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Wolmans disease

Nouf Althonaian, Abdulrahman Alsultan, Eva Morava, Majid Alfadhel
Hemophagocytic lymphohistiocytosis (HLH) is a rare but potentially fatal disease that is characterized by proliferation and infiltration of hyperactivated macrophages and T-lymphocytes. Clinically, it is characterized by prolonged fever, hepatosplenomegaly, hypertriglyceridemia, hypofibrinogenemia, pancytopenia, and hemophagocytosis in the bone marrow, spleen, or lymph nodes. It can be classified as primary if it is due to a genetic defect, or secondary if it is due to a different etiology such as severe infection, immune deficiency syndrome, rheumatological disorder, malignancy, and inborn errors of metabolism such as galactosemia, multiple sulfatase deficiency, lysinuric protein intolerance, Gaucher disease, Niemann-Pick disease, Wolman disease, propionic acidemia, methylmalonic acidemia, biotinidase deficiency, cobalamin C defect, galactosialidosis, Pearson syndrome, and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency...
February 15, 2018: JIMD Reports
Maja Di Rocco, Livia Pisciotta, Annalisa Madeo, Marta Bertamino, Stefano Bertolini
BACKGROUND: Lysosomal acid lipase deficiency is an autosomal recessive metabolic disease with a wide range of severity from Wolman Disease to Cholesterol Ester Storage Disease. Recently enzyme replacement therapy with sebelipase alpha has been approved by drug agencies for treatment of this lysosomal disease. Ezetimibe is an azetidine derivative which blocks Niemann Pick C1-Like 1 Protein; as its consequence, plasmatic concentration of low density lipoproteins and other apoB-containing lipoproteins, that are the substrate of lysosomal acid lipase, are decreased...
January 27, 2018: Orphanet Journal of Rare Diseases
Sophia Masi, Naveen Chennamaneni, Frantisek Turecek, C Ronald Scott, Michael H Gelb
BACKGROUND: Deficiency of lysosomal acid lipase (LAL) causes Wolman disease and cholesterol ester storage disease. With the recent introduction of enzyme replacement therapy to manage LAL deficiency comes the need for a reliable assay of LAL enzymatic activity that can be applied to dried blood spots (DBS). METHODS: We prepared and tested a library of analogs of palmitoyl 4-methylumbelifferyl esters to find a highly active and specific substrate for LAL in DBS. The LAL assay was optimized leading to both LC-MS/MS and fluorometric assay of LAL...
January 16, 2018: Clinical Chemistry
Adam M Lopez, Jen-Chieh Chuang, Stephen D Turley
Although only a small proportion of cholesterol in the body is esterified, in several diseases marked expansion of the esterified cholesterol (EC) pool occurs. These include Wolman disease (WD) and Cholesteryl Ester Storage Disease (CESD) which both result from mutations in LIPA, the gene that encodes lysosomal acid lipase (LAL). The respective contributions that our three cholesterol esterifying enzymes make to EC production, especially in disorders like CESD, are not well defined. The current studies represent a detailed exploration of our earlier findings in young male LAL-deficient mice also missing sterol-O-acyltransferase 2 (SOAT2, also called ACAT2)...
December 12, 2017: Steroids
S Synoracki, S Kathemann, K W Schmid, H Jastrow, H A Baba
BACKGROUND AND CLINICAL SETTING: Lysosomal acid lipase deficiency is an autosomal recessive storage disease caused by mutations in the LIPA gene. The accumulation of cholesteryl esters and triglycerides in hepatocytes lead to hepatomegaly with progressive fibrosis and liver cirrhosis. Characteristically, patients have a hepatomegaly combined with high serum levels of cholesterol, LDL-cholesterol and in some cases triglyceride, whereas HDL-cholesterol is decreased. Histologically, hepatocytes show a microvesicular steatosis with typically ballooned Kupffer cells...
December 12, 2017: Der Pathologe
Thi Hao le, Phan Q Duy, Min An, Jared Talbot, Chitra C Iyer, Marc Wolman, Christine E Beattie
Motoneurons establish a critical link between the CNS and muscles. If motoneurons do not develop correctly, they cannot form the required connections, resulting in movement defects or paralysis. Compromised development can also lead to degeneration because the motoneuron is not set up to function properly. Little is known, however, regarding the mechanisms that control vertebrate motoneuron development, particularly the later stages of axon branch and dendrite formation. The motoneuron disease spinal muscular atrophy (SMA) is caused by low levels of the survival motor neuron (SMN) protein leading to defects in vertebrate motoneuron development and synapse formation...
