Fabry disease

Introduction to Fabry disease Fabry disease is vascular keratomas syndrome or Andeson-Fabrydisease, or alpha-galactosidase Adeficiency, a multi-organ multi-system disease , including skin lesions, neurological diseases, such as no sweating, abnormal acral, cardiovascular disease, ocular lesions, other such as anemia, lymphoid hyperplasia, hepatosplenomegaly, aseptic necrosis of the bone, myopathy and low Agammaglobulinemia and the like. basic knowledge The proportion of illness: 0.001% Susceptible people: no special people Mode of infection: non-infectious Complications: diarrhea, angina pectoris, myocardial infarction

Fabry disease etiology

(1) Causes of the disease

The disease is a sexually linked dominant genetic disease, and the disease-causing gene is located in the middle segment of the X chromosome, Xq21 to Xq24. Therefore, the hemizygous male is seriously ill, while the heterozygous female has various manifestations, and most of the mild abnormalities (such as only corneal ring) Mutant (as turbid), even asymptomatic, a few as heavy as male, this gene mutation leads to the lack of -galactosidase A (a lysosomal hydrolase), making the terminal -galactose residue unable to be from neutral glycosphingolipids ( Neutral glycosphingolipid) dissociates on the molecule, and such a neutral glycosphingolipid, mainly ceramide trihexoside, also has less ceramide serotonin, which is deposited in various organs of the body. Clinically, patients with Fabry disease with type B or AB blood type often have early onset and severe illness. This is because the two blood group also have two other glycosphingolipids, B and B1 glycosphingolipids, when -galactoside When enzyme A is deficient, they also cannot dissociate the alpha-galactose residue at the molecular end. The B and B1 glycosphingolipids are also deposited together in organ tissues, since patients with B or AB blood group have more than patients with O or A blood group. The glycosphingolipid deposits, so the condition is heavy.

(two) pathogenesis

In 1967, Brady et al. clarified the biochemical defects of the disease. They believed that the lysosomal enzyme sphingosine triglucosidase activity deficiency led to a decrease in the breakdown of neuraminidase, resulting in an intracellular neuroglycosyl galactosidase sheath. In the deposition of amino alcohol, a terminal galactosyl residue is attached to the end of the intracellular deposit. Due to the recognition of this specific enzyme deficiency, it is now possible to accurately diagnose a man of hemizygotes and to identify heterozygous female carriers and A fetus that is affected in the palace.

It has been clarified that vascular keratoma syndrome is an X-linked genetic disease. The defective gene is located on the long arm of the X chromosome. The penetrance of the gene is high in the hemizygotes. The clinical manifestations of enzyme deficiency are both family and family. Inter-variation, the entire genomic sequence of -galactosidase has been deciphered, and cD-NA of sufficient length can be obtained. Different families have different molecular arrangements, and there are exon mutations, gene rearrangements and base pair deletions. Affected hemizygous males exhibit multi-system clinical manifestations, and heterozygous females have different clinical manifestations and are asymptomatic, but evidence of lipid storage can be found.

Fabry disease prevention

There is no effective preventive measure for this disease. Active symptomatic treatment can effectively control the progress of the disease and prevent early renal failure.

Fabry disease complications Complications diarrhea angina pectoris myocardial infarction

Common complications include gastrointestinal lesions such as postprandial discomfort, early satiety, nausea, vomiting, diarrhea and abdominal cramps, jejunal diverticulum and intestinal perforation. Renal vascular disease is more complicated than glomerular lesion and may be complicated by renal infarction. Others, such as severe heart damage, may have angina, myocardial infarction and congestive heart failure and death.

