Phenotyping mitochondrial DNA‐related diseases in childhood: A cohort study of 150 patients

Abstract

Background and purpose: Mitochondrial diseases (MDs) are heterogeneous disorders caused by mutations in nuclear DNA (nDNA) or mitochondrial DNA (mtDNA) associated with specific syndromes. However, especially in childhood, patients often display heterogeneity. Several reports on the biochemical and molecular profiles in children have been published, but studies tend not to differentiate between mtDNA-and nDNA-associated diseases, and focus is often on a specific phenotype. Thus, large cohort studies specifically focusing on mtDNA defects in the pediatric population are lacking. Methods:We reviewed the clinical, metabolic, biochemical, and neuroimaging data of 150 patients with MDs due to mtDNA alterations collected at our neurological institute over the past 20 years.Results: mtDNA impairment is less frequent than nDNA impairment in pediatric MDs.Ocular involvement is extremely frequent in our cohort, as is classical Leber hereditary optic neuropathy, especially with onset before 12 years of age. Extraneurological manifestations and isolated myopathy appear to be rare, unlike adult phenotypes. Deep gray matter involvement, early disease onset, and specific phenotypes, such as Pearson syndrome and Leigh syndrome, represent unfavorable prognostic factors. Phenotypes related to single large scale mtDNA deletions appear to be very frequent in the pediatric population. Furthermore, we report for the first time an mtDNA pathogenic variant associated with cavitating leukodystrophy. Conclusions:We report on a large cohort of pediatric patients with mtDNA defects, adding new data on the phenotypical characterization of mtDNA defects and suggestions for diagnostic workup and therapeutic approach.

Leigh Syndrome Spectrum: A Portuguese Population Cohort in an Evolutionary Genetic Era

“…We found m.13094T>C (p.Val253Ala) in homoplasmy in P23, a mutation previously described associated with cerebellar syndromes [ 59 ], CI deficiency, or combined complexes deficiencies [ 60 ], presenting our patient a marked hypotonia. In pediatric populations, LSS appears to represent a less favorable prognosis [ 61 ]. P24 and P25 presented m.13513G>A (p.Asp393Asn), a mutation that has already been outlined by Ruiter et al in a patient with CI deficiency, cardiac rhythm perturbation, and optic atrophy [ 62 ], with our patients presenting cardiomyopathy and hypotonia, and ataxia and apnea, respectively.…”

Consider Non-Syndromic Mitochondrial Disorders as Part of the Pediatric Phenotypic Spectrum

“…There is a discrepancy between the statement in the method section ("only few data were not available from all patients") and the results section ("CSF data were available from only 17 %, follow-up data only from 47%, and biochemical data only from 58 % of patients") [1]. This discrepancy should be clarified.…”

“…With interest we read the article by Ardissone et al about a retrospective, singlecenter study of 150 pediatric patients with a genetically confirmed mitochondrial disorder (MID) due to a pathogenic mtDNA variant (mtDNA point mutation or single mtDNA deletion) [1]. The study is excellent but has limitations that are cause of concerns and should be discussed.…”

“…A limitation of the study is that only syndromic MIDs were included [1]. Since MIDs often do not fit into any of the syndromic phenotypes, we should know whether these patients were deliberately excluded or did not appear at the study center at all.…”

“…Another limitation is that heteroplasmy rates were only determined by estimating the densitometric ratio between wild-type and mutant mtDNA [1]. Heteroplasmy is usually determined by a number of quantitative methods, such as Sanger sequencing, high performance liquid chromatography, pyrosequencing, Snapshot, high resolution melt profiling (HRM), temporal temperature gradient gel electrophoresis (TTGE), invader assay, amplification refractory mutation system (ARMS), endonuclease method using Surveyor nuclease, and next generation sequencing (NGS) [2].…”