scholarly journals Identifying Gene Mutations in Autosomal Recessive Cerebellar Ataxias and Extending the Mutational Spectrum in China

2021 ◽  
Author(s):  
Xueping Chen ◽  
Xiaoqin Yuan ◽  
Qian-Qian Wei ◽  
RuWei Ou ◽  
Bei Cao ◽  
...  
Keyword(s):  
Cerebellar Ataxia ◽  
Autosomal Recessive ◽  
Gene Mutations ◽  
Autosomal Recessive Inheritance ◽  
Chinese Patients ◽  
Missense Mutations ◽  
Genetic Characteristics ◽  
Targeted Next Generation Sequencing ◽  
Cerebellar Ataxias ◽  
Autosomal Recessive Cerebellar Ataxias

Abstract Background: Autosomal recessive cerebellar ataxias (ARCA) are heterogeneous, complex, disabling neurodegenerative diseases characterized by autosomal recessive inheritance and cerebellar ataxia. Numerous mutations are described in several populations. However, in China, few data are available concerning ARCA. In this study, we aimed to identify ARCA-associated ataxia by targeted next-generation sequencing or whole-exome sequencing in a Chinese cohort, trying to determine clinical and genetic characteristics of Chinese patients with ARCA.Results: We identified 15 different mutations in 7 unrelated patients, of which 12 were novel, including seven missense mutations, three frameshift mutations, two splicing mutations, two nonsense mutations, and one inframe deletion mutation. The most frequent gene was ATM (3 patients), followed by SACS (2 patients), SYNE1 (2 patients), and SETX (1 patient). Specifically, 1 patient harbored mutations in both ATM and SYNE1. The phenotype was mainly cerebellar ataxia in all these cases. However, peripheral neuropathy, dystonia, oculomotor abnormalities, pyramidal tract dysfunction, cognitive impairment, and epilepsy were also revealed. Patients who harbored different gene mutations showed mutational heterogeneity. Conclusions: Our results indicate that ARCA-associated gene mutations are uncommon with additional clinical features in the Chinese population, and advanced sequencing is required to aid the diagnosis of undetermined cerebellar ataxia in Chinese patients.

Ataxias

2017 ◽  
Author(s):  
Vikram G. Shakkottai
Keyword(s):  
Cerebellar Ataxia ◽  
Autosomal Recessive ◽  
Friedreich Ataxia ◽  
Specific Treatment ◽  
Specific Gene ◽  
Progressive Cerebellar Ataxia ◽  
Cerebellar Ataxias ◽  
Gene Defects ◽  
Inherited Ataxias ◽  
Autosomal Recessive Cerebellar Ataxias

Autosomal recessive cerebellar ataxias are a group of inherited neurological disorders with progressive balance and gait difficulties. In these disorders, cerebellar ataxia is often accompanied by eye movement abnormalities and peripheral nervous system involvement. A unifying mechanism for disease pathogenesis that is common to all the recessive ataxias likely does not exist. Nevertheless, some pathophysiological pathways are common to several autosomal recessive cerebellar ataxias. Specific gene defects in each disorder are summarized in the chapter. The most common recessively inherited ataxias are Friedreich ataxia and Ataxia telangiectasia. A recessive ataxia must be considered for any individual with progressive cerebellar ataxia with onset less than 30 years. The treatment is primarily supportive, but some recessive ataxias have specific treatment.

scholarly journals Four novel mutations in the ALPL gene in Chinese patients with odonto, childhood, and adult hypophosphatasia

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Lijun Xu ◽  
Qianqian Pang ◽  
Yan Jiang ◽  
Ou Wang ◽  
Mei Li ◽  
...  
Keyword(s):  
Serum Alkaline Phosphatase ◽  
Gene Mutations ◽  
Dominant Negative ◽  
Chinese Patients ◽  
Dominant Negative Effect ◽  
Healthy Controls ◽  
Missense Mutations ◽  
Genetic Characteristics ◽  
Chinese Families ◽  
Negative Effect

