Publications by authors named "Amanda Krause"

84 Publications

Dysphagia: Novel and Emerging Diagnostic Modalities.

Gastroenterol Clin North Am 2021 Dec 6;50(4):769-790. Epub 2021 Oct 6.

Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University, Feinberg School of Medicine, 676 St Clair Street, Suite 1400, Chicago, IL 60611-2951, USA. Electronic address:

Among recent advances in diagnostics for dysphagia and esophageal motility disorders is the update to the Chicago Classification (version 4.0) for interpretation of high-resolution manometry (HRM) and diagnosis of esophageal motility disorders. The update incorporates application of complementary testing strategies during HRM, such as provocative HRM maneuvers, and recommendation for barium esophagram or functional luminal imaging probe (FLIP) panometry to help clarify inconclusive HRM findings. FLIP panometry also represents an emerging technology for evaluation of esophageal distensibility and motility at the time of endoscopy.
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http://dx.doi.org/10.1016/j.gtc.2021.07.003DOI Listing
December 2021

Clinical Updates in Esophageal Motility Disorders Beyond Achalasia.

Clin Gastroenterol Hepatol 2021 09 1;19(9):1789-1792.e1. Epub 2021 Jul 1.

Center for Esophageal Diseases, Division of Gastroenterology, University of California, San Diego School of Medicine, La Jolla, California. Electronic address:

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http://dx.doi.org/10.1016/j.cgh.2021.05.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8604436PMC
September 2021

Prediction of Esophageal Retention: A Study Comparing High-Resolution Manometry and Functional Luminal Imaging Probe Panometry.

Am J Gastroenterol 2021 10;116(10):2032-2041

Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Introduction: High-resolution manometry (HRM) is generally considered the primary method to evaluate esophageal motility; functional luminal imaging probe (FLIP) panometry represents a novel method to do so and is completed during sedated endoscopy. This study aimed to compare HRM and FLIP panometry in predicting esophageal retention on timed barium esophagram (TBE).

Methods: A total of 329 adult patients who completed FLIP, HRM, and TBE for primary esophageal motility evaluation were included. An abnormal TBE was defined by a 1-minute column height >5 cm or impaction of a 12.5-mm barium tablet. The integrated relaxation pressure (IRP) on HRM was assessed in the supine and upright patient positions. Esophagogastric junction (EGJ) opening was evaluated with 16-cm FLIP performed during sedated endoscopy through EGJ-distensibility index and maximum EGJ diameter.

Results: Receiver operating characteristic curves to identify an abnormal TBE demonstrated AUC (95% confidence interval) of 0.79 (0.75-0.84) for supine IRP, 0.79 (0.76-0.86) for upright IRP, 0.84 (0.79-0.88) for EGJ-distensibility index, and 0.88 (0.85-0.92) for maximum EGJ diameter. Logistic regression to predict abnormal TBE showed odds ratios (95% confidence interval) of 1.8 (0.84-3.7) for consistent IRP elevation and 39.7 (16.4-96.2) for reduced EGJ opening on FLIP panometry. Of 40 patients with HRM-FLIP panometry discordance, HRM-IRP was consistent with TBE in 23% while FLIP panometry was consistent with TBE in 78%.

Discussion: FLIP panometry provided superior detection of esophageal retention over IRP on HRM. However, application of a complementary evaluation involving FLIP panometry, HRM, and TBE may be necessary to accurately diagnose esophageal motility disorders.
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http://dx.doi.org/10.14309/ajg.0000000000001402DOI Listing
October 2021

SDHB-Associated Paraganglioma Syndrome in Africa-A Need for Greater Genetic Testing.

J Endocr Soc 2021 Oct 15;5(10):bvab111. Epub 2021 Jun 15.

Division of Endocrinology and Metabolism, Department of Internal Medicine, Helen Joseph Hospital, Johannesburg, 2092, South Africa.

A germline mutation is identified in almost 40% of pheochromocytoma/paraganglioma (PPGL) syndromes. Genetic testing and counseling are essential for the management of index cases as well as presymptomatic identification and preemptive management of affected family members. Mutations in the genes encoding the mitochondrial enzyme succinate dehydrogenase (SDH) are well described in patients with hereditary PPGL. Among patients of African ancestry, the prevalence, phenotype, germline mutation spectrum, and penetrance of mutations is poorly characterized. We describe a multifocal paraganglioma in a young African male with an underlying missense succinate dehydrogenase subunit B () mutation and a history of 3 first-degree relatives who died at young ages from suspected cardiovascular causes. The same mutation, Class V variant c.724C>A p.(Arg242Ser), was detected in one of his asymptomatic siblings. As there are limited data describing hereditary PPGL syndromes in Africa, this report of an -associated PPGL is a notable contribution to the literature in this growing field. Due to the noteworthy clinical implications of PPGL mutations, this work highlights the existing need for broader genetic screening among African patients with PPGL despite the limited healthcare resources available in this region.
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http://dx.doi.org/10.1210/jendso/bvab111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348940PMC
October 2021

Has translational genomics come of age in Africa?

Hum Mol Genet 2021 Oct;30(20):R164-R173

Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, The University of the Witwatersrand, Johannesburg 2193, South Africa.

