Diagnosis Of Cerebellar Ataxia Research Articles

Autoimmune cerebellar ataxia

AbstractAmong the different forms of cerebellar ataxia, autoimmune cerebellar ataxia (ACA) or immune‐mediated cerebellar ataxia (IMCA), which appears to be based on an autoimmune mechanism, has long been considered important from the viewpoint of paraneoplastic syndrome. With the expansion of the concept of immune‐mediated neurological diseases and the identification of many novel autoantibodies, ACA has recently become an important neurological syndrome. Although no definitive diagnostic criteria of ACA exist, Hadjivassilou et al suggested diagnostic criteria for primary ACA in 2020 and Dalmau and Graus showed proposed diagnostic criteria for ACA in 2022. The proposed diagnostic criteria for ACA by Dalmau and Graus emphasize the importance of antibody reliability. In the future, additional studies should be conducted to identify new antibodies associated with ACA and to clarify the importance of each antibody. Moreover, ACA is a disease for which immunological therapeutic intervention is feasible and requires early treatment to maintain cerebellar function. Many cases with ACA have reported the efficacy of immunotherapy. The concept of ACA may have the potential for further expansion and becomes increasingly important in the diagnosis of cerebellar ataxia.

Identification of APTX disease-causing mutation in two unrelated Jordanian families with cerebellar ataxia and sensitivity to DNA damaging agents

Ataxia with oculomotor apraxia type 1 (AOA1) is a rare autosomal recessive cerebellar ataxia, caused by mutations in the APTX gene. The disease is characterized by early-onset cerebellar ataxia, oculomotor apraxia and severe axonal polyneuropathy. The aim of this study was to detect the disease-causing variants in two unrelated consanguineous Jordanian families with cerebellar ataxia using whole exome sequencing (WES), and to correlate the identified mutation(s) with the clinical and cellular phenotypes. WES was performed in three affected individuals and segregation analysis of p.W279* APTX candidate variant was performed. Expression levels of APTX were measured in patients' skin fibroblasts and peripheral blood mononuclear cells, followed by western blot analysis in skin fibroblasts. Genotoxicity assay was performed to detect the sensitivity of APTX mutated cells to H2O2, MMC, MMS and etoposide. A recurrent homozygous nonsense variant in APTX gene (c.837G>A, p.W279*) was revealed in all affected individuals. qRT-PCR showed normal APTX levels in peripheral blood and lower levels in fibroblast cells. However, western blot showed the absence of APTX protein in patients' skin fibroblasts. Significant hypersensitivity to H2O2, MMC and etoposide and lack of sensitivity to MMS were noted. This is the first study to report the identification of a nonsense variant in the APTX gene (c.837G>A; p.W279*) in AOA1 patients within the Jordanian population. This study confirmed the need of WES to assist in the diagnosis of cerebellar ataxia and it emphasizes the importance of studying the pathophysiology of the APTX gene.

CEREBELLAR NEUROTOXICITY OF ARTEMETHER‐LUMEFANTRINE IN PROPHYLACTIC, SUPPRESSIVE AND CURATIVE EXPERIMENTAL MALARIA MODELS

Artemether‐lumefantrine (AL) is drug of choice for the treatment of uncomplicated malaria in most African and Asian countries, though cases of Plasmodium resistance have been reported. Diagnosis of cerebellar ataxia has been associated in some patients taking artemether‐lumefantrine. Here we report the potential neurotoxicity of this drug on the cerebellar histomorphology and glial pathology of Plasmodium infected mice in prophylactic, suppressive and curative experimental malaria models. All procedures adhered to the guiding principles of care and use of laboratory animals, and institutional ethics committee. 30 Swiss male mice were randomized into 6 groups, 2 groups each for the 3 models representing; the control and test. Prophylactic groups received 0.9% normal saline, and AL 5 mg/kg respectively for 3 days before inoculation with parasite; suppressive groups were inoculated with parasite, and treated immediately; while curative groups were inoculated, and treated 5 days later. Result of routine H&E for prophylactic control showed atrophy and loss of purkinje neurons, but test showed clumping of granule cells and lesions in molecular layer; suppressive control showed widespread lesions in molecular layer, atrophy and loss of purkinje cells, while test showed moderate purkinje neuronal shrinkage with mild lesions, and curative control showed severe distortion of cerebellar cell layers with severe clumping of granule cells, atrophy of purkinje cells and degeneration of neuropil in molecular layer; and test showed less severe distortions. Glial pathology of prophylactic model reveals mildly expressed glial fibrillary acidic protein; suppressive model had moderately expressed GFAP; while reactive astrogliosis was severely expressed in the curative model. In conclusion, severe cerebellar distortion and expression of GFAP in malaria models of artemether‐lumefantrine treated Plasmodium infected mice is dependent mainly on degree of parasite exposure than due to drug toxicity; still caution should be applied in the use of artemether‐lumefantrine.Support or Funding InformationTETFUND, Nigeria

