Autosomal recessive spastic ataxia

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Disease severity index - Autosomal recessive spastic ataxia of Charlevoix-Saguenay

Disease severity index - Autosomal recessive spastic ataxia of Charlevoix-Saguenay

2. Schmitz-Hubsch T, du Montcel ST, Baliko L, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 2006;66:1717-1720. 3. Trouillas P, Takayanagi T, Hallett M, et al. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. Journal Of The Neurological Sciences 1997;145:205-211.

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Molecular and clinical study of a cohort of 110 Algerian patients with autosomal recessive ataxia

Molecular and clinical study of a cohort of 110 Algerian patients with autosomal recessive ataxia

of the frataxin gene causing Friedreich ataxia, and the c.744delA mutation in exon 5 of the TTPA gene which causes ataxia with isolated vitamin E deficiency. When these targeted mutations were absent, patients’ DNA was then analyzed by PCR and sequencing of genes accountable for some other forms of ataxia (Ataxia with ocular apraxia 1 and 2 “AOA1, AOA2”; Autosomal recessive spastic ataxia of Charlevoix-Saguenay “ARSACS”; Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract syndrome “PHARC”; and Autosomal recessive cerebellar ataxia 2 “ARCA2”) by taking into account the specific clinical indications, while not always strictly relying on them because of the encountered phenotypic heterogeneity, as well as on the basis of previous reports incriminating these genes in our population.
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Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene.

Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene.

Conclusions: Genetic screening of PEX2 and other PEX genes involved in peroxisomal biogenesis is warranted in children and adults with ARCA. Background Main causes of autosomal recessive cerebellar ataxia (ARCA) include Friedreich ataxia, ataxia telangiectasia and oculomotor apraxia type 1 and 2 [1,2]. Cerebellar ataxia may sometimes be the leading neurologic symp- tom in a limited number of autosomal recessive meta- bolic diseases [1,2] but has not been reported as such in inherited peroxisomal diseases due to isolated enzyme deficiency or peroxisomal biogenesis defect [3,4]. Patients with adrenomyeloneuropathy, the adult form of X-adrenoleukodystrophy, or adult Refsum disease (resulting from mutations in PHYH gene coding for the peroxisomal phytanoyl-CoA hydroxylase enzyme, or in PEX7 gene coding for the peroxin 7 receptor protein) often develop cerebellar ataxia but have always asso- ciated neurological symptoms (peripheral neuropathy, retinitis pigmentosa, spastic paraplegia) [5,6]. Patients with peroxisomal biogenesis defects (Zellweger spectrum disorders) may also display cerebellar dysfunction among many other neurological symptoms when they have prolonged survival [3,4]. Peroxisomal biogenesis disorders (PBDs) are characterized by the loss of multi- ple peroxisomal metabolic functions caused by mutation in 13 PEX genes involved in the import of peroxisomal
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en fr Hereditary spastic paraplegias : clinical spectrum in Sudan, further deciphering of the molecular bases of autosomal recessive forms and new genes emerging Paraplégies spastiques héréditaires : exploration clinique au Soudan, études des origines moléculaires des formes autosomiques récessives et identification de nouveaux gènes en cause

Clinical summary In this family, three sibs presented at the ages of 15, 6.5 and 5 years of age with homogenous clinical picture of globally retarded growth with apparent developmental entrapment/arrest since around 1-3 years of age. They had facial dysmorphism more prominent in the older sib. Hair colour was lighter than their parents and healthy sibs sibs and hair texture smoother. They had scaly seasonal hypopigmented skin rash. Mental retardation and psychiatric signs of irritability and emotional lability were observed. Remarkably, the three sibs were extremely friendly, interactive and welcoming. The neurological syndrome was of complex spastic ataxia with bradykinesia (extrapyramidal signs). Ophthalmological assessment revealed optic atrophy with retinitis punctata albescence (in all three sibs) (mottled retina and a variant from retinitis pigmentosa) and hypermetropia in the older sib with most advanced disease. The older girl was diabetic. In one occasion the boy showed altered liver function test but there was no further investigations to exclude other causes nor a follow up tests [Figure (3-20)] [Table (3-17)] .
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Adaptor Protein Complex 4 Deficiency Causes Severe Autosomal-Recessive Intellectual Disability, Progressive Spastic Paraplegia, Shy Character, and Short Stature