The rapid increase in genomics research in Africa and the growing promise of precision public health (PPH) begs the question of whether African genomics has come of age and is being translated into improved healthcare for Africans. An assessment of the continent's readiness suggests that genetic service delivery remains limited and extremely fragile. The paucity of data on mutation profiles for monogenic disorders and lack of large genome-wide association cohorts for complex traits in African populations is a significant barrier, coupled with extreme genetic variation across different regions and ethnic groups. Data from many different populations are essential to developing appropriate genetic services. Of the proposed genetic service delivery models currently used in Africa-Uncharacterized, Limited, Disease-focused, Emerging and Established-the first three best describe the situation in most African countries. Implementation is fraught with difficulties related to the scarcity of an appropriately skilled medical genetic workforce, limited infrastructure and processes, insufficient health funding and lack of political support, and overstretched health systems. There is a strong nucleus of determined and optimistic clinicians and scientists with a clear vision, and there is a hope for innovative solutions and technological leapfrogging. However, a multi-dimensional approach with active interventions to stimulate genomic research, clinical genetics and overarching healthcare systems is needed to reduce genetic service inequalities and accelerate PPH on the continent. Human and infrastructure capacity development, dedicated funding, political will and supporting legislation, and public education and awareness, are critical elements for success. Africa-relevant genomic and related health economics research remains imperative with an overarching need to translate knowledge into improved healthcare. Given the limited data and genetic services across most of Africa, the continent has not yet come of 'genomics' age.
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http://dx.doi.org/10.1093/hmg/ddab180DOI Listing
October 2021

Validation of Clinically Relevant Thresholds of Esophagogastric Junction Obstruction Using FLIP Panometry.

Clin Gastroenterol Hepatol 2021 Jun 30. Epub 2021 Jun 30.

Department of Medicine, Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago.

Background & Aims: This study aimed to assess the accuracy of functional luminal imaging probe (FLIP) panometry to detect esophagogastric junction (EGJ) obstruction assigned by high-resolution manometry (HRM) and the Chicago Classification version 4.0 (CCv4.0).

Methods: Six hundred eighty-seven adult patients who completed FLIP and HRM for primary esophageal motility evaluation and 35 asymptomatic volunteers (controls) were included. EGJ opening was evaluated with 16-cm FLIP during sedated endoscopy via EGJ-distensibility index (DI) and maximum EGJ diameter. HRM was classified according to CCv4.0 and focused on studies with a conclusive disorder of EGJ outflow (ie, achalasia subtypes I, II, or III; or EGJ outflow obstruction with abnormal timed barium esophagogram) or normal EGJ outflow.

Results: All 35 controls had EGJ-DI >3.0 mm/mmHg and maximum EGJ diameter >16 mm. Per HRM and CCv4.0, 245 patients had a conclusive disorder of EGJ outflow, and 314 patients had normal EGJ outflow. Among the 241 patients with reduced EGJ opening (EGJ-DI <2.0 mm/mmHg and maximum EGJ diameter <12 mm) on FLIP panometry, 86% had a conclusive disorder of EGJ outflow per CCv4.0. Among the 203 patients with normal EGJ opening (EGJ-DI ≥2.0 mm/mmHg and maximum EGJ diameter ≥16 mm) on FLIP panometry, 99% had normal EGJ outflow per CCv4.0.

Conclusions: FLIP panometry accurately identified clinically relevant conclusive EGJ obstruction as defined by CCv4.0 in patients evaluated for esophageal motor disorders. Thus, FLIP panometry is a valuable tool for both independent and complementary evaluation of esophageal motility.
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http://dx.doi.org/10.1016/j.cgh.2021.06.040DOI Listing
June 2021

Normal Values of High-resolution Manometry Parameters With Provocative Maneuvers.

J Neurogastroenterol Motil 2021 Jul;27(3):354-362

Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Background/aims: Incorporation of complementary and provocative test swallows to the high-resolution manometry (HRM) protocol offers potential to address limitations posed by HRM protocols that involve only a single swallow type. The aim of this study is to describe normal findings of a comprehensive HRM testing protocol performed on healthy asymptomatic volunteers.

Methods: Thirty healthy asymptomatic volunteers completed HRM with 5-mL liquid swallows in the supine position. They also completed 5-mL liquid swallows in the upright position, viscous swallows, solid test swallows, multiple rapid swallows, and a rapid drink challenge. HRM studies were analyzed via Chicago classification version 3.0.

Results: The median (5th-95th percentiles) for integrated relaxation pressure (IRP) on supine swallows was 11 (4-16) mmHg; IRP was lower than supine on upright liquid 9 (0-17) mmHg, viscous 6 (0-15) mmHg, solid 9 (1-19) mmHg, multiple rapid swallows 3 (0-12) mmHg, and rapid drink challenge 5 (-3-12) mmHg; < 0.005. While an "elevated" IRP value was observed on 1 to 2 test maneuvers in 8/30 (27%) subjects, all 30 subjects had an IRP value < 12 mmHg on at least one of the test maneuvers.

Conclusions: Normal values and findings from a comprehensive HRM testing protocol are reported based on evaluation of 30 healthy asymptomatic volunteers. Isolated "abnormalities" of IRP and contractile parameters were observed in the majority (80%) of these asymptomatic subjects, while all subjects also had normal features observed. Thus, the definition of "normal" should be recalibrated to focus on the entirety of the study and not individual metrics.
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http://dx.doi.org/10.5056/jnm20118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266507PMC
July 2021

Relationships between social interactions, basic psychological needs, and wellbeing during the COVID-19 pandemic.

Psychol Health 2021 May 17:1-13. Epub 2021 May 17.

Department of Psychology, James Cook University, Townsville, Queensland, Australia.

Objective: Social lockdowns associated with COVID-19 have led individuals to increasingly rely on video conferencing and other technology-based interactions to fulfil social needs. The extent to which these interactions, as well as traditional face-to-face interactions, satisfied psychological needs and supported wellbeing during different periods of the COVID-19 pandemic is yet to be elucidated. In this study, university students' social interactions (both technology-based and face-to-face), psychological needs, and wellbeing were assessed at six time points across four months of government-enforced restrictions in Australia.

Design: Repeated survey assessment.

Main Outcome Measures: Basic psychological need satisfaction; general wellbeing.

