Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation

Verny, Christophe; Guegen, Naig; Desquiret, Valérie; Chevrollier, Arnaud; Prundean, Adriana; Dubas, Frédéric; Cassereau, Julien; Ferré, Marc; Amati‐Bonneau, Patrizia; Bonneau, Dominique; Reynier, Pascal; Procaccio, Vincent

doi:10.1016/j.mito.2010.07.006

Cited by 76 publications

(61 citation statements)

References 32 publications

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“…Adult-onset spastic paraparesis is a feature that is rarely associated with mtDNA disease (26,27); however, our patient had progressive lower limb spasticity. This spasticity might be attributable to axonal and myelin degeneration and loss affecting the left anterior limb and genu of the internal capsule.…”

Section: Discussionmentioning

confidence: 61%

Early-Onset Cataracts, Spastic Paraparesis, and Ataxia Caused by a Novel Mitochondrial tRNA^Glu(MT-TE) Gene Mutation Causing Severe Complex I Deficiency: A Clinical, Molecular, and Neuropathologic Study

Lax

Gnanapavan²,

Dowson³

et al. 2013

J Neuropathol Exp Neurol

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Mitochondrial respiratory chain disease is associated with a spectrum of clinical presentations and considerable genetic heterogeneity. Here we report molecular genetic and neuropathologic findings from an adult with an unusual manifestation of mitochondrial DNA disease. Clinical features included early-onset cataracts, ataxia, and progressive paraparesis, with sequencing revealing the presence of a novel de novo m.14685G9A mitochondrial tRNA Glu (MT-TE) gene mutation. Muscle biopsy showed that 13% and 34% of muscle fibers lacked cytochrome c oxidase activity and complex I subunit expression, respectively. Biochemical studies confirmed a marked decrease in complex I activity. Neuropathologic investigation revealed a large cystic lesion affecting the left putamen, caudate nucleus, and internal capsule, with evidence of marked microvacuolation, neuron loss, perivascular lacunae, and blood vessel mineralization. The internal capsule showed focal axonal loss, whereas brainstem and spinal cord showed descending anterograde degeneration in medullary pyramids and corticospinal tracts. In agreement with muscle biopsy findings, reduced complex I immunoreactivity was detected in the remaining neuronal populations, particularly in the basal ganglia and cerebellum, correlating with the neurologic dysfunction exhibited by the patient. This study emphasizes the importance of molecular genetic and postmortem neuropathologic analyses for furthering our understanding of underlying mechanisms of mitochondrial disorders.

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Section: Discussionmentioning

confidence: 61%

Early-Onset Cataracts, Spastic Paraparesis, and Ataxia Caused by a Novel Mitochondrial tRNA^Glu(MT-TE) Gene Mutation Causing Severe Complex I Deficiency: A Clinical, Molecular, and Neuropathologic Study

Lax

Gnanapavan²,

Dowson³

et al. 2013

J Neuropathol Exp Neurol

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“…We found that SWS knockdown sws 1 and sws 76−15 mutations resulted in more stable MT loops in the NMJ. One of our discoveries is that sws mutations cause mitochondrial dysfunction in NMJs, which is a common efect in other HSP forms [30][31][32]. Mitochondrial transport to synapse is tightly regulated to provide suicient energy for synaptic transmission [33,34].…”

Section: −15mentioning

confidence: 99%

Swiss Cheese, Drosophila Ortholog of Hereditary Spastic Paraplegia Gene NTE, Maintains Neuromuscular Junction Development and Microtubule Network

Ryabova¹,

Matiytsiv²,

Trush³

et al. 2018

Drosophila Melanogaster - Model for Recent Advances in Genetics and Therapeutics

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Neuropathy target esterase (NTE) is a molecular target for the organophosphorus compound-induced delayed neuropathy (OPIDN) and also one of the genetic factors responsible for the development of the hereditary spastic paraplegia (HSP), characterized by axon degeneration of motoneurons causing progressive lower-limb spastic paralysis. Both HSP and OPIDN are characterized by the distal axonopathy. The molecular mechanisms underlying the axonopathy involved in HSP and OPIDN are poorly understood. In order to have a beter understanding of the mechanisms that NTE is involved in, we used one of the homologs, human NTE. Swiss cheese (sws) is a Drosophila melanogaster ortholog of NTE with 39% homology. Mutations in sws as it was shown before lead to age-dependent neurodegeneration, structure alteration of glia cells, and reduced insect life span. To study SWS functions, we used the system of the third-instar larval neuromuscular junctions of D. melanogaster. In this study, we show that mutations in sws (sws 1 and sws 76−1) and SWS knockdown alter neuromuscular junction's morphology and synaptic microtubules organization.

