Fabry disease: what is it, symptoms, treatment, prognosis

What is Fabry disease?

Fabry disease is a rare hereditary disorder of glycosphingolipid (fat) metabolism that occurs in as a result of the absence or markedly insufficient activity of the lysosomal enzyme, α-galactosidase A (α-Gal A). This disorder belongs to a group of conditions known as lysosomal storage diseases. This enzymatic deficiency is caused by changes (mutations) in α-galactosidase A (GLA) a gene that instructs cells to produce the enzyme α-galactosidase A (α-Gal A).

Lysosomes function as the primary cells of the digestive tract. Enzymes in lysosomes destroy or digest certain compounds and intracellular structures. α-Gal A functions by cleaving complex lipid sugar molecules called glycolipids, in particular globotriaosylceramide (GL-3 or Gb3), its deacylated form of lyso-GL-3 / Gb3 and related glycolipids, by removing the terminal galactose sugar from the end of these glycolipid molecules. Enzyme deficiency causes continuous accumulation of GL-3 / Gb3 and related glycolipids in the cells of the body, which leads to cell abnormalities and organ dysfunction, which especially affect the small blood vessels, the heart and kidneys.

Gene GLA is located on the X chromosome, and therefore Fabry disease is inherited as an X-linked disorder. Men with the classic type 1 phenotype and late-onset type 2 phenotypes tend to have significantly more serious diseases than women. Women tend to have a more variable course and the disease can be asymptomatic or have the same serious consequences as men.

There are two main phenotypes of the disease: type 1 "classic" and type 2 "late". Both lead to renal failure and / or heart diseaseas well as premature death. Men with type 1 have little or no functional enzymatic activity of α-Gal A (<3% of normal average activity) and a marked accumulation of GL-3 / Gb3 and related glycolipids in capillaries and small blood vessels that cause major symptoms in childhood or adolescence age. These include:

• acroparesthesias (excruciating pain in the arms and legs that occurs during exercise, fever, stress, etc.);
• angiokeratomas (red to blue skin patches);
• anhidrosis or hypohidrosis (sweating is absent or markedly reduced);
• gastrointestinal symptoms including abdominal pain and cramps;
• corneal dystrophy.

With increasing age, systemic deposition of GL-3 / Gb3, especially in the heart, leads to arrhythmias, left ventricular hypertrophy, and then to hypertrophic cardiomyopathy, and in the kidneys to progressive proteinuria, renal failure and / or to cerebrovascular diseases, including transient ischemic attacks (TIA) and strokes. Before renal replacement therapy (i.e. dialysis and transplantation) and enzyme replacement therapy, the average age of death in male patients with the classic type 1 phenotype was ~ 40 years. The incidence of men with the classic type 1 phenotype is about 1 in 40,000, but varies according to by geographic region and race, from ~ 1 in 18,000 to 1 in 95,000 based on screening studies newborns.

In contrast, males with a late-onset type 2 phenotype (formerly called cardiac or renal variants) have residual α-Gal A activity, lack accumulations of GL-3 / Gb3 in capillaries and small blood vessels and do not show early manifestation as in type 1 (i.e. acroparesthesias, hypohidrosis, angiokeratomas, corneal dystrophy etc.). They generally do well in childhood and adolescence and usually suffer from kidney and / or heart disease during their third to seventh decades of life.

Clinical manifestations in heterozygous women from families with the classic type 1 phenotype are variable due to accidental inactivation of the X chromosome and range from asymptomatic to as severe as in men with classic type 1, Type 2 heterozygotes may be asymptomatic or develop renal or cardiac manifestations at later age. Approximately 90% of type 1 heterozygotes have characteristic corneal dystrophy, while heterozygous women of type 2 usually lack characteristic corneal signs or other early manifestations of type 1. The frequency and severity of manifestations in heterozygous women with type 2 disease was studied systematically only in recently, and they tend to have fewer and less severe symptoms than men with type 2.

Signs and symptoms

- Classic phenotype (type 1).

