Nine HLA-typed multiplex nuclear families segregating ataxia-telangiectasia (A-T), an autosomal recessive disorder, were studied. Linkage analysis performed by lod scores and by a previously published sib pair method revealed no evidence for linkage between A-T and HLA. An alternative method of linkage detection, previously applied to xeroderma pigmentosum (XP) and HLA, was reexamined and found to contain an error. As a consequence, neither of these "DNA repair disorders" appears to be linked to HLA.

26 CURRAN, MD, ROBERT SEDGWICK, MD, HARRY VINTERS, MD (UCLA School Of Medicine and Children’s Hospital of Los Angeles, Los Angeles, CA) Objectives: We present the first report of the neuropsychological functioning of six consecutively sampled patients with ataxia-telangiectasia (A-T) (age-range two to 3 1 years; four males, two females); and the youngest and oldest A-T patients with available MRI studies. A-T is a multisystemic disorder with marked cerebellar degeneration, beginning in infancy. Procedures: Longitudinal assessments (two to three years) with standardized neuropsychological tests were completed for each patient. Brain MRI was performed on two patients. Results: Longitudinal testing showed no evidence of decline. IQ was average (mean 102, range 86 to 124), with above-average concept formation and normal time and rightlleft orientations. Vocabulary, naming and fluency were commensurate with the IQ of each patient. Memory deficits were noted in digit-span and sentences, but not logical prose. Visualperceptual assessments found marked difficulties with spatial orientation and discrimination of geometric forms. Color perception was normal. Ophthalmological findings (presented elsewhere) included mild acuity and contrast sensitivity defects, and marked abnormalities in visual evoked potentials. Visual fields were normal. No structural abnormality was found on MRI, except cerebellar degeneration in the older patient. There were no visual system abnormalities on autopsy of a 45-year-old A-T patient, using standard neuropathological techniques. Conclusions: These findings indicate a need for educational strategies to optimize the visual processing of A-T patients. Prospective morphological autopsy studies with clinicopathological correlations derived from longitudinal neurobehavioral and ophthalmological examinations are needed to establish the full range of changes in patients with A-T.

Ataxia-telangiectasia is a syndrome with many facets, involving a progressive cerebellar ataxia, immunodeficiency, cancer susceptibility, radiosensitivity, defects in DNA repair/processing, chromosomal breakage and rearrangements, elevated serum alphafetoprotein, and premature aging. Ataxia-telangiectasia is an autosomal recessive disorder, rare in outbred populations; carriers of the ataxia-telangiectasia gene may be as common as 1 in 60 and have subclinical radiosensitivity and cancer susceptibility. One estimate suggests that 8.8% of patients with breast cancer could be carriers of ataxia-telangiectasia. These carriers may be responsible for underestimating normal tolerance doses for radiation therapy by 15% to 20%; thus by preselecting and excluding carriers of ataxia-telangiectasia from cohorts of patients with cancer, conventional radiation doses might be increased so as to improve greatly the efficacy of radiotherapy. The genes for the 3 most common ataxia-telangiectasia complementation groups, which include 97% of tested families, have recently been localized to the long arm of chromosome 11.

Roughly one-third of patients with ataxia-telangiectasia (AT) develop malignant tumors, usually of lymphoid origin. AT patients also exhibit progeric changes. We describe three patients, between the ages of 27 and 32 years, with uterine tumors: one with a frank leiomyosarcoma and chronic T-cell leukemia, one with a multilobulated leiomyoma of uncertain malignant potential, and one with an unremarkable leiomyoma. Thus, the spectrum of tumors in AT patients beyond adolescence includes nonlymphoid malignancies and precocious, benign leiomyomas.