November 29, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Kiran M Sargar, Geetika Khanna, Rebecca Hulett Bowling
The adrenal glands in children can be affected by a variety of benign lesions. The diagnosis of adrenal lesions can be challenging, but assessment of morphologic changes in correlation with the clinical presentation can lead to an accurate diagnosis. These lesions can be classified by their cause: congenital (eg, discoid adrenal gland, horseshoe adrenal gland, and epithelial cysts), vascular and/or traumatic (eg, adrenal hemorrhage), infectious (eg, granulomatous diseases), enzyme deficiency disorders (eg, congenital adrenal hyperplasia [CAH] and Wolman disease), benign neoplasms (eg, pheochromocytomas, ganglioneuromas, adrenal adenomas, and myelolipomas), and adrenal mass mimics (eg, extralobar sequestration and extramedullary hematopoiesis)...
October 2017: Radiographics: a Review Publication of the Radiological Society of North America, Inc
Martina Korber, Isabella Klein, Günther Daum
Sterols are essential lipids of all eukaryotic cells, appearing either as free sterols or steryl esters. Besides other regulatory mechanisms, esterification of sterols and hydrolysis of steryl esters serve to buffer both an excess and a lack of free sterols. In this review, the esterification process, the storage of steryl esters and their mobilization will be described. Several model organisms are discussed but the focus was set on mammals and the yeast Saccharomyces cerevisiae. The contribution of imbalanced cholesterol homeostasis to several human diseases, namely Wolman disease, cholesteryl ester storage disease, atherosclerosis and Alzheimer's disease, Niemann-Pick type C and Tangier disease is described...
December 2017: Biochimica et Biophysica Acta
Francis Aguisanda, Charles D Yeh, Catherine Z Chen, Rong Li, Jeanette Beers, Jizhong Zou, Natasha Thorne, Wei Zheng
BACKGROUND: Wolman disease (WD) is a rare lysosomal storage disorder that is caused by mutations in the LIPA gene encoding lysosomal acid lipase (LAL). Deficiency in LAL function causes accumulation of cholesteryl esters and triglycerides in lysosomes. Fatality usually occurs within the first year of life. While an enzyme replacement therapy has recently become available, there is currently no small-molecule drug treatment for WD. RESULTS: We have generated induced pluripotent stem cells (iPSCs) from two WD patient dermal fibroblast lines and subsequently differentiated them into neural stem cells (NSCs)...
June 28, 2017: Orphanet Journal of Rare Diseases
Michael Canfarotta, Douglas Moote, Christine Finck, Rebecca Riba-Wolman, Shefali Thaker, Trudy J Lerer, Richard J Payne, Valerie Cote
Objective The McGill Thyroid Nodule Score (MTNS) is a preoperative tool used to predict the risk for well-differentiated thyroid cancer given a specific nodule in adults. We evaluated the clinical utility of a modified pediatric MTNS with children and adolescents. Study Design Case series with chart review. Setting Tertiary care children's hospital. Subjects and Methods This is a retrospective chart review of 46 patients ≤18 years of age presenting with a solitary or dominant thyroid nodule treated with surgical resection between September 2008 and December 2015...
October 2017: Otolaryngology—Head and Neck Surgery
Kaduveettil G Gopakumar, Priyakumari Thankamony, Sheela Nampoothiri, Deeksha Bali, Jubie Raj, Jayasudha A Vasudevan, Ramachandran K Nair
BACKGROUND: Infant leukemia most commonly present with pallor and hepatosplenomegaly. The possibility of other differential diagnosis also has to be kept in mind during evaluation, as identifying the precise etiology for this clinical presentation is crucial for management. OBSERVATION: An infant, was referred to us with suspected infant leukemia and was subsequently diagnosed to have lysosomal acid lipase deficiency/Wolman disease with a novel 5 bp deletion "c...
November 2017: Journal of Pediatric Hematology/oncology
Jyotsna Verma, Sunita Bijarnia-Mahay, Ishwar C Verma
Prenatal enzymatic diagnosis for an array of lysosomal storage disorders (LSDs) can be performed accurately, provided that a confirmed diagnosis by biochemical/molecular study in the index case is available and a strict defined protocol, specific to each individual disorder is followed. The present chapter describes the protocols for reliable and accurate prenatal enzymatic diagnoses by fluorometric and spectrophotometric methods of lysosomal storage disorders: Gaucher, Fabry, Pompe, Niemann Pick A/B, Tay Sach, Sandhoff, GM1, Mucoplysaccharidoses, Wolman, Krabbe, Metachromatic leukodystrophy, and Batten diseases using uncultured chorionic villi samples...