Adaptor Protein Complex 4 Deficiency Causes Severe Autosomal-Recessive Intellectual Disability, Progressive Spastic Paraplegia, Shy Character, and Short Stature

somes. 27 Ap4b1-deficient mice were fertile, exhibited no anatomical brain abnormalities, and had normal life spans, body weight, and grip power. They exhibited no ataxia but a significantly poorer rotorod performance than wild-type mice did. There was no information about learning ability of the Ap4b1-deficient mice. Analysis of those mice demonstrated that Ap4 mediates the trans-Golgi network to the postsynaptic somatodendritic domain transport of d2 and a-amino-3-hydroxy-5-methyl-4-isoxazolepro- pionic acid (AMPA) glutamate receptors in both cerebellar Purkinje cells and hippocampal neurons. 28 We thus propose that motor disturbances observed in patients with mutations in the AP4 complex might be because of cerebellar dysfunction caused by mislocalization of gluta- mate receptors. Similarly, defective AMPA receptor sorting might impact synaptic plasticity in hippocampal neurons and cause ID.
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The nosology of hereditary cerebellar ataxias : development of a classification for recessive ataxias and phenotypical description of Spinocerebellar ataxia 34

The nosology of hereditary cerebellar ataxias : development of a classification for recessive ataxias and phenotypical description of Spinocerebellar ataxia 34

heterogeneity in known genetically defined disorders. Indeed, ataxia is a presenting feature in degenerative disorders that target mainly the cerebellum, but it may be present in hereditary spastic paraplegias, inborn errors of metabolism, and various encephalopathies. Proper classification and phenotypic understanding is of primary importance in this field where the high prevalence of repeat expansion disorders, which are not adequately covered by next generation sequencing (NGS) techniques (1, 2), precludes NGS as a first diagnostic step and requires phenotypic evaluation to perform custom gene testing when applicable. Nevertheless, autosomal recessive ataxias have remained an ill-defined and disorganized group of disorders for two main reasons. First, unlike the dominant ataxias that have been organized with a numerical naming system, recessive disorders presenting with ataxia have been named in a highly heterogeneous manner according to clinical features, physicians’ surname, or regions of high prevalence. Second, several recessive multisystemic or complex metabolic disorders present with ataxia, such that it is difficult to properly circumscribe this group of disorders and classify it in a meaningful way for both clinicians and researchers. Hence, the Society for Research on the Cerebellum and Ataxias (SRCA) Task Force on the Classification of Recessive Cerebellar Ataxias was created in 2016 to regroup a panel of international ataxia experts in order to propose a classification relevant to clinical practice and researchers. As a first step, we undertook a systematic scoping review of the literature to identify all recessive disorders presenting with ataxia, select those in which cerebellar degeneration was a core feature, and propose a first classification. This systematic scoping review has been previously published (3), and served as the basis for the current work.
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Recurrent Ataxia and Dystonia with Anti-Neurochondrin Autoantibodies

Recurrent Ataxia and Dystonia with Anti-Neurochondrin Autoantibodies

2 Rommel FR, Miske R, Stöcker W, Arneth B, Neubauer BA, Hahn A. Chorea minor associated with anti-neurochondrin autoantibod- ies. Neuropediatrics 2017;48(06):482 –483 3 Weihua Z, Haitao R, Fang F, Xunzhe Y, Jing W, Hongzhi G. Neuro- chondrin antibody serum positivity in three cases of autoimmune cerebellar ataxia. Cerebellum 2019;18(06):1137 –1142

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Pyruvate dehydrogenase deficiency presenting as intermittent isolated acute ataxia

Pyruvate dehydrogenase deficiency presenting as intermittent isolated acute ataxia

