cholesteryl ester storage disease

WordNet

1. an impairment of health or a condition of abnormal functioning
2. (computer science) the process of storing information in a computer memory or on a magnetic tape or disk
3. the act of storing something
4. the commercial enterprise of storing goods and materials
5. caused by or altered by or manifesting disease or pathology; "diseased tonsils"; "a morbid growth"; "pathologic tissue"; "pathological bodily processes" (同)morbid, pathologic, pathological
6. formed by reaction between an acid and an alcohol with elimination of water

PrepTutorEJDIC

1. (体の)『病気』,疾患 / (精神・道徳などの)病気,病弊
2. 女性の話術芸人 =diseur
3. (倉庫などに)貯蔵すること,保管 / 貯蔵所,倉庫 / 保管料
4. 病気にかかった / 病的な,不健全な(morbid)
5. エステル(酸とアルコールから水を分離してできる化合物の総称)

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/08/28 12:09:07」(JST)

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Lysosomal acid lipase deficiency
LAL-D has an autosomal recessive pattern of inheritance
Classification and external resources
Specialty	Endocrinology
ICD-10	E75.5, E75.6
ICD-9-CM	272.7
OMIM	278000
DiseasesDB	31220
MeSH	D015223, D015217
Orphanet	275761

Lysosomal acid lipase deficiency (or LAL deficiency or LAL-D), also known as Wolman disease, happens when the body does not produce enough active lysosomal acid lipase (LAL) enzyme. This enzyme plays an important role in breaking down fatty material (cholesteryl esters and triglycerides) in the body. Infants, children and adults that suffer from LAL Deficiency experience a range of serious health problems. The lack of the LAL enzyme can lead to a build-up of fatty material in a number of body organs including the liver, spleen, gut, in the wall of blood vessels and other important organs.

Very low levels of the LAL enzyme lead to LAL Deficiency. LAL Deficiency typically affects infants in the first year of life. The accumulation of fat in the walls of the gut in early onset disease leads to serious digestive problems including malabsorption, a condition in which the gut fails to absorb nutrients and calories from food. Because of these digestive complications, affected infants usually fail to grow and gain weight at the expected rate for their age (failure to thrive). As the disease progresses, it can cause life-threatening liver dysfunction or liver failure.

Until 2015 there was no treatment, and very few infants with LAL-D survived beyond the first year of life. In 2015 an enzyme replacement therapy, sebelipase alfa was approved in the US and EU. The therapy was additionally approved in Japan in 2016.

Classification and cause

Lysosomal acid lipase deficiency is a genetic disease that is autosomal recessive. It is an inborn error of metabolism that causes a lysosomal storage disease. The condition is caused by a mutation of the LIPA gene, which is responsible for the gene coding of the lysosomal lipase protein (also called lysosomal acid lipase or LAL), which results in a loss of the protein's normal function. When LAL functions normally, it breaks down cholesteryl esters and triglycerides in low density lipoprotein particles into free cholesterol and free fatty acids that the body can reuse; when LAL doesn't function, cholesteryl esters and triglycerides build up in the liver, spleen and other organs. The accumulation of fat in the walls of the gut and other organs in leads to serious digestive problems including malabsorption, a condition in which the gut fails to absorb nutrients and calories from food, persistent and often forceful vomiting, frequent diarrhea, foul-smelling and fatty stools (steatorrhea), and failure to grow.

Lysosomal acid lipase deficiencies occur when a person has defects (mutations) in both copies of the LIPA gene. Each parent of a person with LAL deficiency carries one copy of the defective LIPA gene. With every pregnancy, parents with a son or daughter affected by LAL deficiency have a 1 in 4 (25%) chance of having another affected child. A person born with defects in both LIPA genes is not able to produce adequate amounts of the LAL enzyme.

Diagnosis

Infants may present with feeding difficulties with frequent vomiting, diarrhea, swelling of the abdomen, and failure to gain weight or sometimes weight loss.

As the disease progresses in infants, increasing fat accumulation in the liver leads to other complications including yellowing of the skin and whites of the eyes (jaundice), and a persistent low-grade fever. An ultrasound examination shows accumulation of chalky material (calcification) in the adrenal gland in about half of infants with LAL-D. Complications of LAL-D progress over time, eventually leading to life-threatening problems such as extremely low levels of circulating red blood cells (severe anemia), liver dysfunction or failure, and physical wasting (cachexia).

