Fabry disease

People living with Fabry disease do not have intellectual impairments or learning problems more frequently than average people without Fabry disease. However, they are at higher risk for mini-strokes, TIAs (transient ischemic attacks), and strokes due to the disease's effect on the brain. In addition to damage from strokes, some adults with Fabry disease do report symptoms such as "fuzzy thinking," occasional decreased memory for names and dates, and attention deficit issues, even in the absence of stroke damage. There is evidence that some individuals with Fabry disease have issues with executive functioning (verbal generation, reasoning, problem solving, perseveration), information processing speed, and attention from testing, but the exact cause is unknown. Research on brain functioning in Fabry disease has not discovered an accurate method to measure "fuzzy thinking," despite trying through a variety of neurocognitive testing studies. Dr. Nadia Ali, a health psychologist at the Emory University Lysosomal Storage Disease Center in Atlanta, GA is very interested in learning more about this issue and is conducting research on "fuzzy thinking" in Fabry disease. She can be contacted directly for more details: Dr. Nadia Ali's faculty page.

Gastrointestinal issues (GI) in Fabry disease are different from person to person but often include: alternating cycles of chronic diarrhea and chronic constipation, stomach cramping and pain, bloating, frequent gas, nausea, vomiting, and feeling full early or early satiety. Studies have found that 52-60% of patients with Fabry disease have GI symptoms. GI issues can start as early as one year of age in children with Fabry disease. Many people with Fabry disease are also incorrectly diagnosed with Crohn's disease, celiac disease, or irritable bowel syndrome (IBS). The GI symptoms in Fabry are thought to be caused by the storage of globotriaosylceramide (GL-3) in the body that interferes with nerve and cell function in the GI system. This disrupts how fast the stomach empties, how quickly food moves through the intestine, and other functions of digestion including absorbing nutrients. Treatment with enzyme replacement therapy [Fabrazyme (agalsidase beta) or Replagal (agalsidase alfa)] or chaperone therapy [Galafold (migalastat)] has been shown to help decrease the severity and frequency of GI symptoms. After an evaluation by gastroenterologist and the ruling out other non-Fabry related causes of GI issues, doctors may also try symptom-specific medications such as: Reglan (metoclopramide) to help the stomach empty, Zofran (Ondansetron) to reduce nausea and vomiting, pancreatic enzymes to aid digestion, Loperamide (Imodium) to decrease hyperactive contractions in patients with diarrhea, or Amitriptyline to decrease nerve pain and other issues in the GI system. Some individuals with Fabry also find that eating small meals, taking probiotics, and avoiding spicy, lactose-containing, or greasy foods also help decrease GI issues.

Dr. Claire Zar-Kessler at Massachusetts General Hospital is also enrolling in a study to learn more about gastrointestinal issues in Fabry disease.

The exact reason for gastrointestinal (GI) issues, like cycles of chronic diarrhea and chronic constipation, stomach cramping and pain, bloating, nausea, vomiting, and feeling full early or early satiety, in Fabry disease is still unknown. However, doctors feel that these symptoms are likely due to the inability to move food effectively through the GI system. Doctors and medical professionals may refer to this as gastrointestinal dysmotility (GD). It is possible that the GD in Fabry disease is caused by the storage of globotriaosylceramide (GL-3) and other glycolipids that damages the small nerves that help tell the body to move food through the digestive system. This disrupts how fast the stomach empties, how quickly food moves through the intestine, and other functions of digestion (e.g. absorbing nutrients). Various cell types in patients affected with Fabry disease (e.g. nerve, muscle, blood vessel lining, immune, and epithelial cells) were found to store GL-3, which may explain the GI issues presented. Treatment with enzyme replacement therapy [Fabrazyme (agalsidase beta) or Replagal (agalsidase alfa)] and chaperone therapy [Galafold (migalastat)] have been shown to help decrease the severity and frequency of GI symptoms. After a gastroenterologist has ruled out other non-Fabry related causes of GI issues, doctors may also try symptom specific medications such as: Reglan (metoclopramide) to help the stomach empty, Zofran (Ondansetron) to reduce nausea and vomiting, pancreatic enzymes to aid digestion, Loperamide (Imodium) to decrease hyperactive contractions in patients with diarrhea, Amitriptyline to decrease nerve pain and other issues in the GI system. Some people with Fabry also find that eating small meals, taking probiotics, and avoiding spicy, lactose-containing, or greasy foods also help decrease GI issues. There is an increased interest in the irritable bowel syndrome focused FODMAP diet for Fabry disease. Before beginning any new diet plan, please consult your primary care physician.

