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MedWorm: Ataxia



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Last Build Date: Tue, 22 Mar 2016 08:27:47 +0100

 



Gene suppression strategies for dominantly inherited neurodegenerative diseases: lessons from Huntington's disease and spinocerebellar ataxia

Mon, 21 Mar 2016 00:00:00 +0100

RNA-targeting approaches are emerging as viable therapeutics that offer an alternative method to modulate traditionally ‘undrugable’ targets. In the case of dominantly inherited neurodegenerative diseases, gene suppression strategies can target the underlying cause of these intractable disorders. Polyglutamine diseases are caused by CAG expansions in discrete genes, making them ideal candidates for gene suppression therapies. Here, we discuss the current state of gene suppression approaches for Huntington's disease and the spinocerebellar ataxias, including the use of antisense oligonucleotides, short-interfering RNAs, as well as viral vector-mediated delivery of short hairpin RNAs and artificial microRNAs. We focus on lessons learned from preclinical studies investigating gene...

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Using human pluripotent stem cells to study Friedreich ataxia cardiomyopathy

Mon, 21 Mar 2016 00:00:00 +0100

Friedreich ataxia (FRDA) is the most common of the inherited ataxias. It is an autosomal recessive disease characterised by degeneration of peripheral sensory neurons, regions of the central nervous system and cardiomyopathy. FRDA is usually due to homozygosity for trinucleotide GAA repeat expansions found within first intron of the FRATAXIN (FXN) gene, which results in reduced levels of the mitochondrial protein FXN. Reduced FXN protein results in mitochondrial dysfunction and iron accumulation leading to increased oxidative stress and cell death in the nervous system and heart. (Source: International Journal of Cardiology)



Confirmation of a non-synonymous SNP in PNPLA8 as a candidate causal mutation for Weaver syndrome in Brown Swiss cattle.

Sun, 20 Mar 2016 13:01:02 +0100

CONCLUSIONS: Through combined use of exhaustive sequencing data and SNP genotyping results, we were able to provide evidence that supports the non-synonymous mutation at position 49,878,773 bp as the most likely causal mutation for Weaver syndrome. Further studies are needed to uncover the exact mechanisms that underlie this syndrome. PMID: 26992691 [PubMed - as supplied by publisher] (Source: Genet Sel Evol)



[Refractory encephalitis because of seronegative celiac disease: a case report].

Sun, 20 Mar 2016 04:24:02 +0100

CONCLUSION: The encephalitis is an infrequent clinical manifestation of the celiac disease despite the high prevalence of the celiac disease in the general population. It presents with numerous differential diagnosis, with requires high suspicious diagnosis. PMID: 26988169 [PubMed - in process] (Source: Revista de Neurologia)



PTEN enhances G2/M arrest in etoposide-treated MCF‑7 cells through activation of the ATM pathway.

Sat, 19 Mar 2016 17:53:03 +0100

Authors: Zhang R, Zhu L, Zhang L, Xu A, Li Z, Xu Y, He P, Wu M, Wei F, Wang C Abstract As an effective tumor suppressor, phosphatase and tensin homolog (PTEN) has attracted the increased attention of scientists. Recent studies have shown that PTEN plays unique roles in the DNA damage response (DDR) and can interact with the Chk1 pathway. However, little is known about how PTEN contributes to DDR through the ATM-Chk2 pathway. It is well-known that etoposide induces G2/M arrest in a variety of cell lines, including MCF-7 cells. The DNA damage-induced G2/M arrest results from the activation of protein kinase ataxia telangiectasia mutated (ATM), followed by the activation of Chk2 that subsequently inactivates CDC25C, resulting in G2/M arrest. In the present study, we assessed the co...



Spinocerebellar Ataxia Type 3 in Italy: Time to Change Mind

Sat, 19 Mar 2016 09:19:10 +0100

Neuroepidemiology 2016;46:268 (Source: Neuroepidemiology)

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Coping with genetic burden.

Fri, 18 Mar 2016 04:28:02 +0100

Authors: Tibben A Abstract An increasing number of neurodegenerative diseases have been defined at the molecular level in recent years, making it possible to determine precisely the genotype before the onset of symptoms. Pre-symptomatic testing programs are available for Huntington disease (HD), hereditary cerebral haemorrhage with amyloid-Dutch type, inherited cerebral ataxia, myotonic dystrophy, and Alzheimer disease. Although treatment options such as gene therapy have no widespread application until now, and much has to be developed, the use of predictive DNA-diagnostics has become a clinical application for a number of hereditary diseases. For psychiatric disorders such as schizophrenia or bipolar disorders, there are indications for localisation of the genetic factors, but cl...



Kv3.3 Channels Bind Hax-1 and Arp2/3 to Assemble a Stable Local Actin Network that Regulates Channel Gating

Fri, 18 Mar 2016 00:00:00 +0100

Publication date: Available online 17 March 2016 Source:Cell Author(s): Yalan Zhang, Xiao-Feng Zhang, Matthew R. Fleming, Anahita Amiri, Lynda El-Hassar, Alexei A. Surguchev, Callen Hyland, David P. Jenkins, Rooma Desai, Maile R. Brown, Valeswara-Rao Gazula, Michael F. Waters, Charles H. Large, Tamas L. Horvath, Dhasakumar Navaratnam, Flora M. Vaccarino, Paul Forscher, Leonard K. Kaczmarek Mutations in the Kv3.3 potassium channel (KCNC3) cause cerebellar neurodegeneration and impair auditory processing. The cytoplasmic C terminus of Kv3.3 contains a proline-rich domain conserved in proteins that activate actin nucleation through Arp2/3. We found that Kv3.3 recruits Arp2/3 to the plasma membrane, resulting in formation of a relatively stable cortical actin filam...



Ataxia telangiectasia mutated in cardiac fibroblasts regulates doxorubicin-induced cardiotoxicity

Fri, 18 Mar 2016 00:00:00 +0100

Conclusion ATM-regulated effects within cardiac fibroblasts are pivotal in Dox-induced cardiotoxicity, and antagonism of ATM and its functions may have potential therapeutic implications. (Source: Cardiovascular Research)



Structural characterization of a dimer of RNA duplexes composed of 8-bromoguanosine modified CGG trinucleotide repeats: a novel architecture of RNA quadruplexes

Fri, 18 Mar 2016 00:00:00 +0100

Fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS) are neurodegenerative disorders caused by the pathogenic expansion of CGG triplet repeats in the FMR1 gene. FXTAS is likely to be caused by a ‘toxic’ gain-of-function of the FMR1 mRNA. We provide evidence for the existence of a novel quadruplex architecture comprising CGG repeats. The 8-bromoguanosine (BrG)-modified molecule GCBrGGCGGC forms a duplex in solution and self-associates via the major groove to form a four-stranded, antiparallel (GCBrGGCGGC)4 RNA quadruplex with BrG3:G6:BrG3:G6 tetrads sandwiched between mixed G:C:G:C tetrads. Self-association of Watson–Crick duplexes to form a four-stranded structure has previously been predicted; however, no experimental evidence was provided. This nov...



Relapsing polychondritis and lymphocytic meningitis with varied neurological symptoms

Fri, 18 Mar 2016 00:00:00 +0100

Conclusion Relapsing polychondritis is a challenging disease that can rarely manifest with varied neurological symptoms; recognition is extremely important, because high-dose corticosteroids should be used as soon as possible in suspected cases. (Source: Revista Brasileira de Reumatologia)

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Confirmation of a non-synonymous SNP in PNPLA8 as a candidate causal mutation for Weaver syndrome in Brown Swiss cattle

Fri, 18 Mar 2016 00:00:00 +0100

Bovine progressive degenerative myeloencephalopathy (Weaver syndrome) is a neurodegenerative disorder in Brown Swiss cattle that is characterized by progressive hind leg weakness and ataxia, while sensorium an... (Source: Genetics Selection Evolution)



Crystal Structure of the USP7-NTD{middle dot}vIRF1 Peptide Complex [Enzymology]

Fri, 18 Mar 2016 00:00:00 +0100

Viral interferon regulatory factor 1 (vIRF1), a Kaposi sarcoma herpesvirus protein, destabilizes p53 by inhibiting p53 acetylation and Hdm2 phosphorylation. This leads to increased ubiquitination and degradation of p53 by Hdm2, which cripples the cellular p53-mediated antiviral response. Ubiquitin-specific protease 7 (USP7) deubiquitinates p53 and Hdm2 and regulates their stability. We identified an EGPS consensus sequence in vIRF1, which is identical to that found in Epstein-Barr virus nuclear antigen 1 (EBNA1) that interacts with the N-terminal domain of USP7 (USP7-NTD). GST pulldown assays demonstrated that vIRF1 interacts with USP7-NTD via its EGPS motif. NMR heteronuclear single quantum correlation (HSQC) analysis revealed chemical perturbations after titration of USP7-NTD with vIRF1 ...