People who are older children or adults generally present with a wide range of signs and symptoms that overlap with other disorders. They may have diarrhoea, stomach pain, vomiting, or poor growth, a sign of malabsorption. They may have signs of bile duct problems, like itchiness, jaundice, pale stool, or dark urine. Their feces may be excessively greasy. They often have an enlarged liver, liver disease, and may have yellowish deposits of fat underneath the skin, usually around their eyelids. The disease is often undiagnosed in adults.The person may have a history of premature cardiac disease or premature stroke.

Blood tests may show anaemia and their lipid profiles are generally similar to people with more common familial hypercholesterolemia, including elevated total cholesterol, elevated low-density lipoprotein cholesterol, decreased high-density lipoprotein cholesterol, and elevated serum transaminases.

Liver biopsy findings will generally show a bright yellow-orange color, enlarged, lipid-laden hepatocytes and Kupffer cells, microvesicular and macrovesicular steatosis, fibrosis, and cirrhosis.The only definitive tests are genetic, which may be conducted in any number of ways.

Prevention or screening

Because LAL deficiency is inherited, each sibling of an affected individual has a 25% chance of having pathological mutations in LAL genes from both their mother and their father, a 50% chance of having a pathological mutation in only one gene, and a 25% chance of having no pathological mutations. Genetic testing for family members and genetic prenatal diagnosis of pregnancies for women who are at increased risk are possible if family members carrying pathological mutations have been identified.

Management

LAL deficiency can be treated with sebelipase alfa is a recombinant form of LAL that was approved in 2015 in the US and EU. The disease of LAL affects < 0.2 in 10,000 people in the EU. According to an estimate by a Barclays analyst, the drug will be priced at about US $375,000 per year.

It is administered once a week via intraveneous infusion in people with rapidly progressing disease in the first six months of life. In people with less aggressive disease, it is given every other week.

Before the drug was approved, treatment of infants was mainly focused on reducing specific complications and was provided in specialized centers. Specific interventions for infants included changing from breast or normal bottle formula to a specialized low fat formula, intravenous feeding, antibiotics for infections, and steroid replacement therapy because of concerns about adrenal function.

Statins were used in people with LAL-D prior to the approval of sebelipase alfa; they helped control cholesterol but did not appear to slow liver damage; liver transplantation was necessary in most patients.

Prognosis

Infants with LAL deficiencies typically show signs of disease in the first weeks of life and if untreated, die within 6–12 months due to multi-organ failure. Older children or adults with LAL-D may remain undiagnosed or be misdiagnosed until they die early from a heart attack or stroke or die suddenly of liver failure. The first enzyme replacement therapy was approved in 2015. In those clinical trials nine infants were followed for one year; 6 of them lived beyond one year. Older children and adults were followed for 36 weeks.

Epidemiology

Depending on ethnicity and geography, prevalence has been estimated to be between 1 in 40,000 and 1 in 300,000; based on these estimates the disease may be underdiagnosed. Jewish infants of Iraqi or Iranian origin appear to be most at risk based on a study of a community in Los Angeles in which there was a prevalence of 1 in 4200.

History

In 1956, Moshe Wolman, along with two other doctors, published the first case study of a LAL deficiency in a child born to closely related Persian Jews; 12 years later a case study on an older boy was published, which turned out to be the first case study of LAL-D.

LAL-D was historically referred to as 2 separate disorders:

• Wolman disease, presenting in infant patients
• Cholesteryl Ester Storage Disease, presenting in pediatric and adult patients

Around 2010 both presentations have come to be known as LAL-D, as both are due to a deficiency of the LAL enzyme.

In 2015 an enzyme replacement therapy, sebelipase alfa, was approved in the US and EU for the treatment of human LAL enzyme deficiency. Before the approval of that drug, as of 2009 the two oldest survivors of LAL-D in the world were then aged 4 and 11; both of them had been treated with hematopoietic stem cell treatment.

Research directions

Some children with LAL-D have had an experimental therapy called hematopoietic stem cell transplantation (HSCT), also known as bone marrow transplant, to try to prevent the disease from getting worse. Data are sparse but there is a known high risk of serious complications including death, graft-versus-host disease.

