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Pseudo-Chediak-Higashi granules are large cytoplasmic inclusions commonly encountered in myeloblasts or other myeloid precursors in acute myeloid leukemia and myelodysplastic syndromes. However, pseudo-Chediak-Higashi granules are rarely found in acute lymphoblastic leukemia (ALL). We present the case of an 8-year-old boy who was diagnosed with ALL with pseudo-Chediak-Higashi granules in the initial diagnosis and relapse, acting like a characteristic marker., (© 2024 John Wiley & Sons Ltd.)

Introduction: Chediak-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 in LYST cause CHS. LYST encodes the lysosomal trafficking regulator, a highly conserved 429 kDa cytoplasmic protein with an unknown function., Methods: To 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 pathogenic LYST variants. Additionally, we performed an extensive literature review to curate reported LYST variants and classified these novel and reported variants according to the American College of Medical Genetics/Association for Molecular Pathology variant interpretation guidelines., Results: Our investigation unveiled 11 novel pathogenic LYST variants 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 in LYST , 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., Conclusion: The identification of novel pathogenic LYST variants and improvements in variant classification will provide earlier diagnoses and improved care to individuals with CHS., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Chediak-Higashi syndrome (CHS) is an autosomal recessive disorder characterized by leukocytes with giant secretory granules and a myriad of clinical features. However, it is unknown whether oral lesions are part of the syndrome or are refractory to systemic treatment. Herein, we integrated the available data published in the literature on the oral manifestations of individuals with CHS. Searches on PubMed, Web of Science, Embase, Scopus, and LILACS were conducted to identify studies published up to March/2022. The Joanna Briggs Institute tool was used for the critical appraisal of studies. Fourteen articles (21 cases) were detected. The mean age of individuals was 15.9±8.8 years. There was a slight predominance of males (52.4%). The major manifestation was periodontal disease (81%), although ulceration of the oral mucosa (14.3%), gingival/labial abscess (4.8%), and periodontal abscess (4.8%) were also reported. Oral rehabilitation including dental implants (9.5%) was performed after tooth losses due to the poor prognosis of periodontal therapy. CHS is usually diagnosed in an early stage due to its systemic manifestations such as classic oculocutaneous albinism, recurrent infections, and a propensity for bleeding. Oral health providers should be aware of the manifestations of individuals with CHS. Special care, including oral prophylaxis, is indispensable., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Chediak-Higashi syndrome, caused by mutations in the Lysosome Trafficking Regulator (Lyst) gene, is a recessive hypopigmentation disorder characterized by albinism, neuropathies, neurodegeneration, and defective immune responses, with enlargement of lysosomes and lysosome-related organelles. Although recent studies have suggested that Lyst mutations impair the regulation of sizes of lysosome and lysosome-related organelle, the underlying pathogenic mechanism of Chediak-Higashi syndrome is still unclear. Here we show striking evidence that deficiency in LYST protein function leads to accumulation of photoreceptor outer segment phagosomes in retinal pigment epithelial cells, and reduces adhesion between photoreceptor outer segment and retinal pigment epithelial cells in a mouse model of Chediak-Higashi syndrome. In addition, we observe elevated levels of cathepsins, matrix metallopeptidase (MMP) 3 and oxidative stress markers in the retinal pigment epithelium of Lyst mutants. Previous reports showed that impaired degradation of photoreceptor outer segment phagosomes causes elevated oxidative stress, which could consequently lead to increases of cysteine cathepsins and MMPs in the extracellular matrix. Taken together, we conclude that the loss of LYST function causes accumulation of phagosomes in the retinal pigment epithelium and elevation of several extracellular matrix-remodeling proteases through oxidative stress, which may, in turn, reduce retinal adhesion. Our work reveals previously unreported pathogenic events in the retinal pigment epithelium caused by Lyst deficiency. The same pathogenic events may be conserved in other professional phagocytic cells, such as macrophages in the immune system, contributing to overall Chediak-Higashi syndrome pathology., Competing Interests: The authors declare no conflict of interest.