Results: Results demonstrated that, at the within-subjects level, relatedness satisfaction (feeling understood by, cared for, and connected to others) significantly mediated the relationship between technology-based interaction and wellbeing. Autonomy satisfaction (self-initiation and feeling ownership over decisions and behaviours) mediated the relationship between face-to-face interactions and wellbeing at the within-person level.

Conclusion: Discussion is centred on the importance of technology-based interactions for needs satisfaction and wellbeing during periods of social isolation.
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http://dx.doi.org/10.1080/08870446.2021.1921178DOI Listing
May 2021

Ending a diagnostic odyssey-The first case of Takenouchi-Kosaki syndrome in an African patient.

Clin Case Rep 2021 Apr 2;9(4):2144-2148. Epub 2021 Mar 2.

Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences University of the Witwatersrand Johannesburg South Africa.

First reported case of Takenouchi-Kosaki syndrome in an African patient with a likely pathogenic missense variant identified in the gene.
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http://dx.doi.org/10.1002/ccr3.3966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077267PMC
April 2021

A Qualitative Exploration of Aged-Care Residents' Everyday Music Listening Practices and How These May Support Psychosocial Well-Being.

Front Psychol 2021 5;12:585557. Epub 2021 Mar 5.

The Melbourne Conservatorium of Music, The University of Melbourne, Southbank, VIC, Australia.

Strategies to support the psychosocial well-being of older adults living in aged-care are needed; and evidence points toward music listening as an effective, non-pharmacological tool with many benefits to quality of life and well-being. Yet, the everyday listening practices (and their associated specific psychosocial benefits) of older adults living in residential aged-care remain under-researched. The current study explored older adults' experiences of music listening in their daily lives while living in residential aged-care and considered how music listening might support their well-being. Specifically, what might go into autonomous listening activities? 32 Australian residents (aged 73-98) living in two Australian care facilities participated in semi-structured interviews. The results of a qualitative thematic analysis revealed three themes pertaining to "previous music experiences and interest," "current music listening," and "barriers to listening." While an interest in and access to music did not necessarily result in everyday listening practices, of those participants who did listen to music, perceived benefits included outcomes such as entertainment, enjoyment, relaxation, and mood regulation. Drawing on Ruud's notion of music as a "cultural immunogen" supporting well-being and Self-Determination Theory, theoretical implications of the findings are addressed, relating to how to create and support music activities in aged-care facilities so that they are engaging, meaningful, and promote emotional regulation, community, and well-being.
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http://dx.doi.org/10.3389/fpsyg.2021.585557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973015PMC
March 2021

Evaluating esophageal motility beyond primary peristalsis: Assessing esophagogastric junction opening mechanics and secondary peristalsis in patients with normal manometry.

Neurogastroenterol Motil 2021 10 11;33(10):e14116. Epub 2021 Mar 11.

Department of Medicine, Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Background: Functional luminal imaging probe (FLIP) Panometry assesses the esophageal response to distention and may complement the assessment of primary peristalsis on high-resolution manometry (HRM). We aimed to investigate whether FLIP Panometry provides complementary information in patients with normal esophageal motility on HRM.

Methods: Adult patients that completed FLIP and had an HRM classification of normal motility were retrospectively identified for inclusion. 16-cm FLIP studies performed during endoscopy were evaluated to assess EGJ distensibility, secondary peristalsis, and identify an abnormal response to distention involving sustained LES contraction (sLESC). Clinical characteristics and esophagram were assessed when available.

Key Results: Of 164 patients included (mean(SD) age 48(16) years, 75% female), 111 (68%) had normal Panometry with EGJ-distensibility index (DI) ≥2.0 mm /mmHg, maximum EGJ diameter ≥16mm and antegrade contractions. Abnormal EGJ distensibility was observed in 44/164 (27%), and 38/164 (23%) had an abnormal contractile response to distension. sLESC was observed in 11/164 (7%). Among 68 patients that completed esophagram, abnormal EGJ distensibility was more frequently observed with an abnormal esophagram than normal EGJ opening: 14/23 (61%) vs 10/45 (22%); P=0.003. Epiphrenic diverticula were present in 3/164 patients: 2/3 had sLESC.

Conclusions & Inferences: Symptomatic patients with normal esophageal motility on HRM predominantly have normal FLIP Panometry; however, abnormal FLIP findings can be observed. While abnormal Panometry findings appear clinically relevant via an association with abnormal bolus retention, complementary tests, such as provocative maneuvers with HRM and timed barium esophagram, are useful to determine clinical context.
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http://dx.doi.org/10.1111/nmo.14116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433263PMC
October 2021

Music Listening Predicted Improved Life Satisfaction in University Students During Early Stages of the COVID-19 Pandemic.

Front Psychol 2020 20;11:631033. Epub 2021 Jan 20.

Department of Psychology, James Cook University, Townsville, QLD, Australia.

Quarantine and spatial distancing measures associated with COVID-19 resulted in substantial changes to individuals' everyday lives. Prominent among these lifestyle changes was the way in which people interacted with media-including music listening. In this repeated assessment study, we assessed Australian university students' media use (i.e., listening to music, playing video/computer games, watching TV/movies/streaming videos, and using social media) throughout early stages of the COVID-19 pandemic in Australia, and determined whether media use was related to changes in life satisfaction. Participants ( = 127) were asked to complete six online questionnaires, capturing pre- and during-pandemic experiences. The results indicated that media use varied substantially throughout the study period, and at the within-person level, life satisfaction was positively associated with music listening and negatively associated with watching TV/videos/movies. The findings highlight the potential benefits of music listening during COVID-19 and other periods of social isolation.
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http://dx.doi.org/10.3389/fpsyg.2020.631033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855032PMC
January 2021

The Role and Impact of Radio Listening Practices in Older Adults' Everyday Lives.