Fabry disease symptoms common symptoms dementia myocardial infarction renal failure hypotension bleeding tendency proteinuria

1. Kidney performance

Renal involvement mainly includes hypertension, hematuria, proteinuria and fatty urine. 50% of patients develop edema, renal tubular insufficiency such as concentrated dilution, acidification and other obstacles are early manifestations of the disease, with the progress of the disease, 30% of patients in 20 40 years old and finally enter the end stage of renal failure, when the kidney volume becomes smaller, such as renal vascular disease than glomerular lesions can be complicated by renal infarction, kidney disease is the leading cause of Fabry disease incidence and death, cardiovascular disease And cerebrovascular disease is also a common manifestation of this disease, renal lesions are most often manifested as hidden mild proteinuria between 20 and 30 years old (0.5 ~ 2.0g / 24h), 30 to 50 years of age often develop to uremia with high blood pressure, there are The patient developed to end-stage renal disease as early as 10 to 20 years old. The proteinuria in the general nephropathy range is uncommon. In patients without proteinuria, a Maltese cross in the urine or a round fat in the bright-field microscope can be seen under a polarizing microscope. Plasm, suggesting the possibility of lipid storage disease, such as the discovery of myelin in the urine can be diagnosed with Fabry disease, heterozygous (female) and hemizygous (male) patients with urinary sphingolipids than normal More than 20 to 80 times, the patient may have mild microscopic hematuria, due to the disease X-linked recessive mode of delivery, hemizygous renal failure are common, while heterozygotes also be developed end-stage kidney disease.

2. System performance

(1) skin vascular keratinoma: is a characteristic lesion of this disease, the incidence rate is about 90%, the average age of onset is 17 years old, the most obvious scrotal hemangioma, often accompanied by facial telangiectasia, in the super-surface of the skin Cluster or grape-like punctate bright red, purple or red-black venous vasodilatation area, bleeding tendency, pressure does not fade, large rash may have excessive keratinization, skin vascular endothelial cells and smooth muscle factor glycosphingolipid The deposition is weakened and then expanded. It is only visible at birth, and can be expanded to 4mm later. It can be raised above the surface and distributed in the so-called "sitting bath area" between the umbilicus and the knee (lower trunk, arms, hips, hips and perineum) At the same time, often bilaterally symmetrical, with the increase of age, the number and area of keratinoma also increased.

(2) autonomic nervous system dysfunction: the nervous system manifestations are often the earliest symptoms of this disease, the age of onset is 10 years old, the initial performance can occur in children only 5 years old, can appear before vascular keratinoma many years ago, so It is necessary for pediatricians to understand this phenomenon.

The manifestations of neurological damage in vascular keratomas are mainly paroxysmal palmar pain (Fabrys crisis) and limb ants crawling. The typical manifestations of sputum pain and limb ant crawling in patients with Fabrys disease are hot and cold, exercise, After labor, the palms and soles of the feet intermittently tingling, burning pain, and radiating to the proximal extremities. Severe periodic episodes lasted for several minutes to several weeks, with 77% of patients with periodic pain and 89% with chronic disease. 90% of lifelong persistence, can also be expressed as Renault sign, abdominal pain, the number of pain episodes decreases with age, the degree is reduced, the predisposing factors are fever, the weather is warm, exercise, nervousness, drinking, severe pain, often accompanied There are fatigue, weakness, fever, sweating and erythrocyte sedimentation rate and mistaken rheumatism, physical examination without neurological signs.

In addition, 37% of patients have symptoms of central nervous system damage, the age of onset is generally greater than 26 years old, manifested as stroke (24%), dementia, passive and depressed social interaction disorder (18%), cerebrospinal fluid The examination is normal, and magnetic resonance imaging (MRI) of the brain can detect early lesions of white matter and gray matter.

Impaired autonomic function can occur with less sweat or no sweat, contraction, reduction of tears and sputum, impotence and orthostatic hypotension, etc., about 69% of patients with gastrointestinal symptoms, manifested as postprandial abdominal pain. Diarrhea, nausea and vomiting, fat intolerance, etc., most patients are significantly thin.

(3) ocular lesions: ocular signs are one of the characteristic changes of Fabrys disease. Corneal opacity can be seen in all heterozygotes and most of the hemizygotes. Patients can present abnormalities in the anterior and posterior lens and cataracts. And retinal vascular tortuosity, dilatation, corneal opacity, corneal vortex deposits, although this does not affect vision or mild visual decline, especially in women, 70% to 80% can only show the eye signs of the disease, when the ophthalmologist Fabry disease should be thought of when the patient's corneal degeneration or lens changes are found, and the patient is advised to do a genetic test to find out if other family members of the patient also have the disease. Therefore, the ophthalmologist should start in the diagnosis of Fabrys disease. Very important role.

