Lysosomal Acid Lipase Deficiency
Encyclopedia
Lysosomal Acid Lipase Deficiency happens when the body does not produce enough active LAL enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

. Under normal conditions, the body produces an enzyme called lysosomal acid lipase (LAL or LIPA). This enzyme plays an important role in breaking down fatty material (cholesteryl ester
Cholesteryl ester
A cholesteryl ester is, as its name would imply, an ester of cholesterol. The ester bond is formed between the carboxylate group of a fatty acid and the hydroxyl group of cholesterol. Cholesteryl Esters have a lower solubility in water than Cholesterol and, in other words, are more hydrophobic...

s and triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....

s) 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
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

, spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...

, gut
Intestine
In human anatomy, the intestine is the segment of the alimentary canal extending from the pyloric sphincter of the stomach to the anus and, in humans and other mammals, consists of two segments, the small intestine and the large intestine...

, in the wall of blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...

s and other important organs.


Very low levels of the LAL enzyme lead to early onset LAL Deficiency, sometimes called Wolman disease
Wolman disease
Wolman Disease Wolman Disease Wolman Disease (also known as Wolman’s Disease, early onset LAL Deficiency, and Lysosomal acid lipase deficiency is a rare genetic disorder caused by a deficiency of an enzyme known as lysosomal acid lipase (LAL or LIPA). This enzyme is necessary to break down certain...

 after the physician who first described it. Early onset LAL Deficiency typically affects infants in the first year of life. The accumulation of fat
Fat
Fats consist of a wide group of compounds that are generally soluble in organic solvents and generally insoluble in water. Chemically, fats are triglycerides, triesters of glycerol and any of several fatty acids. Fats may be either solid or liquid at room temperature, depending on their structure...

 in the walls of the gut in early onset disease leads to serious digestive problems including malabsorption
Malabsorption
Malabsorption is a state arising from abnormality in absorption of food nutrients across the gastrointestinal tract.Impairment can be of single or multiple nutrients depending on the abnormality...

, a condition in which the gut fails to absorb nutrient
Nutrient
A nutrient is a chemical that an organism needs to live and grow or a substance used in an organism's metabolism which must be taken in from its environment. They are used to build and repair tissues, regulate body processes and are converted to and used as energy...

s and calorie
Calorie
The calorie is a pre-SI metric unit of energy. It was first defined by Nicolas Clément in 1824 as a unit of heat, entering French and English dictionaries between 1841 and 1867. In most fields its use is archaic, having been replaced by the SI unit of energy, the joule...

s 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
Failure to thrive
Failure to thrive is a medical term which is used in both pediatric and adult human medicine, as well as veterinary medicine ....

). As the disease progresses, other complications develop including increasing liver dysfunction or liver failure
Liver failure
Acute liver failure is the appearance of severe complications rapidly after the first signs of liver disease , and indicates that the liver has sustained severe damage . The complications are hepatic encephalopathy and impaired protein synthesis...

. Very few infants with Wolman disease survive beyond the first year of life.


Late onset LAL Deficiency is sometimes called Cholesteryl ester storage disease
Cholesteryl ester storage disease
Cholesteryl Ester Storage Disease is the late onset phenotype for Lysosomal Acid Lipase Deficiency, a Lysosomal storage disease, which also has an early onset phenotype known as Wolman disease that primarily affects infants. CESD can present in childhood but often goes unrecognized until...

 (CESD) and can affect children and adults. The deficiency of the LAL enzyme leads to a build-up of fat in the liver, spleen and other parts of the body. The build-up of fat in the liver and spleen can cause many problems including:
  • Swelling of the liver (‘fatty’ liver or hepatomegaly
    Hepatomegaly
    Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...

    )
  • Abnormal liver tests (high AST or ALT)
  • Scarring of the liver (liver fibrosis or cirrhosis
    Cirrhosis
    Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...

    )
  • Swelling of the spleen (splenomegaly
    Splenomegaly
    Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...

    )

Infants, children and adults are at risk for significant health problems and premature death from complications due to LAL Deficiency.



What is a Lysosomal Storage Disorder?

Lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...

s are found in the body’s cells and play an important role in digesting nutrients and other materials. Lysosomal Storage Disorders
Lysosomal storage disease
Lysosomal storage diseases are a group of approximately 50 rare inherited metabolic disorders that result from defects in lysosomal function...

 (LSDs) are inherited conditions in which one or more of the enzymes in lysosomes is missing or not functioning effectively. When this happens, materials that would normally be broken down by the lysosome accumulate and this disturbs normal cell function.

Inheritance and Diagnosis

LAL Deficiency is an inherited condition. The gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

 that is responsible for telling the body how to make the LAL enzymes is not normal, and the LAL enzyme either does not work properly or is not made at all.


