Autoantibodies related to ataxia and other central nervous system manifestations of gluten enteropathy

Gluten ataxia and other central nervous system disorders could be linked to gluten enteropathy and related autoantibodies.In this narrative review,we focus on the various neuro-logical manifestations in patients with gluten sensitivity/celiac disease,immunological and autoimmune mechanisms of ataxia in connection to gluten sensitivity and the autoantibodies that could be used as a biomarker for diagnosing and following.We focused on the anti-gliadin antibodies,antibodies to different isoforms of tissue transglutaminase(TG)(anti-TG2,3,and 6 antibodies),anti-glycine receptor antibodies,anti-glutamine acid decarboxylase antibodies,anti-deamidated gliadin peptides antibodies,etc.Most studies found a higher prevalence of these antibodies in patients with gluten sensitivity and neurological dysfunction,presented as different neurological disorders.We also discuss the role of a gluten-free diet on the clinical improvement of patients and also on imaging of these disorders.

Hypergonadotrophic Hypogonadism with Cerebellar Ataxia in a Twenty-Six-Year-Old Female: A Case Report

Gordon Holmes Syndrome is a rare inherited disease characterized by both neurological and reproductive signs and symptoms. Most patients develop neurologic challenges in early adulthood and cerebellar ataxia occurs as the disease progresses. In the majority of patients, hypogonadism is hypogonadotropic but rarely hypergonadotropic. We report a case of a 26-year-old female in Nigeria, with hypergonadotropic hypogonadism and cerebellar atrophy from a non-consanguineous marriage and no family history.

Cell-based therapeutic strategies for treatment of spinocerebellar ataxias:an update

Spinocerebellar ataxias are heritable neurodegenerative diseases caused by a cytosine-adenine-guanine expansion,which encodes a long glutamine tract(polyglutamine)in the respective wild-type protein causing misfolding and protein aggregation.Clinical features of polyglutamine spinocerebellar ataxias include neuronal aggregation,mitochondrial dysfunction,decreased proteasomal activity,and autophagy impairment.Mutant polyglutamine protein aggregates accumulate within neurons and cause neural dysfunction and death in specific regions of the central nervous system.Spinocerebellar ataxias are mostly characterized by progressive ataxia,speech and swallowing problems,loss of coordination and gait deficits.Over the past decade,efforts have been made to ameliorate disease symptoms in patients,yet no cure is available.Previous studies have been proposing the use of stem cells as promising tools for central nervous system tissue regeneration.So far,pre-clinical trials have shown improvement in various models of neurodegenerative diseases following stem cell transplantation,including animal models of spinocerebellar ataxia types 1,2,and 3.However,contrasting results can be found in the literature,depending on the animal model,cell type,and route of administration used.Nonetheless,clinical trials using cellular implants into degenerated brain regions have already been applied,with the expectation that these cells would be able to differentiate into the specific neuronal subtypes and re-populate these regions,reconstructing the affected neural network.Meanwhile,the question of how feasible it is to continue such treatments remains unanswered,with long-lasting effects being still unknown.To establish the value of these advanced therapeutic tools,it is important to predict the actions of the transplanted cells as well as to understand which cell type can induce the best outcomes for each disease.Further studies are needed to determine the best route of administration,without neglecting the possible risks of repetitive transplantation that these approaches so far appear to demand.Despite the challenges ahead of us,cell-transplantation therapies are reported to have transient but beneficial outcomes in spinocerebellar ataxias,which encourages efforts towards their improvement in the future.

Ataxia-telangiectasia mutated plays an important role in cerebellar integrity and functionality

Accumulating evidence indicates that ataxia-telangiectasia mutated kinase is critical for maintaining cellular homeostasis and that it has both nuclear and cytoplasmic functions.However,the functions of ataxia-telangiectasia mutated that when lost lead to cerebellar degeneration are still unknown.In this review,we first describe the role of ataxia-telangiectasia mutated in cerebellar pathology.In addition to its canonical nuclear functions in DNA damage response circuits,ataxia-telangiectasia mutated functions in various cytoplasmic and mitochondrial processes that are critically important for cellular homeostasis.We discuss these functions with a focus on the role of ataxia-telangiectasia mutated in maintaining the homeostatic redox state.Finally,we describe the unique functions of ataxia-telangiectasia mutated in various types of neuronal and glial cells including cerebellar granule neurons,astrocytes,and microglial cells.