Hypophosphatasia (HPP) is a rare inherited disorder characterized by defective bone and/or dental mineralization, and decreased serum alkaline phosphatase (ALP) activity. ALPL, the only gene related with HPP, encodes tissue non-specific ALP (TNSALP). Few studies were carried out in ALPL gene mutations in the Chinese population with HPP. The purpose of the present study is to elucidate the clinical and genetic characteristics of HPP in five unrelated Chinese families and two sporadic patients. Ten clinically diagnosed HPP patients from five unrelated Chinese families and two sporadic patients and fifty healthy controls were genetically investigated. All 12 exons and exon–intron boundaries of the ALPL gene were amplified by PCR and directly sequenced. The laboratory and radiological investigations were conducted simultaneously in these HPP ten patients. A 3D model of the TNSALP was used to predict the dominant negative effect of identified missense mutations. Three odonto, three childhood, and four adult types of HPP were clinically diagnosed. Ten mutations were identified in five unrelated Chinese families and two sporadic patients, including eight missense mutations and two frameshift mutations. Of which, four were novel: one frameshift mutation (p.R138Pfsx45); three missense mutations (p.C201R, p.V459A, p.C497S). No identical mutations and any other new ALPL mutations were found in unrelated 50 healthy controls. Our study demonstrated that the ALPL gene mutations are responsible for HPP in these Chinese families. These findings will be useful for clinicians to improve understanding of this heritable bone disorder.

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

2013 ◽  
Vol 71 (6) ◽  
pp. 345-348 ◽  
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.

scholarly journals Autosomal Recessive Cerebellar Ataxias: Paving the Way toward Targeted Molecular Therapies

Neuron ◽  
2019 ◽  
Vol 101 (4) ◽  
pp. 560-583 ◽  
Author(s):  
Matthis Synofzik ◽  
Hélène Puccio ◽  
Fanny Mochel ◽  
Ludger Schöls
Keyword(s):  
Autosomal Recessive ◽  
Cerebellar Ataxias ◽  
Molecular Therapies ◽  
Targeted Molecular Therapies ◽  
Autosomal Recessive Cerebellar Ataxias ◽  
The Way

Abstract TP269: Distinct Molecular Mechanisms of Htra1 Mutants in Manifesting Heterozygotes With Carasil

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Hiroaki Nozaki ◽  
Taisuke Kato ◽  
Megumi Nihonmatsu ◽  
Yohei Saito ◽  
Ikuko Mizuta ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Molecular Mechanisms ◽  
Small Vessel Disease ◽  
Gel Filtration ◽  
Gene Mutations ◽  
Missense Mutations ◽  
Inherited Disease ◽  
Wild Type ◽  
Vessel Disease ◽  
Activation Cascade

Introduction: Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), an autosomal recessive inherited cerebral small vessel disease (CSVD), involves severe leukoaraiosis, multiple lacunar infarcts, early-onset alopecia, and spondylosis deformans. High-temperature requirement serine peptidase A1 (HTRA1) gene mutations cause CARASIL by decreasing HTRA1 protease activity. Although CARASIL is a recessive inherited disease, heterozygous mutations in the HTRA1 gene were recently identified in 11 families with CSVD. Because CSVD is frequently observed in elderly individuals, it is unclear which mutants truly contribute to CSVD pathogenesis. Here, we found heterozygous mutations in the HTRA1 gene in individuals with CSVD and investigated the differences in biochemical characteristics between these mutant HTRA1s and mutant HTRA1s observed in homozygotes. Methods: We recruited 113 unrelated index patients with clinically diagnosed CSVD. The coding sequences of the HTRA1 gene were analyzed. We evaluated HTRA1 protease activities using casein assays and oligomeric HTRA1 formation using gel filtration chromatography. Results: We found 4 heterozygous missense mutations in the HTRA1 gene (p.G283E, p.P285L, p.R302Q, and p.T319I) in 6 patients from 113 unrelated index patients and in 2 siblings in 2 unrelated families with p.R302Q. These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in CARASIL (A252T and V297M) did not inhibit wild- type HTRA1 activity. Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers. P285L and R302Q HTRA1s formed trimers, but their mutations were located in domains that are important for trimer-associated HTRA1 activation; in contrast, A252T and V297M HTRA1s, which have been observed in CARASIL, also formed trimers but had mutations outside the domains important for trimer- associated HTRA1 activation. Conclusions: The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers.

