Clinical Reasoning: A 50-Year-Old Man With Progressive Limb Weakness and Slurred Speech

Xie, Nina; Yang, Guang; Zhang, Weiru; Xu, Hongwei; Sun, Qiying

doi:10.1212/wnl.0000000000200008

Neurology

2022

DOI: 10.1212/wnl.0000000000200008

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Clinical Reasoning: A 50-Year-Old Man With Progressive Limb Weakness and Slurred Speech

Nina Xie

Guang Yang

Weiru Zhang

et al.

Abstract: Neurology® Published Ahead of Print articles have been peer reviewed and accepted for publication. This manuscript will be published in its final form after copyediting, page composition, and review of proofs. Errors that could affect the content may be corrected during these processes.

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Spectrum of LYST mutations in Chediak-Higashi syndrome: a report of novel variants and a comprehensive review of the literature

Morimoto,

Nicoli,

Kuptanon

et al. 2023

J Med Genet

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IntroductionChediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterised by partial oculocutaneous albinism, a bleeding diathesis, immunological dysfunction and neurological impairment. Bi-allelic loss-of-function variants inLYSTcause CHS.LYSTencodes the lysosomal trafficking regulator, a highly conserved 429 kDa cytoplasmic protein with an unknown function.MethodsTo further our understanding of the pathogenesis of CHS, we conducted clinical evaluations on individuals with CHS enrolled in our natural history study. Using genomic DNA Sanger sequencing, we identified novel pathogenicLYSTvariants. Additionally, we performed an extensive literature review to curate reportedLYSTvariants and classified these novel and reported variants according to the American College of Medical Genetics/Association for Molecular Pathology variant interpretation guidelines.ResultsOur investigation unveiled 11 novel pathogenicLYSTvariants in eight patients with a clinical diagnosis of CHS, substantiated by the presence of pathognomonic giant intracellular granules. From these novel variants, together with a comprehensive review of the literature, we compiled a total of 147 variants inLYST, including 61 frameshift variants (41%), 44 nonsense variants (30%), 23 missense variants (16%), 13 splice site variants or small genomic deletions for which the coding effect is unknown (9%), 5 in-frame variants (3%) and 1 start-loss variant (1%). Notably, a genotype–phenotype correlation emerged, whereby individuals harbouring at least one missense or in-frame variant generally resulted in milder disease, while those with two nonsense or frameshift variants generally had more severe disease.ConclusionThe identification of novel pathogenicLYSTvariants and improvements in variant classification will provide earlier diagnoses and improved care to individuals with CHS.

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Spectrum of LYST mutations in Chediak-Higashi syndrome: a report of novel variants and a comprehensive review of the literature

Morimoto,

Nicoli,

Kuptanon

et al. 2023

J Med Genet

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show abstract

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Clinical Reasoning: A 50-Year-Old Man With Progressive Limb Weakness and Slurred Speech

Abstract: Neurology® Published Ahead of Print articles have been peer reviewed and accepted for publication. This manuscript will be published in its final form after copyediting, page composition, and review of proofs. Errors that could affect the content may be corrected during these processes.

Cited by 1 publication

References 13 publications

Spectrum of LYST mutations in Chediak-Higashi syndrome: a report of novel variants and a comprehensive review of the literature

Spectrum of LYST mutations in Chediak-Higashi syndrome: a report of novel variants and a comprehensive review of the literature

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