Background: Chediak-Higashi syndrome (CHS) is a congenital disease characterized by immunodeficiency, hemophagocytic lymphohistiocytosis, oculocutaneous albinism, and neurological symptoms. The presence of giant granules in peripheral blood leukocytes is an important hallmark of CHS. Here we prepared induced pluripotent stem cells (iPSCs) from CHS patients (CHS-iPSCs) and differentiated them into hematopoietic cells to model the disease phenotypes., Methods: Fibroblasts were obtained from two CHS patients and then reprogrammed into iPSCs. The iPSCs were differentiated into myeloid cells; the size of the cytosolic granules was quantified by May-Grunwald Giemsa staining and myeloperoxidase staining., Results: Two clones of iPSCs were established from each patient. The differentiation efficiency to CD33 + CD45 + myeloid cells was not significantly different in CHS-iPSCs compared with control iPSCs, but significantly larger granules were observed., Conclusions: We succeeded in reproducing a characteristic cellular phenotype, giant granules in myeloid cells, using CHS-iPSCs, demonstrating that iPSCs can be used to model the pathogenesis of CHS patients., (© 2022 Japan Pediatric Society.)

Chediak-Higashi syndrome is a rare immunodeficiency disorder for which hematopoietic stem cell transplant (HSCT) is the only curative treatment option. HSCT only corrects the hematologic and immunologic manifestations of the disease but neurologic complications may still progress after transplant. Haploidentical HSCT (haplo-HSCT) has evolved as a feasible alternative for patients with primary immunodeficiency. More recently, there has been use of haplo-HSCT with post-transplant cyclophosphamide. However, only 4 cases of Chediak-Higashi syndrome have been reported using this approach. Here, the authors describe a case of a 17-month-old boy who was successfully treated by haplo-HSCT with reduced-toxicity conditioning (fludarabine/treosulfan/melphalan) and post-transplant cyclophosphamide., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Chediak-Higashi Syndrome (CHS) is a well-characterized, autosomal recessively inherited lysosomal disease caused by mutations in lysosomal trafficking regulator (LYST). The feline model for CHS was originally maintained for ~20 years. However, the colonies were disbanded and the CHS cat model was lost to the research community before the causative mutation was identified. To resurrect the cat model, semen was collected and cryopreserved from a lone, fertile,  CHS carrier male. Using cryopreserved semen, laparoscopic oviductal artificial insemination was performed on three queens, two queens produced 11 viable kittens. To identify the causative mutation, a fibroblast cell line, derived from an affected cat from the original colony, was whole genome sequenced. Visual inspection of the sequence data identified a candidate causal variant as a ~20 kb tandem duplication within LYST, spanning exons 30 through to 38 (NM_001290242.1:c.8347-2422_9548 + 1749dup). PCR genotyping of the produced offspring demonstrated three individuals inherited the mutant allele from the CHS carrier male. This study demonstrated the successful use of cryopreservation and assisted reproduction to maintain and resurrect biomedical models and has defined the variant causing Chediak-Higashi syndrome in the domestic cat.

Background: Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disease caused by loss of function of the lysosomal trafficking regulator protein. The causative gene LYST/CHS1 was cloned and identified in 1996, which showed significant homology to other species such as bovine and mouse. To date, 74 pathogenic or likely pathogenic mutations had been reported., Case Presentation: Here we describe a compound heterozygote in LYST gene, which was identified in a 4-year-old female patient. The patient showed skin hypopigmentation, sensitivity to light, mild splenomegaly and reduction of platelets in clinical examination. Giant intracytoplasmic inclusions were observed in the bone marrow examination, suggesting the diagnosis of CHS. Amplicon sequencing was performed to detect pathogenic mutation in LYST gene. The result was confirmed by two-generation pedigree analysis base on sanger sequencing., Conclusion: A compound heterozygote in LYST gene, consisting of a missense mutation c.5719A > G and an intron mutation c.4863-4G > A, was identified from the patient by using amplicon sequencing. The missense mutation is reported for the first time. Two-generation pedigree analysis showed these two mutations were inherited from the patient's parents, respectively. Our result demonstrated that amplicon sequencing has great potential for accelerating and improving the diagnosis of rare genetic diseases.

