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Marios Hadjivassiliou - One of the best experts on this subject based on the ideXlab platform.
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Cerebellar Ataxia with sensory ganglionopathy does autoimmunity have a role to play
Cerebellum & Ataxias, 2017Co-Authors: Panagiotis Zis, Ptolemaios G Sarrigiannis, Dasappaiah Ganesh Rao, Nigel Hoggard, David Sanders, Marios HadjivassiliouAbstract:Cerebellar Ataxia with sensory ganglionopathy (SG) is a disabling combination of neurological dysfunction usually seen as part of some hereditary Ataxias. However, patients may present with this combination without a genetic cause. We reviewed records of all patients that have been referred to the Sheffield Ataxia Centre who had neurophysiological and imaging data suggestive of SG and Cerebellar Ataxia respectively. We excluded patients with Friedreich’s Ataxia, a common cause of this combination. All patients were screened for genetic causes and underwent extensive investigations. We identified 40 patients (45% males, mean age at symptom onset 53.7 ± 14.7 years) with combined Cerebellar Ataxia and SG. The majority of patients (40%) were initially diagnosed with Cerebellar dysfunction and 30% were initially diagnosed with SG. For 30% the two diagnoses were made at the same time. The mean latency between the two diagnoses was 6.5 ± 8.9 years (range 0–44). The commonest initial manifestation was unsteadiness (77.5%) followed by patchy sensory loss (17.5%) and peripheral neuropathic pain (5%). Nineteen patients (47.5%) had gluten sensitivity, of whom 3 patients (7.5%) had biopsy proven coeliac disease. Other abnormal immunological tests were present in another 15 patients. Six patients had malignancy, which was diagnosed within 5 years of the neurological symptoms. Only 3 patients (7.5%) were classified as having a truly idiopathic combination of Cerebellar Ataxia with SG. Our case series highlights that amongst patients with the unusual combination of Cerebellar Ataxia and SG, immune pathogenesis plays a significant role.
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Cerebellar Ataxia and sensory ganglionopathy associated with light-chain myeloma
Cerebellum & Ataxias, 2017Co-Authors: Panagiotis Zis, Dasappaiah Ganesh Rao, Nigel Hoggard, Bart E Wagner, Lucinda Nicholson-goult, Marios HadjivassiliouAbstract:Background Cerebellar Ataxia with sensory ganglionopathy is a rare neurological combination that can occur in some hereditary Ataxias including mitochondrial diseases and in gluten sensitivity. Individually each condition can be a classic paraneoplastic neurological syndrome. We report a patient with this combination who was diagnosed with light-chain myeloma ten years after initial presentation. Case presentation A 65-year-old Caucasian lady was referred to our Ataxia Clinic because of a 6-year history of progressive unsteadiness and a 2-year history of slurred speech. Past medical history included arterial hypertension. The patient was a non-smoker was not consuming alcohol excessively. There was no family history of Ataxia. Neurological examination revealed prominent gaze-evoked nystagmus, heel to shin Ataxia, gait Ataxia, reduced reflexes and loss of vibration sensation in the legs. Cerebellar Ataxia was confirmed using magnetic resonance spectroscopy of the cerebellum and sensory ganglionopathy using neurophysiological assessments including blink reflex study. A muscle biopsy that was arranged to explore the possibility of mitochondrial disease revealed amyloidosis. Urinalysis confirmed the presence of light chains. A bone marrow biopsy confirmed the diagnosis of light chain multiple myeloma. Conclusions Whilst it could be argued that this could simply be a coincidence, the rarity of these conditions and the absence of an alternative aetiology for the neurological dysfunction argue in favour of a paraneoplastic phenomenon.
