Scientists agree that most obesity is multifactorial and caused by a complex web of interrelated biological, psychological and environmental factors. Considering the complexity of the processes through which people gain weight, and the extreme difficulty most experience in changing their behaviors and habits to lose it, corporate health programs need to use every tool in the toolbox. This includes genetics.

Genes influence healthy behaviors

Genes contribute to a variety of factors that lead to unhealthy lifestyles and obesity. This happens directly (by influencing how the body uses and stores energy) and indirectly (by influencing specific habits and behaviors).

Geneticists at Newtopia continue to perform exhaustive reviews of the scientific literature to identify consistent associations between candidate genes and relevant traits or behaviors that can be accompanied by actionable recommendations for the development of healthy behaviors and habits. To date, we have selected four genes to test for and incorporate into our habit change experience:

• MC4R (the appetite gene), which regulates how quickly a person feels full after eating
• DRD2 (the cravings gene), which influences reward-seeking behaviors such as the consumption of high-carb foods or alcohol, or emotional eating, in order to trigger the release of dopamine
• FTO (the fat gene), which influences how a person metabolizes fat
• BDNF (the resilience gene), which creates a protein associated with vulnerability to stress

Genetic testing supports the development of actionable recommendations that fit each individual’s specific needs. It’s why Newtopia is exploring new genes to further enhance and demystify our behaviors around sleep and activity.

How behavior genetics works in practice

Let’s take an example of a typical participant in a corporate health and well-being program. Maria is 52 years old, has a BMI of 28 (she’s 5 foot 5 inches tall and weighs 168 pounds) and has one health condition — high cholesterol, for which she’s taking a statin medication. She also has a family history of type 2 diabetes, so she’s been told to be mindful of her weight and lifestyle.

Her goals are to lose 18 pounds (to normalize her BMI to 25), reduce her diabetes risk, improve her cholesterol profile (and possibly get off the statin), and increase her energy and overall self-confidence.

Maria opts into the genetic testing component of the experience and provides a saliva sample using a simple cheek swab. Her test results show that she has variations of three of the four relevant genes — the appetite gene, the cravings gene and the fat gene.

Maria’s coach incorporates this information into her hyper-personalized habit change experience, addressing her delayed sense of feeling full with recommendations such as drinking a glass of water before a meal, filling her plate and immediately putting away the leftovers, and eating more slowly and mindfully to allow her brain to catch up to her stomach. He also helps her identify her triggers for emotional eating and suggests coping mechanisms such as calling a friend or engaging in healthier behaviors like going for a walk to help relieve stress. People with Maria’s variant of the fat gene respond better to a high-protein diet and higher-intensity exercise, so her coach works with her to develop a sustainable diet that is 40% protein, 30% carbs and 30% fats and helps her build up to exercising at 70%-80% of her maximum heart rate.

Enabling precision lifestyle medicine

This precision lifestyle medicine approach works. Research we recently presented to the American Society of Human Genetics highlights the measurable impact of including genetic testing in a corporate lifestyle-intervention program. At the end of 12 months, program participants who had opted into the genetic testing component had achieved 25% greater weight loss (an average of 4% versus 3.2%). They also had 1.3 times higher odds of meeting the critical weight loss threshold of 5% of body weight, which not only results in significant health benefits, but comes with a sharp reduction to the corporate health plan costs.

In some cases, the superior outcomes associated with genetic testing are due not only to the greater precision of the habit change interventions themselves but also to the increase in engagement triggered by the new knowledge. Many people who have given up trying to lose weight after too many unsuccessful efforts find the genetic information liberating. It gives them permission to stop blaming themselves for their weight struggles, leading to increased motivation and a stronger commitment to try again.

Not everyone will feel comfortable using their genetic information in this way, so it’s important to allow participants the opportunity to opt in at a later date — after they’ve established a trusted relationship with their Inspirator (health coach), for example. It’s also important to emphasize that the testing is about behavior genetics; this is aimed at helping people achieve their goals more quickly, not identifying predisposition to diseases. And, of course, all providers and labs must comply with the Genetic Information Nondiscrimination Act — so employers and health insurers will not have access to the test results.

Increasing the odds of success

Studies suggest that in some people, genetics may account for up to 80% of the predisposition to be overweight. Genetic predisposition is not destiny, though. People can change their habits and their future. Identifying the genetically influenced physiological mechanisms that push people to overeat, for example, can enable the creation of a more effective plan to counter those influences through behavior change.

Although genes are just one factor in the complex healthy lifestyle and weight-management equation, the science, and the outcomes both suggest that taking genetic influences into account can help increase the likelihood that corporate health program participants will be able to achieve meaningful, sustainable lifestyle and improvement that leads to long-term improvements in health.

The post How Genetic Testing Helps to Streamline Weight Loss appeared first on Medika Life.

What are lipids?

Lipids are fat-like substances that are important parts of the membranes found within and between cells and in the myelin sheath that coats and protects the nerves.  Lipids include oils, fatty acids, waxes, steroids (such as cholesterol and estrogen), and other related compounds.

These fatty materials are stored naturally in the body’s cells, organs, and tissues. Tiny bodies within cells called lysosomes regularly convert, or metabolize, the lipids and proteins into smaller components to provide energy for the body.  Disorders in which intracellular material that cannot be metabolized is stored in the lysosomes are called lysosomal storage diseases.  In addition to lipid storage diseases, other lysosomal storage diseases include the mucolipidoses, in which excessive amounts of lipids with attached sugar molecules are stored in the cells and tissues, and the mucopolysaccharidoses, in which excessive amounts of large, complicated sugar molecules are stored.