Background/objectives: Chediak-Higashi Disease (CHD) is a rare autosomal disorder, purported to have cognitive and neurological impairments. Prior descriptions of cognitive impairment, however, are solely based on subjective, unstructured observations rather than on formal neuropsychological measures., Methods: Four pediatric and 14 adult patients with diagnostically confirmed CHD were administered a neuropsychological battery assessing memory, attention, processing speed, psychomotor speed, language fluency, executive function, and general intelligence. Nine of the adult patients received follow-up evaluations to elucidate the longitudinal progression or stability of cognition over time., Results: Pediatric CHD patients performed within the average range. Adult patients, however, performed below average on nearly all measures administered, and endorsed subjective reports of learning difficulties and poor academic performance in childhood. In particular, patients struggled with memory and psychomotor speed tasks, with 75% or more of patients scoring in the bottom 2.3 percentile in these two domains. No significant declines in cognition were observed among the patients who completed follow-up evaluations (M = 39.90, SD = 8.03 months between visits). Exploratory analyses suggested that adult patients who had classic CHD and previously received bone marrow transplants (BMTs; n = 3) exhibited moderately greater cognitive impairment than adult patients who had atypical CHD and had not received BMTs (n = 10)., Conclusions: Adult patients with CHD uniformly exhibit deficits in multiple domains, but in psychomotor speed and memory, in particular. Based on their neuropsychological profile, their ability to hold jobs and succeed in school may require support and special accommodations. The source of cognitive deficits is probably multifactorial including central nervous system involvement in CHD, and, for those transplanted, BMT-related side effects and complications. Absence of cognitive decline at three-year follow-up is encouraging but does not exclude progression at a slower time-scale. Future work should elucidate the possible effects and timing of BMT on cognition, as well as the mechanisms driving neuropsychological impairment in CHD.

Background/objectives: Silvery hair syndrome is a rare, autosomal-recessive entity characterized by silvery gray hair, eyebrows, and eyelashes and may be associated or not with immunologic or neurologic alterations. Two main types have been recognized: Chediak-Higashi syndrome and Griscelli syndrome. Hair shaft examination under light microscopy has been a useful tool to differentiate Chediak-Higashi syndrome from Griscelli syndrome, although distribution of melanin varies according to hair color related to ethnicity. The objective was to compare the pattern of melanin in the skin and with the pattern of melanin distribution in the hair shaft., Methods: Sixteen patients with silvery hair syndrome were selected (Chediak-Higashi syndrome 5, Griscelli syndrome 11). The distribution of melanin granules in skin and hair shafts was compared and correlated with clinical diagnoses., Results: Chediak-Higashi syndrome was characterized by small granules of melanin uniformly distributed throughout the thickness of the epidermis. Griscelli syndrome was characterized by an irregular pigment distribution in the epidermal basal layer with large and dense granules alternating with areas lacking melanin pigment. In two cases, study of the hair was not conclusive, but the skin showed the characteristic pattern of Griscelli syndrome., Conclusion: Skin biopsy is a useful tool in differentiating Chediak-Higashi syndrome from Griscelli syndrome and as a complementary study in cases in which hair shaft pigment distribution does not support the diagnosis, especially in patients with fair hair. The distribution of melanin granules in the skin correlates with that observed in the hair shaft, allowing Chediak-Higashi syndrome to be differentiated from Griscelli syndrome, at any age., (© 2018 Wiley Periodicals, Inc.)

