Alport syndrome is a hereditary kidney disease caused by a change in the synthesis of type IV collagen, which forms the basement membranes of the renal glomeruli, the structure of the inner ear, and the lens of the eye. Men suffer from a developed form of the disease with severe symptoms. Women are often carriers of the gene, remaining healthy, or the manifestations of the disease are poorly expressed in them. The main symptoms are microhematuria, proteinuria, renal failure, sensory hearing loss, deformation and dislocation of the lens, cataract. The diagnosis is established according to clinical and anamnestic data, the results of a general urine analysis, a kidney biopsy, audiometry and ophthalmological examination. The treatment is symptomatic, includes therapy with aCEI and ARB.
ICD 10
Q87.8 Other specified syndromes of congenital anomalies, not classified elsewhere
General information
Family cases of hematuric nephropathy first attracted the attention of researchers in 1902. Almost 30 years later, in 1927, the American doctor A. Alport found a frequent combination of hematuria with hearing loss and uremia in men, while in women the symptoms were absent or were weakly expressed. He suggested the hereditary nature of the disease, which was later called Alport syndrome. Synonyms – hereditary nephritis type 1, hematuric nephritis, familial glomerulonephritis. The prevalence is low – 1 case per 5 thousand people. Pathology accounts for 1% of patients with renal insufficiency, 2.3% of patients who underwent kidney transplantation. The disease is diagnosed in people of all races, but the ratio of different forms is not the same.
Causes
By its nature, the syndrome is a heterogeneous hereditary disease – its development is provoked by a defect in genes that encode the structure of various chains of type IV collagen. Genetic changes are represented by deletions, splicing, missense and nonsense mutations. Their localization determines the type of inheritance of the disease:
- X-linked dominant. It is associated with a mutation in the COL4A5 locus, which is located on the X sex chromosome. The gene encodes the a5-chain of type 4 collagen. This genetic defect causes 80-85% of cases of hereditary nephritis. The disease is fully manifested in boys and men, in female representatives, the remaining normal gene in the X chromosome compensates for the production of functional collagen.
- Autosomal recessive. It develops on the basis of mutations in the C0L4A3 and COL4A4 genes. They are localized on the second chromosome, responsible for the structure of the a3 and a4 chains of collagen. Patients with this variant of the syndrome make up about 15% of patients. The severity of symptoms does not depend on gender.
- Autosomal dominant. Nephritis occurs as a result of mutations of the COL4A3-COLA4 genes located on chromosome 2. As in the case of an autosomal recessive form of the disease, the synthesis of a4- and a3-chains of collagen of the fourth type is disrupted. The prevalence is 1% of all cases of genetic nephritis.
Pathogenesis
The glomerular basement membrane has a complex structure, it is formed by a strict geometric sequence of type 4 collagen molecules and polysaccharide components. In Alport syndrome, there are mutations that define the defective structure of spiral collagen molecules. In the early stages of the disease, the basement membrane becomes thinner, begins to split and delaminate. At the same time, thickened areas with uneven clearances appear. A fine-grained substance accumulates inside. The progression of the disease is accompanied by complete destruction of the basal glomerular membrane of the glomerular capillaries, renal tubules, structures of the inner ear and eyes. Thus, pathogenetically, Alport syndrome is represented by four links: a gene mutation, a defect in the structure of collagen, destruction of basement membranes, kidney pathology (sometimes hearing and vision impairment).
Alport syndrome symptoms
The most common manifestation of Alport syndrome is hematuria. Microscopically, this symptom is detected in 95% of women and 100% of men. During routine examination of boys, hematuria is detected already in the first years of life. Another common sign of the disease is proteinuria. Excretion of protein in urine in male patients with X-linked syndrome begins in early childhood, in others – later. In girls and women, the level of protein excretion increases slightly, cases of pronounced proteinuria are extremely rare. All patients have a steady progression of the symptom.
Arterial hypertension is typical for men with the classic type of syndrome and for patients of both sexes with an autosomal recessive variant of inheritance. The severity of hypertension increases with the increase in CRF. In boys and men, the decrease in kidney function reaches the terminal stage by 16-35 years, with a slow course of the disease – by 45-65 years. Sometimes diffuse smooth muscle tumors of the esophagus and bronchi are detected, manifested in late childhood by dysphagia, vomiting, pain in the epigastrium and behind the sternum, shortness of breath, frequent bronchitis.