Dr. Claire Zar-Kessler at Massachusetts General Hospital is also enrolling in a study to learn more about gastrointestinal issues in Fabry disease. In order to find a Fabry disease specialist who can give you more information on treatment for GI symptoms in patients with Fabry disease, please refer to the National Fabry Disease Foundation online resource.

In most cases of classic Fabry disease, boys and girls will present with the same symptoms in childhood. However, because of the way that Fabry disease is passed through families, the severity of symptoms and long term health problems may vary more in girls than in boys. For this reason, it is important that girls have full medical evaluations annually to monitor for symptoms.

In classic Fabry disease, the early signs for both boys and girls usually begin in childhood and can include overheating or sensitivity to hot weather, tingling or pain in the hands and feet, a reddish purple skin rash, protein in the urine, and stomach issues, such as frequent bloating or diarrhea. The most common early symptoms of Fabry disease in kids are a tingling pain in the hands and feet when overheated or sick, and frequent bloating and diarrhea.

Children with non-classic or late onset Fabry disease may also present with some or all of these symptoms and their health should be monitored in either type. Based on the United States expert treatment recommendations, patients of either gender that present with any symptoms due to Fabry disease should be considered for Fabry treatment such as enzyme replacement therapy. Treatment guidelines in other countries may provide insight on when to initiate and cease therapy. In order to find a Fabry disease specialist or more information on Fabry disease treatment, please refer to the National Fabry Disease Foundation online resource.

Fabry disease is a genetic condition caused by a deficiency of an enzyme called alpha-galactosidase A and mutations in the GLA gene. Alpha-galactosidase A, or alpha-Gal, is one of several enzymes in the body's lysosomes or "recycling centers" responsible for breaking down substances in the body called glycolipids such as globotriaosylceramide, also called GL-3 or Gb3. Most importantly, when alpha-Gal is low or missing, GL-3 builds up in lysosomes throughout different body systems, results in inflammation, and interferes with normal functioning.

The kidney problems caused by Fabry disease are due to the build up of GL-3 or Gb3 and other similar products in the cells of the kidney. The build-up of GL-3 causes the kidneys to lose their ability to filter waste and chemicals in your body. Without treatment for Fabry disease, the accumulation of these substances can gradually lead to total and permanent kidney failure called end-stage renal disease (ESRD). People with ESRD must undergo dialysis or transplantation to prolong their lifespan. Individuals with Fabry disease are candidates for kidney transplants and should not be denied that option based on their genetic condition alone.

Individuals with Fabry disease often have protein in their urine (proteinuria). Proteinuria is a sign of kidney disease but can also put stress on the kidneys so it is important to seek the advice of a kidney doctor to decrease the levels of protein in the urine as much as possible using medications such as ACE inhibitors (angiotensin-converting enzyme inhibitors) or ARBs (angiotensin-receptor blockers).

Studies have shown that starting enzyme replacement therapy earlier allows for more effective removal of GL-3 from the kidneys, which aids in stabilizing the disease progression.

Women who have a disease causing change or mutation in one of their GLA genes may experience any or all of the symptoms of Fabry disease. Accordingly, the terminology "carrier" to apply to a woman with Fabry is now considered incorrect. Symptoms of Fabry disease vary more in woman than they do in men due to the inheritance pattern of the condition.

Fabry disease is passed through families in an X-linked inheritance pattern, meaning the GLA gene that causes Fabry disease is located on the X-chromosome. Women have two copies of the X-chromosome (XX) and men have one copy of the X-chromosome and one copy of a Y-chromosome (XY). If men inherit an X chromosome containing the nonworking GLA gene, they are unable to produce alpha-gal enzyme. Without alpha-Gal, GL-3 (Gb3) builds up in the body and causes the symptoms and health problems of Fabry disease. On the other hand, if women inherit an X chromosome with a nonworking or GLA gene they have a second X-chromosome with a working GLA gene that can produce some alpha-Gal enzyme. In the past, it was believed that women who were "carriers" would not have Fabry related health problems because they had a normal second copy of the gene. However, in Fabry disease, unlike many other X-linked disorders, women are not just carriers and they may present with Fabry-related health problems. In some cases, women can have health problems as severe as their male relatives. Since women who carry one copy of a nonworking gene do have symptoms of Fabry disease, it is important that they discuss Fabry disease with their doctor and obtain appropriate referrals to monitor their health. To find a Fabry disease specialist or more information on Fabry disease treatment, please refer to the National Fabry Disease Foundation online resource.

