Spastic paraplegia type 8: A first report from India

Mahale, Rohan; Arunachal, Gautam; Davuluri, Anudeep; Padmanabha, Hansashree; Mailankody, Pooja

doi:10.4103/aian.aian_901_22

Cited by 1 publication

(2 citation statements)

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“…10,11 However, homozygous nonsense variant has recently been reported in a 21-year-old individual with spastic paraparesis, dysarthria, dysphagia, parkinsonism, and mild cerebellar atrophy and bilateral mineralization in GP. 12 Recently, cases reported intermediate clinical phenotypes with new features. Two patients had hypotonia and respiratory failure, linked to brainstem and basal ganglia atrophy without iron overload.…”

Section: Introductionmentioning

confidence: 99%

“…Notably, complete loss‐of‐function COASY variants have been identified in a total of 13 fetuses/newborns with pontocerebellar hypoplasia type 12 (PCH12), which is characterized by a fatal perinatal outcome defined by pons and cerebellar atrophy, microcephaly, and arthrogryposis, but without evidence of brain iron accumulation 10,11 . However, homozygous nonsense variant has recently been reported in a 21‐year‐old individual with spastic paraparesis, dysarthria, dysphagia, parkinsonism, and mild cerebellar atrophy and bilateral mineralization in GP 12 …”

Section: Introductionmentioning

confidence: 99%

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Emerging variants, unique phenotypes, and transcriptomic signatures: an integrated study of COASY‐associated diseases

Cavestro,

Morra,

Legati

et al. 2024

Ann Clin Transl Neurol

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ObjectiveCOASY, the gene encoding the bifunctional enzyme CoA synthase, which catalyzes the last two reactions of cellular de novo coenzyme A (CoA) biosynthesis, has been linked to two exceedingly rare autosomal recessive disorders, such as COASY protein‐associated neurodegeneration (CoPAN), a form of neurodegeneration with brain iron accumulation (NBIA), and pontocerebellar hypoplasia type 12 (PCH12). We aimed to expand the phenotypic spectrum and gain insights into the pathogenesis of COASY‐related disorders.MethodsPatients were identified through targeted or exome sequencing. To unravel the molecular mechanisms of disease, RNA sequencing, bioenergetic analysis, and quantification of critical proteins were performed on fibroblasts.ResultsWe identified five new individuals harboring novel COASY variants. While one case exhibited classical CoPAN features, the others displayed atypical symptoms such as deafness, language and autism spectrum disorders, brain atrophy, and microcephaly. All patients experienced epilepsy, highlighting its potential frequency in COASY‐related disorders. Fibroblast transcriptomic profiling unveiled dysregulated expression in genes associated with mitochondrial respiration, responses to oxidative stress, transmembrane transport, various cellular signaling pathways, and protein translation, modification, and trafficking. Bioenergetic analysis revealed impaired mitochondrial oxygen consumption in COASY fibroblasts. Despite comparable total CoA levels to control cells, the amounts of mitochondrial 4′‐phosphopantetheinylated proteins were significantly reduced in COASY patients.InterpretationThese results not only extend the clinical phenotype associated with COASY variants but also suggest a continuum between CoPAN and PCH12. The intricate interplay of altered cellular processes and signaling pathways provides valuable insights for further research into the pathogenesis of COASY‐associated diseases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%