• CoQ
• CoQ deficiency
• coenzyme Q
• mitochondrial disease
• ubiquinone

• Ubiquinone/metabolism
• Ubiquinone/analogs & derivatives
• Humans
• Animals
• Mitochondria/metabolism
• Mitochondrial Diseases/metabolism
• Oxidation-Reduction
• Antioxidants/metabolism
• Muscle Weakness/metabolism
• Reactive Oxygen Species/metabolism
• Ataxia/metabolism

• FDN-159916 Canadian Government | Canadian Institutes of Health Research (CIHR)

Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group of rare neurodegenerative inherited disorders. The resulting motor incoordination and progressive functional disabilities lead to reduced lifespan. There is currently no cure for ARCAs, likely attributed to the lack of understanding of the multifaceted roles of antioxidant defense and the underlying mechanisms. This systematic review aims to evaluate the extant literature on the current developments of therapeutic strategies that target oxidative stress for the management of ARCAs. We searched PubMed, Web of Science, and Science Direct Scopus for relevant peer-reviewed articles published from 1 January 2016 onwards. A total of 28 preclinical studies fulfilled the eligibility criteria for inclusion in this systematic review. We first evaluated the altered cellular processes, abnormal signaling cascades, and disrupted protein quality control underlying the pathogenesis of ARCA. We then examined the current potential therapeutic strategies for ARCAs, including aromatic, organic and pharmacological compounds, gene therapy, natural products, and nanotechnology, as well as their associated antioxidant pathways and modes of action. We then discussed their potential as antioxidant therapeutics for ARCAs, with the long-term view toward their possible translation to clinical practice. In conclusion, our current understanding is that these antioxidant therapies show promise in improving or halting the progression of ARCAs. Tailoring the therapies to specific disease stages could greatly facilitate the management of ARCAs.

• antioxidant pathway and therapy
• autosomal recessive cerebellar ataxia
• genetic mutation
• oxidative stress
• preclinical model
• rare neurodegenerative disease

Inherited neuromuscular disorders (INMD) are a heterogeneous group of rare diseases that involve muscles, motor neurons, peripheral nerves or the neuromuscular junction. Several different lab abnormalities have been linked to INMD: sometimes they are typical of the disorder, but they usually appear to be less specific. Sometimes serum biomarkers can point out abnormalities in presymtomatic or otherwise asymptomatic patients (e.g., carriers). More often a biomarker of INMD is evaluated by multiple clinicians other than expert in NMD before the diagnosis, because of the multisystemic involvement in INMD. The authors performed a literature search on biomarkers in inherited neuromuscular disorders to provide a practical approach to the diagnosis and the correct management of INMD. A considerable number of biomarkers have been reported that support the diagnosis of INMD, but the role of an expert clinician is crucial. Hence, the complete knowledge of such abnormalities can accelerate the diagnostic workup supporting the referral to specialists in neuromuscular disorders.

• biomarkers
• inherited neuromuscular disorders
• rare diseases

• DNA/RNA repair
• alpha-fetoprotein
• oculomotor apraxia
• recessive ataxia

Ataxia with oculomotor apraxia (AOA1) is characterized by early-onset progressive cerebellar ataxia with peripheral neuropathy, oculomotor apraxia and hypoalbuminemia and hypercholesterolemia.

A 23-year-old previously healthy woman presented with slowly-progressive gait impairment since the age of six years. Neurological examination revealed profound areflexia, chorea, generalized dystonia and oculomotor apraxia. Brain MRI revealed mild cerebellar atrophy and needle EMG showed axonal sensorimotor neuropathy. Whole exome sequencing revealed a mutation in the aprataxin gene.

AOA1 can present with choreoathetosis mixed with dystonic features, resembling ataxia-telangiectasia. This case is instructive since mixed and complex movement disorders is not very common in AOA1.

• ataxia
• ataxia with oculomotor apraxia
• ataxia with oculomotor apraxia type 1
• cerebellum
• movement disorders

Coenzyme Q10 (CoQ10) has a number of vital functions in all cells, both mitochondrial and extramitochondrial. In addition to its key role in mitochondrial oxidative phosphorylation, CoQ10 serves as a lipid soluble antioxidant, plays an important role in fatty acid, pyrimidine and lysosomal metabolism, as well as directly mediating the expression of a number of genes, including those involved in inflammation. In view of the central role of CoQ10 in cellular metabolism, it is unsurprising that a CoQ10 deficiency is linked to the pathogenesis of a range of disorders. CoQ10 deficiency is broadly classified into primary or secondary deficiencies. Primary deficiencies result from genetic defects in the multi-step biochemical pathway of CoQ10 synthesis, whereas secondary deficiencies can occur as result of other diseases or certain pharmacotherapies. In this article we have reviewed the clinical consequences of primary and secondary CoQ10 deficiencies, as well as providing some examples of the successful use of CoQ10 supplementation in the treatment of disease.

