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Medicine Dec 2021Spinocerebellar ataxia (SCA) is a common neurogenetic disease that mainly manifests as ataxia of posture, gait, and limbs, cerebellar dysarthria, and cerebellar and... (Review)
Review
RATIONALE
Spinocerebellar ataxia (SCA) is a common neurogenetic disease that mainly manifests as ataxia of posture, gait, and limbs, cerebellar dysarthria, and cerebellar and supranuclear eye movement disorders. SCA has been found to include many subtypes, which are mainly mapped to 2 genetic patterns: autosomal dominant cerebellar ataxia and autosomal recessive cerebellar ataxia. Molecular genetic diagnosis functions as a necessity in its clinical diagnosis and treatment. In preliminary clinical work, we identified a family of SCA28 with rare gene mutation.
PATIENT CONCERNS
There are 5 patients in this family. The proband is a 32 year-old male, he mainly manifest unsteady steps for more than 7 months. The daughter of his younger maternal uncle gradually had unsteady steps and unclear speech for 5 years. The proband's mother, uncle and grandfather had similar symptoms, but they all died.
DIAGNOSIS
After Brain magnetic resonance imaging, whole exome sequencing and Sanger validation, the patients presented a c.1852A > G missense mutation in the exon region of AFG3L2 gene. The other family members revealed no AFG3L2 mutations. SCA28 is the one uniquely caused by a pathogenic variation in the mitochondrial protein AFG3L2. Combined with the clinical manifestations, auxiliary examinations and sequencing results of the patients (III-3 and III-5), the diagnosis of SCA28 was suspected.
INTERVENTIONS
The patients did not receive any drug treatment and the proband receive rehabilitation treatment.
OUTCOMES
The symptoms of ataxia were still progressively aggravated.
LESSONS
Molecular genetic diagnosis is necessary for ataxia. We here report the case and review the literature.
Topics: ATP-Dependent Proteases; ATPases Associated with Diverse Cellular Activities; Adult; Brain; Cerebellar Ataxia; China; Humans; Magnetic Resonance Imaging; Male; Mutation; Pedigree; Spinocerebellar Ataxias; Exome Sequencing
PubMed: 34918652
DOI: 10.1097/MD.0000000000028008 -
Brain : a Journal of Neurology May 2012Spinocerebellar ataxia 36 has been recently described in Japanese families as a new type of spinocerebellar ataxia with motor neuron signs. It is caused by a GGCCTG...
Spinocerebellar ataxia 36 has been recently described in Japanese families as a new type of spinocerebellar ataxia with motor neuron signs. It is caused by a GGCCTG repeat expansion in intron 1 of NOP56. Family interview and document research allowed us to reconstruct two extensive, multigenerational kindreds stemming from the same village (Costa da Morte in Galicia, Spain), in the 17th century. We found the presence of the spinocerebellar ataxia 36 mutation co-segregating with disease in these families in whom we had previously identified an ~0.8 Mb linkage region to chromosome 20 p. Subsequent screening revealed the NOP56 expansion in eight additional Galician ataxia kindreds. While normal alleles contain 5-14 hexanucleotide repeats, expanded alleles range from ~650 to 2500 repeats, within a shared haplotype. Further expansion of repeat size was frequent, especially upon paternal transmission, while instances of allele contraction were observed in maternal transmissions. We found a total of 63 individuals carrying the mutation, 44 of whom were confirmed to be clinically affected; over 400 people are at risk. We describe here the detailed clinical picture, consisting of a late-onset, slowly progressive cerebellar syndrome with variable eye movement abnormalities and sensorineural hearing loss. There were signs of denervation in the tongue, as well as mild pyramidal signs, but otherwise no signs of classical amyotrophic lateral sclerosis. Magnetic resonance imaging findings were consistent with the clinical course, showing atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivo-ponto-cerebellar atrophy. We estimated the origin of the founder mutation in Galicia to have occurred ~1275 years ago. Out of 160 Galician families with spinocerebellar ataxia, 10 (6.3%) were found to have spinocerebellar ataxia 36, while 15 (9.4%) showed other of the routinely tested dominant spinocerebellar ataxia types. Spinocerebellar ataxia 36 is thus, so far, the most frequent dominant spinocerebellar ataxia in this region, which may have implications for American countries associated with traditional Spanish emigration.