Signs and symptoms in men with the classic type 1 phenotype usually begin in childhood or adolescence. Symptoms worsen with age, mainly due to the progressive accumulation of glycolipids in microvascular system, renal podocytes and cardiomyocytes, leading to renal failure, heart disease and / or strokes. Early and progressive clinical symptoms include:

1. Acroparesthesia. Pain is an early symptom of the classic subtype type 1 and can occur in males aged 2-8 years, and can also occur in childhood or adolescence in heterozygous women, especially with fever. Sufferers may experience episodes of severe burning pain in the arms and legs. Severe bouts of pain (Fabry crises) can last from several hours to several days and are often triggered by exercise, fatigue, stress, and / or fever.
2. Anhidrosis or hypohidrosis. Men and some women with type 1 have reduced or absent sweat production (hypohidrosis or anhidrosis) and discomfort in warm temperatures, exercise, or fever.
3. Angiokeratoma. Early symptoms also include a reddish to dark blue skin rash, especially in the area between the thighs and knees. photo above). These skin lesions can be flat or raised. They are often found in the navel or genitals of men with type 1 disease. Typically, men and women with the late type 2 phenotype do not have these characteristic skin lesions.
4. Gastrointestinal problems. GI symptoms are an early manifestation of type 1 Fabry disease. Abdominal cramps, frequent bowel movements, and diarrhea, especially after a heavy meal.
5. Corneal dystrophy. Patients with the classic type 1 phenotype have abnormal deposits of glycolipids in their cornea, which leads to a characteristic turbidity, which can be seen when viewed with a slit lamp by an experienced an ophthalmologist. These changes do not affect vision. The blood vessels in the eyes may appear twisted (like a corkscrew; curved) and / or slightly enlarged (dilated) due to the accumulation of glycolipids in the walls of blood vessels.

Other additional symptoms that may be associated with type 1 Fabry disease include:

• chronic fatigue;
• dizziness;
• headache;
• general weakness;
• nausea and / or vomiting;
• delayed puberty;
• lack or rare hair growth;
• malformations of the joints of the fingers (rare).

Some men with classic 1 type have an abnormal accumulation of lymph in the feet and legs associated with edema (lymphedema). In these patients, lymph, a body fluid containing certain white blood cells, fats and proteins, accumulates outside the blood vessels in the spaces between cells and drains, or back into the bloodstream through the lymphatic vessels. Lymphedema occurs when the normal drainage (outflow) of lymph is disrupted due to the accumulation of glycolipids in the lymphatic vessels and lymph nodes.

- Common manifestations in men with types 1 and 2 of the disease.

With age in men with type 1 disorder, usually in their third to fourth decades, and in men with type 2 in their third to sixth decades, progressive deposition of GL-3 / Gb3 glycolipids leads to renal and / or cardiac manifestations, as described below. Many of the men with late-onset type 2 who do not have the early manifestations seen with type 1 have kidney problems, heart problems, or strokes.

Patients with a later subtype type 2 usually have no skin lesions (angiokeratoma), normal sweat, do not experience Fabry pains or crises, and do not have heat intolerance or corneal lesions. These people develop heart or kidney disease later in life.

Signs of progressive organ involvement include:

• Renal dysfunction. The progressive decline in renal function is associated with the progressive accumulation of GL-3 / Gb3 in the kidney, especially in endothelial cells, smooth muscle cells, and podocytes. There is histological evidence of this accumulation and subsequent cellular and vascular renal tissue damage from childhood and adolescence in men and women with classic 1 type diseases. In men with type 1, the decline usually begins with the involvement of podocytes and microalbuminuria, leading to overt proteinuria (presence of protein in the urine), increasing loss of function (decreased glomerular filtration rate or GFR), all of which lead to renal failure and the need for dialysis or transplantation, usually at 35-45 years In males with volume 2, kidney damage usually occurs in the fourth decade or later, but some patients do not develop renal failure. Kidney involvement in heterozygous women with type 1 is more variable. Only about 10-15% of women with type 1 develop kidney failure. It is not clear what percentage of women with type 2 develop kidney failure, if any.
• Heart diseases. Deposition of GL-3 / Gb3 can be found in all tissues of the heart, including valves, cardiomyocytes, nerves, and coronary arteries. Heart disease includes an enlarged heart, usually left ventricular hypertrophy (LVH), leading to hypertrophic cardiomyopathy (HCM), arrhythmias (arrhythmias), and heart failure. LVH occurs in about 20% of men and women with an average age of diagnosis at the age of 20-40 years among men with type 1 and at the end of 30-40 years among heterozygous women with type 1. Early heart disease in men usually includes arrhythmias and mitral regurgitation at age 20, after which LVH leads to HCM. Men with late-onset type 2 develop the same cardiac manifestations as men with type 1, but at an older age.
• Cerebrovascular complications. As a result of progressive deposition of GL-3 / Gb3 in the heart, resulting in atrial fibrillation, and in small blood vessels of the brain, about 7% of men and 4% of women with Fabry disease, especially with the phenotype Type 1 experience ischemic or hemorrhagic strokes, usually occurring in the fourth decade of life or later.
• Respiratory disorders. The accumulation of glycosphingolipids and subsequent fibrosis can cause interstitial lung disease. Pathological changes and tissue remodeling can include both the alveoli and the bronchial tree, resulting in restrictive lung disease, obstructive airway disease, or a combination of obstructive and restrictive diseases. Respiratory symptoms in these patients can occur independently of cardiovascular disease.
• Other complications: hearing loss noise in earsdizziness, possibly due to GL-3 / Gb3 deposition in vestibular structures and / or auditory neuropathy, usually are reported in adult patients and, while not life threatening, contribute to the burden of disease and negatively affect the quality of life. Reported on depressionand some of these cases, especially men with classic type 1, were classified as severely depressed.

Causes of Fabry disease

Fabry disease is caused by changes (mutations) in alpha-galactosidase A (GLA) a gene located on the X chromosome. Chromosomes are found in the nucleus of all cells. They carry the genetic characteristics of each person in thousands of specific segments called "genes" that span the length of the chromosomes. Each of these genes has a specific function in the body.

Human chromosomes are organized in pairs numbered 1 through 22, with a 23rd pair of X and Y chromosomes in males and two X chromosomes in females. Humans inherit one chromosome in each pair from each parent. Therefore, in X-linked disorders, including Fabry disease, signs of the disease on the X chromosome may be masked or diminished in women by a normal gene on the other X chromosome.

More specifically, since men and women only need one functioning X chromosome, one of X chromosomes in every cell of a woman are, in fact, "turned off", as a rule, in a random way (accidental inactivation X chromosomes).

This means that in X-linked disorders, some cells will have an activated X chromosome. mutated Fabry gene, while others will have an X chromosome with normal activated genome. Therefore, in Fabry disease, the symptoms and degree of organ damage depend on the percentage of cells in the tissue / organ, where the X chromosome with the gene mutation GLA active, but with no or markedly reduced function, which partly explains why the severity of the disease in women is more variable than in men. Since males only have one X chromosome, if a man has an X chromosome with a mutated gene GLA, he will suffer from this disorder. Consequently, men with classic types 1 and 2 with late onset Fabry disease are more uniformly affected, while symptoms in women due to accidental X-inactivation can range from asymptomatic to as severe as men.

Men with X-linked Fabry disease transmit a gene mutation GLA to all their daughters who are heterozygous, but never to their sons. Heterozygous women have a 50% risk of passing the disease on to each of their children, both daughters and sons, with each pregnancy.

Gene GLA usually instructs the body's cells to produce the enzyme α-Gal A, which breaks down accumulating glycolipids (GL-3 / Gb3) in the lysosomes of the cell. Fabry disease is caused by mutations in a gene GLA. There are over 965 reported mutations in the gene GLAwhich are responsible for Fabry disease causing type 1 or type 2 phenotypes. Thus, the severity and spectrum of symptoms may vary among individuals depending on GLA mutations in their family. Some mutations markedly change the enzyme so that it has little or no activity. These mutations cause the classic type 1 subtype, while other mutations result in little residual enzyme activity and a late onset type 2 subtype.