How are lipid storage diseases inherited?

Lipid storage diseases are inherited from one or both parents who carry a defective gene that regulates a particular lipid-metabolizing enzyme in a class of the body’s cells.  They can be inherited two ways:

• Autosomal recessive inheritance occurs when both parents carry and pass on a copy of the faulty gene, but neither parent is affected by the disorder.  Each child born to these parents has a 25 percent chance of inheriting both copies of the defective gene, a 50 percent chance of being a carrier like the parents, and a 25 percent chance of not inheriting either copy of the defective gene.  Children of either gender can be affected by an autosomal recessive pattern of inheritance.
• X-linked (or sex-linked) recessive inheritance occurs when the mother carries the affected gene on the X chromosome.  The X and Y chromosomes are involved in gender determination.  Females have two X chromosomes and males have one X chromosome and one Y chromosome.  Sons of female carriers have a 50 percent chance of inheriting and being affected with the disorder, as the sons receive one X chromosome from the mother and a Y chromosome from the father.  Daughters have a 50 percent chance of inheriting the affected X chromosome from the mother and are carriers or mildly affected.  Affected men do not pass the disorder to their sons but their daughters will be carriers for the disorder.

What are the types of lipid storage disease?

Gaucher disease is caused by a deficiency of the enzyme glucocerebrosidase.  Fatty material can collect in the brain, spleen, liver, kidneys, lungs, and bone marrow.  Symptoms may include brain damage, enlarged spleen and liver, liver malfunction, skeletal disorders and bone lesions that may cause pain and fractures, swelling of lymph nodes and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelets, and yellow spots in the eyes.  Individuals affected most seriously may also be more susceptible to infection.  The disease affects males and females equally.

Gaucher disease has three common clinical subtypes:

• Type 1 (or nonneuronopathic type) is the most common form of the disease in the U.S. and Europe.  The brain is not affected, but there may be lung and, rarely, kidney impairment.  Symptoms may begin early in life or in adulthood and include enlarged liver and grossly enlarged spleen, which can rupture and cause additional complications.  Skeletal weakness and bone disease may be extensive.  People in this group usually bruise easily due to low blood platelet count.  They may also experience fatigue due to anemia.  Depending on disease onset and severity, individuals with type 1 may live well into adulthood.  Many affected individuals have a mild form of the disease or may not show any symptoms.  Although Gaucher type 1 occurs often among persons of Ashkenazi Jewish heritage, it can affect individuals of any ethnic background.
• Type 2 (or acute infantile neuropathic Gaucher disease) typically begins within 3 months of birth.  Symptoms include extensive and progressive brain damage, spasticity, seizures, limb rigidity, enlarged liver and spleen, abnormal eye movement, and a poor ability to suck and swallow.  Affected children usually die before age 2.
• Type 3 (the chronic neuronopathic form) can begin at any time in childhood or even in adulthood.  It is characterized by slowly progressive but milder neurologic symptoms compared to the acute or type 2 Gaucher disease.  Major symptoms include eye movement disorders, cognitive deficit, poor coordination, seizures, an enlarged spleen and/or liver, skeletal irregularities, blood disorders including anemia, and respiratory problems.  Nearly everyone with type 3 Gaucher disease who receives enzyme replacement therapy will reach adulthood.

For type 1 and most type 3 individuals, enzyme replacement treatment given intravenously every two weeks can dramatically decrease liver and spleen size, reduce skeletal abnormalities, and reverse other manifestations.  Successful bone marrow transplantation cures the non-neurological manifestations of the disease.  However, this procedure carries significant risk and is rarely performed in individuals with Gaucher disease.  Surgery to remove all or part of the spleen may be required on rare occasions (if the person has very low platelet counts or when the enlarged organ severely affects the person’s comfort).  

Blood transfusion may benefit some anemic individuals.  Others may require joint replacement surgery to improve mobility and quality of life.  There is currently no effective treatment for the brain damage that may occur in people with types 2 and 3 Gaucher disease.

Niemann-Pick disease is a group of autosomal recessive disorders caused by an accumulation of fat and cholesterol in cells of the liver, spleen, bone marrow, lungs, and, in some instances, brain.  Neurological complications may include ataxia (lack of muscle coordination that can affect walking steadily, writing, and eating, among other functions), eye paralysis, brain degeneration, learning problems, spasticity, feeding and swallowing difficulties, slurred speech, loss of muscle tone, hypersensitivity to touch, and some clouding of the cornea due to excess buildup of materials.  A characteristic cherry-red halo that can be seen by a physician using a special tool develops around the center of the retina in 50 percent of affected individuals.

