BACKGROUND

Spinocerebellar Ataxia (SCA) represents a rare and heterogeneous group of neurodegenerative disorders, typically characterized by the progressive loss of coordination of movement, resulting primarily from cerebellar dysfunction. This case report discusses the history, clinical presentation, and diagnostic findings of a patient who exhibited symptoms suggestive of SCA. Given the notable familial pattern, further evaluation was undertaken using genetic testing. The objective of this paper is to present the clinical, genetic findings, and inheritance pattern of a patient and her family with SCA.

Our case is a 36-year-old Filipino female with progressive cerebellar dysfunction for over a decade. Cranial Magnetic Resonance Imaging (MRI) revealed bilateral cerebellar atrophy. Genetic testing identified a Variant of Uncertain Significance (VUS) in the inositol 1,4,5- triphosphate receptor type 1 (ITPR1) gene, a finding consistent with Spinocerebellar Ataxia type 15 (SCA 15). This represents the first reported case of SCA 15 in the Philippines and in Asia.

A detailed pedigree assessment revealed that 18 immediate and extended family members had similar symptoms suggestive of hereditary ataxia. Ten relatives had already passed away, and four could not be contacted for further evaluation. Three available family members were examined and likewise demonstrated comparable cerebellar findings, supporting a familial pattern of the disease.

The findings from this case series suggest that SCA 15 may be present in Filipino families, with an autosomal dominant (AD) inheritance pattern. While no data on the prevalence or incidence of SCA15 in the Philippines currently exists, this report calls attention to the need for further research and genetic studies within the Filipino population.

OBJECTIVE: To explore the clinical and genetic characteristics of a child with spinocerebellar ataxia type 29 (SCA29) due to novel variant of the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) gene. METHODS: The child was subjected high-throughput sequencing, and candidate variant was verified by Sanger sequencing of his family members. RESULTS: The child was found to harbor a c.800C>T (p.T267M) variant of the ITPR1 gene, which was not found in his parents and their fetus. The variant has occurred in a hotspot of the ITPR1 gene variants and was unreported before in China. Based on his clinical and genetic characteristics, the child was diagnosed with SCA29. CONCLUSION The novel heterozygous c.800C>T (p.T267M) of the ITPR1 gene probably underlay the SCA29 in this child.
Child ; Humans ; Family ; Inositol 1,4,5-Trisphosphate Receptors/genetics* ; Mutation ; Spinocerebellar Ataxias/genetics* ; Spinocerebellar Degenerations

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare and early-onset neurodegenerative disease caused by variants of the SACS gene which maps to chromosome 13q11 and encodes sacsin protein. Sacsin is highly expressed in large motor neurons, in particular cerebellar Purkinje cells. This article has provided a review for the structure and function of sacsin protein and the mechanisms underlying abnormalities of sacsin in ARSACS disease.
Humans ; Spinocerebellar Ataxias/pathology* ; Ataxia/genetics* ; Muscle Spasticity/genetics*

OBJECTIVE: To explore the clinical feature and genetic variant of a child with autosomal recessive Charlevoix-Saguenay type spastic ataxia (ARSACS). METHODS: Clinical data of a child who was admitted to the West China Second Hospital of Sichuan University on April 30, 2021 was collected. Whole exome sequencing (WES) was carried out for the child and his parents. Candidate variants were verified by Sanger sequencing and bioinformatic analysis based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). RESULTS: The child, a 3-year-and-3-month-old female, had a complain of "walking instability for over a year". Physical and laboratory examination revealed progressive and aggravated gait instability, increased muscle tone of the right limbs, peripheral neuropathy of the lower limbs, and thickening of retinal nerve fiber layer. The results of WES revealed that she has harbored a maternally derived heterozygous deletion of exons 1 to 10 of the SACS gene, in addition with a de novo heterozygous c.3328dupA variant in exon 10 of the SACS gene. Based on the ACMG guidelines, the exons 1-10 deletion was rated as likely pathogenic (PVS1+PM2_Supporting), and the c.3328dupA was rated as a pathogenic variant (PVS1_Strong+PS2+PM2_Supporting). Neither variant was recorded in the human population databases. CONCLUSION The c.3328dupA variant and the deletion of exons 1-10 of the SACS gene probably underlay the ARSACS in this patient.
Female ; Humans ; Heat-Shock Proteins/genetics* ; Muscle Spasticity/genetics* ; Mutation ; Spinocerebellar Ataxias/pathology* ; Child, Preschool