(4) Heart damage: Heart damage is often one of the causes of death in patients with Fabrys disease, mainly manifested as conduction disorders, cardiomyopathy, coronary insufficiency or coronary artery occlusion leading to myocardial infarction, hypertension (renal ischemia leads to renin secretion) Increase), valve and ascending aorta degenerative disease (mitral valve prolapse more common), in general, Fabrys disease patients lysosomal enzyme -galactosidase A enzyme activity is only 1% ~ 17 of normal people %, if the residual enzyme activity is high, the patient may be asymptomatic or only have heart disease, and when the ischemic heart disease occurs, the patient may die of angina pectoris, myocardial infarction and congestive heart failure.

(5) Other systemic organs: In addition to the above clinical manifestations, patients with vascular keratoma syndrome can also experience progressive sensorineural hearing loss (78%); edema on the face, thickening of the lips, increased deformity of the lips and folds (56) In addition, some patients may have hemolytic anemia, lymphadenopathy, hepatosplenomegaly, aseptic necrosis of the bone, myopathy, pulmonary dysfunction, low immune function, increased platelet aggregation and prone to thrombosis and embolism.

Fabry disease examination

1. Urine examination routine examination can be seen hematuria, proteinuria and faturia, renal tubular insufficiency such as concentrated dilution, acidification dysfunction, urine sedimentation can be seen in the presence of lipid inclusion bodies, ultrastructural examination found typical inclusion bodies And intact cells of free myelin, careful microscopic examination of urine sediment, often seen in the foam-like epithelial cells containing bifocal lipids (this lipid cell shaped like a Maltese cross under a polarizer), has implications for this disease.

2. Blood biochemical examination of , galactosidase activity in plasma, leukocytes or fibroblasts is significantly reduced, the principle is due to the lysosomal enzyme -galactosidase A hydrolyzed ceramide to sphingosine and a Free fatty acids, in the absence of this enzyme, the concentration of glycosphingolipids in plasma and deposition in tissues increased, the concentration of ceramide in the plasma of hemizygous patients increased to a normal value of 3 times, increased in some tissues. Up to 300 times.

3. Amniotic membrane or chorionic sac puncture can help prenatal diagnosis by detecting the activity of -galactosidase in amniotic fluid and villus (at 14 weeks of pregnancy).

4. Renal biopsy pathological examination:

1). Light microscopic examination of glomerular visceral epithelial cells (sometimes with parietal epithelial cells, endothelial cells and renal tubular epithelial cells) increased, containing numerous vacuoles, vacuoles filled with lipids, polarizers See double-folded liposomes, resembling the Maltese cross; focal thickening of the glomerular wall, glomerular around and interstitial fibrosis.

The glomerular changes of this disease are the most significant. The paraffin section shows that the glomerular visceral epithelial cells are enlarged and the intracellular vacuoles are formed. The vacuoles are usually small and uniform, so the cells are honeycomb-shaped, and the cytoplasm disappears almost unrecognizable. Epithelial cell involvement is relatively rare, and endothelial cells and mesangial cells can be seen with vacuoles. In early or milder patients, glomeruli can be free of other abnormalities. As the disease progresses to renal failure, it gradually progresses to the glomerulus. Segmental or global sclerosis, cells with vacuolization can still be found in sclerosing globules, providing clues for the diagnosis of patients with progressive renal disease, with similar vacuolar cells in the tubules, with distal convoluted tubules and Henle The most obvious is that the proximal convoluted tubule cells are less affected. There are a lot of vacuolar cells in the arteries and small arteries. The endothelial cells are often involved, and the cells are expanded into foam. The smooth muscle cells in the middle layer of the blood vessels have vacuoles of different sizes.

Fixed plastic embedded tissue sections treated with toluidine or methylene blue, can see fine dark-stained granular inclusions in the corresponding parts of the previously mentioned intracellular inclusion bodies. This technique has a greater diagnostic value. Especially in fully or locally hardened glomeruli, this method can also be used to identify affected interstitial cells.

2). Immunofluorescence immunofluorescence is often negative, and the development of advanced glomeruli, such as segmental sclerosis, IgM, C3 and C1q can be segmental or granular distribution in the vascular wall or mesangium Area.