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Cerebellar Ataxia and sensory ganglionopathy associated with light chain myeloma
Cerebellum & Ataxias, 2017Co-Authors: Panagiotis Zis, Dasappaiah Ganesh Rao, Nigel Hoggard, Bart E Wagner, Lucinda Nicholsongoult, Marios HadjivassiliouAbstract:Cerebellar Ataxia with sensory ganglionopathy is a rare neurological combination that can occur in some hereditary Ataxias including mitochondrial diseases and in gluten sensitivity. Individually each condition can be a classic paraneoplastic neurological syndrome. We report a patient with this combination who was diagnosed with light-chain myeloma ten years after initial presentation. A 65-year-old Caucasian lady was referred to our Ataxia Clinic because of a 6-year history of progressive unsteadiness and a 2-year history of slurred speech. Past medical history included arterial hypertension. The patient was a non-smoker was not consuming alcohol excessively. There was no family history of Ataxia. Neurological examination revealed prominent gaze-evoked nystagmus, heel to shin Ataxia, gait Ataxia, reduced reflexes and loss of vibration sensation in the legs. Cerebellar Ataxia was confirmed using magnetic resonance spectroscopy of the cerebellum and sensory ganglionopathy using neurophysiological assessments including blink reflex study. A muscle biopsy that was arranged to explore the possibility of mitochondrial disease revealed amyloidosis. Urinalysis confirmed the presence of light chains. A bone marrow biopsy confirmed the diagnosis of light chain multiple myeloma. Whilst it could be argued that this could simply be a coincidence, the rarity of these conditions and the absence of an alternative aetiology for the neurological dysfunction argue in favour of a paraneoplastic phenomenon.
Christian Tannier - One of the best experts on this subject based on the ideXlab platform.
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Cerebellar Ataxia with oculomotor apraxia type 1 clinical and genetic studies
Brain, 2003Co-Authors: Mariaceu Moreira, Celine Chamayou, Marie-odile Habert, F. Ochsner, Thierry Kuntzer, Geneviève Demarquay, Gérard Said, Sophie Rivaudpechoux, Marc Tardieu, Christian TannierAbstract:Summary Ataxia with ocular motor apraxia type 1 (AOA1) is an autosomal recessive Cerebellar Ataxia (ARCA) associated with oculomotor apraxia, hypoalbuminaemia and hypercholesterolaemia. The gene APTX, which encodes aprataxin, has been identified recently. We studied a large series of 158 families with non-Friedreich progressive ARCA. We identified 14 patients (nine families) with five different missense or truncating mutations in the aprataxin gene (W279X, A198V, D267G, W279R, IVS5+1), four of which were new. We determined the relative frequency of AOA1 which is 5%. Mutation carriers underwent detailed neurological, neuropsychological, electrophysiological, oculographic and biological examinations, as well as brain imaging. The mean age at onset was 6.8 6 4.8 years (range 2‐18 years). Cerebellar Ataxia with Cerebellar atrophy on MRI and severe axonal sensorimotor neuropathy were present in all patients. In contrast, oculomotor apraxia (86%), hypoalbuminaemia (83%) and hypercholesterolaemia (75%) were variable. Choreic movements were frequent at onset (79%), but disappeared in the course of the disease in most cases. However, a remarkably severe and persistent choreic phenotype was associated with one of the mutations (A198V). Cognitive impairment was always present. Ocular saccade initiation was normal, but their duration was increased by the succession of multiple hypometric saccades that could clinically be confused with ‘slow saccades’. We emphasize the phenotypic variability over the course of the disease. Cerebellar Ataxia and/or chorea predominate at onset, but later on they are often partially masked by severe neuropathy, which is the most typical symptom in young adults. The presence of chorea, sensorimotor neuropathy, oculomotor anomalies, biological abnormalities, Cerebellar atrophy on MRI and absence of the Babinski sign can help to distinguish AOA1 from Friedreich’s Ataxia on a clinical basis. The frequency of chorea at onset suggests that this diagnosis should also be considered in children with chorea who do not carry the IT15 mutation responsible for Huntington’s disease.
Panagiotis Zis - One of the best experts on this subject based on the ideXlab platform.