Niemann-Pick disease is subdivided into three categories:

• Type A, the most severe form, begins in early infancy. Infants appear normal at birth but develop profound brain damage by 6 months of age, an enlarged liver and spleen, swollen lymph nodes, and nodes under the skin (xanthomas). The spleen may enlarge to as great as 10 times its normal size and can rupture, causing bleeding. These children become progressively weaker, lose motor function, may become anemic, and are susceptible to recurring infection. They rarely live beyond 18 months. This form of the disease occurs most often in Jewish families.
• Type B (or juvenile onset) does not generally affect the brain but most children develop ataxia, damage to nerves exiting from the spinal cord (peripheral neuropathy), and pulmonary difficulties that progress with age. Enlargement of the liver and spleen characteristically occurs in the pre-teen years. Individuals with type B may live a comparatively long time but many require supplemental oxygen because of lung involvement. Niemann-Pick types A and B result from accumulation of the fatty substance called sphingomyelin, due to deficiency of an enzyme called sphingomyelinase.
• Type C may appear early in life or develop in the teen or even adult years.  Niemann-Pick disease type C is not caused by a deficiency of sphlingomyelinase but by a lack of the NPC1 or NPC2 proteins.  As a result, various lipids and particularly cholesterol accumulate inside nerve cells and cause them to malfunction.  Brain involvement may be extensive, leading to inability to look up and down, difficulty in walking and swallowing, progressive loss of hearing, and progressive dementia.  People with type C have only moderate enlargement of their spleens and livers.  Those individuals with Niemann-Pick type C who share a common ancestral background in Nova Scotia were previously referred to as type D.  The life expectancies of people with type C vary considerably.  Some individuals die in childhood while others who appear to be less severely affected can live into adulthood.

There is currently no cure for Niemann-Pick disease.  Treatment is supportive.  Children usually die from infection or progressive neurological loss.  Bone marrow transplantation has been attempted in a few individuals with type B with mixed results.

Fabry disease, also known as alpha-galactosidase-A deficiency, causes a buildup of fatty material in the autonomic nervous system (the part of the nervous system that controls involuntary functions such as breathing and heart beat), eyes, kidneys, and cardiovascular system.  Fabry disease is the only X-linked lipid storage disease.  Males are primarily affected, although a milder and more variable form is common in females.  

Occasionally, affected females have severe manifestations similar to those seen in males with the disorder.  Onset of symptoms is usually during childhood or adolescence.  Neurological signs include burning pain in the arms and legs, which worsens in hot weather or following exercise, and the buildup of excess material in the clear layers of the cornea (resulting in clouding but no change in vision).  

Fatty storage in blood vessel walls may impair circulation, putting the person at risk for stroke or heart attack.  Other symptoms include heart enlargement, progressive kidney impairment leading to renal failure, gastrointestinal difficulties, decreased sweating, and fever.  Angiokeratomas (small, non-cancerous, reddish-purple elevated spots on the skin) may develop on the lower part of the trunk of the body and become more numerous with age.

People with Fabry disease often die prematurely of complications from heart disease, renal failure, or stroke.  Drugs such as phenytoin and carbamazepine are often prescribed to treat pain that accompanies Fabry disease but do not treat the disease.  Metoclopramide or Lipisorb (a nutritional supplement) can ease gastrointestinal distress that often occurs in people with Fabry disease, and some individuals may require kidney transplant or dialysis.  Enzyme replacement can reduce storage, ease pain, and preserve organ function in some people with Fabry disease.

Farber’s disease, also known as Farber’s lipogranulomatosis, describes a group of rare autosomal recessive disorders that cause an accumulation of fatty material in the joints, tissues, and central nervous system.  It affects both males and females.  Disease onset is typically in early infancy but may occur later in life.  Children who have the classic form of Farber’s disease develop neurological symptoms within the first few weeks of life that may include increased lethargy and sleepiness, and problems with swallowing.  The liver, heart, and kidneys may also be affected.  Other symptoms may include joint contractures (chronic shortening of muscles or tendons around joints), vomiting, arthritis, swollen lymph nodes, swollen joints, hoarseness, and nodes under the skin which thicken around joints as the disease progresses.  Affected individuals with breathing difficulty may require a breathing tube.  Most children with the disease die by age 2, usually from lung disease.  In one of the most severe forms of the disease, an enlarged liver and spleen can be diagnosed soon after birth.  Children born with this form of the disease usually die within 6 months.

Farber’s disease is caused by a deficiency of the enzyme called ceramidase.  Currently there is no specific treatment for Farber’s disease.  Corticosteroids may be prescribed to relieve pain.  Bone marrow transplants may improve granulomas (small masses of inflamed tissue) on people with little or no lung or nervous system complications.  Older persons may have granulomas surgically reduced or removed.

The gangliosidoses are comprised of two distinct groups of genetic diseases.  Both are autosomal recessive and affect males and females equally.

GM1 gangliosidoses

The GM1 gangliosidoses are caused by a deficiency of the enzyme beta-galactosidase, resulting in abnormal storage of acidic lipid materials particularly in the nerve cells in the central and peripheral nervous systems.  GM1 gangliosidosis has three clinical presentations:

• GM1 (the most severe subtype, with onset shortly after birth) may include neurodegeneration, seizures, liver and spleen enlargement, coarsening of facial features, skeletal irregularities, joint stiffness, distended abdomen, muscle weakness, exaggerated startle response, and problems with gait.  About half of affected individuals develop cherry-red spots in the eye.  Children may be deaf and blind by age 1 and often die by age 3 from either cardiac complications or pneumonia.
• Late infantile GM1 gangliosidosis typically begins between ages 1 and 3 years.  Neurological symptoms include ataxia, seizures, dementia, and difficulties with speech.
• GM1 gangliosidosis develops between ages 3 and 30.  Symptoms include decreased muscle mass (muscle atrophy), neurological complications that are less severe and progress at a slower rate than in other forms of the disorder, corneal clouding in some people, and sustained muscle contractions that cause twisting and repetitive movements or abnormal postures (dystonia).  Angiokeratomas may develop on the lower part of the trunk of the body.  The size of the liver and spleen in most affected individuals is normal.