Fabry disease is a progressive, life-threatening condition that can cause serious damage to the heart, kidneys and central nervous system if left untreated. Early signs and symptoms, such as pain and tingling in the extremities, heat intolerance, stomach issues and skin lesions, can vary from person to person. Regardless of whether or not an individual has very severe symptoms or no symptoms at all, globotriaosylceramide or GL-3 is stored in the body's cells over time and serious organ damage can occur silently before an individual actually feels ill. For example, kidney biopsy studies have shown that there can be kidney damage before protein or other kidney function markers in the urine even appear. In order to stop or slow Fabry disease from causing irreversible damage, a medical evaluation and treatment need to occur as soon as possible. Early intervention with enzyme replacement therapy (ERT) or chaperone therapy offers the opportunity to stabilize many of the complications and health problems related to Fabry disease. In adults, this means beginning Fabry specific treatment as soon as Fabry disease is diagnosed. In children with Fabry disease, the decision to begin therapy is based on the symptoms they have and discussions of the risks and benefits of ERT with a Fabry disease specialist. In order to find a Fabry disease specialist or more information on Fabry disease treatment, please refer to the National Fabry Disease Foundation online resource.

In Fabry disease, the build up of GL-3 and related lipids damages small nerve fibers and interferes with the normal functioning of nerve cells. Individuals often experience itching, numbness, tingling, burning, pain, sensitivity to cold, and problems sweating in their hands and feet due to the damage. Medical professionals and doctors may also refer to this as acroparesthesias or neuropathy. Enzyme replacement therapy (ERT) and/or prescription medications such as diphenylhydantoin, carbamazepine and gabapentin have been successful in some individuals living with Fabry disease in alleviating nerve pain.

There are many ways that individuals living with Fabry disease may describe the pain they feel in their hands and feet. Itchy feet, sand in the shoes, dragon fire in the feet and hands, frostbite, and other terms have all been used to describe this type of pain.

The exact causes for the chronic fatigue and exhaustion in Fabry disease are unknown. It may be related to the disease burden on the body's function, depression, poor sleeping, and/or heart rhythm issues. We do know that many individuals with Fabry disease do report having more energy after several months of enzyme replacement therapy every two weeks. Other strategies to manage fatigue include lifestyle changes to conserve energy and include taking frequent naps, avoiding certain activities, being prepared for changing weather conditions, and increasing water or liquid consumption. If a person diagnosed with Fabry disease is experiencing extreme fatigue, it is important for them to talk to their doctor about secondary causes such as low thyroid function, low Vitamin B levels, low Vitamin D levels, sleep apnea, or heart disease. Some individuals may also be interested in talking to their doctor about taking medications such as Provigil (modafinil) that can address some chronic fatigue issues.

Fabry disease is often divided into two types, "classic" and "non-classic or late onset". Both forms lead to serious medical problems, but most often people with classic Fabry disease have earlier and more severe symptoms. Classic and non-classic Fabry disease affects both women and men, although symptoms vary more in women due to the way Fabry disease is passed through families.

In Classic Fabry disease, the early signs usually begin in childhood and include heat intolerance, sweating abnormalities, overheating while exercising, protein in the urine, a characteristic starburst pattern on the cornea seen during eye exams, a reddish-purple skin rash or lesions, burning or tingling pains in the hands and feet, chronic tiredness, and gastrointestinal issues, such as chronic diarrhea, bloating, and constipation. Usually the first signs of Fabry disease in kids are a tingling or pain in the hands and feet when overheated or sick and frequent bloating and diarrhea. In adults, these symptoms worsen and can also include decreasing kidney function, abnormal heart rhythms, severe abdominal pain, difficulty eating normal sized meals, numbness in the hands and feet, hearing loss, mini-strokes, fuzzy thinking, dizziness/vertigo, depression, anxiety, and panic attacks. Since the condition is progressive, untreated Fabry disease can lead to severe health problems such as kidney failure, heart disease, as well as nerve and brain problems, such as stroke. Not every person with Fabry disease will present with the same symptoms; however, without treatment, the disease will worsen over time. Some people with non-classic Fabry disease typically do not have childhood symptoms, but can have many of the same health problems as people with classic Fabry disease at a later age. Kidney and heart disease may occur much earlier than in the average person, so monitoring for Fabry-related health problems should start at the time of diagnosis.