Coenzyme Q10 deficiency; A treatable autosomal recessive cerebellar ataxias

2017 ◽  
Vol 21 ◽  
pp. e136
Author(s):  
Gül Demet Kaya Ozcora ◽  
Nazlı Basak ◽  
Mehmet Canpolat ◽  
Hamit Acer ◽  
Sefer Kumandas
Keyword(s):  
Coenzyme Q10 ◽  
Autosomal Recessive ◽  
Cerebellar Ataxias ◽  
Autosomal Recessive Cerebellar Ataxias

scholarly journals Detection and Analysis of Gene Mutations in Patients with Glanzmann's Thrombasthenia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2373-2373
Author(s):  
Boyang Sun ◽  
Donglei Zhang ◽  
Huiyuan Li ◽  
Xueqing Dou ◽  
Renchi Yang
Keyword(s):  
Clinical Laboratory ◽  
Conflicts Of Interest ◽  
Gene Mutations ◽  
Adenosine Diphosphate ◽  
Severe Bleeding ◽  
Missense Mutations ◽  
Novel Mutations ◽  
Genetic Characteristics ◽  
Pathogenic Variants ◽  
Standards And Guidelines

Background: Glanzmann thrombasthenia (GT) is a rare inherited disorder of bleeding, and it is characterized by the impaired or absent platelet aggregation to multiple physiologic agonists such as collagen, adenosine diphosphate (ADP), arachidonic acid(AA), but normal reaction to ristocetin. There is qualitative or quantitative defect in platelet integrin αIIbβ3(GPIIb/IIIa). Pathogenic variants of either αIIb or β3 unit could cause GT. The database of gene mutations is continuously updated on the Internet (http://www.hgmd.org); it totally lists 236 variants of ITGA2B gene and 170 variants of ITGB3 gene. Aim: To characterize the clinical manifestation and molecular basis of GT patients in China, and update the pathogenic variants database. Method: Clinical features are evaluated in 104 patients with GT. New generation sequencing was performed with a custom designed panel for the bleeding and platelet disease involving 76 genes, while ITGA2B and ITGB3 were enrolled. Result: The initial bleeding occurred before 1 age in most patients. Incidence of consanguinity is 12.5%. Symptoms lessened with age in about 30% patients. Female patients suffered more severe bleeding than male patients. Fifty different mutations were detected, among which 15 were novel. Most patients were compound heterozygotes and most mutations detected were missense mutations. Among 15 novel mutations, there were 7 missense mutations, 2 nonsense mutations, 2 splicing mutations, 4 frameshift mutations. Pathogenicity of all novel mutations were evaluated according to the standards and guidelines of ACMG. All variants detected were pathogenic or likely pathogenic. Furthermore, c.1750C>T [p.R584X] and c.2333A>C [p.Q778P] in ITGA2B were detected in 10 and 16 unrelated families, strongly suggesting a founder effect. Conclusion: Our study reports the largest cohort of GT in China, describing the clinical, laboratory and genetic characteristics of 104 patients. We found 15 novel pathogenic mutations in ITGA2B and ITGB3 causing GT. Theses novel findings expand the GT mutation spectrum. Disclosures No relevant conflicts of interest to declare.

A Novel Mutation of HINT1 Gene in an Adolescent Female with Axonal Neuropathy and Neuromyotonia

2020 ◽  
Author(s):  
Bülent Kara ◽  
Sedat Gül ◽  
Ayfer Sakarya Güneş ◽  
Serap Mülayim ◽  
Gözde Yeşil
Keyword(s):  
Genetic Testing ◽  
Autosomal Recessive ◽  
Novel Mutation ◽  
Axonal Neuropathy ◽  
Gene Mutations ◽  
Autosomal Recessive Inheritance ◽  
Muscle Stiffness ◽  
Adolescent Female ◽  
Recessive Inheritance ◽  
Exome Analysis

Abstract HINT1 gene mutations cause an axonal neuropathy with some specific findings including presence of neuromyotonia, autosomal recessive inheritance, onset in the first decade, and primary motor involvement. We described an 18-year-old female patient who presented to the clinic with gait instability and muscle stiffness. A homozygous novel c.180_181delAT (p.Ser61Profs*8) variant in the HINT1 gene was found by clinical exome analysis. Parents were heterozygous for the same variant. The patient was diagnosed with autosomal recessive axonal neuropathy with neuromyotonia. The presence of neuromyotonia must be evaluated in patients with hereditary axonal neuropathies as this can help the diagnosis prior to genetic testing.

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