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Cerebellar Ataxia with sensory ganglionopathy does autoimmunity have a role to play
Cerebellum & Ataxias, 2017Co-Authors: Panagiotis Zis, Ptolemaios G Sarrigiannis, Dasappaiah Ganesh Rao, Nigel Hoggard, David Sanders, Marios HadjivassiliouAbstract:Cerebellar Ataxia with sensory ganglionopathy (SG) is a disabling combination of neurological dysfunction usually seen as part of some hereditary Ataxias. However, patients may present with this combination without a genetic cause. We reviewed records of all patients that have been referred to the Sheffield Ataxia Centre who had neurophysiological and imaging data suggestive of SG and Cerebellar Ataxia respectively. We excluded patients with Friedreich’s Ataxia, a common cause of this combination. All patients were screened for genetic causes and underwent extensive investigations. We identified 40 patients (45% males, mean age at symptom onset 53.7 ± 14.7 years) with combined Cerebellar Ataxia and SG. The majority of patients (40%) were initially diagnosed with Cerebellar dysfunction and 30% were initially diagnosed with SG. For 30% the two diagnoses were made at the same time. The mean latency between the two diagnoses was 6.5 ± 8.9 years (range 0–44). The commonest initial manifestation was unsteadiness (77.5%) followed by patchy sensory loss (17.5%) and peripheral neuropathic pain (5%). Nineteen patients (47.5%) had gluten sensitivity, of whom 3 patients (7.5%) had biopsy proven coeliac disease. Other abnormal immunological tests were present in another 15 patients. Six patients had malignancy, which was diagnosed within 5 years of the neurological symptoms. Only 3 patients (7.5%) were classified as having a truly idiopathic combination of Cerebellar Ataxia with SG. Our case series highlights that amongst patients with the unusual combination of Cerebellar Ataxia and SG, immune pathogenesis plays a significant role.
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Cerebellar Ataxia and sensory ganglionopathy associated with light-chain myeloma
Cerebellum & Ataxias, 2017Co-Authors: Panagiotis Zis, Dasappaiah Ganesh Rao, Nigel Hoggard, Bart E Wagner, Lucinda Nicholson-goult, Marios HadjivassiliouAbstract:Background Cerebellar Ataxia with sensory ganglionopathy is a rare neurological combination that can occur in some hereditary Ataxias including mitochondrial diseases and in gluten sensitivity. Individually each condition can be a classic paraneoplastic neurological syndrome. We report a patient with this combination who was diagnosed with light-chain myeloma ten years after initial presentation. Case presentation A 65-year-old Caucasian lady was referred to our Ataxia Clinic because of a 6-year history of progressive unsteadiness and a 2-year history of slurred speech. Past medical history included arterial hypertension. The patient was a non-smoker was not consuming alcohol excessively. There was no family history of Ataxia. Neurological examination revealed prominent gaze-evoked nystagmus, heel to shin Ataxia, gait Ataxia, reduced reflexes and loss of vibration sensation in the legs. Cerebellar Ataxia was confirmed using magnetic resonance spectroscopy of the cerebellum and sensory ganglionopathy using neurophysiological assessments including blink reflex study. A muscle biopsy that was arranged to explore the possibility of mitochondrial disease revealed amyloidosis. Urinalysis confirmed the presence of light chains. A bone marrow biopsy confirmed the diagnosis of light chain multiple myeloma. Conclusions Whilst it could be argued that this could simply be a coincidence, the rarity of these conditions and the absence of an alternative aetiology for the neurological dysfunction argue in favour of a paraneoplastic phenomenon.
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Cerebellar Ataxia and sensory ganglionopathy associated with light chain myeloma
Cerebellum & Ataxias, 2017Co-Authors: Panagiotis Zis, Dasappaiah Ganesh Rao, Nigel Hoggard, Bart E Wagner, Lucinda Nicholsongoult, Marios HadjivassiliouAbstract:Cerebellar Ataxia with sensory ganglionopathy is a rare neurological combination that can occur in some hereditary Ataxias including mitochondrial diseases and in gluten sensitivity. Individually each condition can be a classic paraneoplastic neurological syndrome. We report a patient with this combination who was diagnosed with light-chain myeloma ten years after initial presentation. A 65-year-old Caucasian lady was referred to our Ataxia Clinic because of a 6-year history of progressive unsteadiness and a 2-year history of slurred speech. Past medical history included arterial hypertension. The patient was a non-smoker was not consuming alcohol excessively. There was no family history of Ataxia. Neurological examination revealed prominent gaze-evoked nystagmus, heel to shin Ataxia, gait Ataxia, reduced reflexes and loss of vibration sensation in the legs. Cerebellar Ataxia was confirmed using magnetic resonance spectroscopy of the cerebellum and sensory ganglionopathy using neurophysiological assessments including blink reflex study. A muscle biopsy that was arranged to explore the possibility of mitochondrial disease revealed amyloidosis. Urinalysis confirmed the presence of light chains. A bone marrow biopsy confirmed the diagnosis of light chain multiple myeloma. Whilst it could be argued that this could simply be a coincidence, the rarity of these conditions and the absence of an alternative aetiology for the neurological dysfunction argue in favour of a paraneoplastic phenomenon.