GM2 gangliosidoses

The GM2 gangliosidoses also cause the body to store excess acidic fatty materials in tissues and cells, most notably in nerve cells.  These disorders result from a deficiency of the enzyme beta-hexosaminidase.  The GM2 disorders include:

• Tay-Sachs disease (also known as GM2 gangliosidosis-variant B) and its variant forms are caused by a deficiency in the enzyme hexosaminidase A.  The incidence has been particularly high among Eastern European and Ashkenazi Jewish populations, as well as certain French Canadians and Louisianan Cajuns.  Affected children appear to develop normally for the first few months of life.  Symptoms begin by 6 months of age and include progressive loss of mental ability, dementia, decreased eye contact, increased startle response to noise, progressive loss of hearing leading to deafness, difficulty in swallowing, blindness, cherry-red spots in the retina, and some paralysis.  Seizures may begin in the child’s second year.  Children may eventually need a feeding tube and they often die by age 4 from recurring infection.  No specific treatment is available.  Anticonvulsant medications may initially control seizures.  Other supportive treatment includes proper nutrition and hydration and techniques to keep the airway open.  A rare form of the disorder, called late-onset Tay-Sachs disease, occurs in people in their 20s and early 30s and is characterized by unsteadiness of gait and progressive neurological deterioration.
• Sandhoff disease (variant AB) is a severe form of Tay-Sachs disease.  Onset usually occurs at the age of 6 months and is not limited to any ethnic group.  Neurological signs may include progressive deterioration of the central nervous system, motor weakness, early blindness, marked startle response to sound, spasticity, shock-like or jerking of a muscle (myoclonus), seizures, abnormally enlarged head (macrocephaly), and cherry-red spots in the eye.  Other symptoms may include frequent respiratory infections, heart murmurs, doll-like facial features, and an enlarged liver and spleen.  There is no specific treatment for Sandhoff disease.  As with Tay-Sachs disease, supportive treatment includes keeping the airway open and proper nutrition and hydration.  Anti-seizure medications may initially control seizures.  Children generally die by age 3 from respiratory infections.

Krabbe disease (also known as globoid cell leukodystrophy and galactosylceramide lipidosis) is an autosomal recessive disorder caused by deficiency of the enzyme galactocerebrosidase.  The disease most often affects infants, with onset before age 6 months, but can occur in adolescence or adulthood.  The buildup of undigested fats affects the growth of the nerve’s protective insulating sheath (myelin sheath) and causes severe deterioration of mental and motor skills.  Other symptoms include muscle weakness, reduced ability of a muscle to stretch (hypertonia), muscle stiffening (spasticity), sudden shock-like or jerking of the limbs (myoclonic seizures), irritability, unexplained fever, deafness, blindness, paralysis, and difficulty when swallowing.  Prolonged weight loss may also occur.  The disease may be diagnosed by enzyme testing and by identification of its characteristic grouping of cells into globoid bodies in the white matter of the brain, demyelination of nerves and degeneration, and destruction of brain cells.  In infants, the disease is generally fatal before age 2.  Individuals with a later onset form of the disease have a milder course of the disease and live significantly longer.  No specific treatment for Krabbe disease has been developed, although early bone marrow transplantation may help some people.

Metachromatic leukodystrophy, or MLD, is a group of disorders marked by storage buildup in the white matter of the central nervous system and in the peripheral nerves and to some extent in the kidneys.  Similar to Krabbe disease, MLD affects the myelin that covers and protects the nerves.  This autosomal recessive disorder is caused by a deficiency of the enzyme arylsulfatase A.  Both males and females are affected by this disorder.

MLD has three characteristic forms: late infantile, juvenile, and adult.

• Late infantile MLD typically begins between 12 and 20 months following birth.  Infants may appear normal at first but develop difficulty in walking and a tendency to fall, followed by intermittent pain in the arms and legs, progressive loss of vision leading to blindness, developmental delays and loss of previously acquired milestones, impaired swallowing, convulsions, and dementia before age 2.  Children also develop gradual muscle wasting and weakness and eventually lose the ability to walk.  Most children with this form of the disorder die by age 5.
• Juvenile MLD typically begins between ages 3 and 10. Symptoms include impaired school performance, mental deterioration, ataxia, seizures, and dementia. Symptoms are progressive with death occurring 10 to 20 years following onset.
• Adult symptoms begin after age 16 and may include ataxia, seizures, abnormal shaking of the limbs (tremor), impaired concentration, depression, psychiatric disturbances and dementia. Death generally occurs within 6 to 14 years after onset of symptoms.

There is no cure for MLD.  Treatment is symptomatic and supportive.  Bone marrow transplantation may delay progression of the disease in some cases.  Considerable progress has been made with regard to gene therapies in animal models of MLD and in clinical trials.

Wolman’s disease, also known as acid lipase deficiency, is a severe lipid storage disorder that is usually fatal by age 1.  This autosomal recessive disorder is marked by accumulation of cholesteryl esters (normally a transport form of cholesterol) and triglycerides (a chemical form in which fats exist in the body) that can build up significantly and cause damage in the cells and tissues.  Both males and females are affected by this disorder.  Infants are normal and active at birth but quickly develop progressive mental deterioration, enlarged liver and grossly enlarged spleen, distended abdomen, gastrointestinal problems, jaundice, anemia, vomiting, and calcium deposits in the adrenal glands, causing them to harden.