Topics: Age Factors; Aged; Aged, 80 and over; Brain; Chromosomes, Human, Pair 20; DNA Mutational Analysis; Disease Progression; Family Health; Female; Genetic Linkage; Genotype; Humans; Introns; Magnetic Resonance Imaging; Male; Middle Aged; Nuclear Proteins; Spain; Spinocerebellar Ataxias; Trinucleotide Repeat Expansion
PubMed: 22492559
DOI: 10.1093/brain/aws069 -
Nutritional Neuroscience Jan 2020Spinocerebellar ataxias (SCAs) are a group of neurodegenerative genetic diseases characterized by movement disorders that can affect nutritional status and body... (Comparative Study)
Comparative Study
Spinocerebellar ataxias (SCAs) are a group of neurodegenerative genetic diseases characterized by movement disorders that can affect nutritional status and body composition. This study sought to assess body composition in SCA3 and SCA10 patients. Anthropometric assessments and bioelectric impedance analysis were performed in 46 SCA3 and SCA10 patients and 76 controls of both genders. Of the patients, 69.6% had SCA3 and 58.7% were women. SCA3 patients had significantly lower percentages of body fat (%BF) than controls (15.0 ± 6.1 vs. 20.6 ± 7.1; =0.014) and (22.4 ± 6.9 vs. 30.1 ± 6.0; <0.001), respectively. Among the women, there was a statistically significant difference in %BF between SCA3 and SCA10 patients (22.4 ± 6.9 vs. 32.4 ± 4.9; <0.001). Male and female SCA3 patients had significantly lower fat-free mass (FFM) than controls [50.6 kg (46.9-54.7) vs. 58.6 kg (52.6-63.9); =0.001] and [38.2 kg (35.1-42.6) vs. 42.8 kg (39.7-46.1); =0.004], respectively. Male SCA10 patients also had lower FFM than controls [51.2 kg (47.1-55.4) vs. (52.6-63.9); =0.008]. Female SCA10 patients had significantly higher FFM than controls and SCA3 patients [45.0 kg (43.3-45.6) vs. 42.8 kg (39.7-46.1); =0.004] and [45.0 kg (43.3-45.6) vs. 38.2 kg (35.1-42.6); =0.004], respectively. There was moderate correlation (-0.42) between disease duration and muscle mass (MM), and weak (-0.38) between SARA (Scale for the Assessment and Rating of Ataxia) and MM in SCA3. In SCA10, there was no significant correlation between these variables. Female SCA3 patients had more body composition changes than female SCA10 patients, mainly in relation to FFM. SCA3 and SCA10 patients need nutritional follow-up to minimize body compartment changes.
Topics: Adult; Anthropometry; Body Composition; DNA Repeat Expansion; Female; Humans; Machado-Joseph Disease; Male; Middle Aged; Spinocerebellar Ataxias
PubMed: 29734917
DOI: 10.1080/1028415X.2018.1469282 -
Cell Jan 2003DNA single-strand break repair (SSBR) is critical for the survival and genetic stability of mammalian cells. Three papers have recently associated mutations in putative... (Review)
Review
DNA single-strand break repair (SSBR) is critical for the survival and genetic stability of mammalian cells. Three papers have recently associated mutations in putative human SSBR genes with hereditary spinocerebellar ataxia. The emerging links between SSBR and neurodegenerative disorders are discussed.
Topics: Amino Acid Sequence; Cell Death; Conserved Sequence; DNA Damage; DNA Repair; DNA Topoisomerases, Type I; DNA, Single-Stranded; DNA-Binding Proteins; Gene Expression Regulation; Humans; Models, Genetic; Molecular Sequence Data; Mutation; Neurodegenerative Diseases; Nuclear Proteins; Polynucleotide 5'-Hydroxyl-Kinase; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Spinocerebellar Ataxias
PubMed: 12526788
DOI: 10.1016/s0092-8674(02)01247-3 -
Tremor and Other Hyperkinetic Movements... 2022Spinocerebellar ataxia type-12 (SCA12) is a rare form of SCA, most commonly reported from the Indian and related families. In this study we describe the clinical,...