Compound heterozygous mutations in tripeptidyl peptidase 1 cause rare autosomal recessive spinocerebellar ataxia type 7:A case report

BACKGROUND Spinocerebellar ataxia recessive type 7(SCAR7)is a rare clinical manifestation beginning in childhood or adolescence.SCAR7 is caused by tripeptidyl peptidase 1(TPP1)gene mutations,and presents with cerebellar ataxia,pyramidal signs,neurocognitive impairment,deep paresthesia,and cerebellar atrophy.CASE SUMMARY Here,we describe a 25-year-old female patient in China who presented with increasing difficulty walking,falling easily,shaking limbs,instability holding items,slurred speech,coughing when drinking,palpitations,and frequent hunger and overeating.Magnetic resonance imaging showed cerebellar atrophy.Whole exome sequencing detected two compound heterozygous mutations in the TPP1 gene:c.1468G>A p.Glu490Lys and c.1417G>A p.Gly473Arg.Considering the patient’s clinical presentation and genetic test results,we hypothesized that complex heterozygous mutations cause TPP1 enzyme deficiency,which may lead to SCAR7.CONCLUSION We report the first case of SCAR7 from China.We also identify novel compound heterozygous mutations in the TPP1 gene associated with SCAR7,expanding the range of known disease-causing mutations for SCAR7.

Novel frameshift mutation in the SACS gene causing spastic ataxia of charlevoix-saguenay in a consanguineous family from the Arabian Peninsula:A case report and review of literature

BACKGROUND Familial cases of autosomal recessive spastic ataxia of charlevoix-saguenay have not been reported in the Arabian Peninsula,although the consanguineous marriage rate is very high.We report the first family from the Arabian Peninsula harboring a novel frameshift mutation in the SACS gene.CASE SUMMARY A 33-year-old man presented to our neurology clinic with balance problems and weakness of distal upper and lower limbs.He was previously clinically diagnosed with Friedreich's ataxia.However,the severity of polyneuropathy and the electrodiagnostic studies(EDX)findings are atypical features of Friedreich’s ataxia,and the deterioration was attributed to diabetic neuropathy.Close examination of other family members identified cerebellar ataxia,lower-limb pyramidal signs,peripheral neuropathy,and magnetic resonance imaging findings characterized by pontine linear hypointensities.Genetic testing for Friedreich’s ataxia did not yield a diagnosis.Whole exome sequencing identified a novel frameshift germline mutation in the SACS gene termed c.5824_5827delTACT using the transcript NM_014363.5,which is predicted to cause premature termination of the sacsin protein at amino acid position 1942(p.Tyr1942Metfs*9)and disrupts the sacsin SRR3 and domains downstream from it.The mutation segregated with the disease in the family.CONCLUSION Our data add to the spectrum of mutations in the SACS gene and argues for a need to implement suitably integrated clinical and diagnostic services,including next generation sequencing technology,to better classify ataxia in this area of the world.

Transition of Thalassaemia and Friedreich ataxia from fatal to chronic diseases

Thalassaemia major(TM) and Friedreich's ataxia(FA) are autosomal recessive inherited diseases related to the proteins haemoglobin and frataxin respectively. In both diseases abnormalities in iron metabolism is the main cause of iron toxicity leading to increased morbidity and mortality. Major efforts are directed towards the prevention of these diseases and also in their treatment using iron chelation therapy. Both TM and FA are endemic in Cyprus, where the frequency per total population of asymptomatic heterozygote carriers and patients is the highest worldwide. Cyprus has been a pioneering nation in preventing and nearly eliminating the birth of TM and FA patients by introducing an organized health structure, including prenatal and antenatal diagnosis. Effective iron chelation therapy, improved diagnostic methods and transfusion techniques as well as supportive therapy from other clinical specializations have improved the survival and quality of life of TM patients.Despite the tiresome clinical management regimes many TM patients are successful in their professional lives, have families with children and some are now living well into their fifties. The introduction of deferiprone led to the elimination of cardiac failure induced by iron overload toxicity, which was the major cause of mortality in TM. Effective combinations of deferiprone with deferoxamine in TM patients caused the fall of body iron to normal physiological ranges. In FA different mechanisms of iron metabolism and toxicity apply to that of TM, which can be targeted with specific iron chelation protocols. Preliminary findings from the introduction of deferiprone in FA patients have increased the hopes for improved and effective therapy in this untreatable condition. New and personalised treatments are proposed in TM and FA. Overall, advances in treatments and in particular of chelation therapy using deferiprone are transforming TM and FA from fatal to chronic conditions. The paradigm of Cyprus in the prevention and treatment of TM can be used for application worldwide.