This case report describes common oral inflammatory findings leading to the identification of Chédiak-Higashi syndrome (CHS). A 15-year-old girl presented with an enlarging and painful mass on the upper lip. Two weeks after the initial visit, the mass showed further protrusion in the absence of fever. Magnetic resonance imaging revealed a well-circumscribed cystic lesion with a thick capsule, and suggested an abscess derived from the mucous cyst in the upper lip. Inflammation indices were not elevated; however neutrophils were significantly lower than the normal level. Giant cytoplasmic granules in neutrophils, eosinophils, and lymphocytes, which are pathognomonic of CHS, were noted. The patient displayed brownish-red hair with some grey hair, and partial oculocutaneous albinism. Hepatosplenomegaly was evident on ultrasonography. The final diagnosis was of an oral infection facilitated by the adolescent form of CHS (gene CHS1/LYST at 1q42.1-2). This report offers a reminder that lip swelling may represent the initial manifestation of the inflammatory response in a patient with loss of immunocompetence due to pathologies such as CHS, and may rarely present as the patient's main complaint., (Copyright © 2017 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Introduction: Chediak-Higashi disease (CHD) is a rare autosomal recessive disorder with hematologic, infectious, pigmentary, and neurologic manifestations. Classic CHD (C-CHD) presents in early childhood with severe infectious or hematologic complications unless treated with bone marrow transplantation. Atypical CHD (A-CHD) has less severe hematologic and infectious manifestations. Both C-CHD and A-CHD develop neurological problems., Methods: Eighteen patients with CHD (9 A-CHD and 9 C-CHD) underwent electrodiagnostic studies as part of a natural history study (NCT 00005917). Longitudinal studies were available for 10 patients., Results: All A-CHD patients had either sensory neuropathy, sensorimotor neuropathy, and/or diffuse neurogenic findings. In C-CHD, 3 adults had sensorimotor neuropathies with diffuse neurogenic findings, and 1 adult had a sensory neuropathy. The 5 children with C-CHD had normal electrodiagnostic findings., Conclusions: CHD can result in sensory or sensorimotor neuropathies and/or a diffuse motor neuronopathy. It may take 2-3 decades for the neuropathic findings to develop, because children appear to be spared. Muscle Nerve 55: 359-365, 2017., Competing Interests: The authors have no relevant financial disclosures or conflicts of interest., (© 2016 Wiley Periodicals, Inc.)

Chédiak-Higashi syndrome (CHS) is a rare disorder of immune deficiency with autosomal recessive inheritance. Over the past 20 years, ∼500 cases were published worldwide. The mean age of onset is 5-6 years. We report here a case of CHS in a boy aged 2½ years who presented to us with pneumonia which turned to be Chédiak-Higashi syndrome with a novel variant, not previously described in the literature, which is caused by mutations in the CHS1 gene.This case is reported for its novel mutation, and the absence of the accelerated phase until now. Awareness, early recognition and management of this condition may prevent the preterm morbidity associated with this case., Competing Interests: Conflicts of Interest: None declared., (2017 BMJ Publishing Group Ltd.)

Chediak-Higashi syndrome (CHS) is a rare autosomal recessive lysosomal disorder characterized by frequent infections, oculocutaneous albinism, bleeding diathesis, and progressive neurologic deterioration. In 85% of cases, CHS patients develop the accelerated phase characterized by pancytopenia, high fever, and lymphohistiocytic infiltration of liver, spleen, and lymph nodes. Treatment of accelerated-phase CHS is difficult and the prognosis is poor. Here, we report a case of CHS in a 2-year-old boy who presented in the accelerated phase of the disease. CHS diagnosis was made on the basis of clinical characteristics, hair analysis, and identification of pathognomonic giant azurophilic granules in peripheral blood and bone marrow., (Copyright © 2015 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.)

Chédiak-Higashi syndrome is a rare inherited metabolic disorder characterized by partial oculocutaneous albinism, immunodeficiency, and neurological dysfunction. We present the brain magnetic resonance imaging (MRI) and MR spectroscopy (MRS) findings obtained during the accelerated phase of the disorder in an 8-year-old. The brain MRI manifestations at recurrences 15 months and 24 months later are reported as well.

It has been established that sapphire minks have abnormality of subcellular structure of blood and bone marrow neutrophils and eosinophils. The abnormality consists in forming of abnormal "giant" granules. The si- ze and the number of abnormal granules significantly change during maturation of leucocytes in bone marrow. We have found differences between abnormal granules forming in neutrophils and eosinophils that depend on the maturing stage and the cells life cycle duration as well as morphofunctional features of these granulocytes.