Melatonin as add-on treatment for epilepsy.

Thu, 17 Mar 2016 00:00:00 +0100

CONCLUSIONS: Included studies were of poor methodological quality, and did not systematically evaluate seizure frequency and adverse events, so that it was impossible to summarize data in a meta-analysis. It is not possible to draw any conclusion about the role of melatonin in reducing seizure frequency or improving quality of life in people with epilepsy. PMID: 26986179 [PubMed - as supplied by publisher] (Source: Cochrane Database of Systematic Reviews)



Enhanced gefitinib‐induced repression of the epidermal growth factor receptor pathway by ataxia telangiectasia‐mutated kinase inhibition in non‐small‐cell lung cancer cells

Wed, 16 Mar 2016 00:00:00 +0100

The epidermal growth factor receptor (EGFR) tyrosine kinase signaling pathways regulate cellular activities. The EGFR tyrosine kinase inhibitors (EGFR‐TKIs) repress the EGFR pathway constitutively activated by somatic EGFR gene mutations and have drastically improved the prognosis of non‐small‐cell lung cancer (NSCLC) patients. However, some problems, including resistance, remain to be solved. Recently, combination therapy with EGFR‐TKIs and cytotoxic agents has been shown to improve the prognosis of NSCLC patients. To enhance the anticancer effects of EGFR‐TKIs, we examined the cross‐talk of the EGFR pathways with ataxia telangiectasia‐mutated (ATM) signaling pathways. ATM is a key protein kinase in the DNA damage response and is known to phosphorylate Akt, an EGFR downstrea...



The genetic homogeneity of CAPOS syndrome: four new cases with the c.2452 G>A (p.Glu818Lys) mutation in the ATP1A3 gene

Wed, 16 Mar 2016 00:00:00 +0100

The clinical syndrome of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) was first described twenty years ago, but it was only recently that whole exome sequencing unveiled the underlying mutation in the ATP1A3 gene. We here present four patients from the seventh and eighth family identified worldwide, provide a critical review of all cases published thus far, and speculate about the pathophysiological processes underlying the acute neurological manifestations. (Source: Pediatric Neurology)

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In vivo assessment of riluzole as a potential therapeutic drug for spinocerebellar ataxia type 3

Tue, 15 Mar 2016 00:00:00 +0100

This article is protected by copyright. All rights reserved. (Source: Journal of Neurochemistry)



The Protein Arginine Methylase 5 (PRMT5/SKB1) Gene Is Required for the Maintenance of Root Stem Cells in Response to DNA Damage

Tue, 15 Mar 2016 00:00:00 +0100

Publication date: Available online 14 March 2016 Source:Journal of Genetics and Genomics Author(s): Qiuling Li, Yan Zhao, Minghui Yue, Yongbiao Xue, Shilai Bao Plant root stem cells and their surrounding microenvironment, namely the stem cell niche, are hypersensitive to DNA damage. However, the molecular mechanisms that help maintain the genome stability of root stem cells remain elusive. Here we show that the root stem cells in the skb1 (Shk1 kinase binding protein 1) mutant underwent DNA damage-induced cell death, which was enhanced when combined with a lesion of the Ataxia-telangiectasia mutant (ATM) or the ATM/RAD3-related (ATR) gene, suggesting that the SKB1 play a synergistically effect with ATM and ATR in DNA damage pathway. We also provide evidence that SKB1 is required for...



MRI signs of multiple system atrophy preceding the clinical diagnosis: the case for an imaging-supported probable MSA diagnostic category

Tue, 15 Mar 2016 00:00:00 +0100

Multiple system atrophy (MSA) is a neurodegenerative disorder characterised by autonomic failure in the form of orthostatic hypotension, neurogenic bladder and impotence, in association with a variable combination of parkinsonism, cerebellar ataxia and pyramidal signs.1 MSA is divided into predominant parkinsonism (MSA-P) and cerebellar (MSA-C) forms. Current clinical diagnostic criteria for ‘probable MSA’ require prominent autonomic failure. However, it is widely recognised that these symptoms may develop long after motor features.2 In the case of MSA-P, early parkinsonism in the absence of significant autonomic failure may be impossible to differentiate from Parkinson's disease. Establishing a correct diagnosis early in the course of MSA has direct implications for prognosis ...



Voice Alterations in Patients With Spinocerebellar Ataxia Type 7 (SCA7): Clinical-Genetic Correlations

Tue, 15 Mar 2016 00:00:00 +0100

Spinocerebellar ataxia type 7 (SCA7) is an inherited neurodegenerative disease caused by the expansion of a cytosine-adenine-guanine triplet located in the coding region of the ATXN7 gene, which is characterized by cerebellar ataxia, pigmentary macular degeneration, and dysarthria. Although dysarthria is a common feature in various SCA, its clinical characterization has been barely approached. (Source: Journal of Voice)



Genetic Cause of Spinocerebellar Ataxia (SCA) Identified

Mon, 14 Mar 2016 15:32:00 +0100

Researchers identify new mutation responsible for Spinocerebellar Ataxia (SCA), a degenerative and ultimately fatal movement disorder (Source: Disabled World)

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Clinical presentation and outcome of riboflavin transporter deficiency: mini review after five years of experience

Mon, 14 Mar 2016 00:00:00 +0100

Abstract Introduction Riboflavin (vitamin B2) is absorbed in the small intestine by the human riboflavin transporters RFVT1 and RFVT3. A third riboflavin transporter (RFVT2) is expressed in the brain. In 2010 it was demonstrated that mutations in the riboflavin transporter genes SLC52A2 (coding for RFVT2) and SLC52A3 (coding for RFVT3) cause a neurodegenerative disorder formerly known as Brown-Vialetto-Van Laere (BVVL) syndrome, now renamed to riboflavin transporter deficiency. Five years after the diagnosis of the first patient we performed a review of the literature to study the presentation, treatment and outcome of patients with a molecularly confirmed diagnosis of a riboflavin transporter deficiency. Method A search...



Pearls & Oy-sters: Tacrolimus neurotoxicity presenting as an isolated brainstem lesion

Mon, 14 Mar 2016 00:00:00 +0100

A 52-year-old man with hepatitis C–induced cirrhosis underwent cadaveric liver transplant in July 2014. Postoperative immunosuppression included tacrolimus, mycophenolate mofetil, and prednisone. He presented 3 months later with 2 weeks of intermittent headaches, diplopia mostly with down gaze, and gait unsteadiness. He reported no constitutional symptoms. He was normotensive at 136/73 mm Hg. Pertinent findings on neurologic examination were sustained gaze-evoked direction-beating nystagmus in the horizontal plane, upper and lower extremity dysmetria bilaterally, gait ataxia, and normal deep tendon reflexes. Pinprick and vibratory loss in the right leg were attributed to prior trauma. (Source: Neurology)



Metabotropic glutamate receptor type 1 autoimmunity: Clinical features and treatment outcomes

Mon, 14 Mar 2016 00:00:00 +0100

Conclusions: mGluR1 autoimmunity represents a treatable form of cerebellar ataxia. Dysgeusia may be a diagnostic clue. Paraneoplastic, parainfectious, or idiopathic causes may occur. (Source: Neurology)



[Neuropsychological profile in opsoclonus-myoclonus-ataxia syndrome presenting as neuroblastic tumours].