To learn more about the health issues seen in Fabry disease, visit the Fabry Support and Information Group (FSIG) and the National Fabry Disease Foundation (NFDF).

There is also an excellent summary about Fabry disease written for doctors at Fabry Disease- GeneReviews.

In classic Fabry disease, the early signs usually begin in childhood. Symptoms include tingling or burning pains in the hands and feet, sweating abnormalities, heat intolerance, protein in the urine, reddish-purple skin lesions called angiokeratomas, chronic tiredness, and gastrointestinal issue, such as chronic diarrhea, gas, and constipation. Usually the first signs of Fabry disease in kids are a tingling pain in the hands and feet when overheated or sick, frequent bloating, and diarrhea. Children with non-classic or late onset Fabry disease may have some or all of these symptoms and their health should be monitored in either type. Based on United States expert treatment recommendations and published guidelines from the European Fabry Working Group, patients of either sex with certain symptoms due to Fabry disease should be considered for treatment. Based on published cases of Fabry disease in children we have learned the following information about the possible timing of Fabry related health problems:

Ages 1 to 6:

Some children will have mild or no symptoms throughout their childhood, because the disease can vary in its severity and symptom presentation. As early as age 2, children with classic Fabry disease may have burning or tingling pain in their hands or feet when overheated. Doctors and medical professionals may refer to this pain as acroparethesias. Children may also experience Fabry "pain crises" that consist of episodes of severe pain lasting from a few minutes to several days, usually triggered by illness, fever, stressful conditions, or heat. As children as young as 3 ½ often cannot sweat, they have problems in hot conditions, while working, or during active play, as their body cannot cool correctly. Young children can begin having gastrointestinal problems, including diarrhea, nausea, bloating, abdominal pain, and vomiting as early as 1 year of age if they are affected by classic Fabry disease. They may begin to develop angiokeratomas, small, purple-red bumps that can be mistaken for a rash as early as age 4 years.

Ages 7 to 10:

As they progress through their childhood, many of the previously mentioned symptoms may worsen or become more obvious, like the angiokeratomas and gastrointestinal problems. On heart testing, children with Fabry may have a slow heartbeat (bradycardia) that doesn't appear to cause any symptoms. Some children will have undetectable symptoms in their early childhood and begin to develop obvious problems after age 10.

Ages 11 to 18:

Although young teens tend to have similar symptoms as children, older adolescents and young adults may, in addition, begin developing kidney disease (e.g. proteinuria and worsening kidney function), heart palpitations/chest pain, and an enlarged heart. Evidence of these effects include protein in the urine, more severe pain crisis, heart palpitations, panic attacks, and shortness of breath. Many patients will have have an eye finding called corneal verticillata or more commonly described as a "propeller whorl". Most optometrists can diagnosis this eye finding with a slit lamp examination.

As the symptoms of Fabry disease progress, the quality of life can diminish and living with Fabry disease can cause depression (~46% of patients) and severe clinical depression (~28%). It is important to seek an evaluation for depression.

The best place to learn more about the early signs of Fabry disease in children, is a Fabry center. Find a Fabry center nearby at the National Fabry Disease online resource.

In Fabry disease, the build up of GL-3 and related lipids damages small nerve fibers and interferes with normal functioning of nerve cells. Individuals often experience itching, numbness, tingling, burning, pain, sensitivity to cold, and problems sweating in their hands and feet due to the damage. Medical professionals and doctors may also refer to this as acroparesthesias or neuropathy. Enzyme replacement therapy (ERT) and/or prescription medications such as diphenylhydantoin, carbamazepine and gabapentin have been successful in some individuals living with Fabry disease in alleviating nerve pain.

There are many ways that individuals living with Fabry disease may describe the pain they feel in their hands and feet. Itchy feet, sand in the shoes, dragon fire in the feet and hands, frostbite, and other terms have all been used to describe this type of pain.