Revisiting mitochondrial diagnostic criteria in the new era of genomics

Abstract

PurposeDiagnosing primary mitochondrial diseases (MDs) is challenging in clinical practice. The mitochondrial disease criteria (MDC) have been developed to quantify the clinical picture and evaluate the probability of an underlying MD and the need for a muscle biopsy. In this new genetic era with next-generation sequencing in routine practice, we aim to validate the diagnostic value of MDC.MethodsWe retrospectively studied MDC in a multicenter cohort of genetically confirmed primary MD patients.ResultsWe studied 136 patients (61 male, 91 nuclear DNA (nDNA) mutations). Forty-five patients (33%) had probable MD and 69 (51%) had definite MD according to the MDC. A muscle biopsy was performed in 63 patients (47%). Patients with nDNA mutations versus mitochondrial DNA mutations were younger (6.4 ± 9.7 versus 19.5 ± 17.3 y) and had higher MDC (7.07 ± 1.12/8 versus 5.69 ± 1.94/8). At a cutoff of 6.5/8, the sensitivity to diagnose patients with nDNA mutations is 72.5% with a positive predictive value of 69.5%. In the nDNA mutation group, whole-exome sequencing could diagnose patients with lower scores (MDC (6.84 ± 1.51/8) compared to Sanger sequencing MDC (7.44 ± 1.13/8, P = 0.025)). Moreover 7/8 patients diagnosed with possible MD by MDC were diagnosed by whole-exome sequencing.ConclusionMDC remain very useful in the clinical diagnosis of MD, in interpreting whole-exome results and deciding on the need for performing muscle biopsy.

Mitochondrial DNA mutation analysis from exome sequencing—A more holistic approach in diagnostics of suspected mitochondrial disease

“…Taking the specific challenges for diagnosing MD as shown in Table , our data and recent studies claiming for an “exome first” or a combined diagnostic approach to identify mtDNA and nuclear variants in account, we propose that ES from leucocyte derived DNA (blood) should be done as the initial test in all individuals with suspected mitochondrial disease. Hereby, it is important to know the limitations of this method and the necessary follow test as summarized in Figure .…”

Mitochondrial diseases in North America

“…This may help explain why the proportions of mtDNA and nDNA variants in the Registry differ from those in other recent reports. 27 Other factors such as accessibility and feasibility of mtDNA testing may also have an impact. In the Registry, participants with nDNA pathogenic variants had earlier disease onset than participants with mtDNA pathogenic variants, with onset before age 2 years in 50.4% individuals (table 4).…”

Reply to Comment on: Sideroblastic anemia associated with multisystem mitochondrial disorders

“…We agree that it is still worthwhile for clinicians to know and understand which of the main symptoms and/or additional features are present in any individual patient, even though in the present era the increasing availability of high-throughput methods including whole-exome sequencing (WES) provides a more straightforward way to diagnose patients with multisystem MD in comparison to classical clinical or biochemical approaches. 3 With respect to the characteristics of patients in our study, 1 descriptions of clinical, hematologic, biochemical, and molecular data, including an age-related reference range where applicable (e.g., table…”

“…J. Finsterer points out the well‐known heterogeneity of phenotypes described in patients with multisystem mitochondrial diseases (MD), including the broad spectrum of common, rare, and ultra‐rare symptoms. We agree that it is still worthwhile for clinicians to know and understand which of the main symptoms and/or additional features are present in any individual patient, even though in the present era the increasing availability of high‐throughput methods including whole‐exome sequencing (WES) provides a more straightforward way to diagnose patients with multisystem MD in comparison to classical clinical or biochemical approaches …”