence (45%) and mental retardation (33%). In 1964, Dunn et al. published a case report of two Canadian patients with A-T in which they described neuropathological findings and atrophy of the thymus, adrenals, spleen and lymphoid tissues, as well as bronchiectasis and the presence of bilateral ovarian dysgerminoma. In 1972, Waldmann et al. described the presence of high levels of serum alpha-fetoprotein in patients with A-T. In 1884, Byrne et al. described a sibship of three ataxic patients, associated to dystonia, chorea, dementia, peripheral neuropathy, with IgE deficiency, chromosomal abnormalities, but, without telangiectasias or alpha-fetoprotein elevation. The authors proposed that A-T should be defined as a syndrome of “multiple neurological system degeneration, immunological attrition, chromosomal instability and predisposition to malignancy”. In 1993, Friedman and Weitberg published a case report about a 17-year old boy with cerebellar ataxia associated to dystonia, myoclonus, pyramidal signs, seizures, recurrent sinopulmonary infections, persistent lymphopenia, immunoglobulin deficiency, and elevated alpha-fetoprotein, but without telangiectasia. The authors proposed a new definition for this entity, as “ataxia with immune deficiency”.
Etiopathogenesis
Genome instability or DNA damage response syndrome:
Mutation of Ataxia Telangiectasia, Mutated (ATM) gene
(Chromosome 11)
↓
Dysfunctional ATM protein
↓
Dysregulation of cell-division & damaged DNA repair
↓
Cancer
Presentation
- Early-onset progressive ataxia
- Telangiectasia
- Initially on bulbar conjunctiva
- Immunodeficiency → Sinopulmonary infections
- Dysregulated cell-cycle:
- Excessive chromosomal breakage
- Increased sensitivity to ionizing radiation
Diagnosis
Lab studies:
- ↑ Serum AFP levels
- ↓ Serum IgA, IgG2 subclass and IgE
- ↓ Lymphocyte proliferative responses
- ↑ γδ-T cell
MRI:
- Cerebellar atrophy
Positron emission tomography (PET) scan:
Differential diagnosis:
- Common:
- Cerebral palsy (CP)
- Friedreich ataxia
- Cogan oculomotor apraxia
- Rare:
- Ataxia oculomotor apraxia type 1 (AOA1)
- Ataxia oculomotor apraxia type 2 (AOA2 aka. SCAR1)
- Ataxia-telangiectasia like disorder (ATLD)
- Nijmegen breakage syndrome (NBS)
Management
- IV immunoglobulins
- Antibiotics