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PATIENT RISK FACTORS
TISSUE SPECIFIC RISK FACTORS
anatomical (due its structure)
vascular (due to the local circulation)
physiopathological (due to tissue function and activity)
MUTATIONS IN LYST GENE AND CHEDIAK-HIGASHI SYNDROME
LYSOSOMAL TRAFFICKING REGULATOR; LYST
Alternative titles; symbols : CHS1 GENE; CHS1
HGNC Approved Gene Symbol: LYST
Cytogenetic location: 1q42.3 Genomic coordinates (GRCh37): 1:235,824,342 - 236,030,219
Gene Phenotype Relationships :
Location : 1q42.3
Phenotype : Chediak-Higashi syndrome
Phenotype MIM number: 214500
At least 30 mutations in the LYST gene have been identified in people with Chediak-Higashi Syndrome.
Summary of LYST gene : this gene seems to code for a protein involved in intracellular traffic regulation from and towards lysosomes.
Associated syndrome: Chèdiak-Higashi Syndrome (CHS)
Codified protein : Lysosomial trafficking regulator
3081 aminoacids , 429139 Da , intracytoplasmic localization
Alternative splicing : 3 isoforms Q99698-1 , Q99698-2 , Q99698-3
Protein Lyst expression in whole organism: Blood Plasma , Blood Mononuclear , Platelet , Kidney , Liver .
Gene LYST includes some genetic information indispensable for the coding of a protein known as the Lysosomial Trafficking Regulator. It seems that this protein plays an important role in the transport of materials into cellular structures called lysosomes . Mutations in LYST cause a rare autosomal recessive disorder that is Chèdiak-Higashi syndrome. Lysosomes are cytoplasmatic organules act as recycling center within cells. They use digestive enzymes (acid hydrolases) to break down toxic substances , digest bacteria that invade the cell , and recycle worn-out cell components. They are also able to degrade every biologic polymer including lipids, proteins , nucleic acids ,polysaccharides .
In their simple form they appear like spheric vacuoles , but they also have different forms and dimensions in relations to the transported materials that they must degrade. Mutations in LYST gene impair the normal function of the lysosomial trafficking regulator protein , which disrupts the size , structure and function of lysosomes and related structures in cells throughout the body. In many cells , the lysosome are abnormally large and interfere with normal cell function , for example the fusion between phagosome and lysosome does not happen correctly (that hesitates in recurrent infections) , melanocytes can’t able to generate a melanosome (so patients with CHS show an AOC) and alterated lysosomes are evident in nervous cells causing neurologic symptoms. Enlarged lysosomes originate from the myeloid precursors during maturation : these cells can show lack of lysosomial microbiocidal enzymes ,phagocitosis and chemiotactic activities. NK cells function is very reduced probably because of abnormalities in cytoplasmatic granules . Researchers attempt to prove which proteins can react with LYST protein in order to realize what doesn’t work in this protein and understand the pathogenesis of CHS. Twenty-one proteins that interact with LYST were identified. Four interactions were with proteins important in vescicular transport and signal transduction : SNARE complex proteins ( HRS protein , 14-3-3 , casein kinase II). On the basis of protein interactions , LYST appears to function as an adapter protein that may juxtapose proteins that mediate intracellular membrane fusion reactions.[Tchernev VT et al , 2002]
Chèdiak Higashi syndrome (CHS) is a condition that affects many parts of the body , particularly the immune system. This condition in inherited in an autosomal recessive pattern , which means both copies of the gene in each cell have mutations . The parents of an individual affected each carry one copy of the mutated gene. As mentioned above the mutation that causes the CHS involves chromosome 1 which carry LYST gene.
• EPHIDEMIOLOGY : Although its exact incidence is unknown , fewer than 200 people with the condition have been reported worldwide.
• CLINICAL DESCRIPTION
Chediak-Higashi syndrome (CHS) is characterized by Oculocutaneus Albinism, immunodeficiency, and a mild bleeding tendency. Approximately 85% of affected individuals develop the accelerated phase, a lymphoproliferative infiltration of the bone marrow and reticuloendothelial system.