Hereditary cerebellar ataxias with polyneuropathy

The paper gives a brief clinical characterization of hereditary cerebellar ataxias running with polyneuropathy. Particular attention is paid to the pathogenesis, clinical presentation, and treatment of gluten ataxia. A mutant gene and concurrent symptoms are indicated. The differential diagnosis of cerebellar ataxias should be started by ruling out the hereditary nature of the disease, which is verified by molecular genetic testing. In recent years, some genetic diseases manifesting themselves by a concurrence of ataxia and polyneuropathy have been replenished by a description of new hereditary syndromes. The knowledge of the nature of inheritance, age at disease onset, and concurrent manifestations will assist a practitioner in presuming the diagnosis of a rare disease and in referring a patient for medical genetic testing. Only a precise diagnosis will be able to assess prognosis and to use specific treatment.

The pivotal sign of CANVAS

A 75-year-old woman complained about insecure gait since age 55. Clinical examination revealed signs of cerebellar ataxia, bilateral vestibulopathy, and peripheral sensory impairment. Sensory nerve action potentials were absent. The visually enhanced vestibulo-ocular reflex (VVOR) was impaired (video on the Neurology(®) Web site at www.neurology.org, figure 1) and the diagnosis of cerebellar ataxia (figure 2) with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) was made.(1) CANVAS is considered to be a recessive disorder with a mean age at onset of 60 years.(2) VVOR impairment is its characteristic clinical sign.(2) It can only be elicited if both smooth-pursuit eye movements and the vestibulo-ocular reflex are deficient. Normally, both are redundant at low head velocities.(2.)

Utilization of Genetic Testing Prior to Subspecialist Referral for Cerebellar Ataxia

To evaluate the utilization of laboratory testing in the diagnosis of cerebellar ataxia, including the completeness of initial standard testing for acquired causes, the early use of genetic testing, and associated clinical and nonclinical factors, among a cohort referred for subspecialty consultation. Data were abstracted from records of 95 consecutive ataxia patients referred to one neurogenetics subspecialist from 2006-2010 and linked to publicly available data on characteristics of referral clinicians. Multivariable logistic and linear regression models were used to analyze unique associations of clinical and nonclinical factors with laboratory investigation of acquired causes and with early genetic testing prior to referral. At referral, 27 of 95 patients lacked evidence of any of 14 laboratory studies suggested for initial work-up of an acquired cause for ataxia (average number of tests=4.5). In contrast, 92% of patients had undergone brain magnetic resonance imaging prior to referral. Overall, 41.1% (n=39) had genetic testing prior to referral; there was no association between family history of ataxia and obtaining genetic testing prior to referral (p=0.39). The level of early genetic testing was 31.6%, primarily due to genetic testing despite an incomplete laboratory evaluation for acquired causes and no family history. A positive family history was consistently associated with less extensive laboratory testing (p=0.004), and referral by a neurologist was associated with higher levels of early genetic testing. Among consecutive referrals to a single center, a substantial proportion of sporadic cases had genetic testing without evidence of a work-up for acquired causes. Better strategies to guide decision making and subspecialty referrals in rare neurologic disorders are needed, given the cost and consequences of genetic testing.

