Investigations of Huntington’s Disease and Huntington’s Disease-Like Syndromes in Indian Choreatic Patients

2020 ◽  
Vol 9 (3) ◽  
pp. 283-289 ◽  
Author(s):  
Jaslovleen Kaur ◽  
Shaista Parveen ◽  
Uzma Shamim ◽  
Pooja Sharma ◽  
Varun Suroliya ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Brain Mri ◽  
Repeat Expansion ◽  
Cag Repeats ◽  
Mri Findings ◽  
Cag Expansion ◽  
Choreiform Movement ◽  
C9orf72 Gene ◽  
Reduced Penetrance

Background: The diagnostic workup for choreiform movement disorders including Huntington’s disease (HD) and those mimicking HD like phenotype is complex. Objective: The aim of the present study was to genetically define HD and HD-like presentations in an Indian cohort. We also describe HTT-CAG expansion manifesting as neuroferritinopathy-like disorder in four families from Punjab in India. Materials and methods: 159 patients clinically diagnosed as HD and HD-like presentations from various tertiary neurology clinics were referred to our centre (CSIR-IGIB) for genetic investigations. As a first tier test, CAG-TNR for HTT was performed and subsequently HD-negative samples were screened for JPH3 (HDL2), TBP (SCA17), ATN1 (DRPLA), PPP2R2B (SCA12) and GGGGCC expansion in C9orf72 gene. Four families presenting as neuroferritinopathy-like disorder were also investigated for HTT-CAG expansion. Results: 94 of 159 (59%) patients were found to have expanded HTT-CAG repeats. Pathogenic repeat expansion in JPH3, TBP, ATN1 and C9orf72 were not found in HD negative cases. Two patients were positive for SCA12-CAG expansion in pathogenic length, whereas 5 cases harboured TBP-CAG repeats falling in reduced penetrance range of 41– 48 repeats for SCA17. Four unrelated families, presented with atypical chorea and brain MRI findings suggestive of basal ganglia abnormalities mimicking neuroferritinopathy were found to harbour HTT-CAG expansion. Conclusion: We present SCA12 as a new reported phenocopy of HD which should be considered for diagnostic workout along with SCA17 for HD-like syndromes. This study also illustrates the necessity, to consider evolving HD like phenotype, as a clinical diagnosis for cases with initial manifestations depicting neuroferritinopathy.

scholarly journals Late-onset Huntington’s disease with 40–42 CAG expansion

2019 ◽  
Vol 41 (4) ◽  
pp. 869-876 ◽  
Author(s):  
Elisa Capiluppi ◽  
Luca Romano ◽  
Paola Rebora ◽  
Lorenzo Nanetti ◽  
Anna Castaldo ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Rating Scale ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Late Onset ◽  
Age At Onset ◽  
Clinical Manifestations ◽  
Cag Repeats ◽  
Cag Expansion

Abstract Introduction Huntington’s disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a CAG expansion greater than 35 in the IT-15 gene. There is an inverse correlation between the number of pathological CAG and the age of onset. However, CAG repeats between 40 and 42 showed a wider onset variation. We aimed to investigate potential clinical differences between patients with age at onset ≥ 60 years (late onset-HD) and patients with age at onset between 30 and 59 years (common-onset HD) in a cohort of patients with the same CAG expansions (40–42). Methods A retrospective analysis of 66 HD patients with 40–41–42 CAG expansion was performed. Patients were investigated with the Unified Huntington’s Disease Rating Scale (subitems I–II–III and Total Functional Capacity, Functional Assessment and Stage of Disease). Data were analysed using χ2, Fisher’s test, t test and Pearson’s correlation coefficient. GENMOD analysis and Kaplan-Meier analysis were used to study the disease progression. Results The age of onset ranged from 39 to 59 years in the CO subgroup, whereas the LO subgroup showed an age of onset from 60 to 73 years. No family history was reported in 31% of the late-onset in comparison with 20% in common-onset HD (p = 0.04). No difference emerged in symptoms of onset, in clinical manifestations and in progression of disease between the two groups. Conclusion There were no clinical differences between CO and LO subgroups with 40–42 CAG expansion. There is a need of further studies on environmental as well genetic variables modifying the age at onset.

scholarly journals Somatic CAG expansion in Huntington’s disease is dependent on the MLH3 endonuclease domain, which can be excluded via MLH3 splice redirection to suppress expansion

2020 ◽  
Author(s):  
Jennie C. L. Roy ◽  
Antonia Vitalo ◽  
Marissa A. Andrew ◽  
Eduarda Mota-Silva ◽  
Marina Kovalenko ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mismatch Repair ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Peripheral Tissues ◽  
Dna Mismatch ◽  
Cag Expansion ◽  
Endonuclease Domain ◽  
Primary Fibroblasts