Authors:
Amanda E Krause

Front Psychol 2020 18;11:603446. Epub 2020 Dec 18.

Department of Psychology, James Cook University, Townsville, QLD, Australia.

Previous research has indicated older adults value listening to music as a leisure activity. Yet, recent research into listening practices broadly has often focused on younger adults and the use of newer, digital listening technologies. Nonetheless, the radio, which is familiar to older people who grew up with it at the forefront of family life, is important to consider with regard to listening practices and the potential associated well-being benefits. This research investigated older adults' everyday radio listening practices, in order to begin to understand how the radio fits into their daily lives and how it might influence their sense of well-being. Twenty-five Australian residents (aged 66-87; 56% female, 44% male) participated in semi-structured, one-to-one interviews. The results of a qualitative thematic analysis revealed themes concerning listening preferences, listening routines, access, and motivations/outcomes. While personal preferences (concerning content, stations, and presenters) were diverse, individuals clearly communicated these as well as their established listening routines and habits. Listener motivations varied: some people focused on the enjoyment that listening to the radio creates while some noted benefits to their well-being, such as relaxation, modifying their mood, and feelings of comfort and community. Radio listening practices can be defined in terms of differing engagement styles, as characterized using continua ranging from passive to active, or focused, listening as well as generalized or specific listening. Based on participants' experiences, a proposed engagement space model links how people engage with the radio to the possible outcomes mentioned. Importantly, benefits to well-being can result from varied engagement styles. The findings presented provide an in-depth understanding of how the radio fits into older adults' everyday life, with implications for considering how the radio might be used as a widely accessed, low-cost tool for maintaining and enhancing quality of later life.
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http://dx.doi.org/10.3389/fpsyg.2020.603446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775306PMC
December 2020

The Neuropsychiatry of Huntington Disease-Like 2: A Comparison with Huntington's Disease.

J Huntingtons Dis 2020 ;9(4):325-334

Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Background: Huntington Disease-Like 2 (HDL2) is a rare autosomal dominant disorder caused by an abnormal CAG/CTG triplet repeat expansion on chromosome 16q24. The symptoms of progressive decline in motor, cognitive and psychiatric functioning are similar to those of Huntington's disease (HD). The psychiatric features of the HDL2 have been poorly characterized.

Objective: To describe the neuropsychiatric features of HDL2 and compare them with those of HD.

Methods: A blinded cross-sectional design was used to compare the behavioural component of the Unified Huntington's Disease Rating Scale (UHDRS) in participants with HDL2 (n = 15) and HD (n = 13) with African ancestry.

Results: HDL2 patients presented with psychiatric symptoms involving mood disturbances and behavioural changes that were not significantly different from those in the HD group. Duration of disease and motor performance correlated (p < 0.001) with the Functional Capacity score and the Independence score of the UHDRS. HD patients reported movement dysfunction as the first symptom more frequently than HDL2 Patients (p < 0.001).

Conclusion: The psychiatric phenotype of HDL2 is similar to that of HD and linked to motor decline and disease duration. Psychiatric symptoms seem more severe for HDL2 patients in the early stages of the disease.
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http://dx.doi.org/10.3233/JHD-200422DOI Listing
November 2021

Multiple rapid swallows and rapid drink challenge in patients with esophagogastric junction outflow obstruction on high-resolution manometry.

Neurogastroenterol Motil 2021 03 11;33(3):e14000. Epub 2020 Oct 11.

Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Background: Esophagogastric junction outflow obstruction (EGJOO) as defined by Chicago Classification of esophageal motility disorders (CCv3.0) encompasses a broad range of diagnoses, thus posing clinical challenges. Our aims were to evaluate multiple rapid swallow (MRS) and rapid drink challenge (RDC) during high-resolution manometry (HRM) to aid identifying clinically relevant EGJOO.

Methods: Patients with a HRM diagnosis of EGJOO based on CCv3.0 that also completed MRS and RDC during HRM and barium esophagram were retrospectively identified. Radiographic EGJOO (RAD-EGJOO) was defined by either liquid barium retention or delayed passage of a barium tablet on barium esophagram. Thirty healthy asymptomatic controls that completed HRM were also included. MRS involved drinking 2 mL for 5 successive swallows. RDC involved rapid drinking of 200 mL liquid. Integrated relaxation pressure (IRP) and presence of panesophageal pressurization (PEP) during MRS and RDC were assessed.

Key Results: One hundred one patients, mean (SD) age 56 (16) years, were included; 32% had RAD-EGJOO, 68% did not. RAD-EGJOO patients more frequently had elevated (>12 mmHg) upright IRP (100%), MRS-IRP (56%), RDC-IRP (53%), and PEP during RDC (66%) than both controls [17%; 0%; 7%; 3%] and patients without RAD-EGJOO [83%; 35%; 39%; 41%] Having IRP >12 mmHg during both MRS and RDC was twice as likely to be associated with RAD-EGJOO (19%) than those without RAD-EGJOO (9%) among patients with upright IRP >12 mmHg.

Conclusions And Inferences: Adjunctive HRM maneuvers MRS and RDC appear to help identify clinically significant EGJOO. While future outcome studies are needed, comprehensive multimodal evaluation helps clarify relevance of EGJOO on HRM.
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http://dx.doi.org/10.1111/nmo.14000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902305PMC
March 2021

The effect of episodic future simulation and motivation on young children's induced-state episodic foresight.

Cogn Dev 2020 Oct-Dec;56:100934. Epub 2020 Aug 12.

Department of Psychology, Brock University, Canada.

