Mechanisms of unexpected death and autopsy findings in Leigh syndrome (subacute necrotising encephalomyelopathy)

Wick, Regula; Scott, Grace; Byard, Roger W.

doi:10.1016/j.jcfm.2006.01.002

Cited by 24 publications

(19 citation statements)

References 14 publications

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“…Leigh syndrome is a progressive disease, although patients may be misdiagnosed with "cerebral palsy" or "hypoxic-ischemic encephalopathy" [94]. Leigh syndrome has been reported in some adults, although it is a diagnosis made much more typically in children and usually carries a poor prognosis [47,95,96]. Leigh syndrome has many causes, mainly nuclear-encoded genes, including pyruvate dehydrogenase complex (PDHC) deficiency, deficiencies in complex I subunits and assembly factors, COX subunits, and assembly factors SURF1 and PDSS2 causing primary CoQ10 deficiency [97][98][99][100][101].…”

Section: Stroke-like Lesions In Nonvascular Distributionmentioning

confidence: 99%

Mitochondrial Disease in Childhood: Nuclear Encoded

2013

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Primary mitochondrial disorders are clinically and genetically heterogeneous, caused by an alteration(s) in either mitochondrial DNA or nuclear DNA, and affect the respiratory chain's ability to undergo oxidative phosphorylation, leading to decreased production of adenosine triphosphophate and subsequent energy failure. These disorders may present at any age, but children tend to have an acute onset of disease compared with subacute or slowly progressive presentation in adults. Varying organ involvement also contributes to the phenotypic spectrum seen in these disorders. The childhood presentation of primary mitochondrial disease is mainly due to nuclear DNA mutations, with mitochondrial DNA mutations being less frequent in childhood and more prominent in adulthood disease. The clinician should be aware of the pediatric presentation of mitochondrial disease and have an understanding of the myriad of nuclear genes responsible for these disorders. The nuclear genes can be best understood by utilizing a classification system of location and function within the mitochondria.

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Section: Stroke-like Lesions In Nonvascular Distributionmentioning

confidence: 99%

Mitochondrial Disease in Childhood: Nuclear Encoded

2013

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“…It has also been noted that some patients diagnosed with epilepsy have long QT syndrome [372], which could account for sudden death. Sudden death can occur within neurodegenerative disorders, such as Leigh syndrome [373] and in the presence of dysautonomia in conditions such as Riley-Day and ShyDrager, Guillaume-Barre, and Alzheimer's disease [374; 5510]. Fatal cardiac death can also occur due to arrhythmias in patients with myotonic dystrophy [375,376] and in muscular dystrophies [377,378].…”

Section: Central Nervous System Causes Of Sudden Deathmentioning

confidence: 99%

Sudden adult death

Langlois

2009

Forensic Sci Med Pathol

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In the investigation of sudden death in adults, channelopathies, such as long QT syndrome, have risen to the fore in the minds of forensic pathologists in recent years. Examples of these disorders are touched upon in this review as an absence of abnormal findings at postmortem examination is characteristic and the importance of considering the diagnosis lies in the heritable nature of these conditions. Typically, a diagnosis of a possible channelopathy is evoked as an explanation for a 'negative autopsy' in a case of apparent sudden natural death. However, the one potential adverse effect of this approach is that subtle causes of sudden death may be overlooked. The intention of this article is to review and discuss potential causes of sudden adult death (mostly natural) that should be considered before resorting to a diagnosis of possible channelopathy. Nonetheless, it becomes apparent that many of the potential causes of sudden death can have a genetic basis. Thus, it becomes an important consideration that there may be a genetic basis to sudden death that extends beyond the negative autopsy.

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“…LS is regarded as the most common infantile mitochondrial disorder, and most patients exhibit symptoms before 1 mo of age (4,5). Several cases of adult-onset LS have also been reported recently (6)(7)(8)(9)(10). In vivo imaging techniques such as MRI reveal bilateral hyperintense lesions in the basal ganglia, thalamus, substantia nigra, brainstem, cerebellar white matter and cortex, cerebral white matter, or spinal cord of LS patients (6,(11)(12)(13)(14).…”

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confidence: 99%

“…In vivo imaging techniques such as MRI reveal bilateral hyperintense lesions in the basal ganglia, thalamus, substantia nigra, brainstem, cerebellar white matter and cortex, cerebral white matter, or spinal cord of LS patients (6,(11)(12)(13)(14). The lesions usually correlate with gliosis, demyelination, capillary proliferation, and/or necrosis (10,15). Behavioral symptoms of LS patients can include (with a wide variety of clinical presentation) developmental retardation, hypotonia, ataxia, spasticity, dystonia, weakness, optic atrophy, defects in eye or eyelid movement, hearing impairment, breathing abnormalities, dysarthria, swallowing difficulties, failure to thrive, and gastrointestinal problems (4-6, 16, 17).…”

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confidence: 99%

Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome

Quintana

Kruse

Kapur

et al. 2010

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

253

289

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To explore the lethal, ataxic phenotype of complex I deficiency in Ndufs4 knockout (KO) mice, we inactivated Ndufs4 selectively in neurons and glia (NesKO mice). NesKO mice manifested the same symptoms as KO mice including retarded growth, loss of motor ability, breathing abnormalities, and death by ∼7 wk. Progressive neuronal deterioration and gliosis in specific brain areas corresponded to behavioral changes as the disease advanced, with early involvement of the olfactory bulb, cerebellum, and vestibular nuclei. Neurons, particularly in these brain regions, had aberrant mitochondrial morphology. Activation of caspase 8, but not caspase 9, in affected brain regions implicate the initiation of the extrinsic apoptotic pathway. Limited caspase 3 activation and the predominance of ultrastructural features of necrotic cell death suggest a switch from apoptosis to necrosis in affected neurons. These data suggest that dysfunctional complex I in specific brain regions results in progressive glial activation that promotes neuronal death that ultimately results in mortality.cerebellum | mitochondria | gliosis | neurodegeneration | vestibular nucleus

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Mechanisms of unexpected death and autopsy findings in Leigh syndrome (subacute necrotising encephalomyelopathy)

Cited by 24 publications

References 14 publications

Mitochondrial Disease in Childhood: Nuclear Encoded

Mitochondrial Disease in Childhood: Nuclear Encoded

Sudden adult death

Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome

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