2017: Methods in Molecular Biology
Zhengping Ma, Joelle M Onorato, Luping Chen, David W Nelson, Chi-Liang Eric Yen, Dong Cheng
In mammals, ether lipids exert a wide spectrum of signaling and structural functions, such as stimulation of immune responses, anti-tumor activities, and enhancement of sperm functions. Abnormal accumulation of monoalkyl-diacylglycerol (MADAG) was found in Wolman's disease, a human genetic disorder defined by a deficiency in lysosomal acid lipase. In the current study, we found that among the nine recombinant human lipid acyltransferases examined, acyl-CoA:diacylglycerol acyltransferase (DGAT)1, DGAT2, acyl-CoA:monoacylglycerol acyltransferase (MGAT)2, MGAT3, acyl-CoA:wax-alcohol acyltransferase 2/MFAT, and DGAT candidate 3 were able to use 1-monoalkylglycerol (1-MAkG) as an acyl acceptor for the synthesis of monoalkyl-monoacylglycerol (MAMAG)...
June 2017: Journal of Lipid Research
Francis Aguisanda, Natasha Thorne, Wei Zheng
Wolman disease (WD) and cholesteryl ester storage disease (CESD) are lysosomal storage diseases (LSDs) caused by a deficiency in lysosomal acid lipase (LAL) due to mutations in the LIPA gene. This enzyme is critical to the proper degradation of cholesterol in the lysosome. LAL function is completely lost in WD while some residual activity remains in CESD. Both are rare diseases with an incidence rate of less than 1/100,000 births for WD and approximate 2.5/100,000 births for CESD. Clinical manifestation of WD includes hepatosplenomegaly, calcified adrenal glands, severe malabsorption and a failure to thrive...
2017: Current Chemical Genomics and Translational Medicine
Matthew J Blitz, Burton Rochelson, Monica Sood, Martin G Bialer, Nidhi Vohra
No published case of Wolman's disease has described the prenatal sonographic findings. We present a case in which a third-trimester sonographic examination demonstrated fetal hepatomegaly and bilateral adrenal echogenicity suggestive of diffuse calcification. Wolman's disease, also known as lysosomal acid lipase (LIPA) deficiency, is a rare autosomal-recessive disorder characterized by complete absence of the LIPA enzyme. The diagnosis of Wolman's disease was made postnatally by biochemical testing, which indicated absence of LIPA enzyme activity and gene sequencing, which confirmed homozygosity for the G66V mutation within the LIPA gene...
April 4, 2017: Journal of Clinical Ultrasound: JCU
Jen-Chieh Chuang, Adam M Lopez, Stephen D Turley
Esterified cholesterol (EC) and triglycerides, contained within lipoproteins taken up by cells, are hydrolysed by lysosomal acid lipase (LAL) in the late endosomal/lysosomal (E/L) compartment. The resulting unesterified cholesterol (UC) is transported via Niemann-Pick type C2 and C1 into the cytosolic compartment where it enters a putative pool of metabolically active cholesterol that is utilized in accordance with cellular needs. Loss-of-function mutations in LIPA, the gene encoding LAL, result in dramatic increases in tissue concentrations of EC, a hallmark feature of Wolman disease and cholesteryl ester storage disease (CESD)...
July 1, 2017: Biochemical Pharmacology
Carla Ruiz-Andrés, Elena Sellés, Angela Arias, Laura Gort
Lysosomal acid lipase (LAL) is a lysosomal key enzyme involved in the intracellular hydrolysis of cholesteryl esters and triglycerides. Patients with very low residual LAL activity present with the infantile severe form Wolman disease (WD), while patients with some residual activity develop the less severe disorder known as Cholesteryl ester storage disorder (CESD). We present the clinical, biochemical, and molecular findings of 23 Spanish patients (22 families) with LAL deficiency. We identified eight different mutations, four of them not previously reported...
February 21, 2017: JIMD Reports
James J Maciejko
Lysosomal acid lipase deficiency (LAL-D) is a rare, life-threatening, autosomal recessive, lysosomal storage disease caused by mutations in the LIPA gene, which encodes for lysosomal acid lipase (LAL). This enzyme is necessary for the hydrolysis of cholesteryl ester and triglyceride in lysosomes. Deficient LAL activity causes accumulation of these lipids in lysosomes and a marked decrease in the cytoplasmic free cholesterol concentration, leading to dysfunctional cholesterol homeostasis. The accumulation of neutral lipid occurs predominantly in liver, spleen, and macrophages throughout the body, and the aberrant cholesterol homeostasis causes a marked dyslipidemia...
June 2017: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
Robin M Ireland
No abstract text is available yet for this article.
February 9, 2017: Blood
James E Frampton
Sebelipase alfa (Kanuma®, Kanuma™), the first commercially available recombinant human lysosomal acid lipase (LAL), is approved in various countries worldwide, including those of the EU, the USA and Japan, as a long-term enzyme replacement therapy for patients diagnosed with LAL deficiency (LAL-D), an ultra-rare, autosomal recessive, progressive metabolic liver disease. In an ongoing study in nine infants presenting with early-onset LAL-D (Wolman disease), open-label treatment with sebelipase alfa significantly improved 1-year survival compared with historical controls...
December 2016: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
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