AbstractSomatic expansion of the CAG repeat tract that causes Huntington’s disease (HD) is thought to contribute to the rate of disease pathogenesis. Therefore, factors influencing repeat expansion are potential therapeutic targets. Genes in the DNA mismatch repair pathway are critical drivers of somatic expansion in HD mouse models. Here, we have tested, using genetic and pharmacological approaches, the role of the endonuclease domain of the mismatch repair protein MLH3 in somatic CAG expansion in HD mice and patient cells. A point mutation in the MLH3 endonuclease domain completely eliminated CAG expansion in the brain and peripheral tissues of a HD knock-in mouse model (HttQ111). To test whether the MLH3 endonuclease could be manipulated pharmacologically, we delivered splice switching oligonucleotides in mice to redirect Mlh3 splicing to exclude the endonuclease domain. Splice redirection to an isoform lacking the endonuclease domain was associated with reduced CAG expansion. Finally, CAG expansion in HD patient-derived primary fibroblasts was also significantly reduced by redirecting MLH3 splicing to the endogenous endonuclease domain-lacking isoform. These data indicate the potential of targeting the MLH3 endonuclease domain to slow somatic CAG repeat expansion in HD, a therapeutic strategy that may be applicable across multiple repeat expansion disorders.

scholarly journals Atypical Parkinsonism Revealing a Late Onset, Rigid and Akinetic Form of Huntington's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-3
Author(s):  
A. Ciammola ◽  
J. Sassone ◽  
B. Poletti ◽  
N. Mencacci ◽  
R. Benti ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Brain Mri ◽  
Photon Emission ◽  
Cag Repeats ◽  
Cortical Atrophy ◽  
Emission Computed Tomography ◽  
Initial Symptom ◽  
Caudate Nuclei

Huntington's disease (HD) is a rare hereditary neurodegenerative disorder characterized in over 90 percent of cases by chorea as the presenting motor symptom. We report a 54-year-old male who presented with Parkinsonism as the initial symptom of the disease. Genetic analysis revealed expansion of 40 CAG repeats, and brain MRI showed both severe caudate nuclei and cortical atrophy. Single-photon emission computed tomography (SPECT) imaging of the dopamine transporter showed nigrostriatal pathway degeneration. Here, we also describe his 2 years of clinical followup after ensuing dopaminergic stimulation.

scholarly journals Brain microvascular endothelial cell dysfunction in an isogenic juvenile iPSC model of Huntington’s disease

2021 ◽  
Author(s):  
Raleigh Linville ◽  
Renée Nerenberg ◽  
Gabrielle Grifno ◽  
Diego Arevalo ◽  
Zhaobin Guo ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Immune Cell ◽  
Expression Profiles ◽  
Cag Repeats ◽  
Microvascular Endothelial Cell ◽  
Cag Expansion ◽  
Junction Protein ◽  
Microvascular Endothelial

Abstract Huntington’s disease (HD) is an inherited neurodegenerative disease caused by expansion of cytosine–adenine–guanine (CAG) repeats in the huntingtin gene, which leads to neuronal loss and decline in cognitive and motor function. Increasing evidence suggests that blood-brain barrier (BBB) dysfunction may contribute to progression of the disease. Studies in animal models, in vitro models, and post-mortem tissue suggest that disease progression is associated with increased microvascular density, altered cerebral blood flow, and loss of paracellular and transcellular barrier function. Here we report on changes in BBB phenotype due to expansion of CAG repeats using an isogenic pair of induced pluripotent stem cells (iPSCs) differentiated into brain microvascular endothelial-like cells (iBMECs). We show that CAG expansion alters the trajectory of iBMEC differentiation, producing cells with ~ 2-fold lower purity of adherent endothelial cells. CAG expansion is associated with lower transendothelial electrical resistance, lower tight junction protein expression, and unique gene expression profiles, but no significant changes in paracellular permeability. In addition, CAG expansion results in unique responses to pathological and therapeutic perturbations including angiogenic factors, oxidative stress, and osmotic stress. In a tissue-engineered BBB model, iBMECs show subtle changes in phenotype, including differences in cell turnover and immune cell adhesion. Our results further support that CAG expansion in BMECs may alter BBB phenotype during HD.

scholarly journals Special Issue: DNA Repair and Somatic Repeat Expansion in Huntington’s Disease

2021 ◽  
Vol 10 (1) ◽  
pp. 3-5
Author(s):  
Lesley Jones ◽  
Vanessa C. Wheeler ◽  
Christopher E. Pearson
Keyword(s):  
Dna Repair ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Repeat Expansion ◽  
Special Issue