Another type of acid lipase deficiency is cholesteryl ester storage disease.  This extremely rare disorder results from storage of cholesteryl esters and triglycerides in cells in the blood and lymph and lymphoid tissue.  Children develop an enlarged liver leading to cirrhosis and chronic liver failure before adulthood.  Children may also have calcium deposits in the adrenal glands and may develop jaundice late in the disorder.

Enzyme replacement for both Wolman’s disease and cholesteryl ester storage disease is currently under active investigation.

How are these disorders diagnosed?

In some states, some of these disorders (most notably and controversially Krabbe disease) are screened for at birth.

In older children, diagnosis is made through clinical examination, enzyme assays (laboratory tests that measure enzyme activity), genetic testing, biopsy, and molecular analysis of cells or tissues.  In some forms of the disorder, urine analysis can identify the presence of stored material.  In others, the abnormality in enzyme activity can be detected in white blood cells without tissue biopsy.  Some tests can also determine if a person carries the defective gene that can be passed on to her or his children.  This process is known as genotyping.

Biopsy for lipid storage disease involves removing a small sample of the liver or other tissue and studying it under a microscope.  In this procedure, a physician will administer a local anesthetic and then remove a small piece of tissue either surgically or by needle biopsy (a small piece of tissue is removed by inserting a thin, hollow needle through the skin).  

Genetic testing can help individuals who have a family history of lipid storage disease determine if they are carrying a mutated gene that causes the disorder.  Other genetic tests can determine if a fetus has the disorder or is a carrier of the defective gene.  Prenatal testing is usually done by chorionic villus sampling, in which a very small sample of the placenta is removed and tested during early pregnancy.  The sample, which contains the same DNA as the fetus, is removed by catheter inserted through the cervix or by a fine needle inserted through the abdomen.  Results are usually available within 2-4 weeks.

How are these disorders treated?

Currently there is no specific treatment available for most of the lipid storage disorders but highly effective enzyme replacement therapy is available for type 1 and type 3 Gaucher disease.  Enzyme replacement therapy is also available for Fabry disease, although it is not as effective as for Gaucher disease.  However, anti-platelet medications can help prevent strokes and medications that lower blood pressure can slow the decline of kidney function in people with Fabry disease.  

The U.S.Food and Drug Administration has approved the drug migalastat (Galafold) as an oral medication for adults with Fabry disease who have a certain genetic mutation.  Eligustat tartrate, an oral drug approved for Gaucher treatment, works by administering small molecules that reduce the action of the enzyme that catalyzes glucose to ceramide.   Medications such as gabapentin and carbamazepine may be prescribed to help treat pain (including bone pain).  Restricting one’s diet does not prevent lipid buildup in cells and tissues.

Where can I get more information?

For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute’s Brain Resources and Information Network (BRAIN) at:

BRAIN
P.O. Box 5801
Bethesda, MD 20824
800-352-9424

Information also is available from the following organizations:

Ara Parseghian Medical Research Foundation [For Niemann-Pick Type C Disease]
3530 East Campo Abierto
Suite 105
Tucson, AZ 85718-3327
victory@parseghian.org
Tel: 520-577-5106
Fax: 520-577-5212

Children’s Gaucher Research Fund
P.O. Box 2123
Granite Bay, CA 95746-2123
research@childrensgaucher.org
Tel: 916-797-3700
Fax: 916-797-3707

Fabry Support & Information Group
108 NE 2nd Street, Ste. C
P.O. Box 510
Concordia, MO 64020-0510
info@fabry.org
Tel: 660-463-1355
Fax: 660-463-1356

Hide and Seek Foundation for Lysosomal Storage Disease Research
6475 East Pacific Coast Highway
Suite 466
Long Beach, CA 90803
info@hideandseek.org
Tel: 877-621-1122
Fax: 818-762-2502

Hunter’s Hope Foundation (Krabbe Disease)
P.O. Box 643
6368 West Quaker Street
Orchard Park, NY 14127
Tel: 716-667-1200

ISMRD-International Advocate For Glycoprotein Storage Diseases
20880 Canyon View Drive
Saratoga, CA 95070
info@ismrd.org
Tel: 734-449-1190
Fax: 734-449-9038

March of Dimes
1275 Mamaroneck Avenue
White Plains, NY 10605
askus@marchofdimes.com
Tel: 914-997-4488; 888-MODIMES (663-4637)
Fax: 914-428-8203

MLD Foundation (Metachromatic Leukodystrophy)
21345 Miles Drive
West Linn, OR 97038
503-656-4808
800-617-8387

National Fabry Disease Foundation
4301 Connecticut Avenue, NW
Suite 404
Washington, DC 20008-2369
info@fabrydisease.org
Tel: 800-651-9131
Fax: 800-651-9135

National Gaucher Foundation, Inc.
5410 Edson Lane, Suite 220
Rockville, MD 20852
ngf@gaucherdisease.org
Tel: 800-504-3189
Fax: 770-934-2911

National Niemann-Pick Disease Foundation, Inc.
P.O. Box 49
401 Madison Avenue, Suite B
Ft. Atkinson, WI 53538
nnpdf@nnpdf.org
Tel: 920-563-0930; 877-CURE-NPC (287-3672)
Fax: 920-563-0931

National Organization for Rare Disorders (NORD)
55 Kenosia Avenue
Danbury, CT 06810
orphan@rarediseases.org 
Tel: 203-744-0100; Voice Mail: 800-999-NORD (6673)
Fax: 203-798-2291

National Tay-Sachs and Allied Diseases Association
2001 Beacon Street
Suite 204
Boston, MA 02135
info@ntsad.org
Tel: 800-90-NTSAD (906-8723)
Fax: 617-277-0134

United Leukodystrophy Foundation
224 North 2nd Street, Suite 2
DeKalb, IL 60115
office@ulf.org
Tel: 815-748-3211; 800-728-5483
Fax: 815-748-0844

The post Lysosomal or Lipid Storage Diseases, Symptoms, Diagnosis and Treatment appeared first on Medika Life.