Sat, 12 Mar 2016 16:46:06 +0100

CONCLUSIONS: Data emphasize the role of the cerebellum in complex cognitive processing in child population probably linked to neurodevelopmental deficits in this structure caused by deficiencies of the immune system. The results are interpreted in the framework of child neuropsychology and their interest in studying the brain-behavior relationships in the dynamic context of brain development. PMID: 26961423 [PubMed - in process] (Source: Revista de Neurologia)



Safety and Efficacy of Valproic Acid Treatment in SCA3/MJD Patients

Sat, 12 Mar 2016 00:00:00 +0100

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is one of 10 known polyglutamine (polyQ) diseases. In Drosophila and rat models of polyQ diseases, histone deacetylation (HDAC) inhibitors improved locomotor function and survival time by increasing histone acetylation levels and modulating gene expression. Valproic acid (VPA) is a pan-HDAC inhibitor used clinically to treat bipolar and seizure disorders. We evaluated the clinical safety and efficacy of VPA treatment for SCA3/MJD patients. (Source: Parkinsonism and Related Disorders)

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MedlinePlus: Ataxia telangiectasia

Fri, 11 Mar 2016 05:17:52 +0100

(Source: NLM General Announcements)



Genetic and pharmacological evidence implicates cathepsins in Niemann-Pick C cerebellar degeneration

Fri, 11 Mar 2016 00:00:00 +0100

Niemann-Pick C1 (NPC) disease, an autosomal recessive lipid trafficking disorder caused by loss-of-function mutations in the NPC1 gene, is characterized by progressive neurodegeneration resulting in cognitive impairment, ataxia and early death. Little is known about the cellular pathways leading to neuron loss. Here, we studied the effects of diminishing expression of cystatin B, an endogenous inhibitor of cathepsins B, H and L, on the development of NPC neuropathology. We show that decreased expression of cystatin B in patient fibroblasts enhances cathepsin activity. Deletion of the encoding Cstb gene in Npc1-deficient mice resulted in striking deleterious effects, particularly within the cerebellum where diffuse loss of Purkinje cells was observed in young mice. This severe pathology occ...



Frequent globular neuronal cytoplasmic inclusions in the medial temporal region as a possible characteristic feature in multiple system atrophy with dementia

Fri, 11 Mar 2016 00:00:00 +0100

Multiple system atrophy (MSA) is an adult‐onset neurodegenerative disease, which is characterized clinically by parkinsonism, cerebellar ataxia and/or autonomic dysfunction, and pathologically by alpha‐synuclein‐related multisystem neurodegeneration, so‐called alpha‐synucleinopathy, which particularly involves the striatonigral and olivopontocerebellar systems, with glial cytoplasmic inclusions and neuronal cytoplasmic/nuclear inclusions (NCIs/NNIs). In the recent consensus criteria for the diagnosis of MSA, dementia is described as one of the features not supporting a diagnosis of MSA. However, MSA with dementia has been reported, although the location of the lesion responsible for the dementia remains unclear. In the present study, we aimed to investigate where this lesion may ...



Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients

Fri, 11 Mar 2016 00:00:00 +0100

ObjectiveHereditary spastic paraplegias (HSPs) are genetically driven disorders with the hallmark of progressive spastic gait disturbance. To investigate the phenotypic spectrum, prognostic factors, and genotype‐specific differences, we analyzed baseline data from a continuous, prospective cohort. MethodsWe recruited 608 HSP cases from 519 families of mostly German origin. Clinical severity was assessed by the Spastic Paraplegia Rating Scale. Complicating symptoms were recorded by a standardized inventory. ResultsFamily history indicated dominant (43%), recessive (10%), and simplex (47%) disease. We observed a significant male predominance, particularly in simplex cases without a genetic diagnosis. Disease severity increased with disease duration. Earlier disease onset was associated wit...



Hot topic: PNKP mutations cause ataxia with oculomotor apraxia type 4

Fri, 11 Mar 2016 00:00:00 +0100

(Source: Movement Disorders)

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Does modulation of the endocannabinoid system have potential therapeutic utility in cerebellar ataxia?

Fri, 11 Mar 2016 00:00:00 +0100

This article is protected by copyright. All rights reserved. PMID: 26970080 [PubMed - as supplied by publisher] (Source: The Journal of Physiology)



Testing for cerebellar ataxia in Hungarian vizslas

Thu, 10 Mar 2016 00:00:00 +0100

The Animal Health Trust (AHT) is offering a new DNA test for cerebellar ataxia in smooth-haired Hungarian vizslas. It says that its researchers, together with the neurology team at the Royal Veterinary College, have identified the genetic mutation responsible for the condition, allowing a DNA test to be developed. The trust explains that the neurological condition is rare and has been identified in a small number of smooth-haired Hungarian vizslas. It is a progressive condition affecting gait and coordination from about two to three months of age. There is no treatment and affected dogs are euthanased on welfare grounds in the advanced stages of the condition. Because the condition is rare, the trust is not expecting to find affected dogs through DNA testing, but says that it is crucial to...



Targeting the prodromal stage of spinocerebellar ataxia type 17 mice: G-CSF in the prevention of motor deficits via upregulating chaperone and autophagy levels.

Thu, 10 Mar 2016 00:00:00 +0100

The objective of this study was to assess the effects and molecular mechanisms of granulocyte-colony stimulating factor (G-CSF) therapy during the pre-symptomatic stage in SCA17 mice. Treatment with G-CSF at the pre-symptomatic stage improved the motor coordination of SCA17 mice and reduced the cell loss, insoluble mutant TBP protein, and vacuole formation in the Purkinje neurons of these mice. The neuroprotective effects of G-CSF may be produced by increases in Hsp70, Beclin-1, LC3-II and the p-ERK survival pathway. Upregulation of chaperone and autophagy levels further enhances the clearance of mutant protein aggregation, slowing the progression of pathology in SCA17 mice. Therefore, we showed that the early intervention of G-CSF has a neuroprotective effect, delaying the progression of ...



Generation of spinocerebellar ataxia type 3 patient-derived induced pluripotent stem cell line SCA3.A11

Wed, 09 Mar 2016 00:00:00 +0100

Publication date: Available online 9 March 2016 Source:Stem Cell Research Author(s): Susanne K. Hansen, Helena Borland, Lis F. Hasholt, Zeynep Tümer, Jørgen E. Nielsen, Mikkel A. Rasmussen, Troels T. Nielsen, Tina C. Stummann, Karina Fog, Poul Hyttel Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited neurodegenerative disease caused by a CAG-repeat expanding mutation in ATXN3. We generated induced pluripotent stem cells (iPSCs) from a SCA3 patient by electroporation of dermal fibroblasts with episomal plasmids encoding L-MYC, LIN28, SOX2, KLF4, OCT4 and short hairpin RNA targeting P53. The resulting iPSCs had normal karyotype, were free of genomically integrated episomal plasmids, expressed pluripotency markers, could differentiate into the three germ layers in vi...



Postural Instability in Prodromal Spinocerebellar Ataxia Type 2: Insights into Cerebellar Involvement Before Onset of Permanent Ataxia

Wed, 09 Mar 2016 00:00:00 +0100

(Source: The Cerebellum)

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Postural Instability in Prodromal Spinocerebellar Ataxia Type 2: Insights into Cerebellar Involvement Before Onset of Permanent Ataxia.

Wed, 09 Mar 2016 00:00:00 +0100

Authors: Velázquez-Pérez L, Sánchez-Cruz G, Rodríguez-Labrada R, Velázquez-Manresa M, Hechavarría-Pupo R, Almaguer-Mederos LE PMID: 26956609 [PubMed - as supplied by publisher] (Source: Cerebellum)



The role of glial-specific Kir4.1 in normal and pathological states of the CNS

Wed, 09 Mar 2016 00:00:00 +0100

Abstract Kir4.1 is an inwardly rectifying K+ channel expressed exclusively in glial cells in the central nervous system. In glia, Kir4.1 is implicated in several functions including extracellular K+ homeostasis, maintenance of astrocyte resting membrane potential, cell volume regulation, and facilitation of glutamate uptake. Knockout of Kir4.1 in rodent models leads to severe neurological deficits, including ataxia, seizures, sensorineural deafness, and early postnatal death. Accumulating evidence indicates that Kir4.1 plays an integral role in the central nervous system, prompting many laboratories to study the potential role that Kir4.1 plays in human disease. In this article, we review the growing evidence implicating Kir4.1 in a wide array of neurological disease. Recent liter...



