title: Atypical Chédiak-Higashi syndrome with attenuated phenotype: three adult siblings homozygous for a novel LYST deletion and with neurodegenerative disease.
abstract: BACKGROUND
  Mutations in LYST, a gene encoding a putative lysosomal trafficking protein, cause Chédiak-Higashi syndrome (CHS), an autosomal recessive disorder typically characterized by infantile-onset hemophagocytic syndrome and immunodeficiency, and oculocutaneous albinism. A small number of reports of rare, attenuated forms of CHS exist, with affected individuals exhibiting progressive neurodegenerative disease beginning in early adulthood with cognitive decline, parkinsonism, features of spinocerebellar degeneration, and peripheral neuropathy, as well as subtle pigmentary abnormalities and subclinical or absent immune dysfunction.
  
  
  METHODS
  In a consanguineous Pakistani kindred with clinical phenotypes consistent with attenuated CHS, we performed SNP array-based homozygosity mapping and whole gene sequencing of LYST.
  
  
  RESULTS
  We identified three individuals homozygous for a novel six base pair in-frame deletion in LYST (c.9827_9832ATACAA), predicting the loss of asparagine and threonine residues from the LYST transcript (p.Asn3276_Thr3277del), and segregating with the phenotype in this family.
  
  
  CONCLUSIONS
  We further characterize the neurologic features of the attenuated form of CHS, and discuss pathophysiologic mechanisms underlying the neurodegenerative components of CHS. Attenuated CHS is phenotypically heterogenous and should be considered when young adults develop neurodegenerative disease and have pigmentary abnormalities. We briefly discuss surveillance and management of patients with CHS-related neurodegeneration.
authors.affiliation: Department of Genetics & Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA. james.weisfeld-adams@mssm.edu
authors.forename: James D
authors.initials: JD
authors.lastname: Weisfeld-Adams
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Mehta
authors.forename: Janet C
authors.initials: JC
authors.lastname: Rucker
authors.forename: Francine R
authors.initials: FR
authors.lastname: Dembitzer
authors.forename: Arnold
authors.initials: A
authors.lastname: Szporn
authors.forename: Fred D
authors.initials: FD
authors.lastname: Lublin
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Introne
authors.forename: Vikas
authors.initials: V
authors.lastname: Bhambhani
authors.forename: Michael C
authors.initials: MC
authors.lastname: Chicka
authors.forename: Catherine
authors.initials: C
authors.lastname: Cho
mesh_terms: D000328:Adult; D002609:Chediak-Higashi Syndrome / Q000235:genetics*; D005260:Female; D005820:Genetic Testing; D006801:Humans; D008297:Male; D019636:Neurodegenerative Diseases / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D010154:Pakistan; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D035781:Siblings; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: C102161:LYST protein, human; D033921:Vesicular Transport Proteins