Future simulation and motivation are two strategies that might help children improve their induced-state episodic foresight. In Study 1, 3- to 5-year-old children ( = 96) consumed pretzels (to induce thirst) and were asked what they would prefer the next day, pretzels or water. Children were randomly assigned to an experimental condition: (1) a standard thirsty condition, (2) an episodic simulation condition where they imagined being hungry the next day, (3) a motivation condition where children chose between a cupcake and water, or (4) a control condition (thirst was not induced). Future preferences did not differ by age and children were less likely to choose water (vs. a cupcake) in the motivation condition compared to the standard thirsty condition. Study 2 found that 3- to 5-year-old children ( = 22) were also less likely to choose water for versus a cupcake when thirst was induced.
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http://dx.doi.org/10.1016/j.cogdev.2020.100934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7421301PMC
August 2020

Blown-out myotomy: an adverse event of laparoscopic Heller myotomy and peroral endoscopic myotomy for achalasia.

Gastrointest Endosc 2021 04 25;93(4):861-868.e1. Epub 2020 Jul 25.

Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

Background And Aims: Although laparoscopic Heller myotomy (LHM) or peroral endoscopic myotomy (POEM) is highly effective, 10% to 20% of patients with achalasia remain symptomatic after treatment. In evaluating such patients, we have observed a pattern of failure associated with a pseudodiverticulum, or blown-out myotomy (BOM), in the distal esophagus. We aimed to assess risk factors and patient-reported outcomes associated with a BOM.

Methods: We reviewed our manometry database for patients with achalasia previously treated with LHM or POEM. We included patients who had a post-treatment esophagram within 1 year of their follow-up manometry. A BOM was defined radiographically as a wide-mouthed outpouching (>50% increase in esophageal diameter) in the area of the myotomy.

Results: One hundred twenty-nine patients with achalasia who underwent treatment were included; 23 (17.8%) had a BOM. Comparing patients with a BOM with those without, post-treatment Eckardt scores were significantly greater (5 vs 2, P = .002), type III achalasia was more common (39.1% vs 14.2%, P = .005), and LHM was more common than POEM (73.9% vs 26.1%, P = .013). The integrated relaxation pressure was also significantly greater in the BOM group (15.0 mm Hg vs 11.0 mm Hg, P = .025).

Conclusions: BOM is a common adverse event after myotomy for achalasia but is not seen after pneumatic dilation. Pretreatment type III achalasia, LHM as opposed to POEM, and a greater post-treatment integrated relaxation pressure were risk factors for developing a BOM. We speculate that esophageal wall strain in the area weakened by myotomy, whether from residual spastic contractility or continued esophageal outflow obstruction, may be the underlying mechanism of BOM development.
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http://dx.doi.org/10.1016/j.gie.2020.07.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855725PMC
April 2021

Endocrine profiling in patients with Fanconi anemia, homozygous for a FANCG founder mutation.

Mol Genet Genomic Med 2020 08 11;8(8):e1351. Epub 2020 Jun 11.

Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, The University of the Witwatersrand, Johannesburg, Gauteng, South Africa.

Background: Fanconi anemia (FA) is phenotypically diverse, hereditary condition associated with bone marrow failure, multiple physical abnormalities, and an increased susceptibility to the development of malignancies. Less recognized manifestations of FA include endocrine abnormalities. International discourse has highlighted that these abnormalities are widespread among children and adults with FA. To date there has been no systematic study that has evaluated the endocrine abnormalities in a cohort of patients with FA, homozygous for a founder mutation (c.637_643del (p.Tyr213Lysfs*6)) in FANCG. The objectives of the study were to evaluate endocrine gland function in patients with FA of a single FA genotype, and to determine the frequency and nature of endocrine abnormalities in this group.

Methods: Cross-sectional, descriptive study of 24 South African patients of African ancestry with FA (homozygous for a FANCG founder mutation). Outcomes measured included growth, pubertal status, growth hormone axis screening, thyroid gland function, glucose and insulin metabolism and bone age (BA).

Results: Endocrine dysfunction was present in 70.8% (17 of 24), including abnormal insulin-like growth factor 1 (IGF-1)/insulin-like growth factor-binding protein 3 (IGFBP-3) in 25.0% (6 of 24), insulin resistance in 41.7% (10 of 24), abnormal thyroid function in 16.7% (4 of 24) and short stature in 45.8% (11 of 24). No abnormalities of glucose metabolism were identified. Abnormal pubertal status was seen in three males (12.5%). Abnormal BAs were present in 34.8% (8 of 23).

Conclusion: Endocrine abnormalities occur at a high frequency in patients with FA, homozygous for a FANCG founder mutation, similar to other FA cohorts. Our data are specific to FA patients with a single genotype, and therefore provide the first genotype-phenotype information on endocrine abnormalities in South African patients, homozygous for a FANCG founder mutation. Recommendations regarding endocrine screening in this patient subgroup are made, including, but not limited to, baseline testing of thyroid function, fasted insulin and glucose, and IGF-1 and IGFBP-3.
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http://dx.doi.org/10.1002/mgg3.1351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434606PMC
August 2020

A comparison between the neurocognitive profile of Huntington Disease-Like 2 and Huntington Disease: Exploring the presence of double dissociations.

Appl Neuropsychol Adult 2020 Mar 9:1-11. Epub 2020 Mar 9.

Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Huntington Disease Like-2 (HDL2) is a rare autosomal dominant genetic disease caused by a mutation in the JPH3 gene. HDL2 is the Huntington Disease (HD) phenocopy that has the greatest clinical resemblance to HD. Both are characterized by movement, psychiatric and cognitive dysfunction, which progress to dementia. The present study compared the neuropsychological profile of HDL2 with that of HD. Using a Single Case-Control Methodology in Neuropsychology, three HDL2 and seven matched HD patients were assessed with a comprehensive neuropsychological battery and compared to matched control samples, considering age, years of education, type of school (public/government) and language (all bi/multilingual). Potential double dissociations were explored by using Crawford, Garthwaite, and Wood's Inferential Methods for Comparing the Scores of Two Single-Cases in Case-Control Designs. Double dissociation between HDL2 and HD were identified in three tests, namely Letter Number Sequencing, Rey Auditory Learning Test Delayed and Recognition Trials. These dissociations possible are due to methodological limitations.
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http://dx.doi.org/10.1080/23279095.2020.1734810DOI Listing
March 2020

Spinal Muscular Atrophy in the Black South African Population: A Matter of Rearrangement?