PDH defi ciency is clinically heterogeneous. A small subset of patients presents with an atypically mild course, with intermit- tent neurological symptoms often triggered by infectious illness. This phenotype is incompletely characterized, poorly empha- sized in the medical literature, and possibly underdiagnosed. Blass et al. fi rst reported in 1970 an intermittent movement dis- order in PDH defi ciency [2] . Since this description, only a hand- ful of patients were reported for which intermittent ataxia was the presenting feature ( 䊉 䉴 Table 2 ). Notably, all were male.
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Deferiprone targets aconitase: Implication for Friedreich's ataxia treatment.

Deferiprone targets aconitase: Implication for Friedreich's ataxia treatment.

BMC Neurology 2008, 8:20 http://www.biomedcentral.com/1471-2377/8/20 mal status of mitochondrial iron in Friedreich ataxia pos- sibly at the origin of the hypersensitivity of these cells to oxidative insults – associated or not with an increased mitochondrial iron content – does not protect frataxin depleted cells from the deleterious effect of iron chelation. So far we have no idea of the concentration of deferiprone which might be reached in brain tissues of treated patients. Nevertheless, a mean peak plasma concentration of deferiprone has been estimated to be about 150–200 μM when deferiprone is provided in one daily dose of 25 mg/kg of body weight [17]; a value similar to the 150 μM of deferiprone used in this in vitro study. A lower concen- tration is probably maintained in tissues, however if deferiprone concentration is efficient to empty mitochon- drial iron it should also gradually impair aconitase activity in the mitochondrial matrix. Obviously, the activity of additional iron-requiring enzymes might be affected as well due to excessive lowering of mitochondrial iron, e.g. the mitochondrial ribonucleotide reductase [18]. Assay- ing the iron-sensitive activity of these mitochondrial enzymes might provide useful maker(s) for iron chelator toxicity in future clinical studies.
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Measuring levels of muscle fatigue in spastic cerebral palsy

Measuring levels of muscle fatigue in spastic cerebral palsy

doi: 10.1111/dmcn.14046 This commentary is on the original article by Eken et al. on pages 212– 218 of this issue. Eken et al. 1 provide ample evidence that children with spastic cerebral palsy (CP) fatigue more during walking at a self-selected speed than typically developing peers. This finding was attributed to the greater fatigability of calf muscles in children with CP, as evidenced by the larger increase in electromyographic (EMG) activity of the

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Tolvaptan in autosomal dominant polycystic kidney disease.

Tolvaptan in autosomal dominant polycystic kidney disease.

found that tolvaptan slowed the increase in renal volume and the decline in renal function, as com- pared with placebo, in patients with autosomal dominant polycystic kidney disease[r]

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RNF170-related hereditary spastic paraplegia: confirmation by a novel mutation

RNF170-related hereditary spastic paraplegia: confirmation by a novel mutation

In conclusion, the description of this new family case confirms the involvement of bi-allelic variants in the RNF170 gene in this new autosomal recessive form of HSP. This new clinico- genetic entity is a rare form of hereditary spastic paraplegia since only one affected family was identified among the 141 HSP families of our local reference center (69 exomes, 72 NGS genes panel including RNF170) and has not been found in a cohort of 344 recessive ataxias or in 865 other neurological cases analyzed by exome in our center.

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Friedreich's ataxia: the vicious circle hypothesis revisited

Friedreich's ataxia: the vicious circle hypothesis revisited

Accumulation of mitochondrial iron and decreased cytosolic iron associated with the ABCB7 mutations, mostly missense mutations changing amino acids in the C-terminal end of the transmembrane domain of the protein, results in cerebellar ataxia, albeit different from FA, and includes sideroblastic anaemia [29,30]. This ABC transporter is involved in ISC export from the mitochondria to the cytosol [31] (Figure 1). Yeast stu- dies showed preserved mitochondrial ISP activity despite intramitochondrial iron accumulation [32]. However, as with frataxin depletion, hypersensitivity to oxidative stress has been reported in ABCB7 mutants [33], sug- gesting that a common mechanism resulting in impaired handling of reactive oxygen species may be involved at some point in both types of ataxia.
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Friedreich's ataxia: the vicious circle hypothesis revisited