The signs and symptoms of Fabry disease develop due to the absence or markedly insufficient activity of the α-Gal A enzyme. Patients with the classic type 1 phenotype who have no or very low levels of activity (less than 3% of normal) accumulate glycolipid GL-3 / Gb-3 substance (and related glycolipids) in most body tissues, especially small blood vessels and some heart cells, and kidneys. Patients with a later type 2 phenotype have residual enzyme activity (3-15% of average normal activity) and accumulate GL-3 / Gb3, but to a lesser extent and at a slower rate. They tend to have a slightly less severe form of the disease, but men with type 2 subtype eventually develop severe heart disease and / or kidney failure. There are also mutations in the gene GLAthat are benign and do not cause Fabry disease.

Affected populations

Fabry disease is a rare pan-ethnic disease which means it occurs in all racial and ethnic groups, affecting both men and women. It is estimated that classic Fabry disease type 1 affects about one in 40,000 men. The later-onset type 2 phenotype is 3-10 times more common than the type 1 phenotype, and in some populations it is as common as about 1 in 1500-4000 males. Data from US newborn screening studies show that the incidence of Fabry disease varies across geographic regions.

Diagnostics

The disease has many different symptoms, and doctors of different specialties may suspect its occurrence. It is often recognized by a neurologist after a stroke in a young person, a nephrologist after a kidney disease, or a dermatologist based on characteristic skin changes.

When the disease is known to occur in the family, it can be detected early in other family members, especially in men, as soon as the first symptoms appear.

Fabry disease can be detected even in the fetus during prenatal examination.

Usually, the patient undergoes a series of tests to assess possible damage to various organs. For a stroke, imaging tests such as CT and MRI are done. In case of heart disease, ECG, echocardiography and sometimes coronary angiography. Kidney disease is manifested at first by proteinuria, hematuria, and then by an increased level of blood creatinine.

The presence of the symptoms described above from various organs, especially if they are typical, makes it possible to recognize the disease with confidence. However, some diagnoses require a deficiency or absence of alpha-galactosidase A in blood, leukocytes, or cultured fibroblasts.

Fabry disease treatment

Fabry disease causes multiple organ dysfunction and patients need a comprehensive, interdisciplinary treatment plan that is individually designed and includes special treatment methods aimed at abnormal accumulation of the substrate, and auxiliary treatment methods aimed at damaging the final organ.

Enzyme replacement therapy (ERT) is the cornerstone of treatment for Fabry disease, and a synthetic enzyme produced by recombinant DNA technology is administered intravenously. Two forms of the recombinant enzyme are available, alpha-agalsidase (Replagal®) and beta-agalsidase (Fabrasim®). Fabrazim is the only FZT approved by the Food and Drug Administration in 2003. Replagal and Fabrazim are available in Europe, Russia and other regions of the world. ERT replaces the missing enzyme and reduces the accumulated glycolipids in cells throughout the body. Phase 3 and 4 double-blind, placebo-controlled clinical trials have demonstrated the safety and efficacy of Fabrasim.

It has been shown that ERT slows down or prevents the decline in renal function, especially if it is started at an early stage before progressive kidney damage, improves neuropathic pain and heat intolerance. Early initiation of ERT is important, especially in men with classic type 1. The introduction of ERT is currently recommended for men with classic type 1 with clinical manifestations at any age or without symptoms by the age of 15. Recombinant "biosimilar" enzymes are available in several countries, including Korea and Japan. Several other recombinant enzyme preparations are in clinical development.

Oral therapy with Migalastat has also been approved for the treatment of adults with Fabry disease in the EU (2017) and the US (2018). The drug is an agent that can bind, stabilize and enhance the residual enzymatic activity of certain missense mutations. Clinical studies have demonstrated the effectiveness of this approach. Future research will determine the clinical and biochemical efficacy of specific missense mutations with residual activity.

Additional treatments include low daily doses of diphenylhydantoin, carbamazepine, or Neurontin to help manage acroparesthesia. Other late complications (such as kidney failure or heart problems) should be treated symptomatically after consultation with a physician experienced in caring for patients with Fabry disease. In cases where renal failure has progressed, it may be necessary hemodialysis and kidney transplantation.

Forecast

The life expectancy of men with Fabry disease today is about 58 years, and the life expectancy of women with Fabry disease is just over 75 years. The most common cause of death for both sexes is kidney failure and cardiovascular disease.