Borderline repeat expansion in Huntington's disease

The Lancet ◽  
1993 ◽  
Vol 342 (8885) ◽  
pp. 1491-1492 ◽  
Author(s):  
K.E de Rooij ◽  
P.A.M de Koning Gans ◽  
M Losekoot ◽  
E Bakker ◽  
J.T den Dunnen ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Repeat Expansion

Age of Onset of Huntington's Disease in Carriers of Reduced Penetrance Alleles

2021 ◽  
Author(s):  
Erin I. McDonnell ◽  
Yuanjia Wang ◽  
Jill Goldman ◽  
Karen Marder
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Age Of Onset ◽  
Reduced Penetrance

Electrophysiological and Morphological Changes in Striatal Spiny Neurons in R6/2 Huntington's Disease Transgenic Mice

2001 ◽  
Vol 86 (6) ◽  
pp. 2667-2677 ◽  
Author(s):  
Gloria J. Klapstein ◽  
Robin S. Fisher ◽  
Hadi Zanjani ◽  
Carlos Cepeda ◽  
Eve S. Jokel ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Action Potentials ◽  
Morphological Changes ◽  
Brain Slices ◽  
Cag Repeats ◽  
Membrane Properties ◽  
Striatal Neurons ◽  
Spiny Neurons ◽  
Active Membrane

We examined passive and active membrane properties and synaptic responses of medium-sized spiny striatal neurons in brain slices from presymptomatic (∼40 days of age) and symptomatic (∼90 days of age) R6/2 transgenics, a mouse model of Huntington's disease (HD) and their age-matched wild-type (WT) controls. This transgenic expresses exon 1 of the human HD gene with ∼150 CAG repeats and displays a progressive behavioral phenotype associated with numerous neuronal alterations. Intracellular recordings were obtained using standard techniques from R6/2 and age-matched WT mice. Few electrophysiological changes occurred in striatal neurons from presymptomatic R6/2 mice. The changes in this age group were increased neuronal input resistance and lower stimulus intensity to evoke action potentials (rheobase). Symptomatic R6/2 mice exhibited numerous electrophysiological alterations, including depolarized resting membrane potentials, increased input resistances, decreased membrane time constants, and alterations in action potentials. Increased stimulus intensities were required to evoke excitatory postsynaptic potentials (EPSPs) in neurons from symptomatic R6/2 transgenics. These EPSPs had slower rise times and did not decay back to baseline by 45 ms, suggesting a more prominent component mediated by activation of N-methyl-d-aspartate receptors. Neurons from both pre- and symptomatic R6/2 mice exhibited reduced paired-pulse facilitation. Data from biocytin-filled or Golgi-impregnated neurons demonstrated decreased dendritic spine densities, smaller diameters of dendritic shafts, and smaller dendritic fields in symptomatic R6/2 mice. Taken together, these findings indicate that passive and active membrane and synaptic properties of medium-sized spiny neurons are altered in the R6/2 transgenic. These physiological and morphological alterations will affect communication in the basal ganglia circuitry. Furthermore, they suggest areas to target for pharmacotherapies to alleviate and reduce the symptoms of HD.

scholarly journals The MID1 Protein: A Promising Therapeutic Target in Huntington’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Annika Heinz ◽  
Judith Schilling ◽  
Willeke van Roon-Mom ◽  
Sybille Krauß
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein A ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Progressive Movement ◽  
Promising Therapeutic Target ◽  
Promising Therapeutic Approach ◽  
Exon 1 ◽  
Polyglutamine Protein

Huntington’s disease (HD) is caused by an expansion mutation of a CAG repeat in exon 1 of the huntingtin (HTT) gene, that encodes an expanded polyglutamine tract in the HTT protein. HD is characterized by progressive psychiatric and cognitive symptoms associated with a progressive movement disorder. HTT is ubiquitously expressed, but the pathological changes caused by the mutation are most prominent in the central nervous system. Since the mutation was discovered, research has mainly focused on the mutant HTT protein. But what if the polyglutamine protein is not the only cause of the neurotoxicity? Recent studies show that the mutant RNA transcript is also involved in cellular dysfunction. Here we discuss the abnormal interaction of the mutant HTT transcript with a protein complex containing the MID1 protein. MID1 aberrantly binds to CAG repeats and this binding increases with CAG repeat length. Since MID1 is a translation regulator, association of the MID1 complex stimulates translation of mutant HTT mRNA, resulting in an overproduction of polyglutamine protein. Thus, blocking the interaction between MID1 and mutant HTT mRNA is a promising therapeutic approach. Additionally, we show that MID1 expression in the brain of both HD patients and HD mice is aberrantly increased. This finding further supports the concept of blocking the interaction between MID1 and mutant HTT mRNA to counteract mutant HTT translation as a valuable therapeutic strategy. In line, recent studies in which either compounds affecting the assembly of the MID1 complex or molecules targeting HTT RNA, show promising results.

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