Leigh syndrome

Rahman, Shamima

doi:10.1016/b978-0-12-821751-1.00015-4

Cited by 23 publications

(15 citation statements)

References 119 publications

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“…The genome of case 1 was sequenced and searched for homozygous private protein changing variants by comparing the variants to 1479 control genomes (TableS 1 , S4 ). Further prioritization of resulting variants was then done based on known candidate genes for Leigh syndrome in humans 2 .…”

Section: Resultsmentioning

confidence: 99%

“…Subacute necrotizing encephalopathy, or Leigh syndrome, was first described in human patients in 1951 1 . This predominantly neurological disease encompasses a broad spectrum of mitochondrial encephalopathies, such as defects in oxidative phosphorylation complexes, thiamine transport, or disorders of pyruvate metabolism 2 . A total of 113 gene-disease relationships have been established for the Leigh syndrome spectrum, 16 of which are linked to the mitochondrial DNA 3 .…”

Section: Introductionmentioning

confidence: 99%

“…Clinical progression is then often rapid, and death may occur already in infancy 4 . One of the main criteria for early diagnosis of the disease are bilateral and symmetrical T2 hyperintense lesions involving basal ganglia, thalamus, midbrain, and brainstem on magnetic resonance imaging (MRI) 2 , corresponding to encephalomalacia. These lesions combined with evidence of mitochondrial dysfunction, such as elevated lactate levels, raise the suspicion of Leigh syndrome, which then can be confirmed by genetic testing.…”

Section: Introductionmentioning

confidence: 99%

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NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model

Christen,

Gregor,

Gutierrez-Quintana

et al. 2024

Sci Rep

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Two Jack-Russell Terrier × Chihuahua mixed-breed littermates with Leigh syndrome were investigated. The dogs presented with progressive ataxia, dystonia, and increased lactate levels. Brain MRI showed characteristic bilateral symmetrical T2 hyperintense lesions, histologically representing encephalomalacia. Muscle histopathology revealed accumulation of mitochondria. Whole genome sequencing identified a missense variant in a gene associated with human Leigh syndrome, NDUFS7:c.535G > A or p.(Val179Met). The genotypes at the variant co-segregated with the phenotype in the investigated litter as expected for a monogenic autosomal recessive mode of inheritance. We investigated the functional consequences of the missense variant in a Drosophila melanogaster model by expressing recombinant wildtype or mutant canine NDUFS7 in a ubiquitous knockdown model of the fly ortholog ND-20. Neither of the investigated overexpression lines completely rescued the lethality upon knockdown of the endogenous ND-20. However, a partial rescue was found upon overexpression of wildtype NDUFS7, where pupal lethality was moved to later developmental stages, which was not seen upon canine mutant overexpression, thus providing additional evidence for the pathogenicity of the identified variant. Our results show the potential of the fruit fly as a model for canine disease allele validation and establish NDUFS7:p.(Val179Met) as causative variant for the investigated canine Leigh syndrome.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model

Christen,

Gregor,

Gutierrez-Quintana

et al. 2024

Sci Rep

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“…Leigh syndrome is the most common syndromic presentation of mitochondrial disease in early childhood [ 3 ]. Its clinical hallmark is developmental regression often following a minor illness with symmetrical basal ganglia lesions seen on brain imaging.…”

Section: Discussionmentioning

confidence: 99%

Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene

Matthews,

Whittle,

Khan

et al. 2024

J Hum Genet

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Only five children with pathogenic PMPCB gene variants have been described and all carried missense variants. Clinical features included a Leigh-like syndrome of developmental regression, basal ganglia lesions and ataxia with or without dystonia and epilepsy. Three of the five died in childhood and none was older than age six when described. We report the first splice site variant in the PMPCB gene in a 39-year old individual who experienced developmental regression and ataxia following otitis media in childhood. A minigene assay confirms this variant results in aberrant splicing and skipping of exon 12.

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“…Leigh syndrome (OMIM: #256000) is a rare and severe autosomal recessive mitochondrial disease characterized by the progressive deterioration of the central nervous system ( Rahman, 2023 ). This disorder, also called subacute necrotizing encephalomyelopathy, was first reported by British neuropathologist Denis A. Leigh in 1951 ( Leigh, 1951 ).…”

Section: Introductionmentioning

confidence: 99%

Biallelic variants in HTRA2 cause 3-methylglutaconic aciduria mitochondrial disorder: case report and literature review

Gurusamy,

Ramadesikan,

Marhabaie

et al. 2024

Front. Genet.

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Background: Leigh syndrome is a rare, genetic, and severe mitochondrial disorder characterized by neuromuscular issues (ataxia, seizure, hypotonia, developmental delay, dystonia) and ocular abnormalities (nystagmus, atrophy, strabismus, ptosis). It is caused by pathogenic variants in either mitochondrial or nuclear DNA genes, with an estimated incidence rate of 1 per 40,000 live births.Case presentation: Herein, we present an infant male with nystagmus, hypotonia, and developmental delay who carried a clinical diagnosis of Leigh-like syndrome. Cerebral magnetic resonance imaging changes further supported the clinical evidence of an underlying mitochondrial disorder, but extensive diagnostic testing was negative. Trio exome sequencing under a research protocol uncovered compound-heterozygous missense variants in the HTRA2 gene (MIM: #606441): NM_013247.5:c.1037A>T:(p.Glu346Val) (maternal) and NM_013247.5:c.1172T>A:(p.Val391Glu) (paternal). Both variants are absent from public databases, making them extremely rare in the population. The maternal variant is adjacent to an exon-intron boundary and predicted to disrupt splicing, while the paternal variant alters a highly conserved amino acid and is predicted to be damaging by nearly all in silico tools. Biallelic variants in HTRA2 cause 3-methylglutaconic aciduria, type VIII (MGCA8), an extremely rare autosomal recessive disorder with fewer than ten families reported to date. Variant interpretation is challenging given the paucity of known disease-causing variants, and indeed we assess both paternal and maternal variants as Variants of Uncertain Significance under current American College of Medical Genetics guidelines. However, based on the inheritance pattern, suggestive evidence of pathogenicity, and significant clinical correlation with other reported MGCA8 patients, the clinical care team considers this a diagnostic result.Conclusion: Our findings ended the diagnostic odyssey for this family and provide further insights into the genetic and clinical spectrum of this critically under-studied disorder.

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Leigh syndrome

Cited by 23 publications

References 119 publications

NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model

NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model

Leigh syndrome with developmental regression and ataxia due to a novel splicing variant in the PMPCB gene

Biallelic variants in HTRA2 cause 3-methylglutaconic aciduria mitochondrial disorder: case report and literature review

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