Alport syndrome

Alport syndrome, also known as hereditary nephritis, is an inherited disorder in which the function of the renal glomeruli is impaired (the glomerulus is the basic functional unit of the kidney, consisting of a network of the smallest blood vessels designed to filter blood within the kidney). The dysfunction is caused by thinning of the glomerular basement membranes due to defective synthesis of the α‑chains of type IV collagen. This syndrome is characterized by progressive deterioration of kidney function.

This congenital disorder was described in 1927 by Dr. Cecil A. Alport based on a British family in which several generations of males were affected simultaneously by deafness and progressive renal failure. The underlying mechanism of the disease was not identified until the 1970s.

Alport syndrome is most commonly caused by mutations in the gene encoding the α5 chain of type IV collagen (most frequently COL4A5 mutations on the X chromosome), and less commonly by mutations in the genes encoding the α3 or α4 chains of type IV collagen. The inheritance pattern may be X‑linked, autosomal recessive, or autosomal dominant. Male patients tend to have a more severe form, typically presenting with microscopic hematuria (presence of red blood cells in the urine) early in life (around 3.5 years of age in boys and 9 years in girls). Proteinuria (excess protein in the urine) develops and progresses to chronic kidney disease (gradual loss of kidney function) before the age of 40. In most female patients, the progression is milder due to the presence of a second X chromosome.

The mutation results in production of defective collagen chains, which are subsequently degraded; however, the α3‑α4‑α5 complex fails to form in the basement membrane. As a result, the basement membrane is more susceptible to proteolysis (degradation), which manifests as morphological (structural) changes—thinning of the basement membrane alternating with segments of thickening and splitting. Symptoms of kidney disease develop gradually and are nonspecific. Patients may experience fatigue, weakness, lightheadedness, loss of appetite, swelling of the lower limbs and eyelids, frequent urination, or decreased urine output.

Other signs of Alport syndrome include hearing impairment (often severe) caused by sensorineural hearing loss — damage to the inner ear and its neural pathways to the cerebral cortex.

Classic Alport syndrome is characterized by renal involvement (manifesting as nephritic or nephrotic syndrome — persistent microscopic hematuria, increased proteinuria, recurrent episodes of gross hematuria due to repeated urinary tract infections, and arterial hypertension). In fully developed Alport syndrome (also known as progressive hereditary nephritis), bilateral hearing impairment and ocular abnormalities are also present. Ocular changes occur in approximately one‑third of patients.

Type IV collagen is naturally present in the basal layer of the epidermis (the deepest layer of the skin). This deficiency does not cause clinical problems but can be used to support diagnosis. The term “thin basement membrane syndrome” is used for a milder form of X‑linked Alport syndrome caused by mutations of COL4A3 or COL4A4, located on Xq22.

Diagnosis

Diagnosis is based on physical examination and medical history, detailed family history (presence of genetic syndromes in the family, unexplained renal disorders), and possibly urine analysis in close relatives. Findings may include blood in the urine (microscopic erythrocyturia), increased protein in the urine (nephrotic syndrome), decreased kidney function (progressive renal failure), and impaired vision and hearing.

Further diagnostic methods include immunohistochemical examination of the basement membrane in kidney or skin biopsy, renal biopsy evaluated by electron microscopy, and molecular‑genetic testing of the COL4A3, COL4A4, and COL4A5 genes.

Treatment

Treatment is symptomatic only and focuses on controlling blood pressure and reducing proteinuria (protein loss in urine). Antihypertensive medications from the ACE‑inhibitor group are used. In end‑stage renal failure due to Alport syndrome, the only available therapeutic options are hemodialysis or kidney transplantation, which is usually successful. Graft nephritis develops in approximately 10% of cases (the patient may develop antibodies against the Goodpasture antigen—the α3 chain of type IV collagen—with possible progression to rapidly progressive glomerulonephritis and subsequent graft loss).

Gene therapy is being considered as a potential treatment option in the future.

• obličkové: mikroalbuminúria až veľká proteinúria, artériová hypertenzia a postupné renálne zlyhávanie
• sluchové: obojstranná strata sluchu vo vysokých frekvenciách
• očné: predný lentikonus (15-20% prípadov), perimakulárna hyperpigmentácia (30% prípadov)
• pozitívna rodinná anamnéza - hematúria, ťažká porucha sluchu a / alebo terminálna fáza zlyhania obličiek (neznámeho pôvodu), prítomnosť Alportovho syndrómu v rodine
• medzi klinické príznaky podporujúce podozrenie na syndróm tenkých bazálnych membrán patrí pretrvávajúca mikroskopická hematúria bez zlyhania obličiek ako u chorého jedinca, tak aj v rodinne
• opakujúce sa epizódy močových ciest s prítomnou makroskopickou hematúriou