Every person has two copies of the LAL gene. One copy is inherited from the father and one from the mother. LAL Deficiency occurs when a person has defects in both copies of the LAL gene. Each parent of a patient with LAL deficiency carries one defective LAL gene. With every pregnancy
Pregnancy
Pregnancy refers to the fertilization and development of one or more offspring, known as a fetus or embryo, in a woman's uterus. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets...

, 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 LAL genes is not able to produce adequate amounts of the LAL enzyme.


As is the cases for many rare diseases, making a diagnosis of LAL Deficiency is highly dependent on your physician's awareness of the disease. LAL Deficiency is so rare that many physicians have not had any previous experience with this condition. The diagnosis of LAL Deficiency by your physician begins with an examination, interview, history and preliminary lab tests. The physician makes observations about the symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...

s and other risk factor
Risk factor
In epidemiology, a risk factor is a variable associated with an increased risk of disease or infection. Sometimes, determinant is also used, being a variable associated with either increased or decreased risk.-Correlation vs causation:...

s to identify a suspected diagnosis
Diagnosis
Diagnosis is the identification of the nature and cause of anything. Diagnosis is used in many different disciplines with variations in the use of logics, analytics, and experience to determine the cause and effect relationships...

.
Abnormalities that you may have, and would make your doctor think of late onset LAL Deficiency (Cholesteryl Ester Storage Disease) include:
  • A high cholesterol
    Cholesterol
    Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...

     and high triglyceride
    Triglyceride
    A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....

     level
  • A high 'bad' cholesterol (Low-density lipoprotein, or LDL)
  • A very low (<10mgdl) 'good' cholesterol (HDL)
  • Unexplained hepatomegaly
    Hepatomegaly
    Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...

     (liver enlargement)
  • Elevated liver enzymes (a marker of liver damage)
  • Unexplained fat or lipid
    Lipid
    Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...

     material in the liver
  • Unexplained chronic liver disease
    Chronic liver disease
    Chronic liver disease in the clinical context is a disease process of the liver that involves a process of progressive destruction and regeneration of the liver parenchyma leading to fibrosis and cirrhosis.- Causes :...

     that may be getting worse over time

Abnormalities that your child may have and that would make your doctor think of early onset LAL Deficiency (Wolman Disease) include:
  • Feeding difficulties with frequent vomiting
  • Diarrhea
    Diarrhea
    Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...

     (loose frequent stools)
  • Swelling of the abdomen (abdominal distention)
  • Enlargement of the liver and spleen (hepatosplenomegaly)
  • Failure to gain weight or sometimes weight loss

Once the physician thinks about the possibility of LAL Deficiency as a cause of your medical problems, he or she may order a confirmatory test such as an enzyme assay that measures the level and activity of the enzyme or a genetic sequencing analysis.

Treatment

There are currently no approved treatment
Treatment
Treatment may refer to:* Treatment, therapy used to remedy a health problem* Treatment, a process or intervention in the design of experiments* Treatment group, a collection of items or individuals given the same treatment in an experiment* Water treatment...

s for LAL Deficiency. For early onset LAL Deficiency (Wolman Disease), no treatments have been shown in clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...

s to stop or reverse the abnormalities in these patients. A variety of supportive therapies are used to try to reduce specific complications. These interventions do not, however, change the poor outlook. In the absence of other treatments, bone marrow transplant
Bone marrow transplant
Hematopoietic stem cell transplantation is the transplantation of multipotent hematopoietic stem cell or blood, usually derived from bone marrow, peripheral blood stem cells, or umbilical cord blood...

ation is being used on an experimental basis but has a very high mortality rate
Mortality rate
Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...

.


No treatments have been proven to stop or reverse the liver abnormalities in children and adults with late onset LAL Deficiency (CESD). The high blood lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...

 levels are treated with a combination of low-fat diet and lipid-lowering medications such as statin
Statin
Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver. Increased cholesterol levels have been associated with cardiovascular diseases, and statins are therefore used in the...

s, fibrate
Fibrate
In pharmacology, the fibrates are a class of amphipathic carboxylic acids. They are used for a range of metabolic disorders, mainly hypercholesterolemia , and are therefore hypolipidemic agents.- Members :...

s, cholestyramine
Cholestyramine
Cholestyramine or colestyramine is a bile acid sequestrant, which binds bile in the gastrointestinal tract to prevent its reabsorption. It is a strong ion exchange resin, which means that it can exchange its chloride anions with anionic bile acids in the gastrointestinal tract and bind them...

 and ezetimibe
Ezetimibe
Ezetimibe is a drug that lowers cholesterol. It acts by decreasing cholesterol absorption in the intestine. It may be used alone , when other cholesterol-lowering medications are not tolerated, or together with statins when statins alone do not control cholesterol.Even though ezetimibe decreases...

. Although these treatments can lower the blood lipid levels, there is no evidence that they improve the underlying disease including the severe liver manifestations.


Synageva BioPharma Corp. is recruiting patients to participate in a clinical trial that evaluates an enzyme replacement therapy of Lysosomal Acid Lipase (LAL) Deficiency.

External links

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