Inherited ataxia

Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is a fatal neurodegenerative disease that causes loss of balance and motor co-ordination, eventually leading to paralysis. It is caused by the autosomal dominant inheritance of a long CAG trinucleotide repeat sequence within the ATXN3 gene, encoding for an expanded polyglutamine (polyQ) repeat sequence within the ataxin-3 protein. Ataxin-3 containing an expanded polyQ repeat is known to be highly prone to intraneuronal aggregation, and previous studies have demonstrated that protein quality control pathways, such as autophagy, are impaired in MJD patients and animal models of the disease...

P4-ATPases flip lipids from the exoplasmic to cytoplasmic leaflet of cell membranes, a property crucial for many biological processes. Mutations in P4-ATPases are associated with severe inherited and complex human disorders. We have determined the expression, localization, and ATPase activity of four variants in ATP8A2, the P4-ATPase associated with the neurodevelopmental disorder known as cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4). Two variants, Gly447Arg and Ala772Pro, harboring mutations in catalytic domains, expressed at low levels and mislocalized in cells...

Spinocerebellar ataxia type 3 (SCA3) is the most common dominantly inherited ataxia. Currently, no preventative or disease-modifying treatments exist for this progressive neurodegenerative disorder, although efforts using gene silencing approaches are under clinical trial investigation. The disease is caused by a CAG repeat expansion in the mutant gene, ATXN3, producing an enlarged polyglutamine tract in the mutant protein. Similar to other paradigmatic neurodegenerative diseases, studies evaluating the pathogenic mechanism focus primarily on neuronal implications...

Inhibition of acetylcholinesterase (AChE) is a common used treatment option for Alzheimer's disease. However, there has been limited research on the potential use of AChE inhibitors for the treatment of Machado-Joseph disease (MJD)/Spinocerebellar Ataxia 3 (SCA3), in spite of the positive results using AChE inhibitors in patients with other inherited ataxias. MJD/SCA3, the most common form of dominant Spinocerebellar Ataxia worldwide, is caused by an expansion of the polyglutamine tract within the ataxin-3 protein, and is characterized by motor impairments...

Spinocerebellar degeneration (SCD) is a neurodegenerative disorder characterized by cerebellar ataxia and other multisystem manifestations, such as Parkinsonism and pyramidal tract symptoms. No effective treatment is available for SCD. Approximately one-third of the cases of SCD are inherited, and the remaining two-third are sporadic, including multiple system atrophy. This article provides an overview of hereditary SCD, its clinical features, recent treatment advances, biomarkers, role of genomic medicine, and future treatment prospects...

BACKGROUND: Colorectal cancer (CRC) is the fifth leading cause of death in India. Until now, the exact pathogenesis concerning CRC signaling pathways is largely unknown; however, the diseased condition is believed to deteriorate with lifestyle, aging, and inherited genetic disorders. Hence, the identification of hub genes and therapeutic targets is of great importance for disease monitoring. OBJECTIVE: Identification of hub genes and targets for identification of candidate hub genes for CRC diagnosis and monitoring...

Spinocerebellar ataxia type 3 (SCA3) is an inherited movement disorder characterized by a progressive decline in motor coordination. Despite the extensive functional connectivity (FC) alterations reported in previous SCA3 studies in the cerebellum and cerebellar-cerebral pathways, the influence of these FC disturbances on the hierarchical organization of cerebellar functional regions remains unclear. Here, we compared 35 SCA3 patients with 48 age- and sex-matched healthy controls using a combination of voxel-based morphometry and resting-state functional magnetic resonance imaging to investigate whether cerebellar hierarchical organization is altered in SCA3...

International consortia collaborating on the genetics of rare diseases have significantly boosted our understanding of inherited neurological disorders. Historical clinical classification boundaries were drawn between disorders with seemingly different etiologies, such as inherited peripheral neuropathies (IPNs), spastic paraplegias, and cerebellar ataxias. These clinically defined borders are being challenged by the identification of mutations in genes displaying wide phenotypic spectra and by shared pathomechanistic themes, which are valuable indications for therapy development...

Spinocerebellar ataxias (SCAs) are inherited neurodegenerative diseases characterized by loss of balance, coordination, and slurred speech. Recently, a digenic mode of inheritance of TBP/STUB1 contributing to SCA was demonstrated. The clinical manifestations of SCATBP/STUB1 include not only ataxia but also obvious cognitive and behavioral impairment. Here, we describe a Chinese family with SCATBP/STUB1 and performed a literature search for similar cases. We identified a Chinese family with SCATBP/STUB1 and compare our clinical findings with other cases described in the literature so far...

Hereditary spastic paraparesis (HSP) is a group of central nervous system diseases primarily affecting the spinal upper motor neurons, with different inheritance patterns and phenotypes. SPG46 is a rare, early-onset and autosomal recessive HSP, linked to biallelic GBA2 mutations. About thirty families have been described worldwide, with different phenotypes like complicated HSP, recessive cerebellar ataxia or Marinesco-Sjögren Syndrome. Herein, we report five SPG46 patients harbouring five novel GBA2 mutations, the largest series described in Italy so far...