Friedreich's ataxia: the vicious circle hypothesis revisited

Accumulation of mitochondrial iron and decreased cytosolic iron associated with the ABCB7 mutations, mostly missense mutations changing amino acids in the C-terminal end of the transmembrane domain of the protein, results in cerebellar ataxia, albeit different from FA, and includes sideroblastic anaemia [29,30]. This ABC transporter is involved in ISC export from the mitochondria to the cytosol [31] (Figure 1). Yeast stu- dies showed preserved mitochondrial ISP activity despite intramitochondrial iron accumulation [32]. However, as with frataxin depletion, hypersensitivity to oxidative stress has been reported in ABCB7 mutants [33], sug- gesting that a common mechanism resulting in impaired handling of reactive oxygen species may be involved at some point in both types of ataxia.
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Novel CAPN3 variant associated with an autosomal dominant calpainopathy

Novel CAPN3 variant associated with an autosomal dominant calpainopathy

This autosomal dominant inheritance was recently described for late-onset and mild forms of calpain-opathies [9,10]. Interestingly, patients from the four families described here also presented with a mild phe-notype, with hyperCKaemia, myalgia and/ or moderate The calpain-3 western blot analysis of muscle biop-sies from the four index cases, performed in different laboratories more than 10 years ago, revealed contra-dictory information. Only patient 3/II.6 had total cal-pain-3 loss. Another patient (4/II.2) presented with a partial calpain-3 defect, whereas the other two index cases had seemingly normal expression of calpain-3. However, it is known that it is difficult to obtain reli- able calpain-3 western blot analysis. Moreover, inter-laboratory as well as intralaboratory variability is not rare for this type of analysis. Modified catalytic activity of the calpain-3 p.(Gly445Arg) mutant In order to investigate the effect of c.1333G>A CAPN3 variant on calpain-3 protein function, we transfected mutated CAPN3 constructs into human immortalized myoblasts lacking endogenous calpain-3, alone or in combination with other constructs. Inactive calpain-3 p.(Cys129Ser) was used as a specific substrate to evaluate the catalytic activity of transfected mutants (Figure 3). As expected, the inactive calpain-3 p.(Cys129Ser) was not degraded when transfected alone, as only one specific band is visible corresponding to the full-length calpain-3 p.(Cys129Ser) fused with GFP at 121 kDa (Figure 3A) or fused with V5tag at 92 kDa (Figure 3B). The calpain-3 p.(Gly445Arg) mutant expressed alone had the same proteolytic profile as the calpain-3 p.(Cys129Ser) mutant (Figure 3A), indicating the absence of autolytic activity.
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Spinocerebellar ataxia 17 (SCA17) and Huntington's disease-like 4 (HDL4).

Spinocerebellar ataxia 17 (SCA17) and Huntington's disease-like 4 (HDL4).

79. Loy CT, Sweeney MG, Davis MB, Wills AJ, Sawle GV, Lees AJ et al. Spinocerebellar ataxia type 17: extension of phenotype with putaminal rim hyperintensity on magnetic resonance imaging. Mov Disord. 2005;20:1521-1523. 80. Minnerop M, Joe A, Lutz M, Bauer P, Urbach H, Helmstaedter C et al. Putamen dopamine transporter and glucose metabolism are reduced in SCA17. Ann Neurol. 2005;58:490-491. 81. Stevanin G, Durr A, Brice A. Clinical and molecular advances in autosomal dominant

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Spinocerebellar ataxia type 2 (SCA2): clinical features and genetic analysis.

