Combining Literature Review With a Ground Truth Approach for Diagnosing Huntington's Disease Phenocopy.

Quang Tuan Rémy Nguyen,Katia Youssov,G Bernhard Landwehrmeyer,Juan Dario Ortigoza Escobar,Lena Elisabeth Hjermind,Anne-Catherine Bachoud-Lévi,Caterina Mariotti,Carsten Saft,Jean-Marc Burgunder

doi:10.3389/fneur.2022.817753

Abstract

One percent of patients with a Huntington's disease (HD) phenotype do not have the Huntington (HTT) gene mutation. These are known as HD phenocopies. Their diagnosis is still a challenge. Our objective is to provide a diagnostic approach to HD phenocopies based on medical expertise and a review of the literature. We employed two complementary approaches sequentially: a review of the literature and two surveys analyzing the daily clinical practice of physicians who are experts in movement disorders. The review of the literature was conducted from 1993 to 2020, by extracting articles about chorea or HD-like disorders from the database Pubmed, yielding 51 articles, and analyzing 20 articles in depth to establish the surveys. Twenty-eight physicians responded to the first survey exploring the red flags suggestive of specific disease entities. Thirty-three physicians completed the second survey which asked for the classification of paraclinical tests according to their diagnostic significance. The analysis of the results of the second survey used four different clustering algorithms and the density-based clustering algorithm DBSCAN to classify the paraclinical tests into 1st, 2nd, and 3rd-line recommendations. In addition, we included suggestions from members of the European Reference Network-Rare Neurological Diseases (ERN-RND Chorea & Huntington disease group). Finally, we propose guidance that integrate the detection of clinical red flags with a classification of paraclinical testing options to improve the diagnosis of HD phenocopies.

Highlights

Huntington’s disease (HD) is the most frequent inherited chorea in adults [1,2,3], with an estimated prevalence of about 10 individuals per 100,000
The strategy for ordering paraclinical test were synthetized from ordered lists in four articles [2, 8, 9, 20] and in workups proposed in five additional articles [2, 6, 16, 19, 23]
The first one to validate useful potential red flags in daily clinical practice (DCP) and was answered by 28 experts; the other one on the classification of paraclinical tests in 1st, 2nd, and 3rd-lines was answered by 33 experts and analyzed by clustering algorithms

Summary

Introduction

Huntington’s disease (HD) is the most frequent inherited chorea in adults [1,2,3], with an estimated prevalence of about 10 individuals per 100,000. Its clinical phenotype is defined by a triad of symptoms and signs [3]:. (1) A motor syndrome encompassing a wide range of symptoms, including pyramidal and movement disorders. The essential feature, chorea, is defined by excessive, spontaneous, irregularly timed, non-repetitive, randomly distributed, and abrupt movements which may affect the face, the trunk, and extremities. (3) Psychiatric signs include a wide range of symptoms such as irritability, anxiety, or depression. Cognitive and psychiatric symptoms may appear as prodromal symptoms years before diagnostic motor signs. About 1% of patients with this clinical phenotype do not have CAG expansion in HTT [1]; they are described as HD phenocopies. An HD phenocopy is defined as [2]: 1) a movement disorder consistent with HD when assessed by an experienced neurologist

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