Objective: To explore the heterogeneity and growth factor regulatory network of dermal fibroblasts (dFbs) in mouse full-thickness skin defect wounds based on single-cell RNA sequencing. Methods: The experimental research methods were adopted. The normal skin tissue from 5 healthy 8-week-old male C57BL/6 mice (the same mouse age, sex, and strain below) was harvested, and the wound tissue of another 5 mice with full-thickness skin defect on the back was harvested on post injury day (PID) 7. The cell suspension was obtained by digesting the tissue with collagenase D and DNase Ⅰ, sequencing library was constructed using 10x Genomics platform, and single-cell RNA sequencing was performed by Illumina Novaseq6000 sequencer. The gene expression matrices of cells in the two kinds of tissue were obtained by analysis of Seurat 3.0 program of software R4.1.1, and two-dimensional tSNE plots classified by cell group, cell source, and gene labeling of major cells in skin were used for visual display. According to the existing literature and the CellMarker database searching, the expression of marker genes in the gene expression matrices of cells in the two kinds of tissue was analyzed, and each cell group was numbered and defined. The gene expression matrices and cell clustering information were introduced into CellChat 1.1.3 program of software R4.1.1 to analyze the intercellular communication in the two kinds of tissue and the intercellular communication involving vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF) signal pathways in the wound tissue, the relative contribution of each pair of FGF subtypes and FGF receptor (FGFR) subtypes (hereinafter referred to as FGF ligand receptor pairs) to FGF signal network in the two kinds of tissue, and the intercellular communication in the signal pathway of FGF ligand receptor pairs with the top 2 relative contributions in the two kinds of tissue. The normal skin tissue from one healthy mouse was harvested, and the wound tissue of one mouse with full-thickness skin defect on the back was harvested on PID 7. The multiple immunofluorescence staining was performed to detect the expression and distribution of FGF7 protein and its co-localized expression with dipeptidyl peptidase 4 (DPP4), stem cell antigen 1 (SCA1), smooth muscle actin (SMA), and PDGF receptor α (PDGFRα) protein. Results: Both the normal skin tissue of healthy mice and the wound tissue of full-thickness skin defected mice on PID 7 contained 25 cell groups, but the numbers of cells in each cell group between the two kinds of tissue were different. Genes PDGFRα, platelet endothelial cell adhesion molecule 1, lymphatic endothelial hyaluronic acid receptor 1, receptor protein tyrosine phosphatase C, keratin 10, and keratin 79 all had distinct distributions on two-dimensional tSNE plots, indicating specific cell groups respectively. The 25 cell groups were numbered by C0-C24 and divided into 9 dFb subgroups and 16 non-dFb groups. dFb subgroups included C0 as interstitial progenitor cells, C5 as adipose precursor cells, and C13 as contractile muscle cells related fibroblasts, etc. Non-dFb group included C3 as neutrophils, C8 as T cells, and C18 as erythrocytes, etc. Compared with that of the normal skin tissue of healthy mice, the intercellular communication in the wound tissue of full-thickness skin defected mice on PID 7 was more and denser, and the top 3 cell groups in intercellular communication intensity were dFb subgroups C0, C1, and C2, of which all communicated with other cell groups in the wound tissue. In the wound tissue of full-thickness skin defected mice on PID 7, VEGF signals were mainly sent by the dFb subgroup C0 and received by vascular related cell groups C19 and C21, PDGF signals were mainly sent by peripheral cells C14 and received by multiple dFb subgroups, EGF signals were mainly sent by keratinocyte subgroups C9 and C11 and received by the dFb subgroup C0, and the main sender and receiver of FGF signals were the dFb subgroup C6. In the relative contribution rank of FGF ligand receptor pairs to FGF signal network in the normal skin tissue of healthy mice and the wound tissue of full-thickness skin defected mice on PID 7, FGF7-FGFR1 was the top 1, and FGF7-FGFR2 or FGF10-FGFR1 was in the second place, respectively; compared with those in the normal skin tissue, there was more intercellular communication in FGF7-FGFR1 signal pathway, while the intercellular communication in FGF7-FGFR2 and FGF10-FGFR1 signal pathways decreased slightly or did not change significantly in the wound tissue; the intercellular communication in FGF7-FGFR1 signal pathway in the wound tissue was stronger than that in FGF7-FGFR2 or FGF10-FGFR1 signal pathway; in the two kinds of tissue, FGF7 signal was mainly sent by dFb subgroups C0, C1, and C2, and received by dFb subgroups C6 and C7. Compared with that in the normal skin tissue of healthy mouse, the expression of FGF7 protein was higher in the wound tissue of full-thickness skin defected mouse on PID 7; in the normal skin tissue, FGF7 protein was mainly expressed in the skin interstitium and also expressed in the white adipose tissue near the dermis layer; in the two kinds of tissue, FGF7 protein was co-localized with DPP4 and SCA1 proteins and expressed in the skin interstitium, co-localized with PDGFRα protein and expressed in dFbs, but was not co-localized with SMA protein, with more co-localized expression of FGF7 in the wound tissue than that in the normal skin tissue. Conclusions: In the process of wound healing of mouse full-thickness skin defect wound, dFbs are highly heterogeneous, act as potential major secretory or receiving cell populations of a variety of growth factors, and have a close and complex relationship with the growth factor signal pathways. FGF7-FGFR1 signal pathway is the main FGF signal pathway in the process of wound healing, which targets and regulates multiple dFb subgroups.
Animals ; Dipeptidyl Peptidase 4 ; Epidermal Growth Factor ; Fibroblasts ; Imidazoles ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Receptor, Platelet-Derived Growth Factor alpha ; Sequence Analysis, RNA ; Skin Abnormalities ; Soft Tissue Injuries ; Spinocerebellar Ataxias ; Sulfonamides ; Thiophenes ; Vascular Endothelial Growth Factor A

