The huntingtin protein participates in several cellular processes that are disrupted when the polyglutamine tract is expanded beyond a threshold of 37 CAG DNA repeats in Huntington’s disease (HD). Cellular biology approaches to understand these functional disruptions in HD have primarily focused on cell lines with synthetically long CAG length alleles that clinically represent outliers in this disease and a more severe form of HD that lacks age onset. Patient-derived fibroblasts are limited to a finite number of passages before succumbing to cellular senescence. We used human telomerase reverse transcriptase (hTERT) to immortalize fibroblasts taken from individuals of varying age, sex, disease onset, and CAG repeat length, which we have termed TruHD cells. TruHD cells display classic HD phenotypes of altered morphology, size and growth rate, increased sensitivity to oxidative stress, aberrant adenosine diphosphate/adenosine triphosphate (ADP/ATP) ratios, and hypophosphorylated huntingtin protein. We additionally observed dysregulated reactive oxygen species (ROS)-dependent huntingtin localization to nuclear speckles in HD cells. We report the generation and characterization of a human, clinically relevant cellular model for investigating disease mechanisms in HD at the single-cell level, which, unlike transformed cell lines, maintains functions critical for huntingtin transcriptional regulation and genomic integrity.
The huntingtin protein participates in several cellular processes that are disrupted when the polyglutamine tract is expanded beyond a threshold of 37 CAG DNA repeats in Huntington's disease (HD). Cellular biology approaches to understand these functional disruptions in HD have primarily focused on cell lines with synthetically long CAG length alleles that clinically represent outliers in this disease and a more severe form of HD that lacks age-onset.Patient-derived fibroblasts are limited to a finite number of passages before succumbing to cellular senescence. We used human telomerase reverse transcriptase (hTERT) to immortalize fibroblasts taken from individuals of varying age, sex, disease onset and CAG repeat length, which we have termed TruHD cells. TruHD cells display classic HD phenotypes of altered morphology, size and growth rate, increased sensitivity to oxidative stress, aberrant ADP/ATP ratios and hypophosphorylated huntingtin protein. We additionally observed dysregulated ROS-dependent huntingtin localization to nuclear speckles in HD cells . We report the generation and characterization of a human, clinically relevant cellular model for investigating disease mechanisms in HD at the single cell level, which, unlike transformed cell lines, maintains TP53 function critical for huntingtin transcriptional regulation and genomic integrity.Canada for assistance with flow cytometry experiments.
Griscelli syndrome is a rare autosomal recessive pigmentary dilution syndrome affecting the hair and skin that is categorized into 3 distinct subtypes. 1 Griscelli syndrome type 1 is caused by pathogenic variants in the MYO5A gene. 2 Patients have silver hair, hypopigmented skin, severe neurological impairment, and normal immune systems. Griscelli syndrome type 2 (GS2) is caused by pathogenic variants in RAB27A. 3 Patients with GS2 also have silver hair, light skin, and typically normal neurological development but immune deficiency and dysregulation leading to life-threatening hemophagocytic lymphohistiocytosis (HLH). Griscelli syndrome type 3, associated with the MLPH gene, is characterized by silver hair and light skin without neurological or immune system involvement. 4 Hemophagocytic lymphohistiocytosis is an acquired or inherited overactivation of the immune system, often provoked by infection. 5 It can be diagnosed in symptomatic patients by identifying pathogenic variants in HLH genes such as RAB27A and UNC13D, or if at least 5 of these 8 criteria are met: fever, splenomegaly, cytopenia of 2 or more cell lines, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis evident on bone marrow biopsy, spleen or lymph nodes, reduced natural killer (NK) cell activity, elevated serum ferritin, and elevated soluble interleukin-2 (sIL-2, sCD25) levels. The natural course of familial HLH is rapidly fatal with median survival between 2 to 3 months. The only curative therapy is hematopoietic stem cell transplant (HSCT). Here, we present a girl with GS2 associated with compound heterozygous variants in the RAB27A gene. At the time of writing she is 5 years old and has developed one episode of uncomplicated HLH and is currently awaiting HSCT.
Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that presents with recurrent inflammatory nodules and draining tunnels in the skin. Most HS studies have focused on Western populations, and the understanding of how HS characteristics differ in specific Asian ethnicities is poor. We conducted the first systematic review and metaanalysis to characterize HS patients from East and Southeast Asia. PubMed, Embase, and Ovid MEDLINE databases were searched from inception to June 12, 2020. Englishlanguage case-series, cross-sectional, observational, and randomized controlled trial studies investigating HS in East and Southeast Asian populations were screened by titles, abstracts, and articles in duplicate. Of 136 citations, 10 studies were included in the meta-analysis. Data on gender distribution, lesion distribution in the axilla and gluteal regions, and family history were extracted in duplicate. A random effects model was used for the meta-analysis. A total of 30,125 HS patients were included in the analysis. Most patients were male (66%, 95% CI = 60-72%). About half of Asian patients with HS develop lesions in the axilla (52%, 95% CI = 33-72%) and the buttocks (48%, 95% CI = 38-57%). Only a small subset had positive family history of HS (5%, 95% CI = 2-8%). We report an up-to-date characterization of HS in East and Southeast Asian populations and highlight differences in their Western counterparts. These results will hopefully improve understanding for how HS may manifest, lead to more personalized treatments for Asian patients with HS, and usher in a proper patient-centered approach to treating the disease.
Introduction: Laryngospasm is an involuntary, sustained closure of sphincter musculature that leads to an unpleasant subjective experience of dyspnea and choking. It is an underreported symptom in amyotrophic lateral sclerosis (ALS). In this study we aimed to better characterize the prevalence and clinical characteristics of laryngospasm in ALS patients. Methods:The medical records of 571 patients with ALS followed between 2008 and 2018 were searched for evidence of laryngospasm. A total of 23 patients with laryngospasm were identified and the data related to patient and laryngospasm characteristics were extracted.Results: Laryngospasm was reported in 4% of ALS patients. Females comprised 57% of patients and their mean age was 63.4 years. Laryngospasm frequently manifested in patients with moderate bulbar dysfunction and seemed independent of respiratory function. Among laryngospasm patients, 26% were cigarette smokers and 13% had a history of gastroesophageal reflux. The most common reported trigger was excessive saliva irritating the vocal cords (35%) followed by eating a meal (17%). There was significant variation in laryngospasm frequency (up to 5 per hour) and duration (seconds to minutes). Most patients could not identify an effective coping mechanism, although 13% reported that drinking water was effective.Discussion: Despite its low prevalence in ALS, laryngospasm should be included in the symptom inquiry. The present findings may improve patient care through increased recognition of the clinical features of laryngospasm in ALS patients, identifying a link between laryngospasm and moderate bulbar dysfunction, and highlighting trigger avoidance as a management strategy. Additional research is required to understand the pathophysiology and optimal treatment.
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