Front Genet 2020 13;11:54. Epub 2020 Feb 13.

National Health Laboratory Service and School of Pathology, University of the Witwatersrand, Johannesburg, South Africa.

Spinal muscular atrophy (SMA) is a neuromuscular disorder, characterized by muscle atrophy and impaired mobility. A homozygous deletion of survival motor neuron 1 (), exon 7 is the main cause of SMA in ~94% of patients worldwide, but only accounts for 51% of South African (SA) black patients. and its highly homologous centromeric copy, survival motor neuron 2 (, are located in a complex duplicated region. Unusual copy number variations (CNVs) have been reported in black patients, suggesting the presence of complex pathogenic rearrangements. The aim of this study was to further investigate the genetic cause of SMA in the black SA population. Multiplex ligation-dependent probe amplification (MLPA) testing was performed on 197 unrelated black patients referred for SMA testing (75 with a homozygous deletion of , exon 7; 50 with a homozygous deletion of , exon 7; and 72 clinically suggestive patients with no homozygous deletions). Furthermore, 122 black negative controls were tested. For comparison, 68 white individuals (30 with a homozygous deletion of , exon 7; 8 with a homozygous deletion of , exon 7 and 30 negative controls) were tested. Multiple copies (>2) of , exon 7 were observed in 50.8% (62/122) of black negative controls which could mask heterozygous deletions and potential pathogenic CNVs. MLPA is not a reliable technique for detecting carriers in the black SA population. Large deletions extending into the rest of and neighboring genes were more frequently observed in black patients with homozygous , exon 7 deletions when compared to white patients. Homozygous , exon 7 deletions were commonly observed in black individuals. No clear pathogenic CNVs were identified in black patients but discordant copy numbers of exons suggest complex rearrangements, which may potentially interrupt the gene. Only 8.3% (6/72) of clinically suggestive patients had heterozygous deletions of , exon 7 (1:0) which is lower than previous SA reports of 69.5%. This study emphasizes the lack of understanding of the architecture of the region as well as the cause of SMA in the black SA population. These factors need to be taken into account when counseling and performing diagnostic testing in black populations.
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http://dx.doi.org/10.3389/fgene.2020.00054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033609PMC
February 2020

Five years of screening for galactosaemia in South Africa: Pitfalls of using Benedict's test and thin layer chromatography to screen for galactosaemia in a developing country.

Clin Chim Acta 2020 Jun 21;505:73-77. Epub 2020 Feb 21.

Department of Chemical Pathology, Faculty of Health Sciences, University of Pretoria and National Health Laboratory Service Tshwane Academic Division, Pretoria, South Africa; Division of Chemical Pathology, University of Cape Town, South Africa. Electronic address:

Background: The objective of the study was to investigate the effectiveness of screening for hereditary galactosaemia with Benedict's test and thin layer chromatography (TLC) in a tertiary laboratory from a developing country.

Methods: We retrospectively analysed the results of tests done in suspected galactosaemia patients including Benedict's test, thin layer chromatography, GALT activity and DNA analysis.

Results: 878 paediatric patients were screened with Benedict's test; the age range was 5 days to 19 years. 48% tested positive/trace on the Benedict's test of which 52% of these had galactosuria evident on TLC. 22% of this sample had pathologically low GALT results on follow-up. 8 patients from the screened population were confirmed to have galactosaemia, in addition to 6 more patients diagnosed with galactosaemia without screening tests performed. Median ages at which the diagnoses were made in the screened and non-screened samples were 2 months and 6 months respectively. Confirmatory DNA testing was performed in 2 patients, whom were found to be heterozygous for S135L mutation.

Conclusion: Inadequate performance of Benedict's test and TLC was demonstrated by false positive and false negative results leading us to conclude that screening test results require interpretation with caution.
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http://dx.doi.org/10.1016/j.cca.2020.02.018DOI Listing
June 2020

Single case-control design for the study of the neuropsychological deficits and dissociations in Huntington's disease-like 2.

MethodsX 2020 10;7:100782. Epub 2020 Jan 10.

Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

The Single-Case Methodology in Neuropsychology (Crawford & Howell, 1998) is a research design and robust inferential statistical method that facilitates the neuropsychological description of one case in terms of the differences between its profile and the performance of a carefully matched sample (Crawford & Garthwaite, 2012). The comparison is made by means of a -test statistic that treats the normative sample as a sample and not as a population, with a particular effect-size associated with the size (n) of the sample. It is an ideal method for the neuropsychological investigation of rare diseases, such as Huntington's Disease Like-2 (HDL2), especially when the cases are embedded in contexts of great diversity. This paper presents a step by step guide to the implementation of this method in a series of demographically and clinically diverse group of patients. •The application of a Single-Case Methodology in Neuropsychology enables the characterisation of rare diseases while controlling for demographic and context-related variables.•The implementation Single-Case Methodology in Neuropsychology provides test norms for homogenous groups that can be used by practitioners in their clinical work.•The method was customised for the South African population by controlling variables of specific relevance, such as linguistic diversity and quality of education.
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http://dx.doi.org/10.1016/j.mex.2020.100782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995251PMC
January 2020

Genetic Factors Influencing Warfarin Dose in Black-African Patients: A Systematic Review and Meta-Analysis.

Clin Pharmacol Ther 2020 06 28;107(6):1420-1433. Epub 2020 Jan 28.

