Clinical and molecular genetic description of a new type of mucopolysaccharidosis in Yakutia

Введение. В статье приведены клинические и молекулярно-генетические характеристики нового наследственного заболевания с аутосомно-рецессивным типом наследования - мукополисахаридоз-плюс синдрома, впервые описанного в якутской популяции и в одной турецкой семье. Синдром относится к группе лизосомных заболеваний и был внесен в международную базу наследственных заболеваний OMIM под номером # 617303. Цель: дать клиническую и молекулярно-генетическую характеристику мукополисахаридоз-плюс синдрома у пациентов, наблюдавшихся в Якутии с 2006 по 2020 год. Методы. Объектом исследования послужили клинические данные из генетических карт 17 пациентов из 15 якутских семей, наблюдавшихся и состоявших в Республиканском генетическом регистре наследственной и врожденной патологии Медико-генетического центра «Республиканской больницы №1 - Национального центра медицины» в городе Якутске. Результаты. Клиническая картина у пациентов проявляется типичными признаками мукополисахаридозов, но с более тяжелым течением заболевания, приводящим к ранней младенческой смерти. У всех больных обнаружена мутация p.R498W в гене VPS33A в гомозиготном состоянии, у их родителей - в гетерозиготном. Заключение. Характерным признаком мукополисахаридоз-плюс синдрома является ранняя манифестация, быстропрогрессирующее течение с мультисистемным поражением легких, почек, сердца, центральной нервной и гемопоэтической систем и младенческая смертность. Background. This article provides data on the clinical and molecular genetic description of a new hereditary disease with an autosomal recessive inheritance - mucopolysaccharidosis-plus syndrome, first described in the Yakut population and in one Turkish family. The syndrome belongs to the group of lysosomal diseases and was included into the international database of hereditary diseases OMIM under the number # 617303. Aim. To describe clinical and molecular genetic characteristics of mucopolysaccharidosis-plus syndrome in patients observed in Yakutia from 2006 to 2020. Methods. The material for the study was clinical data from genetic records of 17 patients from 15 Yakut families, who were observed and registered in the «Republican genetic register of hereditary and congenital pathology of the Medical Genetic Center of the Republic hospital No. 1 - National Center of Medicine» in Yakutsk city. Results. The clinical phenotype is manifested by typical clinical signs of mucopolysaccharidosis, but with a more severe course of the disease, leading to early infant death of patients. Mucopolysaccharidosis-plus syndrome cannot be diagnosed enzymatically. All patients were found to have a specific p.R498W mutation in the VPS33A gene in a homozygous state, and in their parents in a heterozygous state. Conclusions. A characteristic sign of mucopolysaccharidosis plus syndrome is early manifestation and infant mortality, as well as multisystem damage to organs: lungs, kidneys, heart, central nervous and hemopoietic systems.

Angiokeratoma corporis diffusum universale: A rare case report from Nepal

Angiokeratoma corporis diffusum universale, a clinical variant of angiokeratoma, is a generalized vascular ectasia that is associated with overlying epidermal changes rather than a true vascular neoplasm. It is the cutaneous hallmark of several rare inherited lysosomal diseases associated with specific enzyme deficiencies in the metabolism of glycoproteins. Herein, we present possibly the first case report from Nepal of angiokeratoma corporis diffusum universale in a 14-year-old female from consanguineous parents who presented herself with characteristic clinical and laboratory features of angiokeratoma corporis diffusum with progressive mental and motor developmental delay along with seizures, dystonia, and recurrent chest infections. Resource constraints limited confirmation with an enzyme assay and electron microscopy. We report this unusual case with the intention of re-emphasizing the importance of clinical evaluation in reaching a diagnosis in a resource-deficient setting.

New paradigms for the treatment of lysosomal storage diseases: targeting the endocannabinoid system as a therapeutic strategy

Over the past three decades the lysosomal storage diseases have served as model for rare disease treatment development. While these efforts have led to considerable success, important challenges remain. For example, no treatments are currently approved for nearly two thirds of all lysosomal diseases, and there is limited impact of the existing drugs on the central nervous system. In addition, the costs of these therapies are extremely high, in part due to the fact that drug development has focused on a “single hit” approach – i.e., one drug for one disease. To overcome these obstacles researchers have begun to focus on defining common disease mechanisms in the lysosomal diseases, particularly in the central nervous system, with the hope of identifying drugs that might be used in several lysosomal diseases rather than an individual disease. With this concept in mind, herein we review a new potential treatment approach for the lysosomal storage diseases that focuses on modulation of the endocannabinoid system. We provide a short introduction to lysosomal storage diseases and the endocannabinoid system, followed by a brief review of data supporting this concept.