3). Electron microscopy shows that the cells contain numerous round or oval layered bodies (these bodies are called "zebra bodies" or "myelin lipids"), which is very meaningful for the diagnosis of this disease.

Almost all kidney cells of this disease can be affected, and the glomerular capillary epithelial cells are the most. The typical cell-like lysosomes in the affected cell lysates can be seen as a layered abnormal inclusion of electrons and dense eosinophilic layer. Body, due to different aspects of the surface can be solar ring, creeping villous or zebra-like structure, a variety of cell cytoplasm with a variety of morphologically enlarged lysosomes, onion skin-like, layer-like, dense solid spherical Or vacuole, so the lysosomal changes of the disease can also be diverse, in addition, epithelial cell foot process fusion, basement membrane thickening and other changes.

Diagnosis of Fabry disease

Diagnostic criteria

Although there are many characteristic manifestations of this disease, it is not uncommon for patients to be misdiagnosed for more than 10 years. Generally speaking, the age of onset of Fabrys disease patients is in late childhood or early adolescence, males are sick, females are carriers or mild patients, B Type and AB type blood type are early and more serious, the average survival age of patients is 50 years old, female gene carriers have a longer survival age, about 70 years old, and the cause of death is mainly renal failure or cardiovascular and cerebrovascular complications.

Due to the lack of function or activity of the lysosomal enzyme -galactosidase A required for the normal catabolism of ceramide trihexosides in patients with Fabry disease, there is a disorder in the metabolism of glycosphingolipids, resulting in nerves during lipid catabolism. Sphingolipids, mainly ceramide trihexoside (CTH), are widely deposited in various tissues of the body, such as intravascular and smooth muscle cells, central nervous system neurons, peripheral nervous system ganglia, skin, eyes, Gastrointestinal tract, heart, kidney, etc., so the clinical symptoms are multi-system damage, sometimes based on a certain systemic symptoms, usually based on clinical manifestations, characteristic signs and positive family history, biopsy tissue and cultured skin fibroblasts It is not difficult to confirm the diagnosis of -galactosidase activity. If the clinical manifestation is -galactosidase A deficiency, the concentration of the enzyme in leukocytes isolated from peripheral blood can be used to diagnose the hemizygous patient. Almost no enzyme activity, if the enzyme activity reaches 6% to 20% of normal people, there is no clinical symptom. In heterozygotes, the activity level of the enzyme is between Between normal and hemizygous, the determination of -galactosidase A activity in leukocytes is not a sensitive method for identifying carriers. It is best to determine the concentration of ceramide galactosidase and trihydroxylate in urine. Prenatal diagnosis can be performed by measuring the level of -galactosidase A in cultured amniocytes.

Only a few storage diseases have the same renal lesions and reservoir distribution as Fabry disease, and the formation of vacuolar formation in glomerular tubule epithelial cells is non-specific, but the ultrastructural characteristics of inclusion bodies have diagnostic significance. For male patients with symptoms and symptoms, such as inclusion bodies and a large number of inclusion bodies in the affected cells, especially in the epithelial cells of glomeruli, the diagnosis should be considered. The urine sediments are found to contain typical inclusion bodies and free The intact cells of the myelin body are of great value for diagnosis.

Differential diagnosis

In the early stages of the disease or when the symptoms are not typical, it should be differentiated from the following diseases:

1. Rheumatic rheumatic fever is more common in clinical practice. It usually has a history of early streptococcal infection, anti-"O" increase, subcutaneous nodules, arthritis and chorea and other symptoms and signs, anti-rheumatic treatment is effective.

2. Drug-induced eye damage Drug-induced eye damage has a clear history of medication, such as chloroquine can cause corneal opacity similar to Fabrys disease.

3. Cardio-cerebral vascular disease in young people with severe painful neuropathy or convulsions, hemiplegia, personality and behavioral changes, with progressive renal, cardiovascular and cerebrovascular dysfunction, should be thought of this disease, MRI can be found early Brain damage.

In addition, attention should be paid to the differentiation of diseases of glomerulonephritis and renal tubular dysfunction caused by other causes.

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