Fabry Disease

Fabry Disease

What Is Fabry's Disease?

What is Fabry's disease?

Fabry disease, Andeson-Fabry disease, or α-galactosidase a deficiency were reported almost simultaneously by two dermatologists Anderson (UK) and Fabry (Germany) in 1898.

Fabry's disease often involves multiple organs and systems, with symptoms such as skin, eyes, ears, heart, kidney, nervous system and gastrointestinal tract. The clinical manifestations of male patients are more than those of female patients.

Is Fabry's disease common? Will it be inherited?

Not common, but inherited.

Up to now, the exact incidence of Fabry's disease in the population is not clear. It is estimated that the incidence of Fabry's disease in Caucasian men ranges from 1/117 000 to 1/17 000. There is no statistical data on the incidence of Fabry's disease in China.

The disease can be seen in all ethnic groups and races, and it is an X-linked recessive disease.

What types can Fabry's disease be divided into?

According to the different clinical manifestations of Fabry disease, Fabry disease can be divided into two types:

  • Classical type: its α-GalA activity is obviously decreased or even completely absent (< 5%), and it can occur in childhood. Generally, boys develop earlier than girls, and pain and angiokeratoma are the most common. Pain gradually spreads from extremities to limbs and other parts of the body. Angiokeratoma can affect the whole body, especially around umbilicus and knees, and it can be accompanied by multiple system damage such as brain, kidney, heart and peripheral nerve.

  • Late-onset: α-GalA activity partially decreased (> 5%), which occurred in adulthood and was often limited to kidney or heart involvement.


What Is The Cause Of Fabry's Disease?

What is the cause of Fabry's disease?

The incidence of Fabry's disease is related to the mutation of α-galactosidase A(α-GalA, a lysosomal enzyme) gene in q22 on X chromosome, which leads to the partial or total loss of the enzyme activity, resulting in the accumulation of its metabolic substrate trihexyl sphingolipid (GL3) and related glycosphingolipids in various organs and tissues of human body, such as heart, kidney, pancreas, skin, nerve, lung, etc.


What Are The Symptoms Of Fabry's Disease?

What are the manifestations of Fabry's disease?

Fabry's disease is a disease involving multiple organs and systems. Because the deposition of α-GalA substrate GL3 is a gradual process, the clinical manifestations of Fabry's disease vary with age:

  • Facial features: Male patients usually have characteristic facial features at the age of 12 ~ 14 years, which are manifested as protrusion of supraorbital ridge, forehead bulge and thickening of lips.

  • Nervous system:

  • About 72% of patients may have neuropathic pain, which is often described as unbearable burning sensation of soles and palms and radiated to the proximal extremities. This severe neuropathic pain or limb pain may be induced by stress, extreme heat or cold and strong physical activity. The average age of onset was about 10 years old.

  • In addition, there may be little or no sweat, and serious autonomic nerve damage may lead to blood pressure regulation disorder and syncope.

  • A few patients showed cranial nerve damage, such as sensorineural deafness. Generally, the central nervous system is characterized by early-onset stroke, and transient ischemic attack (TIA) or ischemic stroke is common, which is characterized by hemiplegia, hemianopia, vertigo, ataxia and dysarthria, while nonspecific symptoms include inattention, headache and cognitive dysfunction.

  • Cutaneous keratoma: It is common in classic patients, showing small and convex red spots on the skin, which are mostly distributed in the "sitz bath" area, i.e., genitals, scrotum, buttocks and inner thighs. The number and distribution range of angiokeratoma can increase with the progress of the disease course. Some patients may have thickened lips or bulbous nose. About 70% of patients can have the above skin manifestations, and the average age of onset is about 17 years old.

  • Eye: The main manifestations are conjunctival vascular tortuosity, corneal vortex opacity, posterior capsular opacification and retinal vascular tortuosity. In severe cases, visual acuity may be reduced or even lost.