Department of Molecular and Clinical Pharmacology, The Wolfson Centre for Personalized Medicine, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK.

Warfarin is the most commonly used oral anticoagulant in sub-Saharan Africa. Dosing is challenging due to a narrow therapeutic index and high interindividual variability in dose requirements. To evaluate the genetic factors affecting warfarin dosing in black-Africans, we performed a meta-analysis of 48 studies (2,336 patients). Significant predictors for CYP2C9 and stable dose included rs1799853 (CYP2C9*2), rs1057910 (CYP2C9*3), rs28371686 (CYP2C9*5), rs9332131 (CYP2C9*6), and rs28371685 (CYP2C9*11) reducing dose by 6.8, 12.5, 13.4, 8.1, and 5.3 mg/week, respectively. VKORC1 variants rs9923231 (-1639G>A), rs9934438 (1173C>T), rs2359612 (2255C>T), rs8050894 (1542G>C), and rs2884737 (497T>G) decreased dose by 18.1, 21.6, 17.3, 11.7, and 19.6 mg/week, respectively, whereas rs7294 (3730G>A) increased dose by 6.9 mg/week. Finally, rs12777823 (CYP2C gene cluster) was associated with a dose reduction of 12.7 mg/week. Few studies were conducted in Africa, and patient numbers were small, highlighting the need for further work in black-Africans to evaluate genetic factors determining warfarin response.
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http://dx.doi.org/10.1002/cpt.1755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217737PMC
June 2020

A Comprehensive Haplotype-Targeting Strategy for Allele-Specific HTT Suppression in Huntington Disease.

Am J Hum Genet 2019 12 7;105(6):1112-1125. Epub 2019 Nov 7.

Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC V5Z4H4, Canada. Electronic address:

Huntington disease (HD) is a fatal neurodegenerative disorder caused by a gain-of-function mutation in HTT. Suppression of mutant HTT has emerged as a leading therapeutic strategy for HD, with allele-selective approaches targeting HTT SNPs now in clinical trials. Haplotypes associated with the HD mutation (A1, A2, A3a) represent panels of allele-specific gene silencing targets for efficient treatment of individuals with HD of Northern European and indigenous South American ancestry. Here we extend comprehensive haplotype analysis of the HD mutation to key populations of Southern European, South Asian, Middle Eastern, and admixed African ancestry. In each of these populations, the HD mutation occurs predominantly on the A2 HTT haplotype. Analysis of HD haplotypes across all affected population groups enables rational selection of candidate target SNPs for development of allele-selective gene silencing therapeutics worldwide. Targeting SNPs on the A1 and A2 haplotypes in parallel is essential to achieve treatment of the most HD-affected subjects in populations where HD is most prevalent. Current allele-specific approaches will leave a majority of individuals with HD untreated in populations where the HD mutation occurs most frequently on the A2 haplotype. We further demonstrate preclinical development of potent and selective ASOs targeting SNPs on the A2 HTT haplotype, representing an allele-specific treatment strategy for these individuals. On the basis of comprehensive haplotype analysis, we show the maximum proportion of HD-affected subjects that may be treated with three or four allele targets in different populations worldwide, informing current allele-specific HTT silencing strategies.
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http://dx.doi.org/10.1016/j.ajhg.2019.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904807PMC
December 2019

The neuropsychological deficits and dissociations in Huntington Disease-Like 2: A series of case-control studies.

Neuropsychologia 2020 01 5;136:107238. Epub 2019 Nov 5.

Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Objectives: Huntington's Disease Like-2 (HDL2) is a rare autosomal dominant genetic disease caused by a mutation in the JPH3 gene. The Huntington's Disease (HD) phenocopy has the greatest clinical resemblance to HD, but its neurocognitive characterisation is poorly researched. This study reports on the neurocognitive profile of seven HDL2 patients including preserved functions, deficits and dissociations (classical and strong) and provides a general characterisation of the cognitive dysfunction of HDL2 in relation to the progression of the disease.

Methods: The neuropsychological performance of seven HDL2 patients were compared to one of four control groups, matched by age and level of education using a Single Case-Control design. All patients were polyglots and with public education (primary and secondary). Deficits, as well as classical and strong dissociations within each case profile, were identified by implementing Crawford and Howell's (1998) t-test and the Revised Standardized Difference Test (Crawford and Garthwaite, 2005), respectively.

Results: The HDL2 neurocognitive syndrome is heterogeneous with a variable rate of progression, with the psychomotor and dexterity domain consistently and severely impaired.

Conclusion: HDL2 has a heterogeneous impact on cognitive functions from early stages in the disease, which evolve to dementia in a non-uniform manner, in keeping with preferential damage in the cerebrocortical-basal ganglia-thalamus-cerebrocortical circuit.
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http://dx.doi.org/10.1016/j.neuropsychologia.2019.107238DOI Listing
January 2020

An unusual presentation of ACE inhibitor-induced visceral angioedema.

BMJ Case Rep 2019 Sep 18;12(9). Epub 2019 Sep 18.

Internal Medicine, McGaw Medical Center of Northwestern University, Chicago, Illinois, USA.

ACE inhibitors (ACEi) are common anti-hypertensive drugs that can cause angioedema. Though classic, or facial angioedema is rare, visceral angioedema is even less common. When angioedema occurs, it typically presents early, within 30 days of initiating therapy. Visceral angioedema most commonly presents with nausea, emesis, abdominal pain and diarrhoea, and thus is often mistaken for an episode of gastroenteritis. When a CT scan is obtained, it typically shows characteristic findings, including ascetic fluid, mild mesenteric oedema and thickening of the small bowel. In this case report, we present a patient who did not experience her first episode of visceral angioedema until after she had been on ACEi therapy for 5-7 years. In addition, she experienced recurrent episodes of visceral angioedema that were separated by approximately 4 years at a time. Both of these features make for a particularly unique presentation.
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http://dx.doi.org/10.1136/bcr-2019-230865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754668PMC
September 2019

Review of 10 years of preimplantation genetic diagnosis in South Africa: implications for a low-to-middle-income country.