The objective of this study was to obtain an estimate of the frequency distribution of spontaneous chromosomal breakage occurring in vivo in oral epithelia of 20 ataxiatelangiectasia patients (A-T homozygotes) and 26 parents (A-T obligate heterozygotes). Samples of exfoliated cells were obtained from each individual by swabbing the oral cavity and preparing air-dried slides. The percentage of exfoliated cells with micronuclei (MEC frequency) was used as an in vivo indicator for the amount of chromosomal breakage occurring in the tissue. As a population group, MEC frequencies of the A-T patients differed significantly from controls (mean for A-T patients, 1.51; for controls, 0.29; P<0.01). However, the values observed in individual patients ranged from MEC frequencies 10- to 12-fold above control values, to frequencies overlapping the upper values observed in the controls. Similarily, MEC frequencies observed among the A-T heterozygotes differed significantly from controls (mean for A-T heterozygotes, 1.02, mean for controls, 0.29; P<0.01). However, only 16 of the 26 individuals sampled had MEC frequencies >0.5%, the 90th percentile for controls (compared with 16 of the 20 A-T patients examined). Of the A-T patients 11 had been previously assigned to complementation groups on the basis of sensitivity to x-irradiation. Seven of the patients belonged to group A and had MEC frequencies ranging from 0.3% to 1.9% with the remaining patients belonging to group C with MEC frequencies of 0.2% to 0.9%. The data presented in this paper suggest that although levels of spontaneous breakage in epithelial tissues of A-T patients and A-T obligate heterozygotes are often significantly elevated, this is not the case in all individuals.

Ataxia-telangiectasia (AT) is a human autosomal recessive disorder of childhood characterized by: (1) progressive cerebellar ataxia with degeneration of Purkinje cells; (2) hypersensitivity of fibroblasts and lymphocytes to ionizing radiation; (3) a 61-fold and 184-fold increased cancer incidence in white and black patients, respectively; (4) non-random chromosomal rearrangements in lymphocytes; (5) thymic hypoplasia with cellular and humoral (IgA and IgG2) immunodeficiencies; (6) elevated serum level of alphafetoprotein; (7) premature ageing; and (8) endocrine disorders, such as insulin-resistant diabetes mellitus. A DNA processing or repair protein is the suspected common denominator in this pathology. Heterozygotes are generally healthy; however, the sensitivity of their cultured cells to ionizing radiation is intermediate between normal individuals and that of affected homozygotes. Furthermore, heterozygous females are at an increased risk of breast cancer. These findings, when coupled with an estimated carrier frequency of 0.5-5.0%, suggest that (1) as many as one in five women with breast cancer may carry the AT gene and that (2) the increased radiation sensitivity of AT heterozygotes may be causing radiation therapists to reduce the doses of radiation used for treating cancer in all patients. To identify the genetic defect responsible for this multifaceted disorder, and to provide effective carrier detection, we performed a genetic linkage analysis of 31 families with AT-affected members. This has allowed us to localize a gene for AT to chromosomal region 11q22-23.

Eight families, including 12 patients with ataxia-telangiectasia (AT), were investigated for parameters which tested the current models of pathogenesis. We found: T cells decreased, B cells elevated, PHA response decreased, variable T suppressor activity, serum IgA and IgG2 decreased. AFP and liver enzymes in serum were elevated. In addition, several parameters related to cell membrane and cytoskeletal functions were abnormal: increased concanavalin A capping and increased cyclic nucleotides of lymphocytes and decreased chemotactic responses of neutrophils. Thymosin-α-1 levels of patients and family members did not differ from age-matched controls. While many of the immunological abnormalities seen in AT could be due to a common immunoregulatory defect, this would not explain the neurological deterioration or the DNA aberrations. We suggest that a broader mechanism be considered in future analyses, such as the possibility that a primary or secondary cytoskeletal disorder might underlie the myriad abnormalities seen in AT.

The clinicalpathological findings in a 32-year old woman with ataxia-telangiectasia are presented. This is the oldest patient with this disease to be studied thoroughly clinically and at autopsy. Multiple small gliovascular malformations in the brain and spinal cord and telangiectasis of the liver were found. Other advanced lesions of ataxia-telangiectasia are illustrated. The vascular malformations of the central nervous system and liver are unique. The patient died of a malignant lymphoproliferative disorder and had five other malignant and benign neoplasms.

The spectrum of eye movement disorders in six patients with ataxia-telangiectasia at different stages of progression was assessed quantitatively by electrooculography. All patients demonstrated abnormalities of voluntary and involuntary saccades. The youngest and least involved patient had significantly incresed reaction times of voluntary saccades, but normal accuracy and velocity. The other patients demonstrated increased reaction times and marked hypometria of horizontal and vertical voluntary saccades. Saccade velocity remained normal. Vestibular and optokinetic fast components (involuntary saccades) had normal amplitude and velocity but the eyes deviated tonically in the direction of the slow component. We conclude that patients with ataxia-telangiectasia have a defect in the initiation of voluntary and involuntary saccades in the earliest stages. These findings are distinctly different from those in other familial cerebellar atrophy syndromes.

