A Novel Coq8a Mutation in a Case with Juvenile Onset Coq10d4: Case Report and Literature Review

Abstract Primary coenzyme Q10 deficiency-4 (COQ10D4) is an autosomal recessive disorder characterized by childhood-onset of cerebellar ataxia and exercise intolerance. Molecular pathology responsible for clinical findings is mitochondrial respiratory chain dysfunction. The main clinical manifestation involves early onset exercise intolerance, progressive cerebellar ataxia and movement disorders. Some affected individuals develop seizures and have mild mental impairment, indicating variable severity. COQ8A gene mutations are responsible for this disease. Here we present a patient with tremor and cerebellar atrophy in which we detected a new mutation in the COQ8A gene. The patient's clinical findings were compatible with juvenile onset COQ10D4. Therefore, we reviewed the clinical, laboratory and genetic findings of 11 juvenile-onset COQ10D4 patients reported to date, as well as the patient's presentation.

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Clinical and Genetic Study of Ataxia With Vitamin E Deficiency

10.21203/rs.3.rs-175944/v1 ◽

2021 ◽

Author(s):

Linwei Zhang ◽

Xiangfei Zhang ◽

Pu Lv ◽

Dantao Peng

Keyword(s):

Vitamin E ◽

Cerebellar Ataxia ◽

Protein Function ◽

Novel Mutation ◽

Brain Mri ◽

Serum Vitamin ◽

Gene Mutations ◽

Chinese Family ◽

Vitamin E Deficiency ◽

Progressive Cerebellar Ataxia

Abstract Background: Ataxia with Vitamin E deficiency (AVED) is a type of autosomal recessive cerebellar ataxia. The main clinical manifestation involves progressive cerebellar ataxia and movement disorders, α-tocopherol transfer protein(TTPA) gene mutations are responsible for this disease. Methods: A female patient from a consanguineous Chinese family underwent detailed physical and auxiliary examination. After exclusion of acquired causes of ataxia, Friedreich’s Ataxia, and common types of spinocerebellar ataxia, the patient was subjected to whole exome sequencing (WES) followed by confirmation of sequence variants using Sanger sequencing. Her asymptomatic parents and younger sister were genotyped for the variant. Results: This patient showed progressive cerebellar ataxia, dysarthria and dystonic tremor, her serum vitamin E concentration was remarkably decreased, brain MRI revealed no obvious cerebellum atrophy. Homozygous variant (c.473T>C, p.F158S) of TPPA gene were identified through WES. Bioinformatic analysis predicted F185S would be harmful to the protein function. After supplementation of vitamin E 400mg three times per day for two years, the patient’s symptom remained stabilization.Conclusions We identified an AVED patient caused by novel mutation in TTPA gene. Our findings widen the spectrum of TTPA gene mutations.

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Clinical spectrum of early onset cerebellar ataxia with retained tendon reflexes: an autosomal recessive ataxia not to be missed

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20130036 ◽

2013 ◽

Vol 71 (6) ◽

pp. 345-348 ◽

Cited By ~ 4

Author(s):

Jose Luiz Pedroso ◽

Pedro Braga-Neto ◽

Irapua Ferreira Ricarte ◽

Marcus Vinicius Cristino Albuquerque ◽

Orlando Graziani Povoas Barsottini

Keyword(s):

Cerebellar Ataxia ◽

Early Onset ◽

Autosomal Recessive ◽

Friedreich Ataxia ◽

Cerebellar Atrophy ◽

Clinical Spectrum ◽

Progressive Cerebellar Ataxia ◽

Cerebellar Ataxias ◽

Autosomal Recessive Cerebellar Ataxias ◽

Tendon Reflexes

Autosomal recessive cerebellar ataxias are a heterogeneous group of neurological disorders. In 1981, a neurological entity comprised by early onset progressive cerebellar ataxia, dysarthria, pyramidal weakness of the limbs and retained or increased upper limb reflexes and knee jerks was described. This disorder is known as early onset cerebellar ataxia with retained tendon reflexes. In this article, we aimed to call attention for the diagnosis of early onset cerebellar ataxia with retained tendon reflexes as the second most common cause of autosomal recessive cerebellar ataxias, after Friedreich ataxia, and also to perform a clinical spectrum study of this syndrome. In this data, 12 patients from different families met all clinical features for early onset cerebellar ataxia with retained tendon reflexes. Dysarthria and cerebellar atrophy were the most common features in our sample. It is uncertain, however, whether early onset cerebellar ataxia with retained tendon reflexes is a homogeneous disease or a group of phenotypically similar syndromes represented by different genetic entities. Further molecular studies are required to provide definitive answers to the questions that remain regarding early onset cerebellar ataxia with retained tendon reflexes.

