Atypical Chédiak-Higashi syndrome with attenuated phenotype: three adult siblings homozygous for a novel LYST deletion and with neurodegenerative disease

Orphanet Journal of Rare Diseases

Catherine Cho⁴  Michael C Chicka³  Vikas Bhambhani¹  Wendy J Introne¹  Fred D Lublin⁴  Arnold Szporn⁵  Francine R Dembitzer⁵  Janet C Rucker⁶  Lakshmi Mehta²  James D Weisfeld-Adams² 

[1] Section on Human Biochemical Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA;Department of Genetics & Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA;Prevention Genetics, Marshfield, WI, USA;Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA;Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA;Department of Ophthalmology, Mount Sinai School of Medicine, New York, NY, USA

关键词: Neurodegenerative disease;    Parkinsonism;    Oxidative stress;    Amyloid;    Lysosomal;    LYST;    Chédiak-Higashi syndrome;   

Others  :  864077
DOI  :  10.1186/1750-1172-8-46

 received in 2013-01-02, accepted in 2013-03-09,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Weisfeld-Adams et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

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