A comprehensive multidisciplinary team approach to the diagnosis and management of school failure, with the pediatrician knowledgeable in the field of behavioral and learning disorders serving as coordinator, is outlined in terms of actual office procedures. An integral part of the expanded neurological examination is an empirically evolved diagnostic screening test for developmental dyslexia which identifies three atypical reading-spelling patterns on the basis of which dyslexic children can be classified into three main subtypes: dysphonetic, dyseidetic, and mixed dysphonetic-dyseidetic, each with its own therapeutic and prognostic implications. The approach outlined here is designed to identify not only the specific educational needs of a given child but all of the causative and contributory factors, physical, emotional, and sociocultural, that may impinge on the child9s ability to learn. Though necessarily time-consuming, the team approach appears in our present state of knowledge to be the most practical and reliable way to get at the roots of the child9s multifaceted problem and to develop a coordinated program of treatment—simultaneous insofar as feasible, and sequential when required. A child referred for school failure is a child in crisis. The challenge to the pediatrician to whom the parents turn for a solution is to find ways as promptly as possible to help the child improve in his school adjustment and self-esteem. It is recognized that special education has a primary and ultimate responsibility for remediating specific learning disabilities. Nevertheless, the complexity of the problem of school failure requires that overall diagnosis and management be a multidisciplinary venture, in which the professionals involved are committed to working together to ensure that the whole child is taken into account.

Although an isolated clinical case report was published in 1926 and another in 1941, ataxia-telangiectasia (A-T) was not established as a distinct entity until 1957, when it was first delineated clinicopathologically. Susceptibility to sinopulmonary infection was identified as the main cause of death and as the third major component of the syndrome; its heredofamilial nature was documented, and it was designated "ataxia-telangiectasia." In a later review of 101 published cases, lymphoreticular malignancy emerged as the second most frequent cause of death. Although the thymus was found to be absent in the first reported autopsy in 1957 and the serum IgA deficiency was first recorded in 1961, A-T was not established as an immunodeficiency disease until 1963. Thymic abnormality and dysgammaglobulinemia explain the 2 main causes of death, sinopulmonary and neoplastic, but the immunodeficiency is probably not the central defect. It does not appear to explain either of the 2 main clinical diagnostic keys, the ataxia and the telangiectasia, or any of the other seemingly unrealted multisystemic facets of this complex disorder. Some of our most provocative long-term clinical observations and recent pathologic findings in our series of 9 autopsies are discussed.

There are a great number of genetic and congenital disorders with skin manifestations ("genodermatoses") with tumor formation. Some of these tumors are benign (hamartomas, in part) and others are malignant. There is a large group of heredodegenerative disorders with such complications as lymphosarcoma and leukemia. There are congenital tumors with malignancy developing. Lastly, there are the chromosomal abnormalities with skin manifestations and tumors, usually malignant. This will be an ever increasing field and the use of fibroblast and virus cultures will become more important in ascertaining the cause of malignancy.

This syndrome was defined by the authors in 1947. Earlier publications of similar disease descriptions were by Syllaba and Henner (1926), Louis-Bar (1941). The authors at present have a stock of 253 cases. The cardinal symptoms of this phakomatosis are: Cerebellar ataxia which begin in infancy and take a slowly progressive course. In the late stages free walking and standing are no longer possible. Progressive atactic speech disorders, cerebellar atrophy in the pneumoencephalogram. Slowly progressing symmetrical skin and mucosal telangiectasia in the face and especially on the conjunctivae at the age of 3 to 6 years. Relapsing sinopulmonary infections with a tendency toward the development of bronchiectases. Apraxia of eye movements. Atrophy of facial skin and premature graying of hair. Recessively hereditary disorder with a high familial manifestation. This syndrome combines the spinocerebellar degeneration, phakomatoses, and infantile dementia processes. Such other conditions as abnormity or absence of thymus, reduction in gamma globulins, amino-aciduria, autosomal-recessive inheritance suggest a genetically determined "error of metabolism".