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Biallelic loss-of-function variations in PRDX3 cause cerebellar ataxia

Brain ◽

10.1093/brain/awab071 ◽

2021 ◽

Author(s):

Adriana P Rebelo ◽

Ilse Eidhof ◽

Vivian P Cintra ◽

Léna Guillot-Noel ◽

Claudia V Pereira ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Cerebellar Ataxia ◽

Cerebellar Atrophy ◽

Neuronal Cell ◽

Reactive Oxygen ◽

Oxygen Species ◽

In Vivo Models ◽

Progressive Cerebellar Ataxia ◽

Parkinson’S Diseases

Abstract Peroxiredoxin 3 (PRDX3) belongs to a superfamily of peroxidases that function as protective antioxidant enzymes. Among the six isoforms (PRDX1–PRDX6), PRDX3 is the only protein exclusively localized to the mitochondria, which are the main source of reactive oxygen species. Excessive levels of reactive oxygen species are harmful to cells, inducing mitochondrial dysfunction, DNA damage, lipid and protein oxidation and ultimately apoptosis. Neuronal cell damage induced by oxidative stress has been associated with numerous neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. Leveraging the large aggregation of genomic ataxia datasets from the PREPARE (Preparing for Therapies in Autosomal Recessive Ataxias) network, we identified recessive mutations in PRDX3 as the genetic cause of cerebellar ataxia in five unrelated families, providing further evidence for oxidative stress in the pathogenesis of neurodegeneration. The clinical presentation of individuals with PRDX3 mutations consists of mild-to-moderate progressive cerebellar ataxia with concomitant hyper- and hypokinetic movement disorders, severe early-onset cerebellar atrophy, and in part olivary and brainstem degeneration. Patient fibroblasts showed a lack of PRDX3 protein, resulting in decreased glutathione peroxidase activity and decreased mitochondrial maximal respiratory capacity. Moreover, PRDX3 knockdown in cerebellar medulloblastoma cells resulted in significantly decreased cell viability, increased H2O2 levels and increased susceptibility to apoptosis triggered by reactive oxygen species. Pan-neuronal and pan-glial in vivo models of Drosophila revealed aberrant locomotor phenotypes and reduced survival times upon exposure to oxidative stress. Our findings reveal a central role for mitochondria and the implication of oxidative stress in PRDX3 disease pathogenesis and cerebellar vulnerability and suggest targets for future therapeutic approaches.

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A Precocious Cerebellar Ataxia and Frequent Fever Episodes in a 16-Month-Old Infant Revealing Ataxia-Telangiectasia Syndrome

Case Reports in Immunology ◽

10.1155/2013/296827 ◽

2013 ◽

Vol 2013 ◽

pp. 1-5

Author(s):

Luigi Nespoli ◽

Annapia Verri ◽

Silvia Tajè ◽

Francesco Paolo Pellegrini ◽

Maddalena Marinoni

Keyword(s):

T Cells ◽

Cerebellar Ataxia ◽

Ataxia Telangiectasia ◽

Gene Mutations ◽

Normal Activity ◽

Recurrent Fever ◽

High Clinical Suspicion ◽

Progressive Cerebellar Ataxia ◽

Serum Alpha Fetoprotein ◽

Febrile Episodes

Ataxia-telangiectasia (AT) is the most frequent progressive cerebellar ataxia in infancy and childhood. Immunodeficiency which includes both cellular and humoral arms has variable severity. Since the clinical presentation is extremely variable, a high clinical suspicion will allow an early diagnosis. Serum alpha-fetoprotein is elevated in 80–85% of patients and therefore could be used as a screening tool. Here, we present a case of a 5-year-old female infant who was admitted to our department at the age of 16 months because of gait disorders and febrile episodes that had begun at 5 months after the cessation of breastfeeding. Serum alfa-fetoprotein level was elevated. Other investigations showed leukocytopenia with lymphopenia, reduced IgG2and IgA levels, and low titers of specific postimmunization antibodies against tetanus toxoid and Haemophilus B polysaccharide. Peripheral lymphocytes subsets showed reduction of T cells with a marked predominance of T cells with a memory phenotype and a corresponding reduction of naïve T cells; NK cells were very increased (41%) with normal activity. The characterization of the ATM gene mutations revealed 2 specific mutations (c.5692C > T/c.7630-2A > C) compatible with AT diagnosis. It was concluded that AT syndrome should be considered in children with precocious signs of cerebellar ataxia and recurrent fever episodes.