• Alagille-Watson Syndrome
• Alagille’s syndrome
• arteriohepatic dysplasia (AHD)
• cardiovertebral syndrome
• cholestasis with peripheral pulmonary stenosis
• hepatic ductular hypoplasia
• hepatofacioneurocardiovertebral syndrome
• paucity of interlobular bile ducts
• Watson-Miller syndrome

Alagille syndrome is a genetic disorder that can affect the liver, heart, and other parts of the body.

One of the major features of Alagille syndrome is liver damage caused by abnormalities in the bile ducts. These ducts carry bile (which helps to digest fats) from the liver to the gallbladder and small intestine. In Alagille syndrome, the bile ducts may be narrow, malformed, and reduced in number (bile duct paucity). As a result, bile builds up in the liver and causes scarring that prevents the liver from working properly to eliminate wastes from the bloodstream. Signs and symptoms arising from liver damage in Alagille syndrome may include a yellowish tinge in the skin and the whites of the eyes (jaundice), itchy skin, and deposits of cholesterol in the skin (xanthomas).

Alagille syndrome is also associated with several heart problems, including impaired blood flow from the heart into the lungs (pulmonic stenosis). Pulmonic stenosis may occur along with a hole between the two lower chambers of the heart (ventricular septal defect) and other heart abnormalities. This combination of heart defects is called tetralogy of Fallot.

People with Alagille syndrome may have distinctive facial features including a broad, prominent forehead; deep-set eyes; and a small, pointed chin. The disorder may also affect the blood vessels within the brain and spinal cord (central nervous system) and the kidneys. Affected individuals may have an unusual butterfly shape of the bones of the spinal column (vertebrae) that can be seen in an x-ray.

Problems associated with Alagille syndrome generally become evident in infancy or early childhood. The severity of the disorder varies among affected individuals, even within the same family. Symptoms range from so mild as to go unnoticed to severe heart and/or liver disease requiring transplantation.

Some people with Alagille syndrome may have isolated signs of the disorder, such as a heart defect like tetralogy of Fallot, or a characteristic facial appearance. These individuals do not have liver disease or other features typical of the disorder.

How common is the condition?

The estimated prevalence of Alagille syndrome is 1 in 70,000 newborns. This figure is based on diagnoses of liver disease in infants, and may be an underestimation because some people with Alagille syndrome do not develop liver disease during infancy.

What Causes Alagille Syndrome

In more than 90 percent of cases, mutations in the JAG1 gene cause Alagille syndrome. Another 7 percent of individuals with Alagille syndrome have small deletions of genetic material on chromosome 20 that include the JAG1 gene. A few people with Alagille syndrome have mutations in a different gene, called NOTCH2.

The JAG1 and NOTCH2 genes provide instructions for making proteins that fit together to trigger interactions called Notch signaling between neighboring cells during embryonic development. This signaling influences how the cells are used to build body structures in the developing embryo. Changes in either the JAG1 gene or NOTCH2 gene probably disrupt the Notch signaling pathway. As a result, errors may occur during development, especially affecting the bile ducts, heart, spinal column, and certain facial features.

Inheritance Pattern

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered or deleted gene in each cell is sufficient to cause the disorder.

In approximately 30 to 50 percent of cases, an affected person inherits the mutation or deletion from one affected parent. Other cases result from new mutations in the gene or new deletions of genetic material on chromosome 20 that occur as random events during the formation of reproductive cells (eggs or sperm) or in early fetal development. These cases occur in people with no history of the disorder in their family.

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• FBN
• FBN1_HUMAN
• fibrillin 1 (Marfan syndrome)
• MFS1
• SGS

The FBN1 gene provides instructions for making a large protein called fibrillin-1. This protein is transported out of cells into the extracellular matrix, which is an intricate lattice of proteins and other molecules that forms in the spaces between cells. In this matrix, molecules of fibrillin-1 attach (bind) to each other and to other proteins to form threadlike filaments called microfibrils.

Microfibrils form elastic fibers, which enable the skin, ligaments, and blood vessels to stretch. Microfibrils also provide support to more rigid tissues such as bones and the tissues that support the nerves, muscles, and lenses of the eyes. Microfibrils store a protein called transforming growth factor beta (TGF-β), a critical growth factor.

TGF-β affects development by helping to control the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (motility), and the self-destruction of cells (apoptosis). Microfibrils help regulate the availability of TGF-β, which is turned off (inactivated) when stored in microfibrils and turned on (activated) when released.

Health Conditions related to genetic changes of FBN1

Acromicric Dysplasia

At least nine FBN1 gene mutations have been identified in people with acromicric dysplasia. This condition is characterized by severely short stature, short limbs, stiff joints, and distinctive facial features.

