Clinical and neuroimaging features of the m.10197G&gt;A mtDNA mutation: New case reports and expansion of the phenotype variability

Tolomeo, Deborah; Rubegni, Anna; Severino, Mariasavina; Pochiero, Francesca; Bruno, Claudio; Cassandrini, Denise; Madeo, Annalisa; Doccini, Stefano; Pedemonte, Marina; Rossi, Andrea; D'Amore, Francesca; Rocco, Maja Di; Santorelli, Filippo M.; Nesti, Claudia

doi:10.1016/j.jns.2019.02.010

Cited by 9 publications

(6 citation statements)

References 29 publications

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“…S6B) is a confirmed pathogenic mutation for Leigh-like syndrome (52). High fraction of m.10197G>A has been found to reduce complex I activity in muscle and ATP production in skin fibroblasts (52).…”

Section: Discussionmentioning

confidence: 99%

Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington’s disease

Wang

Guo

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Mitochondrial dysfunction is found in the brain and peripheral tissues of patients diagnosed with Huntington’s disease (HD), an irreversible neurodegenerative disease of which aging is a major risk factor. Mitochondrial function is encoded by not only nuclear DNA but also DNA within mitochondria (mtDNA). Expansion of mtDNA heteroplasmies (coexistence of mutated and wild-type mtDNA) can contribute to age-related decline of mitochondrial function but has not been systematically investigated in HD. Here, by using a sensitive mtDNA-targeted sequencing method, we studied mtDNA heteroplasmies in lymphoblasts and longitudinal blood samples of HD patients. We found a significant increase in the fraction of mtDNA heteroplasmies with predicted pathogenicity in lymphoblasts from 1,549 HD patients relative to lymphoblasts from 182 healthy individuals. The increased fraction of pathogenic mtDNA heteroplasmies in HD lymphoblasts also correlated with advancing HD stages and worsened disease severity measured by HD motor function, cognitive function, and functional capacity. Of note, elongated CAG repeats in HTT promoted age-dependent expansion of pathogenic mtDNA heteroplasmies in HD lymphoblasts. We then confirmed in longitudinal blood samples of 169 HD patients that expansion of pathogenic mtDNA heteroplasmies was correlated with decline in functional capacity and exacerbation of HD motor and cognitive functions during a median follow-up of 6 y. The results of our study indicate accelerated decline of mtDNA quality in HD, and highlight monitoring mtDNA heteroplasmies longitudinally as a way to investigate the progressive decline of mitochondrial function in aging and age-related diseases.

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Section: Discussionmentioning

confidence: 99%

Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington’s disease

Wang

Guo

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…Individuals harboring nDNA mutations, as opposed to those with mtDNA mutations, had a significantly lower age at movement disorder onset and a higher impairment in activities of daily living at the last follow-up. A predominant gene or a predominant mutation did not appear, reflecting the heterogeneous movement disorder manifestations; however, it appeared that children with hyperkinetic onset had a quite high occurrence of mutations in the MT-ND3 gene [ 36 ]. Identification of a relatively high number of MERRF mutation carriers among patients with ataxic and hyperkinetic onset is not too surprising, since ataxia, myoclonus, and tremor were reported as frequent features in a retrospective database-based study on a large cohort of patients with the m.8344A > G mutation [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Movement Disorders in Children with a Mitochondrial Disease: A Cross-Sectional Survey from the Nationwide Italian Collaborative Network of Mitochondrial Diseases