Background: Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by immunodeficiency, neurological dysfunction, and oculocutaneous albinism. Recently, several clinical CHS phenotypes have been reported. Here, we report results of a nationwide survey performed to clarify clinical characteristics and outcomes of CHS patients in Japan., Methods: Questionnaires were sent to 287 institutions to collect data regarding CHS patients diagnosed between 2000 and 2010, including results of lysosomal trafficking regulator (LYST) gene analysis. Cytotoxicity and degranulation activity of cytotoxic T lymphocytes were analyzed in available patient samples., Results: A total of 15 patients diagnosed with CHS were eligible for enrollment in this study. Of these, 10 (67%) had recurrent bacterial infections, five (33%) developed life-threatening hemophagocytic lymphohistiocytosis (HLH), and one patient had complicated malignant lymphoma. Hematopoietic stem cell transplantation (HSCT) was performed for six patients including three with HLH, and 10 of the enrolled patients have survived at the time of this writing. LYST analysis was performed for 10 patients; seven different mutations were detected in seven patients, whereas no mutation was identified in three patients. Cytotoxicity and degranulation activity were impaired in patients with and without LYST mutation., Discussion: Results of this survey indicate that one or two patients with CHS were newly diagnosed each year in Japan. The incidence of HLH was not as high as expected. Mutations of genes other than LYST were suspected in some cases. We conclude that determining indication for HSCT for CHS patients should be based on genetic and cytotoxic analysis., (Copyright © 2013 Wiley Periodicals, Inc.)

An 8-year-old Taiwanese girl presented with hyperpigmentation and scattered hypopigmentation in her irides and choroids. Her skin showed hyperpigmentation with speckled hypopigmentation over cheeks and sun-exposed areas. Medical history was remarkable for frequent infectious episodes and lower extremity bruising. A peripheral blood smear revealed large inclusion bodies in the cytoplasm of neutrophils. The patient was diagnosed with Chediak-Higashi syndrome and continues to be monitored closely., (Copyright © 2013 American Association for Pediatric Ophthalmology and Strabismus. Published by Mosby, Inc. All rights reserved.)

A fully functional immune system is essential to protect the body against pathogens and other diseases, including cancer. Vesicular trafficking provides the correct localization of proteins within all cell types, but this process is most exquisitely controlled and coordinated in immune cells because of their specialized organelles and their requirement to respond to selected stimuli. More than 60 Rab GTPases play important roles in protein trafficking, but only five Rab-encoding genes have been associated with inherited human disorders, and only one of these (Rab27a) causes an immune defect. Mutations in RAB27A cause Griscelli Syndrome type 2 (GS2), an autosomal recessive disorder of pigmentation and severe immune deficiency. In lymphocytes, Munc13-4 is an effector of Rab27a, and mutations in the gene encoding this protein (UNC13D) cause Familial Hemophagocytic Lymphohistiocytosis Type 3 (FHL3). The immunological features of GS2 and FHL3 include neutropenia, thrombocytopenia, and immunodeficiency due to impaired function of cytotoxic lymphocytes. The small number of disorders caused by mutations in genes encoding Rabs could be due to their essential functions, where defects in these genes could be lethal. However, with the increasing use of next generation sequencing technologies, more mutations in genes encoding Rabs may be identified in the near future., (Published by Elsevier Inc.)

Melanocytes are pigment-producing cells of neural crest (NC) origin that are responsible for protecting the skin against UV irradiation. Pluripotent stem cell (PSC) technology offers a promising approach for studying human melanocyte development and disease. Here, we report that timed exposure to activators of WNT, BMP, and EDN3 signaling triggers the sequential induction of NC and melanocyte precursor fates under dual-SMAD-inhibition conditions. Using a SOX10::GFP human embryonic stem cell (hESC) reporter line, we demonstrate that the temporal onset of WNT activation is particularly critical for human NC induction. Subsequent maturation of hESC-derived melanocytes yields pure populations that match the molecular and functional properties of adult melanocytes. Melanocytes from Hermansky-Pudlak syndrome and Chediak-Higashi syndrome patient-specific induced PSCs (iPSCs) faithfully reproduce the ultrastructural features of disease-associated pigmentation defects. Our data define a highly specific requirement for WNT signaling during NC induction and enable the generation of pure populations of human iPSC-derived melanocytes for faithful modeling of pigmentation disorders., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Delta storage pool deficiency (δ-SPD) is a rare heterogeneous group of platelet disorders characterized by a reduction in the number or content of dense granules. δ-SPD causes a mild to moderate bleeding diathesis characterized mainly by mucocutaneous bleeding. Currently, no specific treatment is available and the therapeutic approach is based on prevention of excessive bleeding. However, during the last few years, important insights into the pathophysiology of δ-SPD have been achieved using mouse models and dense granule deficiency-associated congenital diseases, such as Hermansky-Pudlak syndrome and Chediak-Higashi syndrome. It thus appears that δ-SPD represents a genetically heterogeneous group of intracellular vesicle biogenesis and/or trafficking disorders. This review summarizes recent data regarding the molecular mechanisms together with clinical features of the different types of δ-SPD. Although the molecular basis of isolated inherited δ-SPD remains currently unknown, next-generation sequencing strategies should enable researchers to identify the causative genes. Identification of those genes should contribute to our understanding of the pathophysiology, represent useful tools for genetic diagnosis, and eventually lead to new specific therapeutic approaches., (© 2012 Blackwell Publishing Ltd.)