Often, patients develop sensorineural hearing loss. Hearing disorders make their debut in childhood, but become noticeable in adolescence or youth. In children, hearing loss extends only to high–frequency sounds, it is detected in specially created conditions – with audiometry. As the syndrome matures and progresses, the auditory perception of medium and low frequencies, including human speech, is impaired. With X-linked syndrome, hearing disorder is present in 50% of male patients by the age of 25, and in 90% by the age of 40. The severity of hearing loss is variable, from changes only in the results of the audiogram to complete deafness. There are no pathologies of the vestibular apparatus.
Visual disorders include anterior lenticonus – protrusion of the center of the lens of the eye forward and retinopathy. Both pathologies are manifested by progressive deterioration of visual function, redness, pain in the eyes. Some patients have dysembriogenesis stigmas – anatomical abnormalities of the urinary system, eyes, auricles, limbs. There may be a high location of the palate, shortening and curvature of the little fingers, splice of the toes, widely spaced eyes.
Complications
The lack of treatment of patients with Alport syndrome leads to the rapid progression of deafness and blindness, the formation of cataract. Some patients develop polyneuropathy – nerve damage, accompanied by muscle weakness, pain, convulsions, tremor, paresthesia, decreased sensitivity. Another complication is thrombocytopenia with a high risk of bleeding. The most dangerous condition in hereditary nephritis is considered to be the terminal stage of renal failure. Men with the type of inheritance linked to the sexual X chromosome are most susceptible to it. By the age of 60, 100% of patients in this group need hemodialysis, peritoneal dialysis, and donor kidney transplantation.
Diagnostics
Nephrologists, urologists, therapists and geneticists take part in the diagnostic process. The survey reveals the age of onset of symptoms, the presence of first-line relatives of hematuria, proteinuria or deaths due to CRF. Alport syndrome is characterized by an early onset and a burdened family history. Differential diagnosis is aimed at excluding the hematuric form of glomerulonephritis, secondary nephropathies. To confirm the diagnosis, the following procedures are performed:
- Physical examination. It determines the pallor of the skin and mucous membranes, reduced muscle tone, external and somatic signs of dysembriogenesis – high palate, abnormalities of the structure of the limbs, increased distance between the eyes, nipples. Arterial hypotension is diagnosed in the early stages of the disease, arterial hypertension is diagnosed in the later stages.
- General urinalysis. Red blood cells and an increased protein content are detected – signs of hematuria and proteinuria. The urine protein index directly correlates with the severity of the syndrome, according to its change, the progression of pathology, the probability of nephrotic syndrome, CRF is estimated. There may be signs of leukocyturia of an abacterial nature.
- Examination of a kidney biopsy. Microscopy visualizes the thinned basement membrane, splitting and separation of its layers. At a late stage, thickened dystrophic areas with “honeycombs” of enlightenment, zones of complete destruction of the layer are noted.
- Molecular genetic research. Genetic diagnosis is not mandatory, but it allows you to make a more accurate prognosis, choose the optimal treatment regimen. The structure of genes, mutations in which cause the development of the syndrome, is being studied. In most patients, mutations of the COL4A5 gene are detected.
Audiometry, ophthalmological examination. Additionally, patients may be assigned diagnostic consultations by a sign language specialist and an ophthalmologist. Audiometry reveals hearing loss: in childhood and adolescence – bilateral high–frequency hearing loss, in adulthood – low-frequency and medium-frequency hearing loss. The ophthalmologist determines the distortion of the lens shape, retinal damage, the presence of cataracts, decreased vision.
Treatment
There is no specific therapy. From an early age, active symptomatic treatment is carried out, reducing proteinuria. It helps to prevent damage and atrophy of the renal tubules, the development of interstitial fibrosis. With the help of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, it is possible to stop the progression of the disease, achieve regression of glomerulosclerosis, tubulointerstitial and vascular changes in the kidneys. Patients with end-stage CRF are prescribed hemodialysis, peritoneal dialysis, and the question of the feasibility of kidney transplantation is being resolved.
Prognosis and prevention
The syndrome is prognostically favorable in cases when hematuria occurs without proteinuria, there are no visual disorders and hearing loss. In addition, the prognosis is good for most women – even in the presence of hematuria, the disease progresses slowly, does not worsen the general condition. Due to the hereditary nature of the pathology, it is impossible to prevent its development. In families where the presence of the X-linked form of the syndrome is established, prenatal diagnosis is possible. Genetic screening is especially recommended for women carrying boys.