FBN1 gene mutations that cause acromicric dysplasia are located in an area of the gene called exons 41 and 42, and change single protein building blocks (amino acids) in a region of the fibrillin-1 protein called TGF-β binding-protein-like domain 5. The mutations result in a reduction and disorganization of the microfibrils. Without enough normal microfibrils to store TGF-β, the growth factor is abnormally active. These effects likely contribute to the physical abnormalities that occur in acromicric dysplasia, but the mechanisms are unclear.

It is unknown why the FBN1 gene mutations that cause acromicric dysplasia lead to short stature, while certain other FBN1 gene mutations that also increase TGF-β activity cause a disorder called Marfan syndrome (see below), which is characterized by tall stature.

Isolated Ectopia Lentis

More than 30 mutations in the FBN1 gene have been found to cause isolated ectopia lentis. In this condition, the lens in one or both eyes is off-center (displaced), which leads to vision problems. Most of the FBN1 gene mutations that cause this condition change single amino acids in the fibrillin-1 protein. As a result, the production of normal fibrillin-1 protein is reduced, leading to a decrease in microfibril formation or the formation of impaired microfibrils.

Without enough functional microfibrils to anchor the lens in its central position at the front of the eye, the lens becomes displaced, resulting in isolated ectopia lentis and related vision problems. Ectopia lentis is classified as isolated when it occurs alone, without signs and symptoms affecting other body systems.

However, some people initially diagnosed with isolated ectopia lentis caused by FBN1 gene mutations later develop additional features typical of a condition called Marfan syndrome (described below), such as abnormalities of the large blood vessel that distributes blood from the heart to the rest of the body (the aorta). In these cases, the diagnosis often changes from isolated ectopia lentis to Marfan syndrome.

Marfan Syndrome

Researchers have identified more than 1,300 FBN1 gene mutations that cause Marfan syndrome, a disorder that affects the connective tissue supporting the body’s joints and organs. Abnormalities in the connective tissue lead to heart and eye problems in people with this disorder. In addition, affected individuals are usually tall and slender with elongated fingers and toes and other skeletal abnormalities.

Most of the mutations that cause Marfan syndrome change a single amino acid in the fibrillin-1 protein. The remaining FBN1 gene mutations result in an abnormal fibrillin-1 protein that cannot function properly. FBN1 gene mutations that cause Marfan syndrome reduce the amount of fibrillin-1 produced by the cell, alter the structure or stability of fibrillin-1, or impair the transport of fibrillin-1 out of the cell.

These mutations lead to a severe reduction in the amount of fibrillin-1 available to form microfibrils. Without enough microfibrils, excess TGF-β growth factors are activated and elasticity in many tissues is decreased, leading to overgrowth and instability of tissues and the signs and symptoms of Marfan syndrome.

Weill-Marchesani syndrome

Mutations in the FBN1 gene have also been identified in Weill-Marchesani syndrome. One of the identified mutations deletes part of the gene, leading to the production of an unstable version of the fibrillin-1 protein. The unstable protein likely interferes with the assembly of microfibrils. Abnormal microfibrils weaken connective tissue, which causes the eye, heart, and skeletal abnormalities associated with Weill-Marchesani syndrome.

Other Disorders

Mutations in the FBN1 gene can cause a condition called stiff skin syndrome. This condition is characterized by very hard, thick skin covering most of the body. The abnormal skin limits movement and can lead to joint deformities called contractures that restrict the movement of certain joints. The signs and symptoms of stiff skin syndrome usually become apparent in infancy to mid-childhood.

Mutations in the FBN1 gene can cause another condition called MASS syndrome. This condition involves abnormalities in several parts of the body, including the mitral valve (one of the valves that controls blood flow through the heart), the aorta (a large blood vessel that distributes blood from the heart to the rest of the body), the skeleton, and the skin.

It is unknown why different mutations in the FBN1 gene cause such a variety of disorders.

Chromosomal Location

Cytogenetic Location: 15q21.1, which is the long (q) arm of chromosome 15 at position 21.1

Molecular Location: base pairs 48,408,313 to 48,645,709 on chromosome 15 (Homo sapiens Updated Annotation Release 109.20200522, GRCh38.p13) (NCBI)

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Because connective tissue is found throughout the body, Marfan syndrome can affect many systems, often causing abnormalities in the heart, blood vessels, eyes, bones, and joints. The two primary features of Marfan syndrome are vision problems caused by a dislocated lens (ectopia lentis) in one or both eyes and defects in the large blood vessel that distributes blood from the heart to the rest of the body (the aorta).

The aorta can weaken and stretch, which may lead to a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may cause the aortic valve to leak, which can lead to a sudden tearing of the layers in the aorta wall (aortic dissection). Aortic aneurysm and dissection can be life threatening.

Many people with Marfan syndrome have additional heart problems including a leak in the valve that connects two of the four chambers of the heart (mitral valve prolapse) or the valve that regulates blood flow from the heart into the aorta (aortic valve regurgitation). Leaks in these valves can cause shortness of breath, fatigue, and an irregular heartbeat felt as skipped or extra beats (palpitations).

Individuals with Marfan syndrome are usually tall and slender, have elongated fingers and toes (arachnodactyly), loose joints, and have an arm span that exceeds their body height. Other common features include a long and narrow face, crowded teeth, an abnormal curvature of the spine (scoliosis or kyphosis), stretch marks (striae) not related to weight gain or loss, and either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum).