The present study has used electron microscopic techniques to rapidly detect the success or failure of bone marrow transplantation in three patients with the Chediak-Higashi Syndrome (CHS). The most rapid procedure was the whole mount technique to determine the presence or absence of dense bodies, which are inherently electron-opaque, serotonin-containing storage organelles in platelets. Dense bodies were present in normal numbers in platelets from two patients with successful transplantation and absent in thrombocytes from another patient in whom the transplant had failed.

Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder, characterized by silver hair, recurrent infections, partial oculo-cutaneous albinism, mild coagulation defect and progressive neuropathy. The characteristic feature of CHS is the presence of huge lysosomes and cytoplasmic inclusions within different body cells like the white blood cells. The disease has an early onset but usually presents in an accelerated phase. We present a case of a 2 years old boy with high grade fever, bilateral cervical lymphadenopathy, hepatosplenomegaly, abdominal distention of 28 days duration. He was diagnosed with Chediak-Higashi syndrome in accelerated phase on the basis of clinical presentation, morphological findings on peripheral blood film and bone marrow aspirate.

Chediak-Higashi syndrome is an autosomal recessive disorder that affects vesicle morphology. The Chs1/Lyst protein is a member of the BEige And CHediak family of proteins. The absence of Chs1/Lyst gives rise to enlarged lysosomes. Lysosome size is regulated by a balance between vesicle fusion and fission and can be reversibly altered by acidifying the cytoplasm using Acetate Ringer's or by incubating with the drug vacuolin-1. We took advantage of these procedures to determine rates of lysosome fusion and fission in the presence or absence of Chs1/Lyst. Here, we show by microscopy, flow cytometry and in vitro fusion that the absence of the Chs1/Lyst protein does not increase the rate of lysosome fusion. Rather, our data indicate that loss of this protein decreases the rate of lysosome fission. We further show that overexpression of the Chs1/Lyst protein gives rise to a faster rate of lysosome fission. These results indicate that Chs1/Lyst regulates lysosome size by affecting fission., (© 2011 John Wiley & Sons A/S.)

Disrupted cellular Ca(2+) signaling is believed to play a role in a number of human diseases including lysosomal storage diseases (LSD). LSDs are a group of ∼50 diseases caused predominantly by mutations in lysosomal proteins that result in accumulation of macromolecules within the lysosome. We recently reported that Niemann-Pick type C (NPC) is the first human disease to be associated with defective lysosomal Ca(2+) uptake and defective NAADP-mediated lysosomal Ca(2+) release. These defects in NPC cells leads to the disruption in endocytosis and subsequent lipid storage that is a feature of this disease. In contrast, Chediak-Higashi Syndrome cells have been reported to have enhanced lysosomal Ca(2+) uptake whilst the TRPML1 protein defective in mucolipidosis type IV is believed to function as a Ca(2+) channel. In this review we provide a summary of the current knowledge on the role of lysosomal Ca(2+) signaling in the pathogenesis of this group of diseases., (2011 Elsevier Ltd. All rights reserved.)

This report ultrastructurally illustrates the giant lysosome-related organelles in the various cellular components of a renal biopsy from a 10 year-old female affected by the Chédiak-Higashi syndrome. Albeit similar observations have been made and reported in animal models of the syndrome, to the author's knowledge, this is the first illustration of the changes as demonstrated in a human renal biopsy.