INTRODUCTION
Spinocerebellar ataxia type-12 (SCA12) is a rare form of SCA, most commonly reported from the Indian and related families. In this study we describe the clinical, genetic, and radiological characteristics of a sizeable cohort of genetically proven SCA12.
METHODS
A retrospective chart-review of the genetically confirmed SCA12 patients from our centre. The demographic, clinical, and investigation findings were reviewed. Correlation of expanded repeats length with various demographic and clinical features were studied.
RESULTS
A total of 49 patients (34 males, 42 families) were included of which 79.6% belonged to community. The mean age at onset and age at presentation were 46.38 ± 11.7 years and 53.16 ± 12.78 years respectively. The most common initial symptom was tremor (73.5%), followed by ataxia (18.4%). At presentation, 95.9% of the patients had tremor with predominant distribution in the bilateral upper limbs (85.7%). At presentation, 73.5% of patients had ataxia and 22.4% had cognitive dysfunction. The mean CAG repeat length in in the expanded allele was 53.26 ± 6.10 (40-72). The lowest pathogenic expanded repeat sizes in recorded in our cohort was 40 & 42 repeats from two patients with a consistent clinical phenotype. Another unusual phenotype was the presence of prominent myoclonus. There was no significant correlation between the age at onset of symptoms and the repeat size of CAG repeat.
CONCLUSION
SCA12 is not confined to a single ethnicity. Upper limb tremor and ataxia were the most common presentation. Unusual presentation may cause diagnostic confusion especially when recorded in patients from non- families.
Topics: Ataxia; Cohort Studies; Female; Genetic Profile; Hospitals; Humans; Male; Nerve Tissue Proteins; Retrospective Studies; Spinocerebellar Ataxias; Tremor
PubMed: 35531119
DOI: 10.5334/tohm.686 -
Journal of Neurology Mar 2022Spinocerebellar ataxia type 14 (SCA14) is a dominantly inherited neurological disorder characterized by slowly progressive cerebellar ataxia. SCA14 is caused by...
INTRODUCTION
Spinocerebellar ataxia type 14 (SCA14) is a dominantly inherited neurological disorder characterized by slowly progressive cerebellar ataxia. SCA14 is caused by mutations in PRKCG, a gene encoding protein kinase C gamma (PKCγ), a master regulator of Purkinje cells development.
METHODS
We performed next-generation sequencing targeted resequencing panel encompassing 273 ataxia genes in 358 patients with genetically undiagnosed ataxia.
RESULTS
We identified fourteen patients in ten families harboring nine pathogenic heterozygous variants in PRKCG, seven of which were novel. We encountered four patients with not previously described phenotypes: one with episodic ataxia, one with a spastic paraparesis dominating her clinical manifestations, and two children with an unusually severe phenotype.
CONCLUSIONS
Our study broadens the genetic and clinical spectrum of SCA14.
Topics: Ataxia; Female; Heterozygote; Humans; Mutation; Phenotype; Protein Kinase C; Spinocerebellar Ataxias
PubMed: 34292398
DOI: 10.1007/s00415-021-10712-5 -
Cells May 2022Pentanucleotide expansion diseases constitute a special class of neurodegeneration. The repeat expansions occur in non-coding regions, have likely arisen from elements,... (Review)
Review
Pentanucleotide expansion diseases constitute a special class of neurodegeneration. The repeat expansions occur in non-coding regions, have likely arisen from elements, and often result in autosomal dominant or recessive phenotypes with underlying cerebellar neuropathology. When transcribed (potentially bidirectionally), the expanded RNA forms complex secondary and tertiary structures that can give rise to RNA-mediated toxicity, including protein sequestration, pentapeptide synthesis, and mRNA dysregulation. Since several of these diseases have recently been discovered, our understanding of their pathological mechanisms is limited, and their therapeutic interventions underexplored. This review aims to highlight new in vitro and in vivo insights into these incurable diseases.