Teaching Video NeuroImages: Vertical supranuclear ophthalmoparesis: A diagnostic pearl for Niemann-Pick C

Mon, 07 Mar 2016 00:00:00 +0100

A 30-year-old man presented with 10 years of progressive cognitive decline (poor academic performance followed by forgetfulness and calculation and visuospatial difficulties), 5 years of gait and limb ataxia and dysarthria, and 3 years of dysphagia. His 2 elder siblings had similar symptoms and died in their 20s. Examination revealed splenomegaly, global cognitive impairment, brisk gag reflex, pancerebellar ataxia, bipyramidal signs, and vertical saccade paresis (video on the Neurology® Web site at Neurology.org). Vertical pursuit was preserved. Bone marrow aspirate and trephine biopsy revealed non-Gaucher-type storage foam cells (figure). Considering the diagnosis of Niemann-Pick C, he was treated symptomatically. Vertical supranuclear ophthalmoparesis is a red flag suggestive of Niem...



Holmes tremor: Clinical description, lesion localization, and treatment in a series of 29 cases

Mon, 07 Mar 2016 00:00:00 +0100

Conclusions: The most common causes of HT in our series were vascular lesions. The most common lesion topography was mesencephalic, thalamic, or both. Treatment with levodopa and thalamic stereotactic lesional surgery seems to be effective. (Source: Neurology)



The value of preoperative embolization in large and giant solid cerebellar hemangioblastomas.

Sat, 05 Mar 2016 21:56:01 +0100

CONCLUSION: Preoperative embolization improves safety and efficacy of the microsurgical excision of such tightly located very vascular tumors. Embolization changes the concept of this lesion surgery into piecemeal removal rather than a total mass extraction technique. Liquid agents are superior to particles in obliteration of such lesions. PMID: 26934897 [PubMed - as supplied by publisher] (Source: Interventional Neuroradiology)

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Prevalence of Autoantibodies and the Efficacy of Immunotherapy for Autoimmune Cerebellar Ataxia.

Sat, 05 Mar 2016 12:00:02 +0100

Conclusion Some patients with cerebellar ataxia have autoimmune conditions and diagnosing autoimmune cerebellar ataxia is therefore an important component in the care of patients with this disease entity. PMID: 26935362 [PubMed - in process] (Source: Internal Medicine)



Severe seizures in pigs naturally infected with Taenia solium in Tanzania

Fri, 04 Mar 2016 00:00:00 +0100

Publication date: Available online 3 March 2016 Source:Veterinary Parasitology Author(s): Chiara Trevisan, Ernatus M Mkupasi, Helena A Ngowi, Björn Forkman, Maria V Johansen Neurocysticercosis (NCC) caused by Taenia solium is a serious neurological disease. In humans neurological symptoms have been thoroughly studied and documented, however, there is limited information on clinical signs in pigs infected with T. solium cysticerci. Among the scientific community, it is in fact believed that pigs with NCC rarely show neurological signs. The aim of this study was to describe clinical manifestations associated with NCC in pigs and correlate the manifestations to the number and distribution of cysticerci in brains of naturally infected pigs in Tanzania. Sixteen infected and 15 non-infec...



Cerebellar Transcriptome Profiles of ATXN1 Transgenic Mice Reveal SCA1 Disease Progression and Protection Pathways

Fri, 04 Mar 2016 00:00:00 +0100

Publication date: Available online 3 March 2016 Source:Neuron Author(s): Melissa Ingram, Emily A.L. Wozniak, Lisa Duvick, Rendong Yang, Paul Bergmann, Robert Carson, Brennon O’Callaghan, Huda Y. Zoghbi, Christine Henzler, Harry T. Orr SCA1, a fatal neurodegenerative disorder, is caused by a CAG expansion encoding a polyglutamine stretch in the protein ATXN1. We used RNA sequencing to profile cerebellar gene expression in Pcp2-ATXN1[82Q] mice with ataxia and progressive pathology and Pcp2-ATXN1[30Q]D776 animals having ataxia in absence of Purkinje cell progressive pathology. Weighted Gene Coexpression Network Analysis of the cerebellar expression data revealed two gene networks that significantly correlated with disease and have an expression profile correlating with diseas...



Neuroimaging Findings and Repeat Neuroimaging Value in Pediatric Chronic Ataxia.

Fri, 04 Mar 2016 00:00:00 +0100

CONCLUSIONS: Normal or abnormal neuroimaging findings and repeat neuroimaging are very valuable in the diagnosis and management of disorders associated with pediatric chronic ataxia. PMID: 26940752 [PubMed - as supplied by publisher] (Source: The Canadian Journal of Neurological Sciences)



Significance of ATM Gene Polymorphisms in Chronic Myeloid Leukemia - a Case Control Study from India.

Thu, 03 Mar 2016 10:52:05 +0100

CONCLUSIONS: This study provides the first evidence of association of functional ATM gene polymorphisms with the increased risk of CML development as well as progression. PMID: 26925685 [PubMed - in process] (Source: Asian Pacific Journal of Cancer Prevention)

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Mutations Might Not Be Involved in Epilepsy

Thu, 03 Mar 2016 00:00:00 +0100

To the Editor: Previously in The American Journal of Human Genetics, Tao et al.1 performed a candidate-gene analysis and reported that heterozygous mutations in PRICKLE2 (MIM: 608501) are responsible for causing seizures in several individuals with epilepsy (MIM: 613832). Here, by exome-wide mutation screening, we found that compound-heterozygous mutations in a well-established epilepsy- and ataxia-associated gene are more likely to be the causal factor in one of the individuals reported. Our results thus suggest that PRICKLE2 mutations should presently not be considered as causing epilepsy. (Source: The American Journal of Human Genetics)



Mapping the Interaction Network of Key Proteins Involved in Histone mRNA Generation: A Hydrogen/Deuterium Exchange Study

Thu, 03 Mar 2016 00:00:00 +0100

Publication date: Available online 6 February 2016 Source:Journal of Molecular Biology Author(s): Aleksandra Skrajna, Xiao-cui Yang, Krzysztof Tarnowski, Kinga Fituch, William F. Marzluff, Zbigniew Dominski, Michał Dadlez Histone pre-mRNAs are cleaved at the 3′ end by a complex that contains U7 snRNP, the FLICE-associated huge protein (FLASH) and histone pre-mRNA cleavage complex (HCC) consisting of several polyadenylation factors. Within the complex, the N terminus of FLASH interacts with the N terminus of the U7 snRNP protein Lsm11, and together they recruit the HCC. FLASH through its distant C terminus independently interacts with the C-terminal SANT/Myb-like domain of nuclear protein, ataxia-telangiectasia locus (NPAT), a transcriptional co-activator required for expression...



MHC class I chain-related molecule A and B expression is upregulated by cisplatin and associated with good prognosis in patients with non-small cell lung cancer

Thu, 03 Mar 2016 00:00:00 +0100

Abstract MHC class I chain-related molecule A and B (MICA/B) are NK group 2 member D (NKG2D) ligands, which are broadly expressed in transformed cells. Both DNA damage-induced ataxia-telangiectasia-mutated (ATM)- and ATM and Rad3-related protein kinases (ATM–ATR) signaling and oncogene-induced PI3K–AKT signaling regulate the expression of NKG2D ligands, which promote NK cell-mediated cytotoxicity via NKG2D–NKG2D ligand interactions. NKG2D ligand overexpression was recently reported to be correlated with good prognosis in several types of cancer. However, the prognostic significance of NKG2D ligands in non-small cell lung cancer (NSCLC) remains unclear. Here, MICA/B expression was evaluated based on immunohistochemistry of 91 NSCLC samples from patients following radical sur...