OBJECTIVE: This article provides an overview of genetic myelopathies, a diverse group of inherited, degenerative conditions that may be broadly categorized as motor neuron disorders, disorders of spinocerebellar degeneration, leukodystrophies, and hereditary spastic paraplegia. Clinical examples from each category are provided to illustrate the spectrum of genetic myelopathies and their distinguishing features that aid in differentiating genetic myelopathies from potentially treatable acquired causes of myelopathy...

At least seven dominantly inherited spinocerebellar ataxias (SCA) are caused by expansions of polyglutamine (polyQ)-encoding CAG repeat. The misfolded and aggregated polyQ-expanded proteins increase reactive oxygen species (ROS), cellular toxicity, and neuroinflammation in the disease pathogenesis. In this study, we evaluated the anti-inflammatory potentials of coumarin derivatives LM-021, LMDS-1, LMDS-2, and pharmacological chaperone tafamidis using mouse BV-2 microglia and SCA3 ataxin-3 (ATXN3)/Q75 -GFP SH-SY5Y cells...

Two Jack-Russell Terrier × Chihuahua mixed-breed littermates with Leigh syndrome were investigated. The dogs presented with progressive ataxia, dystonia, and increased lactate levels. Brain MRI showed characteristic bilateral symmetrical T2 hyperintense lesions, histologically representing encephalomalacia. Muscle histopathology revealed accumulation of mitochondria. Whole genome sequencing identified a missense variant in a gene associated with human Leigh syndrome, NDUFS7:c.535G > A or p...

We investigated a syndromic disease comprising blindness and neurodegeneration in 11 Saarlooswolfdogs. Clinical signs involved early adult onset retinal degeneration and adult-onset neurological deficits including gait abnormalities, hind limb weakness, tremors, ataxia, cognitive decline and behavioral changes such as aggression towards the owner. Histopathology in one affected dog demonstrated cataract, retinal degeneration, central and peripheral axonal degeneration, and severe astroglial hypertrophy and hyperplasia in the central nervous system...

Friedreich ataxia (FA) is an inherited autosomal recessive neurodegenerative disease (NDD) characterized primarily by progressive sensory and spinocerebellar ataxia associated with hypertrophic cardiomyopathy. FA is due to an intronic GAA repeat expansion within the frataxin gene (FXN) leading to reduced levels of frataxin (FXN) which causes mitochondrial dysfunction, production of reactive oxygen species (ROS), and altered iron metabolism. To date there is no resolutive cure for FA; however, the FDA has recently approved omaveloxolone - a potent activator of nuclear factor erythroid 2-related factor 2 (NRF2) - as the first treatment for FA...

BACKGROUND: We report the results gathered over 15 years of screening for congenital disorders of glycosylation syndrome (CDGS) in Tunisia according to clinical and biochemical characteristics. METHODS: Our laboratory received 1055 analysis requests from various departments and hospitals, for children with a clinical suspicion of CDGS. The screening was carried out through separation of transferrin isoforms by capillary zone electrophoresis. RESULTS: During the 15-year period, 23 patients were diagnosed with CDGS (19 patients with CDG-Ia, three patients with CDG-IIx, and one patient with CDG-X)...

The inherited disease community in Sri Lanka has been widely neglected. This article aimed to present accumulated knowledge in establishing a pro bono cost-effective national, island-wide, free-of-charge molecular diagnostic service, suggesting a model for other developing countries. The project provided 637 molecular diagnostic tests and reports free of charge to a nation with limited resources. We pioneered the implementation of mobile clinics and home visits, where the research team acted as barefoot doctors with the concept of the doctor and the researcher at the patient's doorstep...

BACKGROUND AND OBJECTIVES: Neurodevelopmental and neurodegenerative disorders have long been considered as different clinical and molecular entities, and only a few genes are known to be involved in both processes. The IRF2BPL (interferon regulatory factor 2 binding protein like) gene was implicated in a severe pediatric phenotype characterized by developmental and epileptic encephalopathy and early regression. In parallel, inherited IRF2BPL variants have been reported in cohorts of patients with late-onset progressive dystonic and ataxic syndrome with few information about the neurodevelopment of these patients...

BACKGROUND: SCN8A-related disorders are a group of variable conditions caused by pathogenic variations in SCN8A. Online Mendelian Inheritance in Man (OMIM) terms them as developmental and epileptic encephalopathy 13, benign familial infantile seizures 5 or cognitive impairment with or without cerebellar ataxia. METHODS: In this study, we describe clinical and genetic results on eight individuals from six families with SCN8A pathogenic variants identified via exome sequencing...

SpinoCerebellar Ataxia type 7 (SCA7) is an inherited disorder caused by CAG triplet repeats encoding polyglutamine expansion in the ATXN7 protein, which is part of the transcriptional coactivator complex SAGA. The mutation primarily causes neurodegeneration in the cerebellum and retina, as well as several forebrain structures. The SCA7140Q/5Q knock-in mouse model recapitulates key disease features, including loss of vision and motor performance. To characterize the temporal progression of brain degeneration of this model, we performed a longitudinal study spanning from early to late symptomatic stages using high-resolution magnetic resonance imaging (MRI) and in vivo 1H-magnetic resonance spectroscopy (1H-MRS)...