Prenatal diagnosis of spinocerebellar ataxia type 3/Machado-Joseph disease in China's Mainland A case report

Spinocerebellar ataxia type 3/Machado-Joseph disease （SCA3/MJD） is a progressive, currently untreatable and ultimately fatal ataxic disorder that belongs to the group of neurological disorders known as CAG-repeat or polyglutamine diseases. Here, we present the first prenatal diagnosis of SCA3/MJD in China's Mainland in a woman who was known to carry an expanded CAG-trinucleotide repeat in the MJD1 gene. After evaluating motivation and psychological tolerance of the couple, amniocentesis was performed after 14 weeks of gestation. Polymerase chain reactions followed by T-vector cloning and direct sequencing were employed to evaluate the CAG-repeat number of the fetal MJD1 gene. We identified a truncated CAG expansion of 78 repeats in the MJD1 gene of the fetus compared with 81 repeats in his mother.

Heart disease in Friedreich's ataxia

Friedreich's ataxia(FRDA), which occurs in 1/50000 live births, is the most prevalent inherited neuromuscular disorder. Nearly all FRDA patients develop cardiomyopathy at some point in their lives. The clinical manifestations of FRDA include ataxia of the limbs and trunk, dysarthria, diabetes mellitus, and cardiac diseases. However, the broad clinical spectrum makes FRDA difficult to identify.The diagnosis of FRDA is based on the presence of suspicious clinical factors, the use of the Harding criteria and, more recently, the use of genetic testing for identifying the expansion of a triplet nucleotide sequence. FRDA is linked to a defect in the mitochondrial protein frataxin; an epigenetic alteration interferes with the folding of this protein, causing a relative deficiency of frataxin in affected patients. Frataxins are small essential proteins whose deficiency causes a range of metabolic disturbances, including oxidative stress, iron-sulfur cluster deficits, and defects in heme synthesis, sulfur amino acid metabolism, energy metabolism, stress responses, and mitochondrial function. The cardiac involvement seen in FRDA is a consequence of mitochondrial proliferation as well as the loss of contractile proteins and the subsequent development of myocardial fibrosis. The walls of the left ventricle become thickened, and different phenotypic manifestations are seen, including concentric or asymmetric hypertrophy and(less commonly) dilated cardiomyopathy. Dilated cardiomyopathy and arrhythmia are associated with mortality in patients with FRDA, whereas hypertrophic cardiomyopathy is not. Systolic function tends to be low-normal in FRDA patients, with an acute decline at the end of life.However, the literature includes only a few long-term prospective studies of cardiac progression in FRDA, and the cause of death is often attributed to heart failure and arrhythmia postmortem. Cardiomyopathy tends to be correlated with the clinical neurologic age of onset and the nucleotide triplet repeat length(i.e.,markers of phenotypic disease severity) rather than the duration of disease or the severity of neurologic symptoms. As most patients are wheelchair-bound within15 years of diagnosis, the clinical determination of cardiac involvement is often complicated by comorbidities. Researchers are currently testing targeted therapies for FRDA, and a centralized database, patient registry, and natural history study have been launched to support these clinical trials. The present review discusses the pathogenesis, clinical manifestations, and spectrum of cardiac disease in FRDA patients and then introduces gene-targeted and pathology-specific therapies as well as screening guidelines that should be used to monitor cardiac disease in this mitochondrial disorder.