Partial OCULOCUTANEUS ALBINISM
Melanocytes contain lysosomial structures specialized called melanosomes , in CHS these organules are enlarged . As a result melanin is trapped within the giant melanosomes and is unable to contribute to skin,hair and eye pigmentation , this is why people with CHS have OCULOCUTANEUS ALBINISM. Pigment dilution is highly variable, but can involve hair, skin, and eyes. In classic forms of CHS, the hair has a “silvery” or metallic appearance. Skin pigment dilution may not be appreciated unless compared to that of more darkly pigmented family members. Reduced iris pigmentation is associated with decreased retinal pigmentation and nystagmus.
Enlarged lysosomes in certain immune system cells prevent these cells from responding appropriately to bacteria and other foreign invaders . As a result , the malfunctioning immune system cannot protect the body from severe and recurrent infections. Bacterial infections are most common, with Staphylococcus and Streptococcus species predominating; viral and fungal infections can also occur [Introne et al 1999].
These abnormally large lysosomes can also invalidate coagulation and nervous central system ; inside platelets they prevent normal activation with thrombocytopenia. Clinical manifestations are generally mild and include epistaxis, gum/mucosal bleeding, and easy bruising.
• ACCELERATED PHASE
Most children with CHS ultimately reach a stage of the disorder known as “accelerated phase” .This severe phase is thought to be triggered by viral infections. Especially EBV infection is thought to hasten development of the accelerated phase, although this relationship has never been proven. Absence of NK cell function is also believed to contribute to development of the accelerated phase. Clinical manifestations include fever, lymphadenopathy, hepatosplenomegaly, anemia, neutropenia, and sometimes thrombocytopenia. Originally, it was thought oto be a disease similar to a lymphoma, but it was later discovered that it is actually a non-malignant hemophagocytic and lymphohistiocitic infiltration in multiple organs. The accelerated phase and its complications are the most common cause of mortality in individuals with CHS [Eapen et al 2007].
• GENOTYPE-PHENOTYPE CORRELATIONS
There seems to be an apparent genotypical-phenotypical correlation in this disease: recently new forms of CHS that present clinical manifestations which differ slightly from the ones described in literature. The studies conducted on this forms shows patients with milder disease that also has a later onset and describes three classes: childhood, adolescent, and adult disease. [Karim et al 2012]. The milder form of CHS usually manifests itself in adolescence and is extremely rare. Some studies show how 10-15% of patients that presents milder phenotypical aspects of the disease survives into adulthood, but developes a progressive and often fatal neurological dysfunction. An ever lesser percentage of patients manifests an intermediate disease phenotype which becomes evident during adolescence. It is characterized by severe infections during childhood but a slow progress during adolescence without presenting the accelerated phase. The genotype-phenotype correlation derives from the fact that in patients with the childhood disease have only a functional mutation in the LYST gene, with total loss of protein activity. In patients with the adolescent and adult forms of the disease the mutations found were missense which codified with a protein that still maintained partial function. [Tchernev et al 2002] This has been confirmed lately in 2013 in recent studies regarding three patients presenting a new mutation in homozygosis of the LYST gene: a deletion (deletion of nucleotides 3073 and 3074 in coding domain). During transcription this mutation brings loss of residues of Arg and Tre [Weisfled Adams JD e all 2013]. These three patients clinically manifested a mild form of the disease with progressive neurodegenerative disease in adult age, cognitive decline, parkinsonisms, signs of spino-cerebellar degeneration, peripherical neuropathy, slight alterations in pigmentation, and subclinic immune dysfunction. It has been shown also that the clinical severity of the disease also correlates with the cellular phenotype. Detailed studies of fibroblasts and melanocytes from individuals with CHS with different clinical phenotypes illustrated the range of enlargement of intracellular granule abnormalities in different CHS cell types [Westbroek et al 2007].