  • Gastrointestinal tract: diarrhea, nausea, vomiting, abdominal distension, abdominal pain, gastrointestinal malabsorption and constipation. 50% ~ 70% of patients will have these manifestations, usually before the age of 40.

  • Kidney: Early manifestations are nocturia, polyuria and enuresis. With the progress of the disease course, proteinuria even reaches the level of nephrotic syndrome, and serum creatinine increases. Generally, uremia occurs around 30 years old. In addition, there may be hematuria.

  • Heart: Most of them are the late manifestations of diseases, with an average onset age of about 42 years. Hypertrophic cardiomyopathy (mainly left ventricular hypertrophy) is common. Peripheral artery involvement can cause hypertension, as well as heart failure, coronary artery disease, abnormal aortic and mitral valves and abnormal conduction. Heart involvement may be the only symptom in some male patients.

  • Respiratory system: Obstructive pulmonary dysfunction such as chronic bronchitis, dyspnea and wheezing, which can be aggravated by smoking.

  • Bone system: Osteoporosis is common in young and adult patients, especially in lumbar vertebrae and femoral neck.

  • Mental illness: common, manifested as depression and anxiety.


How To Check For Fabry's Disease.

What are the characteristics of Fabry's disease, and what are the suspected cases of Fabry's disease?

Men or women who have the following clinical features that suggest the diagnosis of Fabry's disease should be evaluated, especially:

  • Intermittent severe pain at extremities (i.e. abnormal sensation at fingers or toes);
  • Skin lesions (angiokeratoma);
  • Reduce perspiration (less perspiration);
  • Left ventricular hypertrophy of unknown etiology occurred in early adulthood;
  • Early adult stroke of unknown etiology;
  • Early adulthood with CKD; of unknown etiology;
  • Accidentally found multiple renal sinus cysts.

How to diagnose Fabry's disease?

Gene diagnosis is the golden index of Fabry's disease, and GLA gene detection can be carried out by extracting DNA or RNA from peripheral blood or DNA from hair follicle.

When the family history and typical phenotype are clearly determined, if the activity of leukocytes or plasma α-GalA in men is low, the diagnosis can usually be made. For female carriers, mutation analysis of α-GalA gene is needed to make a diagnosis.

What tests should be done for Fabry's disease?

In addition to general routine examination, it is necessary to detect α-GalA enzyme activity, blood and urine GL3 and plasma deacetylated GL3(lyso-GL3), pathological examination and gene detection.

  • Detection of α-GalA enzyme activity: The enzyme activity in the blood of male patients often drops obviously, which can be confirmed by enzyme activity detection. The enzyme activity of 30% female patients can be in the normal range.

  • Determination of blood and urine GL3 and plasma deacetylated GL3(lyso-GL3) can be used as a biochemical diagnostic index of Fabry's disease, which is more sensitive than enzyme activity detection, and the sensitivity of plasma lyso-GL3 detection is higher than that of blood and urine GL3.

  • Pathological examination: kidney, skin, myocardium or nerve tissue can be obtained, which is helpful for disease diagnosis.

Pathological examination: kidney, skin, myocardium or nerve tissue can be obtained, which is helpful for disease diagnosis. What diseases should Fabry's disease be distinguished from?

  • Pain: It needs to be differentiated from growth pain, juvenile rheumatoid arthritis, Raynaud's syndrome, sensory neuropathy caused by other reasons, erythematous limb pain, etc.

  • Gastrointestinal symptoms: It needs to be differentiated from gastroenteritis, indigestion and irritable bowel syndrome.

  • Cutaneous keratoma: Differentiate from allergic purpura or other rashes.

  • Proteinuria, renal dysfunction: Distinguishing from primary glomerulonephritis or other secondary glomerular diseases.

  • Cardiac involvement: hypertrophic cardiomyopathy, arrhythmia and cardiac insufficiency caused by other reasons are distinguished.

  • Brain involvement: premature stroke caused by other factors is distinguished from leukoencephalopathy.