PRICKLE2 Mutations Might Not Be Involved in Epilepsy

Thu, 03 Mar 2016 00:00:00 +0100

To the Editor: Previously in The American Journal of Human Genetics, Tao et al.1 performed a candidate-gene analysis and reported that heterozygous mutations in PRICKLE2 (MIM: 608501) are responsible for causing seizures in several individuals with epilepsy (MIM: 613832). Here, by exome-wide mutation screening, we found that compound-heterozygous mutations in a well-established epilepsy- and ataxia-associated gene are more likely to be the causal factor in one of the individuals reported. Our results thus suggest that PRICKLE2 mutations should presently not be considered as causing epilepsy. (Source: The American Journal of Human Genetics)



Biodex Fall Risk Assessment in the Elderly With Ataxia: A New Age-Dependent Derived Index in Rehabilitation: An Observational Study

Tue, 01 Mar 2016 06:00:00 +0100

Abstract: The aim of this study was to evaluate if the Biodex Fall Risk Assessment could provide an age-adjusted index useful for classifying patients at “risk of fall.” This was a cohort study conducted on 61 chronic patients, in stable conditions, having a history of ataxia, difficulty in walking or loss of balance, and aged >64 years. These patients were coming from home to our Institute undergoing a period of in-hospital standard rehabilitation. Assessment of clinical parameters was performed at entry. Functional scales (Functional Independence Measure [FIM] for motor and cognitive function, Barthel G, Tinetti POMA), and the Biodex Fall Risk Index (FRI) were performed at entry and discharge. The Normalized FRI, obtained adjusting FRI to the reported maximum predictive FRI for the ...

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A cause for childhood ataxia

Tue, 01 Mar 2016 00:00:00 +0100

(Source: eLife)



GIFT-1, a phase IIa clinical trial to test the safety and efficacy of IFNγ administration in FRDA patients

Tue, 01 Mar 2016 00:00:00 +0100

This study is expected to conclusively address the clinical efficacy of IFNγ therapy in patients with Friedreich’s ataxia. (Source: Neurological Sciences)



Reversible Choreoathetosis Due to Lithium Toxicity in an Elderly Patient

Tue, 01 Mar 2016 00:00:00 +0100

Introduction: Lithium remains one of the recommended treatments for bipolar disorder and mania in older patients. Commonly observed Lithium toxicity symptoms in the older adults are inability to concentrate, fatigue, lethargy, tremors and cogwheel rigidity. And, at toxic Lithium levels, more complex neurological side-effects such as ataxia, dysarthria, confusion and seizures have been reported. Out of these, choreoathetosis is one of the rarest neurological symptoms of Lithium toxicity. There are thirteen such case reports in literature with neurotoxic choreoathetoid effects which were directly related to Lithium use and not attributable to other concomitant medications. (Source: The American Journal of Geriatric Psychiatry)



Extraintestinal manifestations of celiac disease: 33‐mer gliadin binding to glutamate receptor GRINA as a new explanation

Tue, 01 Mar 2016 00:00:00 +0100

We propose a biochemical mechanism for celiac disease and non‐celiac gluten sensitivity that may rationalize many of the extradigestive disorders not explained by the current immunogenetic model. Our hypothesis is based on the homology between the 33‐mer gliadin peptide and a component of the NMDA glutamate receptor ion channel – the human GRINA protein – using BLASTP software. Based on this homology the 33‐mer may act as a natural antagonist interfering with the normal interactions of GRINA and its partners. The theory is supported by numerous independent data from the literature, and provides a mechanistic link with otherwise unrelated disorders, such as cleft lip and palate, thyroid dysfunction, restless legs syndrome, depression, ataxia, hearing loss, fibromyalgia, dermatitis...



Teaching Video NeuroImages: Alternating skew deviation with abducting hypertropia following superior colliculus infarction

Mon, 29 Feb 2016 00:00:00 +0100

A 63-year-old patient was admitted with acute ataxia and binocular oblique diplopia. Neuro-ophthalmologic examination revealed abducting hypertropia on lateral gaze, better seen during upgaze, mimicking bilateral inferior oblique palsy (video, figure). There was no ocular cyclotorsion. Brain MRI revealed focal ischemic lesions in the right cerebellar hemisphere and left superior colliculus (figure). The diagnosis of alternating abducting hypertropic skew deviation was made. This rare type of skew deviation is related to central otolithic dysfunction. Similar cases have been described with cerebellar, pretectal, or cervico-medullary junction lesions.1,2 Orthoptic management can help and patients can slowly improve over months. (Source: Neurology)

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Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy

Mon, 29 Feb 2016 00:00:00 +0100

Conclusion: Anti-NF155 IgG4 antibodies were associated with a subgroup of patients with CIDP showing a younger age at onset, ataxia, tremor, CNS demyelination, and a poor response to IV immunoglobulin. The autoantibodies may serve as a biomarker to improve patients' diagnosis and guide treatments. (Source: Neurology)



A human quadrupedal gait following poliomyelitis: From the Dercum-Muybridge collaboration (1885)

Mon, 29 Feb 2016 00:00:00 +0100

Conclusion: Despite Dercum's assertion to the contrary, the limb placement pattern of the boy with a pathologic quadrupedal gait after poliomyelitis was not the typical gait of a primate quadruped, but rather was the typical gait sequence for normal human developmental and volitional quadrupedal gaits. (Source: Neurology)



CSTB null mutation associated with microcephaly, early developmental delay, and severe dyskinesia

Mon, 29 Feb 2016 00:00:00 +0100

The CSTB gene encodes for cystatin B, an inhibitor of lysosomal cysteine protease (cathepsins B, H, L, and S).1 CSTB mutations have been associated with type 1 progressive myoclonic epilepsy, also known as Unverricht-Lundborg (ULD) disease, or Baltic myoclonus.2,3 A total of 90% of all disease alleles consists of an expansion of at least 30 times of an unstable 12-nucleotide stretch (dodecamer 5'-CCCCGCCCCGCG-3') in the CSTB promoter region. Homozygosity for this expansion is considered the founder mutation in the Finnish population. Few other mutations have been described, among these the p.Arg68*, but until now only as compound heterozygous with the dodecamer expansion.4–6 Expression of the p.Arg68* mutation in vitro indicates that the truncated protein is rapidly degraded, confirm...



Miliary cerebral calcifications: A rare presentation of breast cancer metastasis

Mon, 29 Feb 2016 00:00:00 +0100

A 38-year-old woman with a history of breast cancer presented with dysarthria and limb ataxia. She reported a traveling history with destinations in Asia over the past 10 years. CT showed small calcified lesions (figure 1). MRI showed more small ring-like contrast-enhancing intraparenchymal lesions that followed the course of sulci and folia (figure 2). Differential diagnosis included metastasis and neurocysticercosis. Examination of CSF showed no evidence of malignancy or infection. Definitive diagnosis after brain biopsy confirmed metastasis of breast cancer.1 (Source: Neurology)



A case of cystinuria presenting with cerebellar ataxia and dementia.

Mon, 29 Feb 2016 00:00:00 +0100

We report a patient with cystinuria with a heterozygous P482L mutation in the SLC7A9 gene, presenting with atrophy in the cerebellum, brainstem and cerebrum and with no urinary stones. Cystine, an amino acid comprising two cysteine molecules, is transported into cells via a cystine transporter. It is essential for producing hydrogen sulfate and the cellular antioxidant glutathione: these exert neuroprotection in astrocytes and cerebellar Purkinje cells. Although cystinuria is a metabolic disorder associated with renal dysfunction, we suspect that a trafficking defect of transporter rBAT-BAT1 in brain might cause neuronal degeneration, leading to cerebellar and cerebral atrophy. PMID: 26929440 [PubMed - as supplied by publisher] (Source: Practical Neurology)

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Ataxin-1 regulates proliferation of hippocampal neural precursors

Sun, 28 Feb 2016 00:00:00 +0100

In this study, we demonstrate a novel role of ATXN1 in the hippocampus as a regulator of adult neurogenesis. Adult hippocampal neurogenesis is the process of generating new hippocampal neurons and is linked to cognition and mood. We found that loss of ATXN1 causes a decrease in hippocampal neurogenesis in ATXN1 null (Atxn1−/− ) mice. This decrease was caused by reduced proliferation of neural precursors in the hippocampus of Atxn1−/− mice, and persisted even when Atxn1−/− hippocampal neural precursors were removed from their natural environment and grown in vitro, suggesting that ATXN1 affects proliferation in a cell-autonomous manner. Moreover, expression of ATXN1 with a pathological polyglutamine (polyQ) expansion in wild-type neural precursor cells inhibited their proliferat...



