Ceroid-like Material Research Articles

Hermansky‐Pudlak syndrome: Report of two patients with updated genetic classification and management recommendations

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder caused by mutations in one of nine genes involved in the packaging and formation of specialized lysosomes, including melanosomes and platelet-dense granules. The cardinal features are pigmentary dilution, bleeding diathesis, and accumulation of ceroid-like material in reticuloendothelial cells. Pulmonary fibrosis induced by tissue damage is seen in the most severe forms, and one subtype is characterized by immunodeficiency. We describe two patients with HPS type 1 and review the updated gene-based classification, clinical features, and recommendations for evaluation and follow-up.

Hypertension, Chronic Kidney Disease, and Renal Pathology in a Child with Hermansky-Pudlak Syndrome

We report a child with Hermansky-Pudlak Syndrome (HPS) and chronic kidney disease (stage II) with histological diagnosis of focal segmental glomerulosclerosis (FSGS). A 15-year-old male of Puerto Rico ancestry with history of HPS, hypertension (HTN), asthma, obesity, and chronic kidney disease (CKD) stage II presented with new-onset proteinuria without edema. His blood pressure had been controlled, serum creatinine had been 0.9–1.4 mg/dL, and first morning urine protein/creatinine ratio (UPC) ranged from 0.2 to 0.38. Due to persistent nonorthostatic proteinuria with CKD, renal biopsy was performed and FSGS (not otherwise specified) with chronic diffuse tubulopathy (tubular cytoplasmic droplets) and acute tubular injury was reported. Ceroid-like material is known to infiltrate tissues (i.e., lungs, colon, and kidney) in HPS, but the reason for the renal insufficiency is unknown. Nonspecific kidney disease and in one adult case IgA nephropathy with ANCA-positive glomerulonephritis have previously been reported in patients with Hermansky-Pudlak syndrome. To our knowledge, we report the first pediatric renal pathology case of HPS associated with CKD. This paper discusses presentation and management of renal disease in HPS.

High Frequency of Hermansky–Pudlak Syndrome Type 1 (HPS1) Among Japanese Albinism Patients and Functional Analysis of HPS1 Mutant Protein

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism (OCA), bleeding tendency, and lysosomal accumulation of ceroid-like material. Seven genetically distinct subtypes of HPS are known in humans; most are rare outside of Puerto Rico. Here, we describe the analysis of the HPS1 gene in 24 Japanese OCA patients who lacked mutations in the four genes known to cause OCA (TYR/OCA1, P/OCA2, TYRP1/OCA3, and MATP/OCA4), and the identification of eight different HPS1 mutations in ten of these patients, four of which were novel (W583X, L668P, 532insC, 1691delA). An IVS5+5G --> A splice consensus mutation was particularly frequent, the result of a founder effect for this allele in Japanese patients. Functional analysis by transfection of the L668P variant into Hps1-mutant melan-ep mouse melanocytes showed that this missense substitution is pathologic, resulting in an Hps-1 protein that is unable to assemble into the biogenesis of lysosome-related organelles complex-3.

Ungewöhnliche Ursache einer Lungenfibrose bei einer 71-jährigen Patientin

A 71-year-old woman, suffering from spinal stenosis presented interstitial lung disease, albinism, and severe loss of visual acuity. On physical examination she showed tic-like automatism predominantly periorbital in the face and in the fingers. A computed tomography of the chest revealed typical findings of interstitial lung disease and additional mediastinal lymphomas and ground-glass attenuation in the lower regions of the lung. The findings of a transbronchial lung biopsy, presenting alveolar macrophages with ceroid-like material and platelet function studies proving slightly impaired platelet aggregation confirmed the clinical diagnosis of Hermansky-Pudlak syndrome. Sufficient pain control could be achieved without surgery and the patient was discharged home. 11 months after discharge, severe dyspnea and fever developed and finally the patient died of respiratory failure. The Hermansky-Pudlak syndrome is a rare cause of interstitial lung disease. In general, the lung disease presents in younger patients, but it may emerge in the elderly as well. Alveolar macrophages containing ceroid-like material are typical findings in BAL or lung biopsy. Furthermore impaired platelet aggregation and bleeding diathesis may be present. Both findings are useful to identify this rare disorder.

The protein CD63 is in platelet dense granules, is deficient in a patient with Hermansky-Pudlak syndrome, and appears identical to granulophysin.