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ATP1A3 variants and slowly progressive cerebellar ataxia without paroxysmal or episodic symptoms in children

Developmental Medicine & Child Neurology ◽

10.1111/dmcn.14666 ◽

2020 ◽

Vol 63 (1) ◽

pp. 111-115 ◽

Cited By ~ 1

Author(s):

Masayuki Sasaki ◽

Noriko Sumitomo ◽

Yuko Shimizu‐Motohashi ◽

Eri Takeshita ◽

Kenji Kurosawa ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Progressive Cerebellar Ataxia

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A Clinical-Based Diagnostic Approach to Cerebellar Atrophy in Children

Applied Sciences ◽

10.3390/app11052333 ◽

2021 ◽

Vol 11 (5) ◽

pp. 2333

Author(s):

Claudia Ciaccio ◽

Chiara Pantaleoni ◽

Franco Taroni ◽

Daniela Di Bella ◽

Stefania Magri ◽

...

Keyword(s):

Muscle Biopsy ◽

Single Gene ◽

Brain Mri ◽

Genetic Defect ◽

Cerebellar Atrophy ◽

Chain Complex ◽

Clinical Findings ◽

Diagnostic Workup ◽

Diagnostic Approach ◽

Disease Definition

Background: Cerebellar atrophy is a neuroradiological definition that categorizes conditions heterogeneous for clinical findings, disease course, and genetic defect. Most of the papers proposing a diagnostic workup for pediatric ataxias are based on neuroradiology or on the literature and experimental knowledge, with a poor participation of clinics in the process of disease definition. Our study aims to offer a different perspective on the way we approach cerebellar atrophy in developmental age, building a clinical-based diagnostic workup to guide molecular diagnosis. Methods: we recruited 52 patients with pediatric-onset cerebellar atrophy and definite disease categorization. Children underwent brain MRI, neurophysiological exams, metabolic investigations, and muscle biopsy with respiratory chain complex study. Single-gene sequencing, next-generation sequencing NGS panels, whole-exome sequencing (WES), and disease-specific techniques have been used to reach genetic confirmation. Results: Brain MRI is the main method of diagnosis, followed by tests on muscle biopsy and peripheral nervous system study. Other exams (e.g., metabolic investigations or evoked potentials) may be useful to narrow the list of diagnostic possibilities. Conclusions: We propose a diagnostic approach to cerebellar atrophy in children based on clinical findings, and support the evidence that a precise phenotypic definition may lead to the formulation of a definite diagnosis or otherwise guide the back phenotyping process derived from large molecular data.

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Rare Gain-of-Function KCND3 Variant Associated with Cerebellar Ataxia, Parkinsonism, Cognitive Dysfunction, and Brain Iron Accumulation

International Journal of Molecular Sciences ◽

10.3390/ijms22158247 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8247

Author(s):

Cheng-Tsung Hsiao ◽

Thomas F. Tropea ◽

Ssu-Ju Fu ◽

Tanya M. Bardakjian ◽

Pedro Gonzalez-Alegre ◽

...

Keyword(s):

Cerebellar Ataxia ◽

Iron Accumulation ◽

Molecular Spectra ◽

Loss Of Function ◽

Brain Iron ◽

Gain Of Function ◽

Progressive Cerebellar Ataxia ◽

Voltage Dependent ◽

Window Current

Loss-of-function mutations in the KV4.3 channel-encoding KCND3 gene are linked to neurodegenerative cerebellar ataxia. Patients suffering from neurodegeneration associated with iron deposition may also present with cerebellar ataxia. The mechanism underlying brain iron accumulation remains unclear. Here, we aim to ascertain the potential pathogenic role of KCND3 variant in iron accumulation-related cerebellar ataxia. We presented a patient with slowly progressive cerebellar ataxia, parkinsonism, cognitive impairment, and iron accumulation in the basal ganglia and the cerebellum. Whole exome sequencing analyses identified in the patient a heterozygous KCND3 c.1256G>A (p.R419H) variant predicted to be disease-causing by multiple bioinformatic analyses. In vitro biochemical and immunofluorescence examinations revealed that, compared to the human KV4.3 wild-type channel, the p.R419H variant exhibited normal protein abundance and subcellular localization pattern. Electrophysiological investigation, however, demonstrated that the KV4.3 p.R419H variant was associated with a dominant increase in potassium current amplitudes, as well as notable changes in voltage-dependent gating properties leading to enhanced potassium window current. These observations indicate that, in direct contrast with the loss-of-function KCND3 mutations previously reported in cerebellar ataxia patients, we identified a rare gain-of-function KCND3 variant that may expand the clinical and molecular spectra of neurodegenerative cerebellar disorders associated with brain iron accumulation.

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