Atypical phenotypes are characterized by the following:
1. OCA that is generally subtle or absent
2. Insignificant infections or severe infections during childhood that become much less frequent later in life (especially in adolescent)
3. Reduced platelet-count
4. Progressive neurologic symphtoms that can include intellectual disabilities, peripheral neuropathy, balance abnormalities, and tremor.
PATIENT RISK FACTORS : CHS is a rare disease , risk factors sre not accerted . Some riks factors may unclude ionizing radiations and toxic substances during pregnancy that can provoke genatic mutations.
Research of the genetic mutation with : Northen Blot , Western Blot , RT-PCR
Neurologic examination and TC , RMN ,EEG , EMG
Research of signs of accelerated phase : [Filipovich 2006]
Cytopenia of at least two cell lines
Signs of liver dysfunction including hypertriglyceridemia and/or hypofibrinogenemia
Elevated serum ferritin concentration
Elevated soluble interleukin-2 receptor level
Evidence of hemophagocytosis in bone marrow and/or cerebrospinal fluid
The only treatment that cures the hematologic and immunologic defects is allogenic HSCT. The most favorable outcome is achieved when HSCT is performed prior to development of the accelerated phase.
Correction of refractive errors may improve visual acuity.Sunglasses should be used to protect sensitive eyes from UV light.
Neurologic abnormalities. Because of the progressive nature of the neurologic symptoms, older patients should engage rehabilitation specialists early in the course of the disease.
• Tchernev VT , Mandfield TA , Giot L ,Kumar AM , Nandabalan K , Li Y , Mishra VS , Detter JC , Rothberg JM , Southwick FS , Kingsmore SF. The Chediak-Higashi protein interacts with SNARE complex and signal transduction proteins. Mol.Med 2002 Jan; 8 (1):56-64
• Introne W, Boissy RE, Gahl WA. Clinical, molecular, and cell biological aspects of Chediak-Higashi syndrome. Mol Genet Metab. 1999 Oct;68(2):283-303. Review
• Eapen M, DeLaat CA, Baker KS, Cairo MS, Cowan MJ, Kurtzberg J, Steward CG, Veys PA, Filipovich AH. Hematopoietic cell transplantation for Chediak-Higashi syndrome. Bone Marrow Transplantation. 2007;39:411–5.
• Karim et All . Apparent genotype-phenotype correlation in childhood, adolescent , and adult Chediak-Higashi Syndrome . AmJ Med Genet.2002 Feb 15; 108 (1):16-22.
• Weisfeld-Adams JD , Mehta L , Rucker JC , Dembitzer FR , Szporn A , Lublin FD , Introne WJ, Bhambhani V , Chicka MC , Cho C. Atypical Chèdiak-Higashi syndrome with attenuated phenotype: three adult siblings homozygous for a novel LYST deletion and neurodegenerative disease. Orphanet J rare Dis. 2013 Mar 22;8: 46. Review
• Westbroek et All. Cellular defects in Chediak-higashi syndrome correlate with the molecular genotype and clinical phenotype. J Invest Dermatol. 2007 Nov; 127(11): 2674-7.
• Filipovich AH. Hemophagocytic lymphohistiocytosis and related disorders. Curr Opin Allergy Clin Immunol. 2006;6:410–15.
Kaplan J, De Domanico I , Ward DM. Chediak-Higashi Syndrome . Curr Opin Hematol. 2008 Jan ; 15(1): 22-9. Review
Shiflett SL , Kaplan J, Ward DM . Chediak-Higashi Syndrome: a rare disorders of lysosomes and lysosome related organelles . Pigment cell Res. 2002 Aug ; 15 (4) : 251-7 . Review.
Ward DM , Shiflett SL, Kaplan J. Chediak-Higashi : a clinical e molecular view of a rare lysosomial storage disorder. Curr Mol Med .2002 Aug; 2 (5): 469-77. Review.
MedlinePlus Encyclopedia : Chediak-Higashi syndrome