Autosomal dominant PKD is the prototype, and by far the most prevalent, inherited cystic kidney disease. Diagnosis is based mainly on renal ultrasonographic findings, in at-risk subjects belonging to ADPKD families . Normal renal ultrasonography after 30 years of age excludes the diagnosis, but this is not true for younger subjects. Genetic diagnosis may therefore be required in rare instances: (i) when living related kidney donation is considered in at-risk subjects aged less than 30 years; (ii) in young at-risk subjects belonging to families with intracranial aneurysms; (iii) in young subjects who 'need-to-know' for various reasons, including family planning or professional choice; and (iv) in the very rare PKD families in which rapidly progressive ADKD appears in the first years of life and carries a high risk of recurrence in siblings. In these cases, linkage analysis is often the only method available. Indeed, the direct identification of mutations has been performed so far in a limited number of ADPKD families. The disease is genetically heterogeneous, with two different genes being involved: the PKD1 gene located on
Table 6.1. Classification of the main inherited kidney disorders
1. Cystic kidney diseases
Autosomal dominant polycystic kidney disease Autosomal recessive polycystic kidney disease Other cystic kidney diseases
2. Inherited diseases with glomerular involvement
Alport's syndrome and variants Benign familial haematuria
Congenital nephrotic syndrome of the Finnish type Nail-patella syndrome
Metabolic diseases with glomerular involvement Fabry's disease
LCAT (lecithin: cholesterol acyltransferase)/deficiency Type I glycogen storage disease Familial primary glomerulonephritis
3. Inherited tubulointerstitial disorders
4. Genetic diseases with nephrolithiasis
5. Inherited tubular disorders
Cystinuria; Lowe's syndrome and other causes of Fanconi syndrome Bartter's syndrome Gitelman's syndrome Liddle's syndrome
Nephrogenic diabetes insipidus (vasopressin resistant)
chromosome 16p and the PKD2 gene on 4q . The structure of the PKD1 gene has been shown to be complex, with a number of duplicated regions, rendering detection of mutations rather tricky and tedious. The PKD2 gene is simpler and smaller in size, and, although the gene has been identified more recently, mutations have been detected more easily and numerously .
The prevalence of intracranial aneurysm is five times higher in ADPKD than in the general population. In addition, intracranial aneurysms (IAs) are approximately 2.5 times more frequent in families with a history of IA than in other families. Rupture is the main complication of IA, leading to subarachnoid haemorrhage. This complication has a very poor prognosis with a mortality rate of about 50%. Detection of occult, asymptomatic IA can be achieved today by noninvasive means such as magnetic resonance imaging-angiography. Treatment of IA can be considered, according to size and site, either by surgical clipping or by detachable coil-induced thrombosis performed by an interventional radiologist . Thus, early identification of IA may be necessary in some families. In a retrospective European study, it was found that 10% of IA rupture accidents occurred at 20 years of age or less . Such a strategy of early identification may imply genetic testing in young at-risk subjects.
Apart from ADPKD, other inherited cystic kidney diseases are known. For example, autosomal recessive PKD, which has a low prevalence when compared with ADPKD (1/40000 versus 1/500-1000 individuals) and becomes manifest in childhood, although patients may require renal replacement therapy later in life, is consistently associated with congenital hepatic fibrosis (interestingly, a few families with ADPKD and congenital hepatic fibrosis have been reported). Other examples of inherited cystic kidney disease include: (i) glomerulocystic kidney disease which may be dominantly inherited; (ii) X-linked oro-facio-digital syndrome type I with lethality in males; and (iii) autosomal dominant phakomatoses - namely, tuberous sclerosis and von Hippel-Lindau (VHL) disease which includes many extrarenal systemic abnormalities. Correct clinical diagnosis is the first step in genetics. However, this diagnosis may be occasionally difficult in cystic kidney diseases, especially when renal cysts are discovered in utero or early in life.
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