J Assist Reprod Genet 2019 Sep 26;36(9):1909-1916. Epub 2019 Jul 26.

Division of Human Genetics, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.

Purpose: To evaluate the preimplantation genetic diagnosis (PGD) service, for the period of January 2006 to December 2016, through a South African academic and diagnostic Human Genetics Unit, and to assess the outcomes and cost of PGD.

Methods: A retrospective review of PGD files available at the Human Genetics Unit was performed. Data was collected from genetic counseling, fertility, and PGD-specific records.

Results: Amongst the 22 couples who had PGD, 42 in vitro fertilisation cycles were completed with 228 embryos biopsied and included in the analysis. Most (59%) of the conditions for which PGD was requested were autosomal recessive. Of the biopsied embryos, 71/228 (31.1%) were suitable for transfer and 41/71 (57.7%) were transferred. Of these, 14/41 (34.0%) successfully implanted and 11/14 (78.6%) resulted in a liveborn infant. The clinical pregnancy rate per embryo transfer was 29.3%. Overall, 10/22 (45.5%) couples had a successful cycle resulting in a liveborn infant. On average, one cycle of PGD costs USD 9525.

Conclusions: This is the first study to assess the success rates and the cost of PGD in South Africa and provides evidence for the feasibility in a low-to-middle-income country. The success rates in this sample are comparable to those achieved globally. South Africa has the infrastructure and expertise to provide PGD; the limiting factor is the lack of funding initiatives for PGD. Although the sample size was small, the findings from this study will enable genetic counselors to offer couples in South Africa evidence-based and locally accurate information regarding outcomes, success rates, and costs.
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http://dx.doi.org/10.1007/s10815-019-01537-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730725PMC
September 2019

Panel-Based Exome Sequencing for Neuromuscular Disorders as a Diagnostic Service.

J Neuromuscul Dis 2019 ;6(2):241-258

Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Neuromuscular disorders (NMDs) are clinically and genetically heterogeneous. Accurate molecular genetic diagnosis can improve clinical management, provides appropriate genetic counseling and testing of relatives, and allows potential therapeutic trials.

Objective: To establish the clinical utility of panel-based whole exome sequencing (WES) in NMDs in a population with children and adults with various neuromuscular symptoms.

Methods: Clinical exome sequencing, followed by diagnostic interpretation of variants in genes associated with NMDs, was performed in a cohort of 396 patients suspected of having a genetic cause with a variable age of onset, neuromuscular phenotype, and inheritance pattern. Many had previously undergone targeted gene testing without results.

Results: Disease-causing variants were identified in 75/396 patients (19%), with variants in the three COL6-genes (COL6A1, COL6A2 and COL6A3) as the most common cause of the identified muscle disorder, followed by variants in the RYR1 gene. Together, these four genes account for almost 25% of cases in whom a definite genetic cause was identified. Furthermore, likely pathogenic variants and/or variants of uncertain significance were identified in 95 of the patients (24%), in whom functional and/or segregation analysis should be used to confirm or reject the pathogenicity. In 18% of the cases with a disease-causing variant of which we received additional clinical information, we identified a genetic cause in genes of which the associated phenotypes did not match that of the patients. Hence, the advantage of panel-based WES is its unbiased approach.

Conclusion: Whole exome sequencing, followed by filtering for NMD genes, offers an unbiased approach for the genetic diagnostics of NMD patients. This approach could be used as a first-tier test in neuromuscular disorders with a high suspicion of a genetic cause. With uncertain results, functional testing and segregation analysis are needed to complete the evidence.
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http://dx.doi.org/10.3233/JND-180376DOI Listing
December 2019

Comparison of the Huntington's Disease like 2 and Huntington's Disease Clinical Phenotypes.

Mov Disord Clin Pract 2019 Apr 12;6(4):302-311. Epub 2019 Mar 12.

Division of Human Genetics National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, The University of the Witwatersrand Johannesburg South Africa.

Background: Huntington's disease like 2 (HDL2) is the most common Huntington's disease (HD) phenocopy in many countries and described as the phenocopy with the greatest resemblance to HD. The current clinical description of HDL2 is based on retrospective data. It is unknown whether HDL2 has clinical features that distinguish it from HD.

Objective: To describe the HDL2 phenotype and compare it to HD systematically.

Methods: A blinded cross-sectional design was used to compare the HDL2 (n = 15) and HD (n = 13) phenotypes. African ancestry participants underwent assessments, including the Unified Huntington's Disease Rating Scale (UHDRS). The UHDRS motor component was video recorded and evaluated by blinded experts and the inter-rater reliability calculated.

Results: Both groups were homogeneous in terms of demographics and disease characteristics. However, HDL2 patients presented three years earlier with more prominent dysarthria and dystonia. Raters could not distinguish between the two diseases with a high level of agreement. No significant differences in the TMS between HDL2 and HD were found. In both disorders, disease duration correlated with motor scores, with the exception of chorea. Psychiatric and cognitive scores were not significantly different between the groups.

Conclusions: The HDL2 phenotype is similar to HD and is initially characterized by dementia, chorea, and oculomotor abnormalities, progressing to a rigid and bradykinetic state, suggesting the UHDRS is useful to monitor disease progression in HDL2. Although HDL2 patients scored higher on some UHDRS domains, this did not differentiate between the two diseases; it may however be emerging evidence of HDL2 having a more severe clinical phenotype.
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http://dx.doi.org/10.1002/mdc3.12742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6476590PMC
April 2019
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