Chediak-Higashi syndrome

Abstract

Purpose of review: Chediak-Higashi syndrome is a rare autosomal recessive disorder characterized by congenital immunodeficiency, bleeding diathesis, pyogenic infection, partial oculocutaneous albinism, and progressive neurodegeneration. Treatment is hematopoietic stem cell transplantation or bone marrow transplantation; however, this does not treat the neurologic aspect of the disease. Mutations in the lysosomal trafficking regulator (LYST) gene were identified to be causative of Chediak-Higashi, but despite many analyses, there is little functional information about the LYST protein. This review serves to provide an update on the clinical manifestations and cellular defects of Chediak-Higashi syndrome.

Recent findings: More recent papers expand the neurological spectrum of disease in CHS, to include hereditary spastic paraplegia and parkinsonism. Granule size and distribution in NK cells have been investigated in relation to the location of mutations in LYST. Patients with mutations in the ARM/HEAT domain had markedly enlarged granules, but fewer in number. By contrast, patients with mutations in the BEACH domain had more numerous granules that were normal in size to slightly enlarged, but demonstrated markedly impaired polarization. The role of LYST in autophagosome formation has been highlighted in recent studies; LYST was defined to have a prominent role in autophagosome lysosome reformation for the maintenance of lysosomal homeostasis in neurons, while in retinal pigment epithelium cells, LYST deficiency was shown to lead to phagosome accumulation.

Summary: Despite CHS being a rare disease, investigation into LYST provides an understanding of basic vesicular fusion and fission. Understanding of these mechanisms may provide further insight into the function of LYST.

Figure 1.. Clinical features of patients with Chediak Higashi syndrome.

Patients with CHS manifest with light colored or silvery hair that can have a metallic sheen (A); viewed under a light microscope, pigment clumping can be seen in the hair shaft (B). Peripheral blood smear reveals the pathognomonic giant inclusions (arrow) within the cytoplasm of leucocyte (C). By transmission electron microscopy (EM) of plastic-embedded leucocyte-rich samples, these giant inclusions, G, appear to be membrane bound inclusions of amorphous materials (D) outside the nucleus, N. Another finding that supports the diagnosis of CHS is the paucity of platelet dense granules visible by whole mount EM of unfixed platelets (E). Patients with CHS also present with cerebral (arrowheads) and cerebellar atrophy (arrow) later in the disease course, as seen in representative brain MRI image (F).

Figure 2.. Defects of LYST- deficient cells.

An illustration of the comparison of cells with functional LYST and LYST-deficient cells. Cells with functional LYST and their normal lysosome-related organelles (LROs) (A). LYST-deficient cells and their abnormal LROs, as well as the clinical manifestation related to the LYST deficiency (B). Melanocytes are observed to have enlarged melanosomes, which lead to abnormal pigmentation. Neutrophils have enlarged, dysfunctional azurophil granules, presumably a factor in the recurrent infections of CHS patients. Platelets are observed to have absent or diminished dense granules, leading to coagulation defects and a propensity to bleeding. Natural killer cells and cytotoxic T lymphocytes both present with enlarged lytic granules, leading to recurrent infection and decreased cytotoxicity, respectively.

Figure 3.. Domains of LYST.

The LYST gene consists of 53 exons and a 13.5 Kb mRNA transcript (A) that encodes a protein of 3801 amino acids (B). Several functional domains have been identified in the LYST amino acid sequence. An Armadillo (ARM) repeat resides at the amino terminus from amino acids 247–2385. The pleckstrin homology (PH) domain is located at amino acids 3012–3115. The beige and CHS (BEACH) domain follows the PH domain from amino acids 3120–3422. A WD-40 repeat is located at the carboxyl terminus, amino acids 3540–3787.