The Cerebellar Cognitive Affective Syndrome in Ataxia-Telangiectasia.

Ataxia-telangiectasia (AT) is an autosomal recessive, multisystem disease causing cerebellar ataxia, mucocutaneous telangiectasias, immunodeficiency, and malignancies. A pilot study reported cognitive and behavioral manifestations characteristic of the cerebellar cognitive affective / Schmahmann syndrome (CCAS). We set out to test and further define these observations because a more comprehensive understanding of the spectrum of impairments in AT is essential for optimal management. Twenty patients (12 males; 9.86 ± 5.5 years, range 4.3 to 23.2) were grouped by age: AT-I (toddlers and preschoolers, n = 7, 4.3-5.9 years), AT-II (school children, n = 7, 5.9-9.8 years), AT-III (adolescents/young adults, n = 6, 12.6-23.2 years). Standard and experimental tests investigated executive, linguistic, visual-spatial, and affective/social-cognitive domains. Results were compared to standard norms and healthy controls. Cognitive changes in AT-I were limited to mild visual-spatial disorganization. Spatial deficits were greater in AT-II, with low average scores on executive function (auditory working memory), expressive language (vocabulary), academic abilities (math, spelling, reading), social cognition (affect recognition from faces), and emotional/psychological processing. Full Scale IQ scores were low average to borderline impaired. AT-III patients had the greatest level of deficits which were evident particularly in spatial skills, executive function (auditory working memory, sequencing, word/color interference, set-shifting, categorization errors, perseveration), academic achievement, social cognition (affect recognition from faces), and behavioral control. Full Scale IQ scores in this group fell in the impaired range, while language was borderline impaired for comprehension, and low average for expression. Cognitive deficits in AT at a young age are mild and limited to visual-spatial functions. More widespread cognitive difficulties emerge with age and disease progression, impacting executive function, spatial skills, affect, and social cognition. Linguistic processing remains mildly affected. Recognition of the CCAS in children with AT may facilitate therapeutic interventions to improve quality of life.

Cognitive phenotype in ataxia-telangiectasia.

BACKGROUND: Pediatric cerebrocerebellar neurodegenerative disorders such as ataxia-telangiectasia (AT) have not been examined in detail for neuropsychologic changes. Such studies may contribute to the further understanding of ataxia-telangiectasia and to the role of the cerebrocerebellar system in the development of cognitive function in childhood. METHODS: Twenty-two patients with the classic phenotype of ataxia-telangiectasia were grouped into early stage cerebellar disease (group AT-I) versus late stage cerebrocerebellar disease (group AT-II) and examined for neurocognitive features. Results were compared with those of healthy control subjects and with standard norms. RESULTS: Patients in AT-I group scored low average compared with standard norms on all tests and were impaired compared with healthy control subjects for verbal intelligence quotient (P < 0.001), vocabulary and comprehension (P = 0.007), processing speed (P = 0.005), visuospatial processing (P = 0.020), and working memory (P = 0.046). Patients in AT-II group scored below average compared with standard norms on all tests and were impaired compared with control subjects for attention (P < 0.001), working memory (P < 0.001), and abstract reasoning (P < 0.001). Comprehension scores were lower for patients in AT-II than in AT-I group (P = 0.002), whereas vocabulary scores showed no difference between groups (P = 0.480). CONCLUSION: Cognitive impairments in ataxia-telangiectasia present early, coinciding with cerebellar pathology and are characteristic of the cerebellar cognitive affective syndrome. Widespread and deeper cognitive deficits manifest in later stages of ataxia-telangiectasia when additional noncerebellar pathology develops. These results are the first indications of distinct cerebellar and extracerebellar and/or subcortical contributions to the range of cognitive domains affected in ataxia-telangiectasia and need to be confirmed in future studies.

Cognitive and speech-language performance in children with ataxia telangiectasia.

OBJECTIVE: To describe cognitive and speech-language functioning of patients with ataxia-telangiectasia (A-T) in relation to their deteriorating (oculo)motor function. DESIGN: Observational case series. METHODS: Cognitive functioning, language, speech and oral-motor functioning were examined in eight individuals with A-T (six boys, two girls), taking into account the confounding effects of motor functioning on test performance. RESULTS: All patients, except the youngest one, suffered from mild-to-moderate/severe intellectual impairment. Compared to developmental age, patients showed cognitive deficits in attention, (non)verbal memory and verbal fluency. Furthermore, dysarthria and weak oral-motor performance was found. Language was one of the patients' assets. CONCLUSION: In contrast to the severe deterioration of motor functioning in A-T, cognitive and language functioning appeared to level off with a typical profile of neuropsychological strengths and weaknesses. Based on our experiences with A-T, suggestions are made to determine a valid assessment of the cognitive and speech-language manifestations.

Judgment of duration in individuals with ataxia-telangiectasia.

Several clinical investigations with adults suggest that the cerebellum may be critical for judgment of explicit time intervals; however, little work has been done in populations with lesions of the cerebellum acquired during development. We evaluated 17 individuals with ataxia-telangiectasia (AT), an autosomal recessive disorder with on-set in early childhood characterized by diffuse, almost selective, degeneration of the cerebellar cortex, and 21 normal controls, matched for age. Because patients with AT have motor impairment, verbal IQ (VIQ) was used to estimate intelligence; VIQ was significantly lower in the group with AT (p < .0001). Participants were tested using a test of judgment of duration that has been found to be impaired in adults with cerebellar lesions and a contrasting auditory control task (not impaired in adults with cerebellar lesions) involving judgment of pitch. After statistically controlling for VIQ, the 2 groups did not differ significantly on judgment of pitch, but those with AT performed significantly worse than controls on judgment of duration (p = .01). Children and adolescents with AT show deficits in judgment of duration but not of pitch, suggesting that the cerebellum may be critical for judgment of explicit time intervals at all ages.