Spinocerebellar ataxia type 2 (SCA2): clinical features and genetic analysis.

tide expansion in German SCA patients. Neurogenetics 1997;1:59–64. 12. Moseley ML, Benzow KA, Schut LJ, et al. Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families. Neurology 1998;51:1666–71. 13. Giunti P, Sabbadini G, Sweeney MG, et al. The role of the SCA2 trinucleotide repeat expansion in 89 auto- somal dominant cerebellar ataxia families. Frequency, clinical and genetic correlates. Brain 1998;121(Pt 3):459–67.

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Targeting chloride transport in autosomal dominant polycystic kidney disease.

Targeting chloride transport in autosomal dominant polycystic kidney disease.

CLS-D-20-00256.R1. Invited Review – Special Issue: Cell signaling in PKD. Introduction Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited disease of the kidney, accounting for up to 10% of patients requiring dialysis or transplantation [ 1 ]. ADPKD is genetically heterogeneous, with mutations in PKD1 and PKD2 accounting for ~80% and ~ 15% of the cases, respectively [ 2 ]. The PKD1 and PKD2 genes encode the membrane proteins, polycystin-1 and polycystin-2 respectively, which are expressed in distinct domains and play multiple roles in kidney tubular cells homeostasis [ 3–7 ]. It is generally accepted that the polycystins interact and are expressed in the primary cilia; mutations in PKD1/PKD2 impact multiple ciliary-dependent signaling pathways and alter intracellular Ca 2+ homeostasis [ 3 , 5 , 6 ]. Mutations of at least 5 genes (i.e., GANAB, PRKCSH, ALG8, SEC61B, and SEC63), which encode proteins in the endoplasmic reticulum involved in ma- turation and proper surface localization of integral membrane proteins including polycystin-1 and polycystin-2, have been shown to cause mild forms of ADPKD with variable cystic liver disease severity [ 2 , 8–10 ].
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en fr Pathophysiological and molecular characterization of a mouse model of ARCA2, a recessive cerebellar ataxia associated to Coenzyme Q10 deficiency Caractérisation physiopathologique et moléculaire d'un modèle murin de ARCA2, une ataxie cérébelleuse récessive associée à un déficit en coenzyme Q10

al., 2010) where a decrease in the glutamate transporter EAAT4 was observed. Five distinct glutamate transporters have been found in the mammalian central nervous system (EAAT1 to 5). They are considered to play an important role in the maintenance of low extracllular concentrations of glutamate and in the clearance of synapses, preventing the neurotoxic effect of glutamate (Takayasu et al., 2009) . Interestingly, downregulation of EAAT1 (also known as GLAST) was found in the cereballa of mutant mice expressing polyglutamine- expanded ataxin-7 in Bergmann glia (Custer et al., 2006) . Moreover, a heterozygous mutation in EAAT1 with a dominant negative effect was reported in a patient with episodic ataxia and seizure (Jen et al., 2005) . Altogether this evidence strongly suggests that impairment of glutamate homeostasis can lead to Purkinje cell degeneration. However, no change in glutamate transporters was observed by qRT-PCR in the cerebella of Adck3 -/- mice (data not shown). Therefore, it would be interesting to determine whether levels of glutamate transporters change at the protein level, in order to determine if this can be a pathological mechanism in Adck3 -/- mice.
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Endogenous cerebellar neurogenesis in adult mice with progressive ataxia

Endogenous cerebellar neurogenesis in adult mice with progressive ataxia

INTRODUCTION Inherited cerebellar ataxias, a heterogeneous group of neurodegenerative disorders characterized by progressive degeneration and resulting in impaired balance, gait and movement coordination 1 , are a major cause of disability and reduced life-span, with few treatment options. The Harlequin (Hq) mouse is a spontaneous genetic mouse model of cerebellar ataxia with an 80-90% reduction in the mitochondrial protein Apoptosis-inducing factor 2 , which leads to progressive ataxia with selective cerebellar granule neuron loss and subsequently, Purkinje cell death 2 . Although the first signs of ataxia begin at 4-5 months of age, the degenerative process is already underway by 2 months, with visible signs of mitochondrial degeneration in both granule and Purkinje neurons, accompanied by widespread inflammatory changes including astrogliosis and microgliosis 3 .
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