[Spinocerebellar ataxia-27: description of the clinical phenotype of two twin sisters with a deletion in the FGF14 gene].

Sat, 27 Feb 2016 11:40:20 +0100

Authors: Blanco-Barca O, Amado-Puentes A, Reparaz A, Melcon C, Torreira C PMID: 26916329 [PubMed - in process] (Source: Revista de Neurologia)



Aberrant cerebellar development in mice lacking dual oxidase maturation factors.

Sat, 27 Feb 2016 03:42:02 +0100

CONCLUSIONS: Our results indicate that the anatomical catch-up growth of the cerebellum did not normalize its function because of the disturbance of neuronal circuits by the combined effect of hypothyroidism and functional disruption of Duox/Duoxa complex. PMID: 26914863 [PubMed - as supplied by publisher] (Source: Thyroid : official journal of the American Thyroid Association)



The nucleo-shuttling of the ATM protein as a basis for a novel theory of radiation response: resolution of the linear-quadratic model.

Sat, 27 Feb 2016 01:33:06 +0100

Conclusions Our model provides a very general picture of human radiosensitivity, independently of the dose, the cell type and the genetic status. PMID: 26907628 [PubMed - in process] (Source: International Journal of Radiation Biology)



Mutations in GALC cause late-onset Krabbe disease with predominant cerebellar ataxia

Fri, 26 Feb 2016 00:00:00 +0100

Abstract Mutations in GALC cause Krabbe disease. This autosomal recessive leukodystrophy generally presents in early infancy as a severe disorder, but sometimes manifests as a milder adult-onset disease with spastic paraplegia as the main symptom. We recruited a family with five affected individuals presenting with adult-onset predominant cerebellar ataxia with mild spasticity. Whole exome sequencing (WES) revealed one novel and one previously reported compound heterozygous variants in GALC. Magnetic resonance imaging (MRI) confirmed the presence of typical Krabbe features. Our findings expand the phenotypic spectrum of adult-onset Krabbe disease and demonstrate the usefulness of combining WES and pattern-specific MRI for the diagnosis of neurodegenerative diseases. (Source: Neuro...

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Movement disorders: Targeted RNA or BDNF gene transfer protects against frataxin deficiency

Fri, 26 Feb 2016 00:00:00 +0100

Nature Reviews Neurology 12, 125 (2016). doi:10.1038/nrneurol.2016.19 Author: Ian Fyfe Friedreich ataxia is a genetic disorder caused by a GAA expansion in intron 1 of the FXN gene, which encodes frataxin. In two recently published studies, the pathological consequences of this FXN mutation have been successfully counteracted in in vitro and in (Source: Nature Reviews Neurology)



Ataxia Telangiectasia Masquerading as Hyper IgM Syndrome

Thu, 25 Feb 2016 19:34:54 +0100

(Source: Indian Journal of Pediatrics)



Clinical Spectrum and Genetic Variability in Bulgarian Patients with Niemann-Pick Disease Type C

Thu, 25 Feb 2016 17:08:22 +0100

Conclusions: This Bulgarian NP-C cohort showed wide variability in terms of NPC1 mutations and predominant forms of neurological involvement. Diagnosing NP-C is challenging, and it was often delayed in this cohort due to the heterogeneity of patients' clinical signs and symptoms.Eur Neurol 2016;75:113-123 (Source: European Neurology)






Reply: Autosomal recessive cerebellar ataxia caused by a homozygous mutation in PMPCA

Thu, 25 Feb 2016 00:00:00 +0100

(Source: Brain)

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The Differential Diagnosis and Treatment of Atypical Parkinsonism.

Wed, 24 Feb 2016 22:11:02 +0100

CONCLUSION: Causal treatments for neurodegenerative diseases are now being developed and tested, and thus a molecular diagnosis is desirable. This will require the cooperation of primary care physicians with specialized centers. PMID: 26900156 [PubMed - in process] (Source: Deutsches Arzteblatt International)



Proteostasis and RNA Binding Proteins in Synaptic Plasticity and in the Pathogenesis of Neuropsychiatric Disorders.

Wed, 24 Feb 2016 11:11:02 +0100

Authors: Klein ME, Monday H, Jordan BA Abstract Decades of research have demonstrated that rapid alterations in protein abundance are required for synaptic plasticity, a cellular correlate for learning and memory. Control of protein abundance, known as proteostasis, is achieved across a complex neuronal morphology that includes a tortuous axon as well as an extensive dendritic arbor supporting thousands of individual synaptic compartments. To regulate the spatiotemporal synthesis of proteins, neurons must efficiently coordinate the transport and metabolism of mRNAs. Among multiple levels of regulation, transacting RNA binding proteins (RBPs) control proteostasis by binding to mRNAs and mediating their transport and translation in response to synaptic activity. In addition to synthe...



Double Disassociation of Anosognosia for Alexia and Simultanagnosia but Quantitative Awareness of Optic Ataxia

Wed, 24 Feb 2016 08:19:34 +0100

ABSTRACT: A 66-yr-old man with a history of atrial fibrillation and a pacemaker developed sudden onset confusion, disorientation, and visual disturbance without motor weakness. Clinically, significant deficits were found in reading (alexia) and simultaneous multiobject perception (simultanagnosia), both of which the patient denied limitation in, and in vision—right hemianopsia—which he readily acknowledged. Visual acuity in the left visual field was normal. The patient also demonstrated a symptom of optic ataxia—a lack of coordination between visual inputs and hand movements—a deficit he also acknowledged. Work-up with computed topography revealed a left posterior cerebral artery infarct affecting the occipital lobe and extending to involve the parietal lobe and the splenium of the...



Paediatric neurological melioidosis: a rehabilitation case report.

Tue, 23 Feb 2016 23:53:02 +0100

Authors: White ME, Hunt J, Connell C, Langdon K Abstract CONTEXT: Melioidosis is a rare condition, endemic to northern Australia and south-east Asia, caused by an infection from the bacteria Burkholderia pseudomallei. The largest epidemiological review to date describes 540 cases of melioidosis seen at Darwin Hospital, in northern Australia, over a 20-year period. Of these, 14 (less than 3%) presented with neurological manifestation, with three deaths. Reports of paediatric cases of melioidosis are rarer. In a review of paediatric cases in northern Australia only eight cases were identified in 10 years. Three of these patients presented with neurological melioidosis, of whom two died in hospital. ISSUES: Whilst the literature refers to prolonged periods of ho...



“Mitochondrial neuropathies”: a survey from the large cohort of the Italian Network

Tue, 23 Feb 2016 00:00:00 +0100

• Clinical data analyses of 1200 patients with mitochondrial disorders showed that the minimum prevalence of a peripheral neuropathy is 12.4%• Mitochondrial neuropathic patients have an increased prevalence of ataxia, hearing loss, muscle weakness and muscle wasting• Mitochondrial DNA single deletions and LHON mutations are rarely associated with neuropathy• POLG mutations may cause a potentially painful, axonal/mixed, mainly sensory polyneuropathy• TYMP and SURF1 mutations lead to a demyelinating sensory-motor polyneuropathy (Source: Neuromuscular Disorders)

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Foveal hypoplasia in autosomal recessive spastic ataxia of Charlevoix-Saguenay

Tue, 23 Feb 2016 00:00:00 +0100

Publication date: February 2016 Source:Journal of American Association for Pediatric Ophthalmology and Strabismus, Volume 20, Issue 1 Author(s): Christopher T. Shah, Tyson S. Ward, Julie A. Matsumoto, Yevgeniy Shildkrot A 14-year-old boy presented with a presumed diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The neurological examination, nerve conduction study, and brain imaging results were all consistent with the diagnosis. The ophthalmologic examination was notable for a prominent myelinated nerve fiber layer extending from the disk along the major temporal arcades in both eyes. Loss of foveal depression was noted clinically and on spectral domain optical coherence tomography. This case highlights a novel finding that may aid in the diagnosis of ...



