Причины ложной диагностики полимиозита у пациентов с дисферлинопатией: клинический случай

Differential diagnosis of inflammatory myopathies with hereditary muscular dystrophies accompanied by a secondary inflammatory process is a time‑consuming clinical and pathomorphological task. In particular, false diagnosis of polymyositis in patients with dysferlinopathy reaches 25 % of cases.A 40‑year‑old female patient with a limb‑girdle phenotype of dysferlinopathy, initially diagnosed as polymyositis, is presented. The reasons that led to the erroneous diagnosis were: sporadic case; subacute onset; proximal muscle weakness; myalgia, which stopped on the glucocorticosteroid therapy; high levels of creatine phosphokinase (up to 17 times); the presence of lymphocytic‑macrophage infiltrate in the muscle biopsy and the absence of magnetic resonance imaging data in primary examination of the patient.The refractoriness of clinical and laboratory signs to complex immunosuppressive therapy was the reason for revising the muscle biopsy with typing of the inflammatory infiltrate. The predominantly unexpressed perivascular infiltrate was characterized by the predominance of macrophages and, to a lesser extent, CD4+, which indicated the secondary nature of the inflammation in the muscle observed in some hereditary muscular dystrophies. When conducting an immunohistochemical reaction, the absence of the dysferlin protein in the sarcoplasmic membrane was revealed.Whole‑exome sequencing (NGS) revealed a mutation in exon 39 of the DYSF gene (p.Gln1428Ter) in the heterozygous state, which leads to the appearance of a stop codon and premature termination of protein translation. MLPA method registered 3 copies of exons 18, 19, 20, 22, 24 of the DYSF gene.Thus, this clinical example reflects the main methodological errors and possible effects of immunosuppressive therapy in patients with dysferlinopathy.Дифференциальная диагностика воспалительных миопатий, сопровождающихся вторичным воспалительным процессом, с наследственными мышечными дистрофиями является сложной и трудоемкой клинико‑патоморфологической задачей. В частности, ложная диагностика полимиозита у пациентов с дисферлинопатией достигает 25 % случаев.Представлена пациентка 40 лет с поясно‑конечностным фенотипом дисферлинопатии, первично диагностированной как полимиозит. Причины, повлекшие ошибочную диагностику: спорадическое происхождение; подострый дебют; проксимальная мышечная слабость; миалгия, купировавшаяся на фоне глюкокортикостероидной терапии; повышение уровня креатинфосфокиназы (до 17 раз); наличие лимфоцитарно‑макрофагального инфильтрата в мышечном биоптате и отсутствие данных магнитно‑резонансной томографии при первичном обследовании.Рефрактерность клинико‑лабораторных признаков к комплексной иммуносупрессивной терапии послужила причиной пересмотра результатов биопсии мышцы с типированием воспалительного инфильтрата. Невыраженный, преимущественно периваскулярный инфильтрат характеризовался преобладанием макрофагов и, в меньшей степени, CD4+, что указывало на вторичный характер воспаления в мышечной ткани, наблюдаемого при некоторых наследственных мышечных дистрофиях. При проведении иммуногистохимической реакции выявлено отсутствие белка дисферлина в саркоплазматической мембране.В ходе полноэкзомного секвенирования (NGS) выявлена мутация в 39‑м экзоне гена DYSF (p.Gln1428Ter) в гетерозиготном состоянии, приводящая к появлению стоп‑кодона и преждевременной терминации трансляции белка. Методом MLPA зарегистрировано по 3 копии 18, 19, 20, 22, 24‑го экзонов гена DYSF. Клинический случай отражает основные ошибки оценки результатов обследования и эффективности иммуносупрессивной терапии у пациентов с дисферлинопатией

Клинико-генетические характеристики ранней эпилептической энцефалопатии 66‑го типа (обзор литературы и собственное наблюдение)