• antioxidant
• coenzyme Q10
• deficiencies
• mitochondria
• oxidative stress

Ataxia with oculomotor apraxia type 1 (AOA1) is a rare autosomal recessive cerebellar ataxia, caused by mutations in the APTX gene. The disease is characterized by early-onset cerebellar ataxia, oculomotor apraxia and severe axonal polyneuropathy. The aim of this study was to detect the disease-causing variants in two unrelated consanguineous Jordanian families with cerebellar ataxia using whole exome sequencing (WES), and to correlate the identified mutation(s) with the clinical and cellular phenotypes.

WES was performed in three affected individuals and segregation analysis of p.W279* APTX candidate variant was performed. Expression levels of APTX were measured in patients’ skin fibroblasts and peripheral blood mononuclear cells, followed by western blot analysis in skin fibroblasts. Genotoxicity assay was performed to detect the sensitivity of APTX mutated cells to H₂O₂, MMC, MMS and etoposide.

A recurrent homozygous nonsense variant in APTX gene (c.837G>A, p.W279*) was revealed in all affected individuals. qRT-PCR showed normal APTX levels in peripheral blood and lower levels in fibroblast cells. However, western blot showed the absence of APTX protein in patients’ skin fibroblasts. Significant hypersensitivity to H₂O₂, MMC and etoposide and lack of sensitivity to MMS were noted.

This is the first study to report the identification of a nonsense variant in the APTX gene (c.837G>A; p.W279*) in AOA1 patients within the Jordanian population. This study confirmed the need of WES to assist in the diagnosis of cerebellar ataxia and it emphasizes the importance of studying the pathophysiology of the APTX gene.

• Cerebellar Ataxia/genetics
• Child
• Child, Preschool
• Codon, Nonsense
• Consanguinity
• DNA/drug effects
• DNA Damage
• DNA-Binding Proteins/genetics
• Female
• Humans
• Male
• Mutagens/pharmacology
• Nuclear Proteins/genetics
• Exome Sequencing

• deanship of scientific research, University of Jordan,

• Hereditary autosomal recessive ataxias
• NGS
• Southeast Anatolia

• Adolescent
• Age of Onset
• Ataxia/epidemiology
• Ataxia/genetics
• Ataxia/pathology
• Brain/pathology
• Child
• Child, Preschool
• Cross-Sectional Studies
• Humans
• Infant
• Infant, Newborn
• Spinocerebellar Ataxias/epidemiology
• Spinocerebellar Ataxias/genetics
• Spinocerebellar Ataxias/pathology
• Turkey/epidemiology

• Distal motor sensory neuropathy
• Recessive ataxia
• TDP1 mutation

• Antioxidants
• ataxias
• cerebellar ataxia
• coenzyme Q10
• idebenone
• oxidative stress.

• Animals
• Antioxidants/therapeutic use
• Cerebellar Ataxia/drug therapy
• Cerebellar Ataxia/metabolism
• Humans
• Oxidative Stress/drug effects

• APTX
• Ataxia Oculomotor Apraxia 1
• DNA repair
• X‐ray crystallography
• missense mutation

• ataxia
• autosomal recessive
• cerebellar ataxia
• exome
• friedreich ataxia
• genetic disease
• genome

• Friedreich Ataxia/genetics
• Genes, Recessive/genetics
• Humans
• Iron-Binding Proteins/genetics
• Frataxin

• apraxia
• ataxia
• athetosis
• progressive cerebellar ataxia

Whether the recessive ataxias, Ataxia with oculomotor apraxia type 1 (AOA1) and 2 (AOA2) and Ataxia telangiectasia (AT), can be distinguished by video-oculography and alpha-fetoprotein level remains unknown. We compared 40 patients with AOA1, AOA2 and AT, consecutively referred between 2008 and 2015 with 17 healthy subjects. Video-oculography revealed constant impairments in patients such as cerebellar signs, altered fixation, impaired pursuit, hypometric saccades and abnormal antisaccades. Horizontal saccade latencies could be highly increased reflecting oculomotor apraxia in one third of patients. Specific distinctive alpha-fetoprotein thresholds were determined for AOA1 (7–15 µg/L), AOA2 (15–65 µg/L) and AT (>65 µg/L). Early age onset, severe walking disability, movement disorders, sensori-motor neuropathy and cerebellar atrophy were all shared. In conclusion, alpha-fetoprotein level seems to permit a distinction while video-oculography does not and therefore is not mandatory, even if an appropriate oculomotor examination remains crucial. Our findings are that AOA1, AOA2 and AT form a particular group characterized by ataxia with complex oculomotor disturbances and elevated AFP for which the final diagnosis is relying on genetic analysis. These findings could guide genetic analysis, assist reverse-phenotyping and provide background for the interpretation of the numerous variants of unknown significance provided by next-generation sequencing.

