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

BACKGROUND: Large-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. METHODS: A retrospective multicentre study was performed in patients with clinical onset <16 years of age, diagnosed and followed in seven European mitochondrial disease centres. RESULTS: A 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%). CONCLUSION: Our 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.

Ophthalmoplegia in Mitochondrial Disease.

PURPOSE: To evaluate the classification, diagnosis, and natural course of ophthalmoplegia associated with mitochondrial disease. MATERIALS AND METHODS: Among 372 patients with mitochondrial disease who visited our hospital between January 2006 and January 2016, 21 patients with ophthalmoplegia were retrospectively identified. Inclusion criteria included onset before 20 years of age, pigmentary retinopathy, and cardiac involvement. The 16 patients who were finally included in the study were divided into three groups according to disease type: Kearns-Sayre syndrome (KSS), KSS-like, and chronic progressive external ophthalmoplegia (CPEO). RESULTS: The prevalences of clinical findings were as follows: ptosis and retinopathy, both over 80%; myopathy, including extraocular muscles, 75%; lactic acidosis, 71%; and elevated levels of serum creatine kinase, 47%. Half of the patients had normal magnetic resonance imaging findings. A biochemical enzyme assay revealed mitochondrial respiratory chain complex I defect as the most common (50%). The prevalence of abnormal muscle findings in light or electron microscopic examinations was 50% each, while that of large-scale mitochondrial DNA (mtDNA) deletions in a gene study was 25%. We compared the KSS and KSS-like groups with the CPEO patient group, which showed pigmentary retinopathy (p<0.001), cardiac conduction disease (p=0.013), and large-scale mtDNA deletions (p=0.038). KSS and KSS-like groups also had gastrointestinal tract disorders such as abnormal gastrointestinal motility (p=0.013) unlike the CPEO group. CONCLUSION: Patients with KSS had gastrointestinal symptoms, which may indicate another aspect of systemic involvement. The presence of large-scale mtDNA deletions was an objective diagnostic factor for KSS and a gene study may be helpful for evaluating patients with KSS.

MERRF and Kearns-Sayre overlap syndrome due to the mitochondrial DNA m.3291T>C mutation.

A 48-year-old man presented with a complex phenotype of myoclonus epilepsy with ragged-red fibers (MERRF) syndrome and Kearns-Sayre syndrome (KSS), which included progressive myoclonus epilepsy, cerebellar ataxia, hearing loss, myopathic weakness, ophthalmoparesis, pigmentary retinopathy, bifascicular heart block, and ragged-red fibers. The m.3291T>C mutation in the tRNA(Leu(UUR)) gene was found with 92% heteroplasmy in muscle. This mutation has been reported with MELAS, myopathy, and deafness with cognitive impairment. This is the first description with a MERRF/KSS syndrome.

The clinical diagnosis and molecular genetics of kearns-sayre syndrome: a complex mitochondrial encephalomyopathy.

From the first description by Kearns and Sayre in 1958, this syndrome has been diagnosed in several hundred patients. However, the labile character of its clinical manifestations makes diagnosis difficult and delayed. Only recently, some thirty years from the first diagnosis, have we recognized mitochondrial DNA rearrangements as the molecular basis of the disease. This has lead to increasing interest in the contribution which mtDNA deletions make to Kearns-Sayre Syndrome (KSS) and other disorders. Although the true prevalence of this syndrome in the general population is unknown, a basic awareness of the KSS phenotype, as well as of the essential elements of patient evaluation is important for appropriate patient management. Although methods of assessing patients for mtDNA rearrangements are well developed, ambiguity in patient diagnosis often remains even after detailed, multisystem testing. Advances in our understanding of the genetic background and the tissue specific effects of mtDNA deletions, in addition to resolving the inheritance pattern, will also increase our ability to diagnose, manage and counsel patients with this disorder.

Prevalence of large-scale mitochondrial DNA deletions in an adult Finnish population.

BACKGROUND: Large-scale mitochondrial DNA (mtDNA) deletions are associated with clinical conditions such as Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia in adults and Pearson syndrome in children. Reported case series have suggested that deletions are not uncommon in the population, but their prevalence has not been documented. METHODS: The authors ascertained patients with clinical features associated with mtDNA deletions in a defined adult population in northern Finland. Buccal epithelial samples were requested from each patient fulfilling the selection criteria, and full-length mtDNA was amplified using the long PCR method. Deletion breakpoints were identified using sequencing. Patients with deletions were examined clinically. RESULTS: The authors identified four patients with single large-scale mtDNA deletions. The prevalence of deletions was calculated to be 1.6/100,000 in the adult population in the province of Northern Ostrobothnia (0.0 to 3.2; 95% CI). Analysis of incident cases from a neighboring province revealed two patients with deletions and yielded a similar population frequency. CONCLUSIONS: The frequency of large-scale mitochondrial DNA deletions is similar among populations, suggesting that there is a constant rate of new deletions.

Clinical features of A3243G mitochondrial tRNA mutation.

Mitochondrial cytopathy is a heterogeneous group of disorders with a wide range of clinical features. To evaluate the incidence and clinical heterogeneity of A3243G mitochondrial tRNA mutation in the Korean population, we evaluated patients who were clinically suggestive of having mitochondrial encephalomyopathy. Eighty-five patients were included in this study. All showed clinical features of mitochondrial encephalomyopathy and had three or more of the following clinical manifestations: (1) psychomotor regression, (2) hyperlacticacidemia, (3) recurrent stoke-like episodes, (4) idiopathic cardiomyopathy, (5) sensoryneural hearing loss, (6) diabetes mellitus, (7) myopathy, (8) renal disease and (9) relatives with known mitochondrial disease. The patients were clinically classified as MELAS, MERRF, Leigh syndrome, Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia and uncertain. Of the 85 patients, 19 had the A3243G mutation (22.3%). Thirty-one patients showed typical clinical characteristics of MELAS. Fourteen of those 31 patients had A3243G mutation (45.1%). Four patients harboring A3243G mutations showed atypical and heterogeneous clinical features, unlike MELAS. This study revealed the frequent occurrence of A3243G mutation in Korean patients with mitochondrial disorders and their clinical features can be heterogeneous. It will be helpful to screen the presence of A3243G mutation for the genetic diagnosis of mitochondrial encephalomyopathy in Korea.