Early epileptic encephalopathy-66 was first diagnosed in a male patient from Russia using whole-exome sequencing. Early epileptic encephalopathy- 66 is a unique disorder in the group of early epileptic encephalopathies. The same recurrent heterozygous variant of the nucleotide sequence was found in all known patients, but the severity of seizures and dysmorphic signs significantly vary between patients. The current study of a recurrent pathogenic variant in PACS2 gene expands the phenotype spectrum of early epileptic encephalopathy-66 and will improve the management of patients with that disorder in Russia in the future.Представлено первое описание клинико-генетических характеристик российского больного с ранней эпилептической энцефалопатией 66‑го типа. С помощью полноэкзомного секвенирования обнаружена ранее описанная гетерозиготная мутация NM_001100913.2: c.625G>A (p.Glu209Lys) в гене PACS2. Данное моногенное заболевание является уникальным в группе ранних эпилептических энцефалопатий – у всех пациентов обнаруживается одинаковый патогенный вариант нуклеотидной последовательности, но клинические проявления отличаются по степени тяжести и выраженности дизморфических признаков, что пред- положительно обусловлено разным генетическим фоном. Клиническое изучение серий случаев рекуррентных патогенных вариантов позволяет оптимизировать тактику ведения новых пациентов при обнаружении уже известного генетического варианта

Clinical and genetic characteristics of the early 66th type epileptic encephalopathy (literature review and own observation)

Early epileptic encephalopathy-66 was first diagnosed in a male patient from Russia using whole-exome sequencing. Early epileptic encephalopathy- 66 is a unique disorder in the group of early epileptic encephalopathies. The same recurrent heterozygous variant of the nucleotide sequence was found in all known patients, but the severity of seizures and dysmorphic signs significantly vary between patients. The current study of a recurrent pathogenic variant in PACS2 gene expands the phenotype spectrum of early epileptic encephalopathy-66 and will improve the management of patients with that disorder in Russia in the future

Genetic screening of an endemic mutation in the DYSF gene in an isolated, mountainous population in the Republic of Dagestan

Abstract Background Dysferlinopathy has a high prevalence in relatively isolated ethnic groups where consanguineous marriages are characteristic and/or the founder effect exists. However, the frequency of endemic mutations in most isolates has not been investigated. Methods The prevalence of the pathological DYSF gene variant (NM_003494.4); c.200_201delinsAT, p. Val67Asp (rs121908957) was investigated in an isolated Avar population in the Republic of Dagestan. Genetic screenings were conducted in a remote mountainous region characterized by a high level of consanguinity among its inhabitants. In total, 746 individuals were included in the screenings. Results This pathological DYSF gene variant causes two primary phenotypes of dysferlinopathy: limb‐girdle muscular dystrophy (LGMD) type R2 and Miyoshi muscular dystrophy type 1. Results indicated a high prevalence of the allele at 14% (95% confidence interval [CI]: 12–17; 138 out of 1518 alleles), while the allele in the homozygous state was detected in 29 cases—3.8% (CI: 2.6–5.4). The population load for dysferlinopathy was 832.3 ± 153.9 per 100,000 with an average prevalence of limb‐girdle muscular dystrophies ranging from 0.38 ± 0.38 to 5.93 ± 1.44 per 100,000. Conclusion A significant burden of the allele was due to inbreeding, as evidenced by a deficiency of heterozygotes and the Wright fixation index equal to 0.14 (CI 0.06–0.23)

Biallelic variants in PPP1R13L cause paediatric dilated cardiomyopathy

Childhood dilated cardiomyopathy (DCM) is a leading cause of heart failure requiring cardiac transplantation and approximately 5% of cases result in sudden death. Knowledge of the underlying genetic cause can aid prognostication and clinical management and enables accurate recurrence risk counselling for the family. Here we used genomic sequencing to identify the causative genetic variant(s) in families with children affected by severe DCM. In an international collaborative effort facilitated by GeneMatcher, biallelic variants in PPP1R13L were identified in seven children with severe DCM from five unrelated families following exome or genome sequencing and inheritance-based variant filtering. PPP1R13L encodes inhibitor of apoptosis-stimulating protein of p53 protein (iASPP). In addition to roles in apoptosis, iASPP acts as a regulator of desmosomes and has been implicated in inflammatory pathways. DCM presented early (mean: 2?years 10?months; range: 3?months-9?years) and was progressive, resulting in death (n = 3) or transplant (n = 3), with one child currently awaiting transplant. Genomic sequencing technologies are valuable for the identification of novel and emerging candidate genes. Biallelic variants in PPP1R13L were previously reported in a single consanguineous family with paediatric DCM. The identification here of a further five families now provides sufficient evidence to support a robust gene-disease association between PPP1R13L and severe paediatric DCM. The PPP1R13L gene should be included in panel-based genetic testing for paediatric DCM.The article is available via Open Access. Click on the 'Additional link' above to access the full-text.Published version, accepted version, submitted versio