Characteristic Eye Movements in Ataxia-Telangiectasia-Like Disorder: An Explanatory Hypothesis

Abstract

ObjectiveTo investigate cerebellar dysfunctions and quantitatively characterize specific oculomotor changes in ataxia-telangiectasia-like disorder (ATLD), a rare autosomal recessive disease caused by mutations in the MRE11 gene. Additionally, to further elucidate the pathophysiology of cerebellar damage in the ataxia-telangiectasia (AT) spectrum disorders.MethodsSaccade dynamics, metrics, and visual fixation deficits were investigated in two Italian adult siblings with genetically confirmed ATLD. Visually guided saccades were compared with those of 40 healthy subjects. Steady fixation was tested in primary and eccentric positions. Quantitative characterization of saccade parameters, saccadic intrusions (SI), and nystagmus was performed.ResultsPatients showed abnormally hypermetric and fast horizontal saccades to the left and greater inaccuracy than healthy subjects in all saccadic eye movements. Eye movement abnormalities included slow eye movements that preceded the initial saccade. Horizontal and vertical spontaneous jerk nystagmus, gaze-evoked, and rebound nystagmus were evident. Fixation was interrupted by large square-wave jerk SI and macrosaccadic oscillations.ConclusionSlow eye movements accompanying saccades, SI, and cerebellar nystagmus are frequently seen in AT patients, additionally our ATLD patients showed the presence of fast and hypermetric saccades suggesting damage of granule cell-parallel fiber-Purkinje cell synapses of the cerebellar vermis. A dual pathogenetic mechanism involving neurodevelopmental and neurodegenerative changes is hypothesized to explain the peculiar phenotype of this disease.

A toolkit for genetics providers in follow‐up of patients with non‐diagnostic exome sequencing

“…Review of the primary literature describing ATLD1 revealed a strong correlation with the patient's phenotype and disease course (Table ). Additional overlapping features included: myoclonus; action tremor; nystagmus with hypometric saccades; sensory neuropathy on EMG; cerebellar atrophy on brain MRI; and a plateau of disease progression in early adulthood (Federighi et al, ; Regal, Festerling, Buis, & Ferguson, ). Unlike Ataxia‐Telangiectasia, individuals with ATLD1 lack immunodeficiency and have not yet been demonstrated to have a strong susceptibility to malignancy, despite showing cellular sensitivity to ionizing radiation on chromosomal breakage studies.…”

Beyond Typical Ataxia Telangiectasia: How to Identify the Ataxia Telangiectasia‐Like Disorders

“…Moreover, telangiectasia, immunodeficiency and increased alpha-fetoprotein are rarely observed in ATLD. 7,19 Clinical features of ATLD1 are characterized by cerebellar ataxia, eye movement abnormalities, radiosensitivity, choreoathetosis and dystonia. 20 Rarely, short stature, microcephaly, cognitive impairment, facial dyskinesia and neuropathy may be found in ATLD1.…”

“…20 The most common oculomotor abnormalities in ATLD1 are slow and dysmetric saccades, oculomotor apraxia, delayed convergence and gaze-evoked nystagmus. [19][20][21][22] ATLD2 was firstly described in 2014, although function in DNA repair and replication of the PCNA gene is known since 1986. 4 Clinical features of ATLD2 include cerebellar ataxia, short stature, hearing loss, premature aging, telangiectasia and photosensitivity.…”

“…In opposite, peripheral neuropathy has not been described in ATLD2. 19 Cranial neuropathy characterized by sensorineural hearing loss is more frequent in ATLD2. 5,23 Alpha-fetoprotein, albumin, vitamin E, cholesterol and immunoglobulin serum levels are frequently used as biomarkers in the investigation of autosomal recessive cerebellar ataxias.…”

“…Nonetheless, these biomarkers are rarely abnormal in ATLD patients. [4][5][6]19,21,32 Hypersegmented neutrophils in peripheral blood smear, that is known to be present in several conditions that affect DNA replication, are possible biomarkers for ATLD1. 33 In Table 1 we describe the main differences between AT, ATLD1 and ATLD2 concerning clinical features, biomarkers, genetics, neuroimaging and pathophysiological mechanisms.…”