Abstract
Mitochondrial DNA (mtDNA) deletions are a common cause of mitochondrial disorders. Large mtDNA deletions can lead to a broad spectrum of clinical features with different age of onset, ranging from mild mitochondrial myopathies (MM), progressive external ophthalmoplegia (PEO), and Kearns-Sayre syndrome (KSS), to severe Pearson syndrome. The aim of this study is to investigate the molecular signatures surrounding the deletion breakpoints and their association with the clinical phenotype and age at onset. MtDNA deletions in 67 patients were characterized using array comparative genomic hybridization (aCGH) followed by PCR-sequencing of the deletion junctions. Sequence homology including both perfect and imperfect short repeats flanking the deletion regions were analyzed and correlated with clinical features and patients' age group. In all age groups, there was a significant increase in sequence homology flanking the deletion compared to mtDNA background. The youngest patient group (<6 years old) showed a diffused pattern of deletion distribution in size and locations, with a significantly lower sequence homology flanking the deletion, and the highest percentage of deletion mutant heteroplasmy. The older age groups showed rather discrete pattern of deletions with 44% of all patients over 6 years old carrying the most common 5 kb mtDNA deletion, which was found mostly in muscle specimens (22/41). Only 15% (3/20) of the young patients (<6 years old) carry the 5 kb common deletion, which is usually present in blood rather than muscle. This group of patients predominantly (16 out of 17) exhibit multisystem disorder and/or Pearson syndrome, while older patients had predominantly neuromuscular manifestations including KSS, PEO, and MM. In conclusion, sequence homology at the deletion flanking regions is a consistent feature of mtDNA deletions. Decreased levels of sequence homology and increased levels of deletion mutant heteroplasmy appear to correlate with earlier onset and more severe disease with multisystem involvement.
Highlights
Mitochondria are energy producing cellular organelles that contain their own genetic material, mitochondrial DNA
There are numerous reports of young children severely affected with multisystem mitochondrial DNA (mtDNA) deletion syndrome who did not have direct repeats at the breakpoints [8]
Regardless of the presence of a direct repeat, most mtDNA deletion regions have a significant increase in sequence homology surrounding the breakpoints
Summary
Mitochondria are energy producing cellular organelles that contain their own genetic material, mitochondrial DNA (mtDNA). MtDNA deletions were first discovered in the skeletal muscle of patients with mitochondrial myopathies (MM) and Kearns-Sayre syndrome (KSS) [2,3,4] These patients typically present with progressive external opthalmoplegia (PEO), pigmentary retinopathy, and one or more of the following: cerebellar ataxia, a cardiac conduction defect, and elevated protein concentration in the cerebrospinal fluid [5]. Symptoms in young children and infants can be quite heterogeneous and severe Many of these patients develop Pearson syndrome, which is characterized by infantile onset of sideroblastic anemia, with vacuolization of bone marrow precursor cells and pancreatic dysfunction [7]. In young patients it is possible to use the less invasive blood samples for mtDNA deletion testing since the mtDNA molecules carrying deletions are expected to be present in all tissues due to the severe multisystem disorder. The deletion mtDNA molecules are usually not present in blood specimens and it is necessary to use muscle for the detection of mtDNA deletion [8]
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