OBJECTIVE: To analyze the dynamic variant and clinical subtype of a pedigree affected with spinocerebellar ataxia (SCA) by using fluorescent-labeled primer combined with capillary electrophoresis. METHODS: Genomic DNA was extracted from 8 members including 6 patients and 2 healthy individuals from the pedigree. Six pairs of fluorescent-labeled primers were designed to screen pathological variants in association with common subtypes of SCA including SCA1, SCA2, SCA3, SCA6, SCA12 and SCA17.The PCR products were detected by capillary electrophoresis. RESULTS: The number of CAG repeats in the SCA3 gene of the proband were determined as 8 and 70, exceeded the normal range(12 to 40), which suggested a diagnosis of SCA3. The other five patients were all detected with abnormal CAG repeats in the SCA3 gene, while the two healthy individuals were determined to be within the normal range. CONCLUSION The abnormal expansion of CAG repeats in the SCA3 gene probably underlay the pathogenesis of the disease in this pedigree. Combined fluorescent-labeled primers PCR and capillary electrophoresis can detect dynamic variants among SCA patients with efficiency and accuracy.
Ataxin-3/genetics* ; Genetic Variation ; Humans ; Machado-Joseph Disease/genetics* ; Pedigree ; Repressor Proteins/genetics* ; Trinucleotide Repeats/genetics*

OBJECTIVE: To carry out mutation analysis for a Chinese family affected with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). METHODS: Whole exome sequencing (WES) was used to screen potential mutations within genomic DNA extracted from the proband. Suspected mutation was validated by combining clinical data and results of Sanger sequencing. RESULTS: A homozygous deletional mutation c.3665_3675delGTGCTGTCTTA (p.S1222fs) was found in the proband, for which her parents were both heterozygous carriers. CONCLUSION WES is capable of detecting mutation underlying this disorder and facilitating genetic counseling and prenatal diagnosis for the affected family. A novel pathogenic mutation of the SACS gene was discovered.
Female ; Genes, Recessive ; Heat-Shock Proteins ; genetics ; Humans ; Muscle Spasticity ; Mutation ; Spinocerebellar Ataxias ; congenital