Ocular motor characteristics of different subtypes of spinocerebellar ataxia: Distinguishing features

Because of frequent involvement of the cerebellum and brainstem, ocular motor abnormalities are key features of spinocerebellar ataxias and may aid in differential diagnosis. Our objective for this study was to distinguish the subtypes by ophthalmologic features after head-shaking and positional maneuvers, which are not yet recognized as differential diagnostic tools in most common forms of spinocerebellar ataxias. Of the 302 patients with a diagnosis of cerebellar ataxia in 3 Korean University Hospitals from June 2011 to June 2012, 48 patients with spinocerebellar ataxia types 1, 2, 3, 6, 7, or 8 or with undetermined spinocerebellar ataxias were enrolled. All patients underwent a video-oculographic recording of fixation abnormalities, gaze-evoked nystagmus, positional and head-shaking nystagmus, and dysmetric saccades. Logistic regression analysis controlling for disease duration revealed that spontaneous and positional downbeat nystagmus and perverted head-shaking nystagmus were strong predictors for spinocerebellar ataxia 6, whereas saccadic intrusions and oscillations were identified as positive indicators of spinocerebellar ataxia 3. In contrast, the presence of gaze-evoked nystagmus and dysmetric saccades was a negative predictor of spinocerebellar ataxia 2. Positional maneuvers and horizontal head shaking occasionally induced or augmented saccadic intrusions/oscillations in patients with spinocerebellar ataxia types 1, 2, and 3 and undetermined spinocerebellar ataxia. The results indicated that perverted head-shaking nystagmus may be the most sensitive parameter for SCA6, whereas saccadic intrusions/oscillations are the most sensitive for spinocerebellar ataxia 3. In contrast, a paucity of gaze-evoked nystagmus and dysmetric saccades is more indicative of spinocerebellar ataxia 2. Head-shaking and positional maneuvers aid in defining ocular motor characteristics in spinocerebellar ataxias. © 2013 Movement Disorder Society.

A cloning strategy for identification of genes containing trinucleotide repeat expansions.

Until today, nineteen trinucleotide repeat expansions larger than forty repeat copies have been found in the human genome. Of these, the CAG/CTG repeat is predominant motif with twelve loci identified, ten of which have been associated with the development of neurodegenerative diseases. We have developed a cloning approach which isolates disease genes containing trinucleotide repeat expansions. The method is based on size separation of genomic fragments, followed by subcloning and library hybridization with an oligonucleotide probe. Fractions and clones containing expanded repeats are identified by the repeat expansion detection (RED) method throughout the cloning procedure. Large family materials are not required and as little as 10 microg genomic DNA from a single individual is sufficient for this method. Using this strategy we have cloned two DNA fragments containing expanded repeats from two unrelated patients with a clinical diagnosis of cerebellar ataxia. Sequencing of the two fragments showed sequence identities with two disease genes, the Huntington gene and the ataxin 3 gene, respectively. The method should be adaptable to the cloning of any long repeat motif in any species. Furthermore the experimental steps can be performed in less than a month, making it very effective and time efficient to disease gene identification.

Coeliac disease in patients with cerebellar ataxia of unknown origin

BACKGROUND. Neurological symptoms of unknown origin are common in coeliac disease (CD). Evidence suggests that CD may also contribute to the development of idiopathic late-onset ataxia.AIM. To evaluate the frequency of CD in patients with cerebellar ataxia of unknown origin.METHODS. The medical files of adult patients with the diagnosis of cerebellar ataxia of unknown origin (n = 44) were evaluated. Serum gliadin, endomysial, and serum tissue transglutaminase antibodies were used as screening tests for CD. Subjects with positive results were referred to small-bowel biopsy.RESULTS. The frequency of CD was as high as 9.1% in all patients. A thorough interview and review of the patient files indicated alcohol abuse as a cause for cerebellar disease in almost half (45.5%) of our patients. When the cases with alcohol abuse were omitted, the calculated frequency of CD was 16.7% in patients with ataxia of unknown origin.CONCLUSION. CD is a common association with cerebellar disease and the disease should be considered in all patients with ataxia of unknown origin.