  • Corneal opacity: distinguished from corneal opacity with amiodarone and chloroquine treatment.


How To Prevent Fabry Disease

How can fabry disease reduce the probability of disease in the next generation?

  • Patients diagnosed with Fabry disease require a detailed family investigation, and all patients require appropriate genetic counseling and heterozygosity testing for high-risk adult women.

  • For male patients who need to give birth, it is recommended to give birth to a son to avoid the inheritance of the mutation gene, and gender identification is enough before the third month of pregnancy. For female patients who need to give birth, prenatal diagnosis is required.For male patients who need to give birth, it is recommended to give birth to a son to avoid the inheritance of the mutation gene, and gender identification is enough before the third month of pregnancy. For female patients who need to give birth, prenatal diagnosis is required.

  • Fetal villi were taken around 11 weeks of pregnancy or amniotic fluid was taken around 18 weeks of pregnancy for amniotic fluid cell GLA gene testing or α-GalA enzyme activity testing.


How To Treat Fabry Disease

Which department should I visit for Fabry disease?

Because Fabry disease is a disease involving multiple systems, patients can visit dermatology, cardiovascular medicine, renal medicine and other relevant departments according to their own symptoms.

How is fabry disease treated?

Treatment of Fabry's disease focuses on supplementation with missing or insufficient enzymes (α-GalA). It is mainly divided into specific treatment and non-specific treatment:

  • Non-specific treatment: The corresponding treatment is mainly applied to the affected organs. For example, renin-angiotensin system (RAS) inhibitors are used to treat hypertensive patients with Fabry's disease. Standard treatment is given for complications in patients with CKD, with dialysis and/or transplantation when needed. ;

  • Specific treatments:

    • Enzyme replacement therapy,ERT), which is the enzyme therapy for Fabry disease using gene recombination technology to synthesize α-GalA in vitro to replace defects in vivo.

    • The results of multiple randomized controlled and open-label extended clinical trials have shown that the recombinant human α-GalA replacement therapy for Fabry disease can reduce the deposition of intracellular GL3 in patients, effectively alleviate limb pain and gastrointestinal symptoms in patients, improve myocardial hypertrophy, and stabilize renal function, thereby improving the quality of life and prognosis of patients.

    • Two recombinant human α-Gala enzymes, α galactosidase and β galactosidase, have been developed. But the cost is now higher.

What are the conditions that warrant enzyme replacement therapy (ERT) for Fabry disease?

ERT therapy should be actively used in the following situations:

  • For male patients with classic Fabry disease with renal manifestations [i.e., very low or undetectable levels of α -galactosidase A(α-GalA)], ERT therapy should be actively pursued;

  • For asymptomatic men with classic Fabry disease, ERT therapy should be initiated as soon as a definite diagnosis is made;

  • Early initiation of ERT therapy is recommended in patients with end-stage renal disease (ESRD) due to Fabry disease, including those who have undergone renal transplantation;

  • For patients with Fabry's disease with a large number of non-renal manifestations, start ERT therapy as soon as a diagnosis is made;

For asymptomatic female carriers or men with nonclassical presentation (i.e., α-GalA at a critical level), ERT is recommended on a patient-specific basis due to the unclear benefits, high cost, and treatment burden of ERT.

Is there a better treatment for Fabry disease?

Enzyme-enhanced therapy is a new specific treatment. It is treated by improving the enzyme activity. Currently, deoxygalactose nojirimycin (DGJ) has completed the Phase II clinical trial. The results show that it can improve the enzyme activity of some patients with mutations with good safety. The disadvantage is that the treatment is selective to mutations.

Specifically, only for patients with certain gene mutations. In addition, some new treatments such as substrate degradation, protein stability regulation, and gene therapy are being investigated.


What Should Fabry Disease Patients Pay Attention To In Life

What should Fabry disease patients pay attention to in life?

Avoid overwork, quit smoking, and keep a happy mood.

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