The human δ2 glutamate receptor gene is not mutated in patients with spinocerebellar ataxia

The human glutamate receptor delta 2 gene （GRID2） shares 90%homology with the orthologous mouse gene. The mouse Grid2 gene is involved with functions of the cerebellum and sponta-neous mutation of Grid2 leads to a spinocerebellar ataxia-like phenotype. To investigate whether such mutations occur in humans, we screened for mutations in the coding sequence of GRID2 in 24 patients with familial or sporadic spinocerebellar ataxia and in 52 normal controls. We de-tected no point mutations or insertion/deletion mutations in the 16 exons of GRID2. However, a polymorphic 4 nucleotide deletion （IVS5-121_-118 GAGT） and two single nucleotide polymor-phisms （c.1251G〉T and IVS14-63C〉G） were identiifed. The frequency of these polymorphisms was similar between spinocerebellar ataxia patients and normal controls. These data indicate that spontaneous mutations do not occur in GRID2 and that the incidence of spinocerebellar ataxia in humans is not associated with GRID2 mutation or polymorphisms.

Improvement of ataxia in a patient with cerebellar infarction by recovery of injured cortico-ponto-cerebellar tract and dentato-rubro-thalamic tract: a diffusion tensor tractography study

Coordinated movement is generated by communication between the cerebrum and cerebellum via the cerebellar peduncles (CPs). The CPs are classified into three types (superior, middle, and inferior), and each includes a variety of neural tracts. Among those tracts, the cortico-ponto-cerebellar tract (CPCT), a middle CP, is involved in motor planning and initiation of movement, while the dentato-rubro-thalamic tract (DRTT), a superior CP, is involved in motor coordination, movement timing, verbal fluency, and working memory (Kase et al., 1993.

Vitamin E in ataxia and neurodegenerative diseases:A review

Vitamin E is one of the most important lipid-soluble antioxidants. It is essential for the neurological function but its role in the central nervous system has not fully been elucidated. It is known that tocopherol acts in protecting cell membranes from oxidative damage and it can act as an anti-in?ammatory agent, which may also be neuroprotective, as well as regulating speci?c enzymes. There is growing evidence that oxidative stress plays a key role in the pathophysiology of several neurodegenerative disorders. These diseases are defined by the progressive loss of speci?c neuronal cell populations and are associated with protein aggregates. We reviewed some aspects related to the role of antioxidant properties of Vitamin E in preventing and/or curing neurodegenerative disorders such as the Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, ataxia, tardive dyskinesia and Huntington’s disease.

Clinical and Genetic Study of Friedreich’s Ataxia and Ataxia with Vitamin E Deficiency in 44 Moroccan Families

Introduction: Friedreich ataxia (FRDA) is a multi-system autosomal-recessive disease, the most common one of the genetically inherited ataxias. FRDA occurs as a consequence of mutations in the frataxin gene, with an expansion of a GAA trinucleotide. Ataxia with vitamin E deficiency (AVED) is characterized clinically by neurological symptoms with often striking resemblance to those of Friedreich’s ataxia (FA) but serum concentrations of vitamin E are low. Aim of study: To study clinical and genetic features of the Friedreich’s ataxia and AVED patients in 44 Moroccan families. Patients and Methods: Retrospective series of 72 Moroccan patients displaying Friedreich’s ataxia syndrome was recruited over a period of 22 years (1987-2009). All patients had a clinical and ophtalmological examinations, 30 patients underwent electromyography, and CT scan was performed in 29 patients. GAA repeats in the frataxin gene and the 744 del A mutation α-TTP gene were performed in all patients. Results: 17 patients (24% of cases) had the 744 del A mutation in the α-TTP gene responsible of ataxia with vitamin E deficiency (AVED) phenotype. 55 patients ?(76% of cases) had GAA expanded allele in the first intron of the frataxin gene. Phenotype-genotype correlation revealed a high frequency of head titubation, decreased visual acuity and slower disease progression in AVED than in Friedreich’s ataxia phenotype (p Our study represents a large series which highlight the clinical and genetic differences between AVED and Friedreich’s ataxia. AVED patients have a better prognosis after alpha-tocopherol treatment.