External links

• National Organization for Rare Disorders (NORD)
• Article - LYSOSOMAL ACID LIPASE/NIH.gov
• Article - LYSOSOMAL ACID LIPASE DEFICIENCY/NIH.gov
• Lipid Storage Diseases Fact Sheet at ninds.nih.gov

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 先天性代謝異常：疫学、病因、および臨床的特徴 inborn errors of metabolism epidemiology pathogenesis and clinical features
• 2. 肝肥大：鑑別診断および評価 hepatomegaly differential diagnosis and evaluation
• 3. 小児における原発性副腎不全の原因および臨床症状 causes and clinical manifestations of primary adrenal insufficiency in children
• 4. 新生児や乳児に生じる胆汁うっ滞の原因 causes of cholestasis in neonates and young infants
• 5. 副腎ステロイド生合成 adrenal steroid biosynthesis

English Journal

• Disorders in the initial steps of steroid hormone synthesis.

• Miller WL1.
• The Journal of steroid biochemistry and molecular biology.J Steroid Biochem Mol Biol.2017 Jan;165(Pt A):18-37. doi: 10.1016/j.jsbmb.2016.03.009. Epub 2016 Mar 6.
• Steroidogenesis begins with cellular internalization of low-density lipoprotein particles and subsequent intracellular processing of cholesterol. Disorders in these steps include Adrenoleukodystrophy, Wolman Disease and its milder variant Cholesterol Ester Storage Disease, and Niemann-Pick Type C Di
• PMID 26960203

• Sebelipase Alfa: A Review in Lysosomal Acid Lipase Deficiency.

• Frampton JE1.
• American journal of cardiovascular drugs : drugs, devices, and other interventions.Am J Cardiovasc Drugs.2016 Dec;16(6):461-468.
• 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
• PMID 27878737

Japanese Journal

• Wolman disease and cholesteryl ester storage disease diagnosed by histological and ultrastructural examination of intestinal and liver biopsy

• Pathology, research and practice 200(3), 231-240, 2004-03-01
• NAID 10017395502

• Enhanced Susceptibility of LDL to Oxidative Modification in a CTX Patient:<BR>— Role of Chenodeoxycholic Acid in Xanthoma Formation —

• Ｊｏｕｒｎａｌ　ｏｆ　Ａｔｈｅｒｏｓｃｌｅｒｏｓｉｓ　ａｎｄ　Ｔｈｒｏｍｂｏｓｉｓ 11(3), 167-172, 2004
• NAID 130004444106

• New lysosomal acid lipase gene mutations explain the phenotype of Wolman disease and cholesteryl ester storage disease

• J. Lipid Res. 39, 1382-1388, 1998
• NAID 80010532823

Related Links

• Cholesteryl Ester Storage Disease - NORD (National ...

General Discussion Summary Cholesteryl ester storage disease (CESD) is a type of lysosomal acid lipase (LAL) deficiency; a rare genetic disorder characterized by a deficiency of the lysosomal acid lipase (LIPA or LAL) enzyme.

• cholesteryl ester storage disease - Genetics Home Reference

Cholesteryl ester storage disease is a rare inherited condition involving the breakdown and use of fats and cholesterol in the body (lipid metabolism). In affected individuals, harmful amounts of lipids accumulate in cells and tissues ...

Related Pictures

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★リンクテーブル★

リンク元	「cholesterol ester storage disease」「コレステロールエステル蓄積症」
関連記事	「disease」「storage」「cholesteryl ester」

「cholesterol ester storage disease」

　　[★]

コレステロールエステル蓄積症

関

cholesteryl ester storage disease

同

CESD

「コレステロールエステル蓄積症」

　　[★]

英

cholesteryl ester storage disease、cholesterol ester storage disease

「disease」

　　[★]

• n.

疾患：illnessより厳密な概念。「ある臓器に明確な障害が確認され、それによって症状が出ているとはっきり説明できる場合」 (PSY.9)

特定の原因、病態生理、症状、経過、予後、病理組織所見が全てそろった場合 (PSY.9)

• something that is very wrong with people's attitudes, way of life or with society.

関

ail、ailment、disease entity、disorder、ill、illness、malady、sick、sickness

• 注意

disease ≠ illness ≠ disorder

　 　 　

「storage」

　　[★]

• n.

• 貯蔵

関

pool、pooling、preservation、preserve、reserve、store

　 　 　 　

「cholesteryl ester」

　　[★]

コレステリルエステル、コレステロールエステル

関

cholesterol ester