The levels and expression of the proteins CD63 and granulophysin in platelets from control and from a Hermansky-Pudlak syndrome subject (a condition characterized by dense granule and lysosomal deficiencies and the accumulation of ceroid-like material in reticuloendothelial cells) were examined. Immunofluorescence studies indicated that anti-CD63 and anti-granulophysin antibodies recognized similar numbers of granules; coapplication of antibodies did not identify more granules than the individual antibodies. Significantly fewer granules were recognized in Hermansky-Pudlak syndrome platelets than in control using either antibody. Immunoblotting studies demonstrated that anti-CD63 and anti-granulophysin antibodies apparently recognize the same protein, which was deficient in Hermansky-Pudlak platelets. Analysis by fluorescence-activated cell sorter (FACS) showed biphasic expression of CD63 and granulophysin after thrombin stimulation of control but not Hermansky-Pudlak platelets. Anti-CD63 effectively blocked detection of the protein by anti-granulophysin using immunofluorescence, ELISA, immunoblotting, and FACS analysis. Amino-terminal sequencing over the first 37 amino acids revealed that granulophysin was homologous to CD63, melanoma antigen ME491, and pltgp40. These results suggest that granulophysin and CD63 are possibly identical proteins. This is the first report of a protein present in platelet dense granules, lysosomes, and melanocytes, but deficient in a patient with Hermansky-Pudlak syndrome.

Abnormal lysosomal cathepsin activities in leukocytes and cultured skin fibroblasts in late infantile, but not in juvenile neuronal ceroid-lipofuscinosis (Batten disease)

The neuronal ceroid-lipofuscinoses (NCLs) are a group of recessively inherited severe neurodegenerative disorders for which the basic defect(s) remain unknown and for which there is no established treatment. The collective frequency of the disorders is of the order of l/12,500, making them a common neurodegenerative problem [ 11. The disorders are characterized histologically by the presence of stored autofluorescent material similar to ceroid in lysosome-like organelles, and are generally classified by age of clinical presentations, by clinical phenotype and by the electron-microscopic nature of the stored ceroid material [2,3]. Infantile NCL (Santavuori-Haltia disease) presents as a seizure disorder within the first 2 years of life, with death by the age of 10 years. The electron microscopic nature of the ceroidlike material in lysosomes is that of dense granular osmiophilic bodies [4]. Late Infantile NCL (Jansky-Bielschowsky disease) presents from age 2-3 years, as a seizure disorder and secondary retinal degeneration and leads to death in the second decade. The storage material is described by its curvilinear appearance [5]. Juvenile NCL (Spiehneyer-Vogt-Batten disease) usually presents at age 8-10 years, with a slowly progressive retinal degeneration leading to seizures and death in the second to third

Elevated urinary dolichol excretion in the hermansky-pudlak syndrome. Indicator of lysosomal dysfunction

The Hermansky-Pudlak syndrome, a triad of albinism, platelets lacking dense bodies, and storage of ceroid-like material in tissues, occurs approximately once in 2,000 northwestern Puerto Ricans. The manifestations of storage disease are variable and include granulomatous colitis, restrictive lung disease, kidney failure, and cardiomyopathy. The autofluorescent material stored in the Hermansky-Pudlak syndrome is histochemically similar to that stored in neuronal ceroid/lipofuscinosis. The material in neuronal ceroid/lipofuscinosis contains dolichols, which are components of lysosomes, and patients show increased urinary excretion of dolichols. This study of 49 patients with the Hermansky-Pudlak syndrome found that urinary dolichol levels are increased in those patients with evidence of ceroid storage in the kidneys but are not elevated when storage occurs in tissues other than the kidneys. The excretion of ceroid was not influenced by the saturation state of dietary fat. A defect in processing of membranes of lysosomes, melanosomes, and dense bodies may be involved in the syndrome.

Hermansky-Pudlak syndrome: Pulmonary manifestations of a ceroid storage disorder

The Hermansky-Pudlak syndrome is a form of oculocutaneous albinism, characterized by a qualitative platelet defect and deposition of ceroid-like material throughout the reticuloendothelial system. During a 16 month period five patients with Hermansky-Pudlak syndrome presented with symptoms, chest films and pulmonary function studies consistent with restrictive pulmonary disease. In two patients, lung biopsies revealed diffuse interstitial fibrosis. However, light and electron microscopy demonstrated ceroid-like material within alveolar macrophages. In addition, two patients presented with inflammatory bowel disease with deposition of ceroid-like material in the colon. This disorder appears to be more common than is currently recognized and should be considered in the differential diagnosis of diffuse interstitial pulmonary disease and inflammatory bowel disease. A relationship between the deposition of ceroid-like material and pulmonary fibrosis is discussed in light of recent research concerning inflammatory processes. In view of the serious pulmonary, gastrointestinal and hematologic consequences of this syndrome, there is a need for genetic counseling of these patients.

Natural aging and radiation-induced life shortening in Drosophila melanogaster

Various tissues of control and γ-irradiated male Drosophila melanogaster have been investigated by light and electron microscopy. Old flies showed involutionary changes in the fat body, oenocytes, muscle, mid-gut, Malpighian tubules, brain and sex organs. There was an accumulation of electron-dense bodies in the oenocytes and of ceroid-like material in the cytoplasm of the mid-gut cells. Also, senescent flies showed a striking reduction in the ribosomes and endoplasmic reticulum in the Malpighian tubules. In 28–33-day-old flies which were exposed to 50 kR of γ-irradiation at 1 day of age, the most consistent pathological changes were focal cytoplasmic edema and virus accumulation in the nuclei. Our present results support the view that irradiation results in life-shortening through a radiation syndrome mechanism which is essentially unrelated to aging.