Progressive ataxia of cerebrotendinous xanthomatosis with a rare c.255+1G>T splice site mutation:A case report

BACKGROUND Cerebrotendinous xanthomatosis is an autosomal recessive disorder of lipid metabolism caused by the mutation of the CYP27A1 gene encoding sterol 27-hydroxylase,an essential enzyme for the conversion of cholesterol to chenodeoxycholic and cholic acids.Cerebrotendinous xanthomatosis is a rare neurological dis-ease with a wide range of clinical symptoms that are easily misdiagnosed.CASE SUMMARY Here we report the clinical,biochemical,and molecular characterization of a 33-year-old female patient with cerebrotendinous xanthomatosis.The patient developed ataxia and had the typical symptoms of juvenile cataracts,tendon xanthomata,and progressive nervous system dysfunction.Magnetic resonance imaging of the brain revealed bilateral dentate nucleus lesions and white matter abnormalities.This patient was misdiagnosed for 2 years resulting in severe neurological complications.After 2 years of chenodeoxycholic acid treatment,she still presented with ataxia and dysarthria.The pathogenic sites of CYP27A1 were identified as c.255+1G>T and c.1263+1G>T,which were both caused by shear denaturation.CONCLUSION Cerebrotendinous xanthomatosis requires a multidisciplinary diagnosis that must be made early to avoid progressive neurological degeneration.c.1263+1G>T is a known mutation,but c.255+1G>T is a rare mutation site.

Clinico-Radiological Correlation in Children with Ataxia Telangiectasia in Qatar

Introduction: Ataxia telangiectasia (AT) is a rare disease characterized by immunodeficiency and neurological manifestations. Ataxia, resulting from cerebella atrophy, runs a progressive incapacitating course. Clinical monitoring of the disease course is mandatory for early treatment. Aim: To study clinical severity of AT and correlate it with the degree of cerebellar atrophy. Patients and Methods: We retrospectively studied all children (less than 14 years) with AT seen at Hamad General Hospital Clinics between 1998-2013. We collected basic demographic data, parental consan-guinity, family history, AT clinical severity scores, and reviewed CBC with differential counts;alpha-fetoprotein, serum immunoglobulins and lymphocyte subsets. Cranial MRI scans of each subject were reviewed by a neuroradiologist. Cerebellar atrophy was visually and semi-quantitatively scored. Results: We analyzed data on 18 AT children (10 males and 8 females), mean age of 76.9 months. 77.8% had a positive family history of AT and 41.7% parental consanguinity. Lymphopenia was observed in 77.8% and high serum alpha-fetoprotein in 87.5% of children. Clinical severity of ataxia was 17.1 ± 8.4 (mean ± SD);86.7% of patients were moderate-severe. MRI cerebellar atrophy score was 1.9 ± 1.3 (mean ± SD), and moderate in 51% of patients. AT clinical severity score correlated (coefficient r = 0.566) but not statistically significant p = 0.088) with MRI cerebellar atrophy scores. Conclusions: Moderate to severe ataxia and marked cerebellar atrophy are quite common in AT children. There is a correlation between AT clinical severity and cerebellar atrophy. Larger prospective studies might further determine the significance of our observations and help practicing practitioners monitor the progression of the disease.

Clinical and genetic study of ataxia with vitamin E deficiency: A case report

BACKGROUND Ataxia with vitamin E deficiency(AVED)is a type of autosomal recessive cerebellar ataxia.Clinical manifestations include progressive cerebellar ataxia and movement disorders.TTPA gene mutations cause the disease.CASE SUMMARY We report the case of a 32-year-old woman who presented with progressive cerebellar ataxia,dysarthria,dystonic tremors and a remarkably decreased serum vitamin E concentration.Brain magnetic resonance images showed that her brainstem and cerebellum were within normal limits.Acquired causes of ataxia were excluded.Whole exome sequencing subsequently identified a novel homozygous variant(c.473T>C,p.F158S)of the TPPA gene.Bioinformatic analysis predicted that F185S is harmful to protein function.After supplementing the patient with vitamin E 400 mg three times per day for 2 years,her symptoms remained stable.CONCLUSION We identified an AVED patient caused by novel mutation in TTPA gene.Our findings widen the known TTPA gene mutation spectrum.

