Phenotypic spectrum and clinical course of single large-scale mitochondrial DNA deletion disease in the paediatric population: a multicentre study

Abstract

BackgroundLarge-scale mitochondrial DNA deletions (LMD) are a common genetic cause of mitochondrial disease and give rise to a wide range of clinical features. Lack of longitudinal data means the natural history remains unclear. This study was undertaken to describe the clinical spectrum in a large cohort of patients with paediatric disease onset.MethodsA retrospective multicentre study was performed in patients with clinical onset <16 years of age, diagnosed and followed in seven European mitochondrial disease centres.ResultsA total of 80 patients were included. The average age at disease onset and at last examination was 10 and 31 years, respectively. The median time from disease onset to death was 11.5 years. Pearson syndrome was present in 21%, Kearns-Sayre syndrome spectrum disorder in 50% and progressive external ophthalmoplegia in 29% of patients. Haematological abnormalities were the hallmark of the disease in preschool children, while the most common presentations in older patients were ptosis and external ophthalmoplegia. Skeletal muscle involvement was found in 65% and exercise intolerance in 25% of the patients. Central nervous system involvement was frequent, with variable presence of ataxia (40%), cognitive involvement (36%) and stroke-like episodes (9%). Other common features were pigmentary retinopathy (46%), short stature (42%), hearing impairment (39%), cardiac disease (39%), diabetes mellitus (25%) and renal disease (19%).ConclusionOur study provides new insights into the phenotypic spectrum of childhood-onset, LMD-associated syndromes. We found a wider spectrum of more prevalent multisystem involvement compared with previous studies, most likely related to a longer time of follow-up.

The clinical, myopathological, and genetic analysis of 155 Chinese mitochondrial ophthalmoplegia patients with mitochondrial DNA single large deletions

“…Consistent with previous studies, our study also showed that KSS had more frequent multi‐system involvement than CPEO, while sharing the most common features as ptosis and oculomotor restriction (Björkman et al., 2023; Yamashita et al., 2008). However, it was noteworthy that the involvement of other organs beyond extraocular muscles was not rare in this series of CPEO patients, including exercise intolerance, weakness of bulbar muscles, hearing loss, and cardiac conduction abnormalities.…”

Advancing the neuroimaging diagnosis and understanding of mitochondrial disorders

“…Single large-scale deletions in the mtDNA (SLSMD) are rare and devastating disorders encompassing three major syndromes: Kearns-Sayre (KSS), Pearson, and Congenital Progressive Ophthalmoplegia (CPEO). These syndromes are defined by a range of systemic clinical features that vary in severity and age of onset among patients [ 34 , 35 ]. The most common symptoms include pigmentary retinopathy, progressive external ophthalmoplegia (CPEO), cardiac conduction abnormalities, cerebellar ataxia, sensorineural hearing loss, dementia, short stature, hypotonia, dysphagia, and endocrine and hematological problems [ 34 , 35 ].…”

“…These syndromes are defined by a range of systemic clinical features that vary in severity and age of onset among patients [ 34 , 35 ]. The most common symptoms include pigmentary retinopathy, progressive external ophthalmoplegia (CPEO), cardiac conduction abnormalities, cerebellar ataxia, sensorineural hearing loss, dementia, short stature, hypotonia, dysphagia, and endocrine and hematological problems [ 34 , 35 ]. Some intrinsic variables of the disease including the location and size of the deletion in the mitochondrial genome, and the levels of heteroplasmy, are considered potential markers to help define severity and disease progression [ 36 ].…”

Reanálise fenotípica e genotípica de indivíduos com diagnóstico clínico de diabetes monogênico sem etiologia molecular estabelecida

“…Como as CNVs mitocondriais são associadas somente a fenótipos sindrômicos pela literatura 94 , esta etapa priorizou achados identificados pelo software eKLIpse em pacientes que possuíam além de hiperglicemia, outros comemorativos clínicos que o caracterizem como DM sindrômico. Estas etapas de priorização ocorreram com auxílio do visualizador genômico Franklin by Genoox (https://franklin.genoox.com), sendo elas:…”