Extracerebellar MRI—Lesions in Ataxia Telangiectasia Go Along with Deficiency of the GH/IGF-1 Axis, Markedly Reduced Body Weight, High Ataxia Scores and Advanced Age

Abstract

Ataxia telangiectasia (AT) is a rare autosomal recessive disorder characterized by progressive ataxia, neurodegeneration, immunodeficiency, and cancer predisposition. Pathoanatomical studies reported a degeneration of cerebellar Purkinje cells as the striking feature of the disease. Although recent studies suggested the involvement of extracerebellar structures such as the brainstem and basal ganglia, this has rarely been studied in human AT. Thus, we performed a detailed cliniconeuroradiological investigation of 11 AT patients, aged 8 to 26 years by collecting clinical neurological data, ataxia scores, growth status, body mass index (BMI), growth hormone (GH), and insulin-like-growth factor 1 (IGF-1) and correlated them to extracerebellar neuroimaging findings in human AT. Neuroimaging was done by cranial and spine magnetic resonance imaging (MRI) with T1- and T2-weighted spin-echo and fluid attenuated inversion recovery sequences. We compared clinical and neuroradiological findings of six patients with IGF-1 levels and BMI below the third percentile to five patients with normal IGF-1 serum levels and BMI above the third percentile. Three of the six first mentioned patients older than 20 years and two patients older than 12 years showed noticeable high Klockgether ataxia scores above 25 points. Three of these patients presented with marked hyperintense lesions in the cerebral white matter of T2-weighted MR images. Interestingly, all six patients suffered from marked spinal atrophy. Two of the patients presented with severe extra-pyramidal symptoms, but only one patient showed associated MRI abnormalities of the basal ganglia. MRI in patients with normal IGF-1 levels showed the expected cerebellar lesions in four patients, whereas spinal atrophy was found only in two patients. There was no affection of the cerebral white matter or basal ganglia in this group. We conclude that central cerebral white matter affection, spinal atrophy, and extrapyramidal symptoms are more often present in patients with pronounced deficiency of the GH/IGF-1 axis accompanied by markedly reduced body weight and high ataxia scores. This may point to a major role of IGF-1 and nutritional status in neuroprotective signaling.

Growth retardation and growth hormone deficiency in patients with Ataxia telangiectasia

“…In the present study, we clearly showed that the majority of patients with A-T are short in stature and many of them have altered IGF-1 and IGF-BP3 levels. This finding is not entirely new, and it has been recently reported by many authors (Arasimowicz et al, 2009;Hong & Ammann, 1970;Kieslich et al, 2010;Schubert et al, 2005;Woods & Taylor, 1992). Although the IGF-1 levels are reduced in A-T, the temporal and/or causal relationships between the lower IGF-1 levels, growth retardation and the disease process in A-T remain uncertain.…”

Investigating neural connectivity of corticomotor networks in ataxia telangiectasia: improving our understanding of the clinical phenotype

“…Basal ganglia pathological conditions were not explicitly seen in our study, despite the array of A-T characteristics observed in our clinical observations (Table 3.1); however, abnormalities in this structure have been previously recorded both in post-mortem study 92 and in radiological findings, 155 particularly in older patients. As we have already mentioned, our particular A-T cohort consisted of very young patients; therefore, future work in A-T should include older A-T subjects as well as younger patients to provide an age-specific timeline of neuropathology in A-T.…”

“…148,154 Both of these lesions were displayed with low intensity on T1-weighted images and high intensity on T2-weighted images. 148 General spinal atrophy and abnormalities in the basal ganglia have also been reported in older A-T patients, 155 supporting post-mortem spinal study findings in older A-T patients, but lacking specific anatomical detail (see 'Spinal Cord' section).…”

“…Very few studies have focused on reporting radiological findings in A-T. 133,[143][144][145][146][147][148][150][151][152][153][154][155][156][157] Of these, studies using standard T1-and T2-weighted MRI sequences have consistently shown diffuse cerebellar atrophy, predominantly within the vermis and cerebellar hemispheres. This reflects the loss of Purkinje cells on a histological level, which is a well-established neuropathological hallmark of A-T. Foci of T2-weighted WM hypo-and hyper-intensity have also been observed and attributed to capillary telangiectasia and focal extracerebellar demyelination.…”

Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites

“…Classic A-T occurs with cerebellar and extracerebellar pathology 33,34 and imaging abnormalities, [35][36][37] with cerebellar granular and Purkinje cell loss being the most consistent feature. 35 MRI examinations in classic A-T revealed, in 1 of 2 patients with prominent movement disorders, obvious basal ganglia pathology 37 ; 1 patient with prominent dystonia had a unilateral putaminal hyperintensity on T2-weighted images and bilateral decreased striatal [ 123 I]iodobenzamine binding with SPECT imaging. 24 It is unlikely that dystonia in variant A-T can be attributed solely to cerebellar atrophy, because this feature was not prominent on MRI in any of our subjects, and in another subject with variant A-T with prominent early-onset dystonia, nonspecific cerebellar atrophy without a cerebellar functional correlate was present.…”