Never again joy without sorrow: the effect on parents of a child with ataxia-telangiectasia.

The purpose of this study was to explore the impact of having a child with ataxia-telangiectasia (A-T) as well as to assess parental understanding of the genetics of A-T and attitudes toward carrier testing. Sixty-eight parents of individuals with A-T were interviewed. Ninety percent of the parents correctly believed if there is a child with A-T, both are obligate heterozygotes. Only 9% knew each well sib had a two-thirds chance of being a carrier. Eighty-four percent would have their unaffected child tested for carrier status prior to age 18 years. Eighty-two percent believed heterozygosity is associated with increased health risks. We offer the following recommendations. 1) Physicians must realize that communicating the possibility of early death is difficult; parents need guidelines so they know what to expect, but diagnosis should not be a death sentence. Clinicians should stress individual variations in expression of the disorder and offer hope for future progress in treatment. 2) Parents underestimated carrier risks for the well sib and the frequency of carrier status in the general population. Although these distortions are self-protective, they interfere with transmission of accurate genetic information to their children. Parents should be referred to genetic counseling. 3) Psychological counseling should be offered to families at the time of diagnosis so parents can support each other, the affected, and unaffected offspring.

"My crooked vision": the well sib views ataxia-telangiectasia.

The ataxia-telangiectasia gene (designated ATM) has been identified by positional cloning. Retrospective studies in cystic fibrosis (CF) have shown that the illness and death of a sib have far-reaching ramifications on the surviving sib's life. However, there have been no studies on sibs of children and adults with ataxia-telangiectasia (A-T). Thirty-five sibs from 24 families, including 26 adults and 9 adolescents, were drawn from the University of California, Los Angeles; the A-T Clinical Center at the Johns Hopkins University School of Medicine; and the A-T Children's Project Interviews indicated that, unlike CF, the visibility of A-T caused less resentment of time or attention given to the affected, less guilt, and less identification or idealization of the affected, but more embarrassment and shame. It may be said that, unlike CF, the dynamic is one of burden rather than trauma. The specific phenotypic expression of a genetic illness predisposes the way in which the well sib will encounter problems. In A-T affected families, one must help families locate caregiving resources so they will not burden their well children; sibs need help with managing feelings of embarrassment and shame. Geneticists must be alert to understanding characteristic differences of disorders they encounter in order to offer the most appropriate support to affected families.

The missing link in linkage analysis: the well sibling revisited.

Linkage analysis is a powerful tool for gene localization. Although the impact of genetic testing of minors has been debated, the impact of genetic sampling of minors has been ignored. Inclusion of the well sibling in linkage analysis represents a unique situation in that the sibling has not sought testing and therefore encounters genetic possibilities without the offer of genetic counseling. Thirty-five siblings of individuals with ataxia-telangiectasia (A-T), including 26 adults and 9 adolescents, drawn from the University of California, Los Angeles, The A-T Clinical Center at the Johns Hopkins University School of Medicine, and the A-T Children's Project, were interviewed; 27 reported having given blood sometime before the age of 18. They reported that sampling during their childhood or adolescence stimulated fears of the procedure itself, apprehension concerning follow-up reporting of carrier results, and confusion about the possibility of having A-T. The investigator's direct encounter with minor siblings of persons affected with genetic disorders represented a highly charged event in the lives of these individuals. Although the visit may increase anxiety, this intervention may in fact be a healthy change, offering permission to speak of difficult concerns, as well as serving as a powerful vehicle of conveying important information of a medical and genetic nature.

A mark on the arm: myths of carrier status in sibs of individuals with ataxia-telangiectasia.

The ATM gene, mutated in ataxia-telangiectasia (A-T), was identified by positional cloning. The discovery of the ATM gene now allows the identification of A-T heterozygotes [Telatar et al., 1998], who may be at increased risk of cancer. The purpose of this study was to (a) identify sib's interest in carrier testing, (b) explore perception of carrier status, and (c) assess levels of understanding of genetics of A-T. This is the sib component of a study of 103 parents and sibs (68 parents and 35 sibs) of individuals with A-T. Thirty-five sibs from 24 families, including 26 adults and 9 adolescents, drawn from the University of California, Los Angeles, the A-T Clinical Center at the Johns Hopkins University School of Medicine, and the A-T Children's Project, were interviewed. Eighty-five percent of adult sibs stated correctly that if a child has A-T, both parents are heterozygotes; 76% knew the A-T gene had been identified. Ninety-two percent would request carrier testing for themselves if available. Seventy-nine percent would want their child tested for carrier status prior to the age of 18. Seventy-three percent believed that being a carrier is associated with increased health risks. Sibs have numerous misconceptions surrounding carrier status and genetics of A-T. Provision of factual information about genetic transmission is necessary, but unfortunately insufficient, to counter deeply held views of self and others. Genetic counseling, which explores the way in which this information is filtered and interpreted, could be an effective tool in dispelling family myths. We conclude that A-T sibs need comprehensive support in relation to carrier testing.

Patterns of intellectual change in the dementing school child.

Four children with intellectual deterioration are discussed. The importance of a developmental and educational history and sequential psychological testing is emphasized. Progressive visual impairment, clumsiness and increasingly poorly-controlled fits should alert teachers and doctors to the possibility of associated intellectual deterioration. As well as global loss, tests of memory and mental arithmetic, manipulative and perceptual skills were the most sensitive index of dementia. We propose a further subcategory of the present codes of classification of childhood psychiatric disorders.