Bilateral maculopathy in a patient with ataxia telangiectasia

Tue, 23 Feb 2016 00:00:00 +0100

We report a case of toxoplasmosis with bilateral maculopathy in a 7-year-old boy diagnosed with ataxia telangiectasia (AT) at age 6. AT manifests as ataxia, apraxia, telangiectasia, and dysarthria. Common ophthalmologic findings in AT include fine conjunctival telangiectasia. Patients also suffer from recurrent sinopulmonary infections; however, serious opportunistic infection is rarely diagnosed. At 8 years of age he developed disseminated Toxoplasma gondii (toxoplasmosis) infection and meningoencephalitis. This ophthalmologic finding and the subsequent toxoplasmosis meningoencephalitis have not been previously reported in AT. (Source: Journal of American Association for Pediatric Ophthalmology and Strabismus)



Friedreich ataxia is not only a GAA repeats expansion disorder: implications for molecular testing and counselling.

Tue, 23 Feb 2016 00:00:00 +0100

Authors: Hoffman-Zacharska D, Mazurczak T, Zajkowski T, Tataj R, Górka-Skoczylas P, Połatyńska K, Kępczyński Ł, Stasiołek M, Bal J Abstract Friedreich ataxia (FRDA) is the most common hereditary ataxia. It is an autosomal recessive disorder caused by mutations of the FXN gene, mainly the biallelic expansion of the (GAA)n repeats in its first intron. Heterozygous expansion/point mutations or deletions are rare; no patients with two point mutations or a point mutation/deletion have been described, suggesting that loss of the FXN gene product, frataxin, is lethal. This is why routine FRDA molecular diagnostics is focused on (GAA)n expansion analysis. Additional tests are considered only in cases of heterozygous expansion carriers and an atypical clinical picture. Analyses of th...



Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools and Remodel One-Carbon Metabolism.

Tue, 23 Feb 2016 00:00:00 +0100

We report that mtDNA replication disorders caused by TWINKLE mutations-mitochondrial myopathy (MM) and infantile onset spinocerebellar ataxia (IOSCA)-remodel cellular dNTP pools in mice. MM muscle shows tissue-specific induction of the mitochondrial folate cycle, purine metabolism, and imbalanced and increased dNTP pools, consistent with progressive mtDNA mutagenesis. IOSCA-TWINKLE is predicted to hydrolyze dNTPs, consistent with low dNTP pools and mtDNA depletion in the disease. MM muscle also modifies the cytoplasmic one-carbon cycle, transsulfuration, and methylation, as well as increases glucose uptake and its utilization for de novo serine and glutathione biosynthesis. Our evidence indicates that the mitochondrial replication machinery communicates with cytoplasmic dNTP pools and that...



The role of the clinical biochemist in detection of zinc-induced copper deficiency

Mon, 22 Feb 2016 00:00:00 +0100

A middle-aged woman with neutropenia and ataxia was found to have raised plasma zinc and profoundly low plasma copper concentrations. When found that she had been prescribed 135 mg zinc/day for seven years, a diagnosis of zinc-induced copper deficiency was made. After the zinc prescription was stopped, her copper and zinc concentrations and neutropenia normalized but she only had partial improvement in neurological status. The diagnosis of zinc-induced copper deficiency can be facilitated by the laboratory through measurement of plasma zinc concentration in patients with a low plasma copper concentration. (Source: Annals of Clinical Biochemistry)

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Acute bulbar palsy as a variant of Guillain-Barre syndrome

Mon, 22 Feb 2016 00:00:00 +0100

Conclusions: We propose that ABP-plus syndrome without neck or limb weakness is a variant of GBS that is distinct from the MFS and PCB variants. The presence of IgG anti-GT1a antibodies can explain the relationships between the distinct clinical characteristics and the underlying pathomechanisms. (Source: Neurology)



Combined Cerebellar Proton MR Spectroscopy and DWI Study of Patients with Friedreich’s Ataxia

Sat, 20 Feb 2016 00:00:00 +0100

Abstract Friedreich’s ataxia (FRDA) is the commonest autosomal recessive ataxia, caused by GAA triplet expansion in the frataxin gene. Neuropathological studies in FRDA demonstrate that besides the primary neurodegeneration of the dorsal root ganglia, there is a progressive atrophy of the cerebellar dentate nucleus. Diffusion-weighted imaging (DWI) detected microstructural alterations in the cerebellum of FRDA patients. To investigate the biochemical basis of these alterations, we used both DWI and proton MR spectroscopy (1H-MRS) to study the same cerebellar volume of interest (VOI) including the dentate nucleus. DWI and 1H-MRS study of the left cerebellar hemisphere was performed in 28 genetically proven FRDA patients and 35 healthy controls. In FRDA mean diffusivity (MD) value...



Case report: Superficial siderosis after brachial plexus avulsion

Sat, 20 Feb 2016 00:00:00 +0100

Superficial siderosis is a slow but progressive neurodegenerative disease caused by a chronic bleed in the subarachnoid space, resulting in hemosiderin deposition alongside the central nervous system [1]. Bilateral sensorineural hearing loss, ataxia and pyramidal signs are the most common symptoms, the diagnosis is confirmed by MRI showing hemosiderin deposition as a dark hypointense layer on T2 and gradient-echo sequences. (Source: Clinical Neurology and Neurosurgery)



Combined Cerebellar Proton MR Spectroscopy and DWI Study of Patients with Friedreich's Ataxia.

Sat, 20 Feb 2016 00:00:00 +0100

Authors: Gramegna LL, Tonon C, Manners DN, Pini A, Rinaldi R, Zanigni S, Bianchini C, Evangelisti S, Fortuna F, Carelli V, Testa C, Lodi R Abstract Friedreich's ataxia (FRDA) is the commonest autosomal recessive ataxia, caused by GAA triplet expansion in the frataxin gene. Neuropathological studies in FRDA demonstrate that besides the primary neurodegeneration of the dorsal root ganglia, there is a progressive atrophy of the cerebellar dentate nucleus. Diffusion-weighted imaging (DWI) detected microstructural alterations in the cerebellum of FRDA patients. To investigate the biochemical basis of these alterations, we used both DWI and proton MR spectroscopy ((1)H-MRS) to study the same cerebellar volume of interest (VOI) including the dentate nucleus. DWI and (1)H-MRS study of the ...



Cognitive Deficits Correlate with White Matter Deterioration in Spinocerebellar Ataxia Type 2

Fri, 19 Feb 2016 12:37:57 +0100

Brief ReportCarlos R. Hernandez-Castillo, Israel Vaca-Palomares, Víctor Galvez, Aurelio Campos-Romo, Rosalinda Diaz, Juan Fernandez-Ruiz Journal of the International Neuropsychological Society,FirstView Article(s), 6 pagesAbstract (Source: Journal of the International Neuropsychological Society)

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Small Molecules Targeting Ataxia Telangiectasia and Rad3-Related (ATR) Kinase: An Emerging way to Enhance Existing Cancer Therapy.

Fri, 19 Feb 2016 01:58:01 +0100

Authors: Andrs M, Korabecny J, Nepovimova E, Jun D, Hodny Z, Kuca K Abstract The main aim of current cancer research is to find a way to selectively affect the tumor cells, while leaving normal cells intact. Ataxia telangiectasia and Rad3-related kinase (ATR), a member of the phosphatidylinositol-3-related protein kinases (PIKK), represents a candidate target for achieving this goal. ATR kinase is one of the main kinases of the DNA damage response signaling pathway and responds to DNA damage caused by replication stress and various genotoxic agents (i.e. chemotherapy, ionizing radiation, ultraviolet light). ATR activation triggers cell cycle checkpoints, DNA repair and apoptosis, but also resistance of tumor cells to DNA damaging agents, through stress support under replication str...



Miglustat Reverts the Impairment of Synaptic Plasticity in a Mouse Model of NPC Disease.

