Review: Central nervous system involvement in mitochondrial disease

Lax, Nichola Z.; Gorman, Gráinne; Turnbull, Doug M.

doi:10.1111/nan.12333

Cited by 50 publications

(36 citation statements)

References 115 publications

(120 reference statements)

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“…These findings are consistent with the role of CoA in energy metabolism as muscle tissues have high‐metabolic demands and are frequently involved in disorders associated with defects in energy metabolism, including mitochondrial disorders . Neurological involvement, which is common in mitochondrial disorders, was surprisingly lacking in the original patient. In this report, however, we describe the phenotype of 12 individuals with the same previously published SLC25A42 mutation [c.871A > G[p.N291D]) and show that it is much more variable than originally suggested …”

Section: Introductionsupporting

confidence: 79%

Expanding the phenotype of SLC25A42‐associated mitochondrial encephalomyopathy

et al. 2018

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SLC25A42 gene encodes an inner mitochondrial membrane protein that imports Coenzyme A into the mitochondrial matrix. A mutation in this gene was recently reported in a subject born to consanguineous parents who presented with mitochondrial myopathy with muscle weakness and lactic acidosis. In this report, we present 12 additional individuals with the same founder mutation who presented with variable manifestations ranging from asymptomatic lactic acidosis to a severe phenotype characterized by developmental regression and epilepsy. Our report confirms the link between SLC25A42 and mitochondrial disease in humans, and suggests that pathogenic variants in SLC25A42 should be interpreted with the understanding that the associated phenotype may be highly variable.

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Section: Introductionsupporting

confidence: 79%

Expanding the phenotype of SLC25A42‐associated mitochondrial encephalomyopathy

et al. 2018

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“…The megaloblastic anemia associated with SLC19A2 mutations appears to be due to impaired TKT activity, which, by reducing the availability of nucleotides, causes red cell precursors to continue to grow in size without dividing. The coexistence of sensorineural deafness and the other neurological and cardiovascular abnormalities found in the TRMA syndrome are suggestive of an underlying mitochondrial dysfunction, which might be due, in part, to impaired PDH (7) and a-KGDH (8) activities causing defective energy production, to which tissues with a high demand for energy, such as the auditory, visual, cardiovascular, and central nervous systems, are particularly sensitive (9)(10)(11).…”

mentioning

confidence: 99%

Loss-of-Function Mutation in Thiamine Transporter 1 in a Family With Autosomal Dominant Diabetes

et al. 2019

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Solute Carrier Family 19 Member 2 (SLC19A2) encodes thiamine transporter 1 (THTR1), which facilitates thiamine transport across the cell membrane. SLC19A2 homozygous mutations have been described as a cause of thiamine-responsive megaloblastic anemia (TRMA), an autosomal recessive syndrome characterized by megaloblastic anemia, diabetes, and sensorineural deafness. Here we describe a loss-of-function SLC19A2 mutation (c.A1063C: p.Lys355Gln) in a family with early-onset diabetes and mild TRMA traits transmitted in an autosomal dominant fashion. We show that SLC19A2-deficient β-cells are characterized by impaired thiamine uptake, which is not rescued by overexpression of the p.Lys355Gln mutant protein. We further demonstrate that SLC19A2 deficit causes impaired insulin secretion in conjunction with mitochondrial dysfunction, loss of protection against oxidative stress, and cell cycle arrest. These findings link SLC19A2 mutations to autosomal dominant diabetes and suggest a role of SLC19A2 in β-cell function and survival.

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“…5 Neuronal cells rely heavily on OXPHOS while glial cells also contain glycogen as an energy source. 47 Most energy consumption in the brain is used for synaptic transmission and delivered by mitochondria, preferentially localized to pre-and postsynaptic sites.…”

Section: Mitochondria: Structure Function and Pathologymentioning

confidence: 99%

Mitochondrial Migraine: Disentangling the angiopathy paradigm in m.3243A>G patients

Smeitink¹,

Koene²,

Saris³

et al. 2019

JIMD Reports

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Migraine, characterized by recurrent attacks of predominantly unilateral throbbing headache, affects approximately 15% of the adult population and is an important cause of disability worldwide. Knowledge required for the development of new classes of antimigraine drugs might come from studying rare metabolic diseases associated with migraine. An illustrative example of a monogenetic disorder associated with migraine is the spectrum of disorders caused by the m.3243A>G mutation in the mitochondrial transfer RNA Leucine. Reported migraine prevalence figures in patients with this particular mutation vary considerably, but compared to the general population, m.3243A>G patients have a higher migraine prevalence. This burdensome symptom might sometimes even be the only clinical feature in maternal relatives carrying the m.3243A>G mutation. Although the exact sequence of events and the relative importance of factors underlying migraine in m.3243A>G MELAS spectrum disorders are still enigmatic, substantial evidence in man exist that dysfunctional mitochondria in both the vascular, the smooth muscle cells and the neuronal system and the interaction between these are at the starting point of the migraine developing pathophysiological cascade. Exclusively based on results of studies performed in patients harboring the m.3243A>G mutation, either in vivo or ex vivo, we here summarize our current understanding of mitochondrial angiopathy associated migraine in m.3243A>G patients which knowledge might lead to potential new avenues for migraine drug development.

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Review: Central nervous system involvement in mitochondrial disease

Cited by 50 publications

References 115 publications

Expanding the phenotype of SLC25A42‐associated mitochondrial encephalomyopathy

Expanding the phenotype of SLC25A42‐associated mitochondrial encephalomyopathy

Loss-of-Function Mutation in Thiamine Transporter 1 in a Family With Autosomal Dominant Diabetes

Mitochondrial Migraine: Disentangling the angiopathy paradigm in m.3243A>G patients

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