Spinocerebellar ataxia type 3 with dopamine-responsive dystonia:A case report

BACKGROUND Spinocerebellar ataxia type 3(SCA3)is a rare neurodegenerative disease with high genetic heterogeneity.SCA3 mainly manifests as progressive cerebellar ataxia accompanied by paralysis of extraocular muscles,dysphagia,lingual fibrillation,pyramidal tract sign,and extrapyramidal system sign.However,it rarely has clinical manifestations similar to Parkinson-like symptoms,and is even rarer in patients sensitive to dopamine.We report a patient initially diagnosed with dopamine-responsive dystonia who was ultimately diagnosed with SCA3 by genetic testing,which was completely different from the initial diagnosis.CASE SUMMARY A 40-year-old Chinese woman was admitted to hospital due to severe inflexibility.At the beginning of the disease,she presented with anxiety and sleep disorder.At the later stage,she presented with gait disorder,which was similar to Parkinson's disease.Her medical history was unremarkable,but her mother,grandmother,and uncle all had similar illnesses and died due to inability to take care of themselves and related complications.Laboratory and imaging examinations showed no abnormalities,but electromyography and electroencephalography revealed delayed somatosensory evoked potentials and slow background rhythm,respectively.Her symptoms fluctuated during the daytime,and we initially diagnosed her with dopamine-responsive dystonia.After treatment with lowdose levodopa,the patient’s symptoms were significantly improved,but the final genetic diagnosis was SCA3.CONCLUSION SCA3 has various clinical phenotypes and needs to be differentiated from Parkinson's syndrome and dopamine-responsive dystonia.

Molecular diagnosis of autosomal recessive cerebellar ataxia in the whole exome/genome sequencing era

Autosomal recessive cerebellar ataxias(ARCA) are a clinically and genetically heterogeneous group of rare neurodegenerative disorders characterized by autosomal recessive inheritance and an early age of onset. Progressive ataxia is usually the prominent symptom and is often associated with other neurological or additional features. ARCA classification still remains controversial even though different approaches have been proposed over the years. Furthermore, ARCA molecular diagnosis has been a challenge due to phenotypic overlap and increased genetic heterogeneity observed within this group of disorders. Friedreich's ataxia and ataxia telangiectasia have been reported as the most frequent and well-studied forms of ARCA. Significant progress in understanding the genetic etiologies of the ARCA has been achieved during the last 15 years. The methodological revolution that has been observed in genetics over the last few years has contributed significantly to the molecular diagnosis of rare diseases including the ARCAs. Development of high throughput technologies has resulted in the identification of new ARCA genes and novel mutations in known ARCA genes. Therefore,an improvement in the molecular diagnosis of ARCA is expected. Moreover, based on the fact that many patients still remain undiagnosed, additional forms of ataxia are expected to be identified. We hereby review the current knowledge on the ARCAs, focused on the genetic findings of the most common forms that were molecularly characterized before the whole exome/genome era, as well as the most recently described forms that have been elucidated with the use of these novel technologies. The significant contribution of wholeexome sequencing or whole-genome sequencing in the molecular diagnosis of ARCAs is discussed.

Acute Cerebellar Ataxia—Uncommon Manifestation of Typhoid Fever

Enteric fever is widely prevalent in the tropics. Central nervous system involvement is not rare and reported incidence varies from 5% to 35% [1]. Various well-known neuropsychiatric manifestations include confusional state, encephalopathy, meningism, convulsions and focal neurological deficits. Acute cerebellar ataxia as an isolated neurological complication of enteric fever is very rare and limited to only a few case reports [2]. Here we report a case of enteric fever who presents Acute Cerebellar Ataxia.

Spinocerebellar Ataxia with Oculomotor Apraxia and Severe Corneal Astigmatism

Purpose: To disclose the association between spinocerebellar ataxia with oculomotor apraxia and high grade (7 diopters) congenital astigmatism. Methods: Single observational case report. A 39-year-old patient affected by spinocerebellar ataxia from the age of 20 was submitted to genetic and ophthalmic investigations to reach a diagnosis. Results: Genetic testing did not lead to a sure diagnosis, while clinical and instrumental ophthalmic examinations pointed out an oculomotor apraxia and a congenital severe astigmatism. Conclusion: To conclude the eye movement recording permitted to identify an oculomotor apraxia in this case of spinocerebellar ataxia. This is the first report of severe astigmatism in cases of ataxia with oculomotor apraxia.