Thu, 18 Feb 2016 11:12:02 +0100

Authors: D'Arcangelo G, Grossi D, Racaniello M, Cardinale A, Zaratti A, Rufini S, Cutarelli A, Tancredi V, Merlo D, Frank C Abstract Niemann-Pick type C disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endolysosomal compartment of cells and accumulation of gangliosides and other sphingolipids. Progressive neurological deterioration and insurgence of symptoms like ataxia, seizure, and cognitive decline until severe dementia are pathognomonic features of the disease. Here, we studied synaptic plasticity phenomena and evaluated ERKs activation in the hippocampus of BALB/c NPC1-/- mice, a well described animal model of the disease. Our results demonstrated an impairment of both induction and maintena...



The Vitamin A Derivative All-Trans Retinoic Acid Repairs Amyloid-β-Induced Double-Strand Breaks in Neural Cells and in the Murine Neocortex.

Thu, 18 Feb 2016 11:12:02 +0100

Authors: Gruz-Gibelli E, Chessel N, Allioux C, Marin P, Piotton F, Leuba G, Herrmann FR, Savioz A Abstract The amyloid-β peptide or Aβ is the key player in the amyloid-cascade hypothesis of Alzheimer's disease. Aβ appears to trigger cell death but also production of double-strand breaks (DSBs) in aging and Alzheimer's disease. All-trans retinoic acid (RA), a derivative of vitamin A, was already known for its neuroprotective effects against the amyloid cascade. It diminishes, for instance, the production of Aβ peptides and their oligomerisation. In the present work we investigated the possible implication of RA receptor (RAR) in repair of Aβ-induced DSBs. We demonstrated that RA, as well as RAR agonist Am80, but not AGN 193109 antagonist, repair Aβ-induced DSBs in SH-SY5Y cell...



Cough ability measurements and recurrent respiratory symptoms in individuals with Ataxia Telangiectasia.

Thu, 18 Feb 2016 02:58:02 +0100

CONCLUSIONS: The cough flow-volume curve can be applied as a method to follow cough ability in patients with A-T who showed a significantly reduced cough capacity. Further studies are needed to establish if the findings may aid decisions regarding cough assistance. PMID: 26364772 [PubMed - as supplied by publisher] (Source: Journal of Asthma)



Growth retardation and growth hormone deficiency in patients with Ataxia telangiectasia.

Thu, 18 Feb 2016 02:40:02 +0100

CONCLUSION: Our results show that a disturbance in the GH/IGF-1 axis was present in 58.3% of A-T patients. Low levels of GH were the result of reduced central GH secretion. GH treatment may be a therapeutic option for A-T patients with severe growth failure. PMID: 25060036 [PubMed - indexed for MEDLINE] (Source: Growth Factors)

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The ATM inhibitor KU55933 sensitizes radioresistant bladder cancer cells with DAB2IP gene defect.

Thu, 18 Feb 2016 01:49:02 +0100

CONCLUSIONS: Loss of DAB2IP expression in BCa cells signifies their radioresistance. KU55933, which suppresses ATM phosphorylation upon irradiation, could be applied in the radiotherapy of BCa patients with a DAB2IP gene defect. PMID: 25585815 [PubMed - indexed for MEDLINE] (Source: International Journal of Radiation Biology)



Endocrine Abnormalities in Ataxia Telangiectasia - Findings from a National Cohort.

Thu, 18 Feb 2016 00:00:00 +0100

CONCLUSIONS: Our results suggest a primary growth abnormality in AT, rather than secondary to nutritional impairment or disease severity. Sex hormone replacement should be considered for female patients. Vitamin D levels should be followed and supplementation given if needed.Pediatric Research (2016); doi:10.1038/pr.2016.19. PMID: 26891003 [PubMed - as supplied by publisher] (Source: Pediatric Research)



Abstract PD7-06: Multi-gene testing in a male breast cancer cohort: Insights and unexpected results

Thu, 18 Feb 2016 00:00:00 +0100

CONCLUSION: In this cohort of male breast cancer patients, multi-gene testing identified mutations in patients that would not previously have been identified with a single gene testing approach and allowed for identification of families with multiple mutations. Age at diagnosis and family history were not predictive of positive test results in general, although men with CHEK2 100delC mutations were diagnosed at a significantly younger age. Although 30% of this cohort was not tested for CHEK2, the CHEK2 mutation rate in the men tested was second in frequency to BRCA2, suggesting a role for CHEK2 testing in male breast cancer patients.Citation Format: Pritzlaff M, Summerour P, McFarland R, Li S, Laduca H. Multi-gene testing in a male breast cancer cohort: Insights and unexpected results. [ab...



Abstract P4-07-08: The prognostic significance of ataxia-telangiectasia-mutated (ATM) and p53 expression in breast cancer

Thu, 18 Feb 2016 00:00:00 +0100

The purpose of this study was to investigate the correlation of ataxia-telangiectasia-mutated (ATM) protein and p53 expression with clinicopathological features and prognosis in patients with sporadic breast cancers. The expression of ATM and p53 was determined by immunohistochemistry in 420 surgically resected breast cancers. Loss of ATM was observed in 126 out of 407 evaluable cases (31.0%), and was significantly associated with aggressive features with large tumor size, lymph node metastasis, higher tumor grade, and negativity of ER and/or PR. ATM loss was associated with a significantly shorter disease-free survival (DFS) (p = 0.019). Abnormal p53 expression was found in 39.3% of tumors (157 out of 400), conferring a worse DFS as well (p = 0.002). When investigated together, combined A...



Abstract P5-05-05: Inhibition of enhanced glucose uptake and glycolysis by KU-55933 as a novel strategy against aggressive breast cancer

Thu, 18 Feb 2016 00:00:00 +0100

The ability of cancer cells to produce large amounts of lactate through aerobic glycosis (Warburg effect) is coupled to high rates of glucose uptake. Enhanced glucose uptake and glycolysis are closely correlated to increased breast tumor aggressiveness and poor prognosis. However, despite the importance of glucose uptake in supplying energy and preventing apoptosis of cancer cells, the majority of current efforts in searching for therapeutic agents targeting glucose metabolism have been aimed at modulating activities of different metabolic enzymes that are involved in glycolysis. Very limited studies have been done in developing novel therapeutic agents against glucose uptake in breast cancer cells.Ataxia-telangiectasia (A-T) is a monogenic, autosomal recessive disorder characterized by ce...

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Mild Sedation Exacerbates or Unmasks Focal Neurologic Dysfunction in Neurosurgical Patients with Supratentorial Brain Mass Lesions in a Drug-specific Manner

Wed, 17 Feb 2016 16:34:30 +0100

Conclusions Midazolam and propofol augmented or revealed neurologic dysfunction more frequently than fentanyl and dexmedetomidine at equivalent sedation levels. Patients with high-grade gliomas were more susceptible than those with low-grade gliomas. (Source: Anesthesiology)



UT Southwestern scientists find potential treatment for Friedreich's ataxia

Tue, 16 Feb 2016 05:00:00 +0100

(UT Southwestern Medical Center) Researchers at UT Southwestern Medical Center have identified synthetic RNA and DNA that reverses the protein deficiency causing Friedreich's ataxia, a neurological disease for which there is currently no cure. (Source: EurekAlert! - Biology)



Tyrosyl-DNA phosphodiesterase I resolves both naturally and chemically induced DNA adducts and its potential as a therapeutic target.

Tue, 16 Feb 2016 03:37:02 +0100

Authors: Comeaux EQ, van Waardenburg RC Abstract DNA is subject to a wide range of insults, resulting from endogenous and exogenous sources that need to be metabolized/resolved to maintain genome integrity. Tyrosyl-DNA phosphodiesterase I (Tdp1) is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts. As a phospholipase D superfamily member Tdp1 utilizes two catalytic histidines each within a His-Lys-Asn motif. Tdp1 was discovered for its ability to hydrolyze the 3'-phospho-tyrosyl that in the cell covalently links DNA Topoisomerase I (Topo1) and DNA. Tdp1's list of substrates has since grown and can be divided into two groups: protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleot...



Central motor conduction time as prodromal biomarker in spinocerebellar ataxia type 2

Tue, 16 Feb 2016 00:00:00 +0100

(Source: Movement Disorders)