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“…An mtDNA mutation in MTATP6 (m.9176T>C) was identifi ed in a large HSP pedigree [ 150 ] and a mutation in the mitochondrial 12 s rRNA (m.1432A>G) was identifi ed in an Amish family who demonstrated abnormal mRNA maturation [ 151 ]. A single study investigating the role of mtDNA haplogroups appears negative, but is largely inconclusive due to low sample size and genetic heterogeneity [ 152 ].…”

Section: Hereditary Spastic Paraplegiamentioning

confidence: 99%

The Ageing Brain, Mitochondria and Neurodegeneration

Hudson

2016

Mitochondrial Dysfunction in Neurodegenerative Disorders

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The brain is a complex and energy-demanding organ, which like any organ is subject to the ravages of time. Mitochondria are synonymous with their role in energy production, which is particularly critical to high-energy-demanding cells such as neurons.Here we discuss ageing of the brain, initially setting the scene by introducing the core concepts associated with brain ageing; discussing the physiological, genetic and cognitive changes which occur over time; and subsequently introducing the roles that mitochondria play in the 'normal' brain ageing process.The fi nal section of the chapter discusses the role of both inherited and somatic mitochondrial DNA variation in neurodegeneration, initially in the context of primary mitochondrial disorders (such as Leber's hereditary optic neuropathy, myoclonic epilepsy and ragged-red fi bres and mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes) and subsequently in the context of common, but more complex, neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, Friedreich's ataxia, hereditary spastic paraplegia and multiple sclerosis. Keywords The 'Normal' Ageing BrainLike any organ, the human brain is susceptible to the endless march of time with the effects of ageing often manifesting as diverse pathologies. To understand the role of mitochondrial DNA (mtDNA) variation in brain ageing, we must fi rst understand what brain ageing entails.

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Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation

Cited by 76 publications

References 32 publications

Early-Onset Cataracts, Spastic Paraparesis, and Ataxia Caused by a Novel Mitochondrial tRNA^Glu(MT-TE) Gene Mutation Causing Severe Complex I Deficiency: A Clinical, Molecular, and Neuropathologic Study

Early-Onset Cataracts, Spastic Paraparesis, and Ataxia Caused by a Novel Mitochondrial tRNA^Glu(MT-TE) Gene Mutation Causing Severe Complex I Deficiency: A Clinical, Molecular, and Neuropathologic Study

Swiss Cheese, Drosophila Ortholog of Hereditary Spastic Paraplegia Gene NTE, Maintains Neuromuscular Junction Development and Microtubule Network

The Ageing Brain, Mitochondria and Neurodegeneration

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Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation

Cited by 76 publications

References 32 publications

Early-Onset Cataracts, Spastic Paraparesis, and Ataxia Caused by a Novel Mitochondrial tRNAGlu(MT-TE) Gene Mutation Causing Severe Complex I Deficiency: A Clinical, Molecular, and Neuropathologic Study

Early-Onset Cataracts, Spastic Paraparesis, and Ataxia Caused by a Novel Mitochondrial tRNAGlu(MT-TE) Gene Mutation Causing Severe Complex I Deficiency: A Clinical, Molecular, and Neuropathologic Study

Swiss Cheese, Drosophila Ortholog of Hereditary Spastic Paraplegia Gene NTE, Maintains Neuromuscular Junction Development and Microtubule Network

The Ageing Brain, Mitochondria and Neurodegeneration

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Product

Resources

About

Early-Onset Cataracts, Spastic Paraparesis, and Ataxia Caused by a Novel Mitochondrial tRNA^Glu(MT-TE) Gene Mutation Causing Severe Complex I Deficiency: A Clinical, Molecular, and Neuropathologic Study

Early-Onset Cataracts, Spastic Paraparesis, and Ataxia Caused by a Novel Mitochondrial tRNA^Glu(MT-TE) Gene Mutation Causing Severe Complex I Deficiency: A Clinical, Molecular, and Neuropathologic Study