This chapter discusses hereditary disorders of the glomerulus. These conditions can be categorized on the basis of the demonstrated or predicted function(s) of the affected proteins. It should be recognized that this is a somewhat arbitrary categorization that likely simplifies the cell-cell and cell-matrix interactions that produce disease phenotypes.
GLOMERULAR BASEMENT MEMBRANE DISORDERS
Familial Hematurias: Alport Syndrome Complex
A substantial fraction of children with persistent hematuria (30–50% in several published series) have an inherited disorder of glomerular basement membranes (GBMs). Accurate diagnosis of familial hematuria is crucial for predicting prognosis and providing accurate reproductive counseling.
The Alport syndrome complex (ASC) encompasses genetic disorders of the collagen IV α345 network, the predominant collagen IV species in mature GBM. ASC accounts for most children and adolescents with familial glomerular hematuria. Genetic loci associated with ASC include the COL4A3 and COL4A4 genes on chromosome 2 and the COL4A5 gene on the X chromosome. ASC is genetically heterogeneous, with X-linked and autosomal forms. The majority of patients have X-linked ASC due to mutations in COL4A5, the gene encoding the α5 chain of type IV collagen [α5(IV)]. Autosomal ASC is caused by mutations in 1 or both alleles of COL4A3 or COL4A4. Heterozygous mutations in COL4A3 or COL4A4 are inherited in a dominant fashion, while patients with mutations in both alleles present in a recessive manner. Patients with heterozygous mutations in COL4A3 or COL4A4 and isolated hematuria are commonly classified as having “thin basement membrane nephropathy,” although this term describes a renal pathologic finding rather than a discrete disease entity.
Persistent microscopic hematuria is the hallmark of ASC, occurring in 100% of males and 95% of females with X-linked disease and all patients with autosomal recessive ASC. About 50% of individuals with heterozygous mutations in COL4A3 or COL4A4 are asymptomatic and are considered carriers of autosomal ASC. Episodic gross hematuria is common. Since only 10% to 15% of children with X-linked ASC have de novo mutations, most will have a parent with hematuria. However, normal parental urinalyses does not exclude a diagnosis of X-linked ASC. Each parent of a child with autosomal recessive ASC is heterozygous for a mutation in COL4A3 or COL4A4. Since about 50% of these parents are asymptomatic carriers, hematuria may be found in both, 1, or neither parent of a child with autosomal ASC.
Children with ASC frequently present with gross or microscopic hematuria similar to children with acquired forms of hematuria. A family history of kidney failure or deafness in a child with hematuria should suggest a possible diagnosis of ASC. Sensorineural deafness develops in 80% of males with X-linked ASC and most patients with autosomal recessive ASC, but deafness is unusual in those with heterozygous mutations in COL4A3 or COL4A4. The onset of measurable hearing deficits ...