Topics: Ataxia; Cerebellum; Humans; Microsatellite Repeats; RNA; Spinocerebellar Ataxias
PubMed: 35563872
DOI: 10.3390/cells11091567 -
Stem Cell Reviews and Reports Feb 2022Dominant spinocerebellar ataxias (SCAs) constitute a large group of phenotypically and genetically heterogeneous disorders that mainly present with dysfunction of the... (Review)
Review
Dominant spinocerebellar ataxias (SCAs) constitute a large group of phenotypically and genetically heterogeneous disorders that mainly present with dysfunction of the cerebellum as their main hallmark. Although animal and cell models have been highly instrumental for our current insight into the underlying disease mechanisms of these neurodegenerative disorders, they do not offer the full human genetic and physiological context. The advent of human induced pluripotent stem cells (hiPSCs) and protocols to differentiate these into essentially every cell type allows us to closely model SCAs in a human context. In this review, we systematically summarize recent findings from studies using hiPSC-based modelling of SCAs, and discuss what knowledge has been gained from these studies. We conclude that hiPSC-based models are a powerful tool for modelling SCAs as they contributed to new mechanistic insights and have the potential to serve the development of genetic therapies. However, the use of standardized methods and multiple clones of isogenic lines are essential to increase validity and reproducibility of the insights gained.
Topics: Animals; Cerebellum; Genetic Therapy; Humans; Induced Pluripotent Stem Cells; Reproducibility of Results; Spinocerebellar Ataxias
PubMed: 34031815
DOI: 10.1007/s12015-021-10184-0 -
Neurologic Clinics Nov 2013The autosomal dominant spinocerebellar ataxias are a diverse and clinically heterogeneous group of disorders characterized by degeneration and dysfunction of the... (Review)
Review
The autosomal dominant spinocerebellar ataxias are a diverse and clinically heterogeneous group of disorders characterized by degeneration and dysfunction of the cerebellum and its associated pathways. Clinical and diagnostic evaluation can be challenging because of phenotypic overlap among causes, and a stratified and systematic approach is essential. Recent advances include the identification of additional genes causing dominant genetic ataxia, a better understanding of cellular pathogenesis in several disorders, the generation of new disease models that may stimulate development of new therapies, and the use of new DNA sequencing technologies, including whole-exome sequencing, to improve diagnosis.
Topics: Animals; Disease Models, Animal; Genetic Testing; Humans; Machado-Joseph Disease; Mice; Peptides; Rats; Spinocerebellar Ataxias
PubMed: 24176420
DOI: 10.1016/j.ncl.2013.04.006 -
Cerebellum (London, England) 2008Spinocerebellar ataxia type 7 (SCA7) is unique among CAG/polyglutamine (polyQ) repeat diseases due to dramatic intergenerational instability in repeat length and an... (Review)
Review
Spinocerebellar ataxia type 7 (SCA7) is unique among CAG/polyglutamine (polyQ) repeat diseases due to dramatic intergenerational instability in repeat length and an associated cone-rod dystrophy retinal degeneration phenotype. SCA7 is caused by a polyQ expansion in the protein ataxin-7. Like other neurodegenerative diseases caused by polyQ expansion mutations, the spectrum of clinical severity and disease progression worsens with increasing polyQ length. Several potential mechanisms for the molecular pathogenesis of polyQ-expanded ataxin-7 have been suggested. These include, but are not limited to, alteration of endogenous ataxin-7 function, abnormal processing and stability of polyQ ataxin-7, and alteration of transcriptional regulation via interaction of polyQ-expanded ataxin-7 with other transcriptional regulators. Ataxin-7's normal function as a transcription factor may contribute to the selective vulnerability of specific cellular populations in SCA7, and the resolution of the mechanistic basis of this pathogenic cascade is a major focus of SCA7 disease research. PolyQ-expanded ataxin-7 can cause non-cell autonomous neurodegeneration in cerebellar Purkinje cells. Advances in understanding SCA7's molecular basis have led to important insights into cell-type specific neurodegeneration. We expect that further study of ataxin-7 normal function, insights into the molecular basis of SCA7 neurodegeneration, and the development of therapeutic interventions for SCA7 will greatly influence related endeavors directed at other CAG/polyQ repeat diseases.
Topics: Ataxin-7; Brain; Humans; Magnetic Resonance Imaging; Mutation; Nerve Degeneration; Nerve Tissue Proteins; Neurons; Spinocerebellar Ataxias; Transcription, Genetic; Trinucleotide Repeat Expansion; Trinucleotide Repeats
PubMed: 18418675
DOI: 10.1007/s12311-008-0027-y