Some individuals develop an abnormal accumulation of air in the chest cavity that can result in the collapse of a lung (spontaneous pneumothorax). A membrane called the dura, which surrounds the brain and spinal cord, can be abnormally enlarged (dural ectasia) in people with Marfan syndrome. Dural ectasia can cause pain in the back, abdomen, legs, or head.

Most individuals with Marfan syndrome have some degree of nearsightedness (myopia). Clouding of the lens (cataract) may occur in mid-adulthood, and increased pressure within the eye (glaucoma) occurs more frequently in people with Marfan syndrome than in those without the condition.

The features of Marfan syndrome can become apparent anytime between infancy and adulthood. Depending on the onset and severity of signs and symptoms, Marfan syndrome can be fatal early in life; however, with proper treatment, many affected individuals have normal lifespans.

Causes of Marfan

The prevalence of Marfan Syndromw among the general public is approximately 1 in 5000 people.

Mutations in the FBN1 gene cause Marfan syndrome. The FBN1 gene provides instructions for making a protein called fibrillin-1. Fibrillin-1 attaches (binds) to other fibrillin-1 proteins and other molecules to form threadlike filaments called microfibrils. Microfibrils become part of the fibers that provide strength and flexibility to connective tissue. Additionally, microfibrils bind to molecules called growth factors and release them at various times to control the growth and repair of tissues and organs throughout the body.

A mutation in the FBN1 gene can reduce the amount of functional fibrillin-1 that is available to form microfibrils, which leads to decreased microfibril formation. As a result, microfibrils cannot bind to growth factors, so excess growth factors are available and elasticity in many tissues is decreased, leading to overgrowth and instability of tissues in Marfan syndrome.

Inheritance Pattern

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

At least 25 percent of Marfan syndrome cases result from a new mutation in the FBN1 gene. These cases occur in people with no history of the disorder in their family.

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There are five types of Loeys-Dietz syndrome, labelled types I through V, which are distinguished by their genetic cause. Regardless of the type, signs and symptoms of Loeys-Dietz syndrome can become apparent anytime from childhood through adulthood, and the severity is variable.

Loeys-Dietz syndrome is characterized by enlargement of the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. The aorta can weaken and stretch, causing a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection). People with Loeys-Dietz syndrome can also have aneurysms or dissections in arteries throughout the body and have arteries with abnormal twists and turns (arterial tortuosity).

Individuals with Loeys-Dietz syndrome often have skeletal problems including premature fusion of the skull bones (craniosynostosis), an abnormal side-to-side curvature of the spine (scoliosis), either a sunken chest (pectus excavatum) or a protruding chest (pectus carinatum), an inward- and upward-turning foot (clubfoot), flat feet (pes planus), or elongated limbs with joint deformities called contractures that restrict the movement of certain joints.

A membrane called the dura, which surrounds the brain and spinal cord, can be abnormally enlarged (dural ectasia). In individuals with Loeys-Dietz syndrome, dural ectasia typically does not cause health problems. Malformation or instability of the spinal bones (vertebrae) in the neck is a common feature of Loeys-Dietz syndrome and can lead to injuries to the spinal cord.

Some affected individuals have joint inflammation (osteoarthritis) that commonly affects the knees and the joints of the hands, wrists, and spine.

People with Loeys-Dietz syndrome may bruise easily and develop abnormal scars after wound healing. The skin is frequently described as translucent, often with stretch marks (striae) and visible underlying veins. Some individuals with Loeys-Dietz syndrome develop an abnormal accumulation of air in the chest cavity that can result in the collapse of a lung (spontaneous pneumothorax) or a protrusion of organs through gaps in muscles (hernias).

Other characteristic features include widely spaced eyes (hypertelorism), eyes that do not point in the same direction (strabismus), a split in the soft flap of tissue that hangs from the back of the mouth (bifid uvula), and an opening in the roof of the mouth (cleft palate).

Individuals with Loeys-Dietz syndrome frequently develop immune system-related problems such as food allergies, asthma, or inflammatory disorders such as eczema or inflammatory bowel disease. The prevalence of Loeys-Dietz syndrome is unknown. Loeys-Dietz syndrome types I and II appear to be the most common forms.

Causes

The five types of Loeys-Dietz syndrome are distinguished by their genetic cause: TGFBR1 gene mutations cause type I, TGFBR2 gene mutations cause type II, SMAD3 gene mutations cause type III, TGFB2 gene mutations cause type IV, and TGFB3 gene mutations cause type V.

These five genes play roles in a cell signaling pathway called the transforming growth factor beta (TGF-β) pathway, which directs the functions of the body’s cells during growth and development. This pathway also regulates the formation of the extracellular matrix, an intricate lattice of proteins and other molecules that forms in the spaces between cells and is important for tissue strength and repair.

Mutations in the TGFBR1, TGFBR2, SMAD3, TGFB2, or TGFB3 gene result in the production of a protein with reduced function. Even though the protein is less active, signaling within the TGF-β pathway occurs at an even greater intensity than normal in tissues throughout the body.

Researchers speculate that the activity of other proteins in this signaling pathway is increased to compensate for the protein whose function is reduced; however, the exact mechanism responsible for the increase in signaling is unclear. The overactive TGF-β pathway disrupts the development of the extracellular matrix and various body systems, leading to the signs and symptoms of Loeys-Dietz syndrome.

Inheritance Factors

Loeys-Dietz syndrome has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In about 75 percent of cases, this disorder results from a new gene mutation and occurs in people with no history of the disorder in their family. In other cases, an affected person inherits the mutation from one affected parent.

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