Ticci

Orsucci²,

Ardissone

et al. 2021

JCM

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Movement disorders are increasingly being recognized as a manifestation of childhood-onset mitochondrial diseases (MDs). However, the spectrum and characteristics of these conditions have not been studied in detail in the context of a well-defined cohort of patients. We retrospectively explored a cohort of individuals with childhood-onset MDs querying the Nationwide Italian Collaborative Network of Mitochondrial Diseases database. Using a customized online questionnaire, we attempted to collect data from the subgroup of patients with movement disorders. Complete information was available for 102 patients. Movement disorder was the presenting feature of MD in 45 individuals, with a mean age at onset of 11 years. Ataxia was the most common movement disorder at onset, followed by dystonia, tremor, hypokinetic disorders, chorea, and myoclonus. During the disease course, most patients (67.7%) encountered a worsening of their movement disorder. Basal ganglia involvement, cerebral white matter changes, and cerebellar atrophy were the most commonly associated neuroradiological patterns. Forty-one patients harbored point mutations in the mitochondrial DNA, 10 carried mitochondrial DNA rearrangements, and 41 cases presented mutations in nuclear-DNA-encoded genes, the latter being associated with an earlier onset and a higher impairment in activities of daily living. Among our patients, 32 individuals received pharmacological treatment; clonazepam and oral baclofen were the most commonly used drugs, whereas levodopa and intrathecal baclofen administration were the most effective. A better delineation of the movement disorders phenotypes starting in childhood may improve our diagnostic workup in MDs, fine tuning management, and treatment of affected patients.

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“…Meire et al [37] , 1995 Simon et al [39] , 2003 MT-ND3 m.10197G > A Dystonia LS/LLS, vertebral and arterial malformations LHON Tolomeo et al [24] , 2019 Wang et al [26] , 2009 MT-ND4 m.11178G > A Dystonia…”

Section: Segmental Dystonia Kssmentioning

confidence: 99%

“…Different mtDNA mutations are reported in patients with dystonia and LS or LLS including mainly mtDNA encoded complex subunits such as ATP6, ND3, or ND6 [8,24,25] .…”

Section: Polg1mentioning

confidence: 99%

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Spectrum of movement disorders in mitochondrial diseases

Musumeci¹,

Oteri²,

Toscano³

2020

JTGG

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Mitochondrial disorders (MD) include a large group of maternally inherited, autosomal dominant, or recessive genetic syndromes caused by mitochondrial dysfunction. MD can be diagnosed at any age and many of them show a multisystem presentation with variable combinations of symptoms. Given the important role of mitochondria in neuronal homeostasis, neurological manifestations, including movement disorders, can accompany MD. Movement disorders (MoD), either hypo-or hyperkinetic type, are reported in MD, but the real incidence and a detailed characterization of these features are not addressed in population-based studies. Dystonia, usually in the context of Leigh syndrome, is the main extrapyramidal movement disorder in pediatric MD patients; whereas parkinsonism is the most prevalent hypokinetic disorder in adult MD patients. Ataxia is a common feature in MD, in both the pediatric and adult MD populations. Other MoD, such as myoclonus, chorea, or tremor, may also occur in MD. MoD manifest more frequently in the context of a complex phenotype but rarely can be isolated. From a genetic point of view, MoD are described in patients with either mutations in mtDNA or in nuclear genes related to mitochondria, and the same gene can be associated with different types of MoD. Recent studies demonstrate that the dopaminergic nigrostriatal system is very vulnerable to mitochondrial dysfunction and defects of mtDNA maintenance are frequently associated with a nigrostriatal degeneration, which may explain the pathophysiological mechanism. Therapeutic interventions for MoD in MD do not differ from treatment options used for MoD with different etiopathological background. Some forms benefit from specific treatments, e.g., primary Coenzyme Q10 deficiencies. Newer therapeutic strategies have been pursued which act on different mechanisms of mitochondrial dysfunction, but clinical trials are warranted to improve the management of MD patients.

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Clinical and neuroimaging features of the m.10197G>A mtDNA mutation: New case reports and expansion of the phenotype variability

Cited by 9 publications

References 29 publications

Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington’s disease

Accelerated expansion of pathogenic mitochondrial DNA heteroplasmies in Huntington’s disease

Movement Disorders in Children with a Mitochondrial Disease: A Cross-Sectional Survey from the Nationwide Italian Collaborative Network of Mitochondrial Diseases

Spectrum of movement disorders in mitochondrial diseases

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