• Alternative splicing
• Aprataxin
• Mild phenotype

• DNA damage
• DNA damage response
• DNA repair defects
• Neurodegeneration

• Aprataxin
• DNA repair
• DNA strand breaks
• Neurodegeneration
• Polynucleotide kinase/phosphatase
• Tyrosyl DNA-phosphodiesterase 1

The autosomal recessive ataxias are a heterogeneous group of disorders that are characterized by complex neurological features in addition to progressive ataxia. Hyperkinetic movement disorders occur in a significant proportion of patients, and may sometimes be the presenting motor symptom. Presentations with involuntary movements rather than ataxia are diagnostically challenging, and are likely under-recognized.

A PubMed literature search was performed in October 2015 utilizing pairwise combinations of disease-related terms (autosomal recessive ataxia, ataxia–telangiectasia, ataxia with oculomotor apraxia type 1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2), Friedreich ataxia, ataxia with vitamin E deficiency), and symptom-related terms (movement disorder, dystonia, chorea, choreoathetosis, myoclonus).

Involuntary movements occur in the majority of patients with ataxia–telangiectasia and AOA1, and less frequently in patients with AOA2, Friedreich ataxia, and ataxia with vitamin E deficiency. Clinical presentations with an isolated hyperkinetic movement disorder in the absence of ataxia include dystonia or dystonia with myoclonus with predominant upper limb and cervical involvement (ataxia–telangiectasia, ataxia with vitamin E deficiency), and generalized chorea (ataxia with oculomotor apraxia type 1, ataxia-telangiectasia).

An awareness of atypical presentations facilitates early and accurate diagnosis in these challenging cases. Recognition of involuntary movements is important not only for diagnosis, but also because of the potential for effective targeted symptomatic treatment.

• Choreoathetosis
• ataxia with oculomotor apraxia
• ataxia with vitamin E deficiency

• AOA1
• Aprataxin
• Aptx
• DNA damage response
• DNA ligase
• Neurodegenerative disease

• Cerebellar ataxia
• Coenzyme Q10 deficiency
• Encephalomyopathy
• Steroid-resistant nephrotic syndrome

• Ataxia/complications
• Humans
• Kidney Diseases/genetics
• Mitochondrial Diseases/complications
• Mitochondrial Diseases/genetics
• Muscle Weakness/complications
• Ubiquinone/deficiency

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 whole-exome sequencing or whole-genome sequencing in the molecular diagnosis of ARCAs is discussed.

• Autosomal recessive cerebellar ataxia
• Whole-exome sequencing
• Whole-genome sequencing
• Homozygosity mapping
• Next generation sequencing

Ataxia with oculomotor apraxia defines a group of genetically distinct recessive ataxias including ataxia-telangectasia (A-T, ATM gene), ataxia with oculomotor apraxia type 1 (AOA1, APTX gene) and type 2 (AOA2, SETX gene). Although, a few unique clinical features differentiate each of these forms, the patients also share common clinical signs, such as the presence of cerebellar atrophy, sensorimotor axonal neuropathy, and elevated alpha-fetoprotein (AFP) serum level.

We selected 22 Italian patients from 21 families, presenting progressive cerebellar ataxia, axonal neuropathy, and elevated serum AFP. We screened the coding regions of ATM, APTX and SETX genes for point mutations by direct sequencing or DHPLC, and searched genomic rearrangements in SETX by MLPA analysis. In selected cases, quantification of ATM and senataxin proteins was performed by Western blot. Clinical, neurophysiological, and neuroimaging data were collected.

Thirteen patients (12 families) carried SETX mutations (AOA2, 57%), two were mutated in ATM (A-T), and three in APTX (AOA1). In three remaining patients, we could not find pathogenic mutations, and in one case we found, in homozygosis, the SETX p.K992R polymorphism (population frequency 1-2%). In AOA2 cases, we identified 14 novel and three reported SETX mutations. Signs at onset were gait ataxia and facial dyskinesia, and the age ranged between 11 and 18 years. None had obvious oculomotor apraxia at the latest examination (age 14–45 years). The patient carrying the p.K992R SETX polymorphism had a phenotype similar to that of the diagnosed AOA2 patients, while the other three undiagnosed subjects had a very late onset and a few distinguishing clinical features.

We describe a large series of 13 AOA2 Italian patients. The phenotype was consistent with previous descriptions of AOA2, except for a higher frequency of strabism, and for the absence of oculomotor apraxia. In our survey ~60% of juvenile-to-adult cases with cerebellar ataxia, sensorimotor neuropathy and increased AFP are due to mutations in the SETX gene, and a smaller percentage to APTX and ATM gene mutations.