Sylvia Dobrzeniecka - One of the best experts on this subject based on the ideXlab platform.
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syne1 mutations in autosomal recessive Cerebellar Ataxia
JAMA Neurology, 2013Co-Authors: Anne Noreau, Cynthia V Bourassa, Anna Szuto, Annie Levert, Sylvia DobrzenieckaAbstract:Importance Autosomal recessive Cerebellar Ataxia type I, also known as recessive Ataxia of Beauce, is a slowly progressive Ataxia that leads to moderate disability with gait Ataxia, dysarthria, dysmetria, mild oculomotor abnormalities, and diffuse Cerebellar atrophy on brain imaging. Mutations in the synaptic nuclear envelope protein 1 ( SYNE1 ) gene, located on chromosome 6p25, were first reported in patients who originated from a region known as “Beauce” in the province of Quebec, Canada. Objective To better evaluate the prevalence of SYNE1 mutations in individuals with mild pure Cerebellar Ataxia and Cerebellar atrophy, we screened the gene in additional French-Canadian (FC) families and individuals from other populations. Design, Setting, and Participants Study participants were referred by their treating physician on the basis of core features of autosomal recessive Cerebellar Ataxia type I. After excluding individuals with known SYNE1 mutations, our cohort was composed mainly of 19 FCs and 21 individuals from other ethnic backgrounds. Interventions Extraction of DNA from blood samples and complete resequencing of the SYNE1 gene. Main Outcomes and Measures The involvement of SYNE1 mutations in individuals with Ataxia worldwide by resequencing the SYNE1 gene. Results Two novel truncating mutations were found among the FC participants, and 2 other novel mutations were found in a patient from France and a patient from Brazil (1 mutation each). Conclusions and Relevance This is the second report, to our knowledge, of SYNE1 gene mutations in a population other than FCs. These data suggest that mutations in SYNE1 should be investigated in families with Cerebellar Ataxia who live outside the FC region.
Rita Guerreiro - One of the best experts on this subject based on the ideXlab platform.
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novel mag variant causes Cerebellar Ataxia with oculomotor apraxia molecular basis and expanded clinical phenotype
Journal of Clinical Medicine, 2020Co-Authors: Mariana Santos, Celia Kunrodrigues, Joana Damásio, Clara Barbot, Jorge Sequeiros, Isabel Alonso, Jose Bras, Rita GuerreiroAbstract:Homozygous variants in MAG, encoding myelin-associated glycoprotein (MAG), have been associated with complicated forms of hereditary spastic paraplegia (HSP). MAG is a glycoprotein member of the immunoglobulin superfamily, expressed by myelination cells. In this study, we identified a novel homozygous missense variant in MAG (c.124T>C; p.Cys42Arg) in a Portuguese family with early-onset autosomal recessive Cerebellar Ataxia with neuropathy and oculomotor apraxia. We used homozygosity mapping and exome sequencing to identify the MAG variant, and cellular studies to confirm its detrimental effect. Our results showed that this variant reduces protein stability and impairs the post-translational processing (N-linked glycosylation) and subcellular localization of MAG, thereby associating a loss of protein function with the phenotype. Therefore, MAG variants should be considered in the diagnosis of hereditary Cerebellar Ataxia with oculomotor apraxia, in addition to spastic paraplegia.