OBJECTIVE: Machado-Joseph disease (MJD) is a spinocerebellar ataxia, and osteoporosis is a multifactor disease that may affect patients with neurologic conditions. The frequency of osteoporosis among MJD patients, however, has not been studied. The purpose of this study is to evaluate bone mineral density (BMD) and identify correlations between clinical factors and frequency of vertebral fractures in patients with MJD. METHODS: Clinical data, lumbar X-rays and BMD data were obtained in 30 patients with MJD. RESULTS: Ten patients (33.3%) showed low BMD in at least one of the sites studied based on Z-scores. The Z-score correlated directly with body mass index, and the femoral neck Z-score was inversely correlated with cytosine-adenine-guanine (CAG) expansion. There was no correlation between BMD and other clinical factors. Forty-three percent of the patients reported previous pathologic fractures. Five patients (16.7%) had at least one fracture detected by lumbar X-ray. CONCLUSION: Low BMD and fractures are frequent among MJD patients, and careful management of BMD may be beneficial for these patients.
Body Mass Index ; Bone Density ; Femur Neck ; Fractures, Spontaneous ; Humans ; Machado-Joseph Disease ; Osteoporosis ; Spinocerebellar Ataxias

Spinocerebellar ataxia type 2 (SCA2) is a rare autosomal dominant progressive degenerative disease of the nervous system, which is characterized by a progressive cerebellar syndrome associated with saccadic eye scan, peripheral neuropathy, cognitive disorders, and other multisystem features. The gene predisposing to SCA2 has been mapped, which encodes the ataxin 2 protein. A CAG repeat expansion in the coding region of ATXN2 gene can cause extension of polyglutamine chain in the protein. This paper reviews recent progress made in the research on SCA2 in regard to its clinical features, pathology, etiology, pathogenesis and treatment.
Animals ; Ataxin-2 ; genetics ; Humans ; Spinocerebellar Ataxias ; etiology ; genetics ; pathology ; therapy

BACKGROUND AND PURPOSE: Autosomal recessive cerebellar ataxias constitute a highly heterogeneous group of neurodegenerative disorders. This study was carried out to determine the clinical and genetic causes of ataxia in two families from Pakistan. METHODS: Detailed clinical investigations were carried out on probands in two consanguineous families. Magnetic resonance imaging was performed. Exome sequencing data were examined for likely pathogenic variants. Candidate variants were checked for cosegregation with the phenotype using Sanger sequencing. Public databases including ExAC, GnomAD, dbSNP, and the 1,000 Genome Project as well as ethnically matched controls were checked to determine the frequencies of the alleles. Conservation of missense variants was ensured by aligning orthologous protein sequences from diverse vertebrate species. RESULTS: Reverse phenotyping identified spinocerebellar ataxia, autosomal recessive 1 [OMIM 606002, also referred to as ataxia oculomotor apraxia type 2 (AOA2)] and ataxia telangiectasia (OMIM 208900) in the two families. A novel homozygous missense mutation c.202 C>T (p.Arg68Cys) was identified within senataxin, SETX in the DNA of both patients in one of the families with AOA2. The patients in the second family were homozygous for a known variant in ataxia-telangiectasia mutated (ATM) gene: c.7327 C>T (p.Arg2443Ter). Both variants were absent from 100 ethnically matched control chromosomes and were either absent or present at very low frequencies in the public databases. CONCLUSIONS: This report extends the allelic heterogeneity of SETX mutations causing AOA2 and also presents an asymptomatic patient with a pathogenic ATM variant.
Alleles ; Apraxias* ; Ataxia Telangiectasia ; Ataxia* ; Cerebellar Ataxia ; DNA ; Exome ; Genome ; Humans ; Magnetic Resonance Imaging ; Movement Disorders ; Mutation, Missense ; Neurodegenerative Diseases ; Pakistan ; Phenotype ; Population Characteristics ; Spinocerebellar Ataxias ; Vertebrates