Progressive Hereditary Nephritis

Ewa Elenberg

Alport syndrome or hereditary nephritis is characterized by hematuria, proteinuria, progressive renal failure, sensorineural hearing loss, and ocular lesions. Affected male patients typically have severe disease, whereas the course in female patients tends to be mild. Alport syndrome at the molecular level results from inherited disorder of type IV collagen, a major constituent of basement membranes. To date, six chains of type IV collagen have been described: alpha1(IV) and alpha2(IV) collagens are products of the COL4A1 and COL4A2 genes located on chromosome 13; alpha3(IV) and alpha4(IV) collagens are products of the COL4A3 and COL4A4 genes located on chromosome 2; and alpha5(IV) and alpha6(IV) collagens are products of the COL4A5 and COL4A6 genes located on the X chromosome. The alpha1(IV) and alpha2(IV) chains form a collagen network in all basement membranes. In contrast, the alpha3(IV), alpha4(IV), and alpha5(IV) chains appear to form a unique collagen network in only those basement membranes (glomerular, cochlear, and ocular) involved in the pathogenesis of Alport syndrome, consistent with the finding of COL4A3, COL4A4, or COL4A5 collagen gene mutations in many patients with Alport syndrome.

TABLE 326.1. MODES OF INHERITANCE OF ALPORT SYNDROME

Mode of Inheritance	Frequency of Inheritance	Chromosomal Localization of Affected Genes	Affected Gene	Affected Alpha Chain of Type IV Collagen
X-linked dominant	Most common	Xq22	COL4A5 COL4A6	alpha5(IV) alpha6(IV)
Autosomal recessive	Less common	2q35	COL4A3 COL4A4	alpha3(IV) alpha4(IV)
Autosomal dominant	Rare	2q35	COL4A3 COL4A4	alpha3(IV) alpha4(IV)

GENETICS

Alport syndrome has three genetic forms of inheritance (Table 326.1). The most common, X-linked form, results from mutations of the COL4A5 or COL4A6 collagen gene; the less frequent, autosomal recessive form results from mutations of the COL4A3 or COL4A4 collagen gene. The third, very rare form
is the autosomal dominant, which has been linked to COL4A3 and COL4A4 genes.

Eighty-five percent of patients have the X-linked dominant form of Alport syndrome, caused by mutations in the COL4A5 gene located in the Xq22 region that encodes for the alpha5(IV) chain of type IV collagen. Mutations of the COL4A5 gene result in the loss of alpha5(IV) chain in basement membranes. More than 300 unique COL4A5 mutations have been reported thus far. However, COL4A5 mutations have been identified in only 50% of patients with X-linked Alport syndrome. Because of the X-linked dominant inheritance pattern, male patients are much more likely to develop severe disease, and affected male patients nearly always develop end-stage renal disease (ESRD). Male patients with mutations that significantly affect function of the alpha5(IV) chain develop ESRD and deafness by the third decade of life. However, male patients with mutations that have only a minor effect on the biology of the alpha5(IV) chain may not develop ESRD until later in life and may not develop deafness at all. In women, the risk of progression to ESRD is less than that in men. One specific mutation involving deletion of the 5′ ends of both the COL4A5 and COL4A6 genes is associated with development of leiomyomas of the esophageal tract, tracheobronchial tree, and female genital tract, in addition to early ESRD (Table 326.2).

TABLE 326.2. CLINICAL CHARACTERISTICS OF ALPORT SYNDROME

Mode of Inheritance	Genetic Features	Urinalysis	Clinical Characteristics
X-linked dominant	Males
	Males inherit disease from mother Father-to-son transmission not possible	Persistent proteinuria and microscopic hematuria with episodic gross hematuria	Males develop severe disease Deafness occurs early Ocular changes associated with more severe renal involvement HTN increases with age ESRD by fourth decade of life
	Females
	Females inherit disease from affected father or mother Females asymptomatic or with mild symptoms	Intermittent or no hematuria Proteinuria rare	Usually benign prognosis Deafness, ocular changes and HTN less frequent Low risk of progression to ESRD (increased risk of ESRD if gross hematuria, proteinuria, deafness, ocular changes) Mutation involving deletion of the 5′ ends of both the COL4A5 and COL4A6 genes associated with leiomyomas of the esophageal tract, tracheobronchial tree, and female genital tract, in addition to early ESRD
Autosomal recessive	History of consanguinity	Hematuria and proteinuria persistent in both male and female patients	Severe disease in affected females with mild or no symptoms in the parents Ocular changes, deafness, and HTN associated with more severe renal involvement Early onset of ESRD before age 30 years regardless of gender
Autosomal dominant	Father-to-son transmission possible	Hematuria and proteinuria	ESRD and deafness may develop early, although male patients have better prognosis than with X-linked inheritance Some families with Alport syndrome have thrombocytopenia with large platelets and deafness (Epstein syndrome)
ESRD, end-stage renal disease; HTN, hypertension.