Introduction to hereditary kidney diseases

 

Introduction to hereditary kidney diseasesIntroduction:

For about two decades, the spectrum of hereditary nephropathies, the emergence and practice of “nephrogenetics” have evolved considerably. Clinical interest in these diseases has been driven by advances in molecular genetics: mutated genes in many hereditary nephropathies have been identified and genetic tests for mutations have been made in practice for routine clinical diagnosis and for prenatal diagnosis in some cases.

Thanks to these advances, new genetic diseases have been discovered, grouping together previously considered independent sets, but united by mutations of the same gene. Similarly, genetic tests have shown that some diseases observed in childhood may have their counterpart in adults in the form of late-onset nephropathies, the nature and mechanism of which were previously unknown. It can be seen for certain “new” hereditary diseases such as those due to TCF2 / HNF1- b mutations or genes encoding podocyte molecules.

This introduction is limited to diseases that progress to chronic renal failure (CRF), excluding most hereditary tubulopathies.

Diversity of hereditary renal diseases:

Diseases of renal development, syndromic or not, Bardet-Biedl syndrome, Alagille, kidney-coloboma, BOR; renal hypodysplasia change as the function of normal and mutated genes is better known). Heterogeneity is also clinical (phenotypic): the clinical manifestations of the same genetic disease vary from one family to another, but also within the same family (which shares the same mutation).

Modifying genes (which modulate the effect of the mutation) and / or environmental factors probably explain these disparities; other epigenetic phenomena could be involved.

Finally, heterogeneity is genetic (or genotypic). The same phenotype can be created by different gene mutations: for example, two genes for autosomal dominant polycystic disease (ADPKD), PKD1 and PKD2 (by far the most common inherited kidney disease), six genes for “nephronophtis”, more than 10 genes today for Bardet-Biedl syndrome. The genetic heterogeneity is even greater for the clinician when several modes of transmission are identified: in X-linked Alport syndrome, autosomal recessive or rarely dominant where the defect concerns various genes encoding all the various chains has collagen of type IV. The nomenclature of genetic diseases will change in the coming decades: we will abandon syndromes and eponyms to choose the molecular defect that characterizes the disease (when possible).

Scarcity (excluding ADPKD) and the diversity of genetic renal diseases justify the importance of associations (such as the Association for Information and Research on Genetic Kidney Diseases, AIRG) for patients and their families, on the other hand the creation of reference centers for rare diseases, including three (in Paris, Lyon and

Toulouse) are centered entirely or largely on renal genetic diseases.

Simplicity and complexity of genetic tests:

Genetic testing has entered the medical practice of nephrology. They help in the diagnosis of certain genetic diseases: for example, nephronophtise juvenile, disease by mutation of TCF2 / HNF1- b , familial nephrotic syndromes and / or corticoresistant, etc. They allowed prenatal diagnosis when it is requested by a couple. The practice of these tests meets regulatory and ethical requirements defined by an implementing decree, including written informed consent.

Detection of the mutation is not simple. The size of the gene or its structure can make detection difficult and tedious.Most often, we encounter a wide variety of mutations of a gene, each family (or almost) carrying a particular mutation, called “private”. This does not simplify the demonstration of the mutation but when it is known, it is easy by the genetic test to identify the carriers (and vectors) in the family.

In some cases, a mutation predominates (hot-spot) and this facilitates the work of geneticists: for example the deletion of the NPHP1 gene demonstrated in about 70% of cases of juvenile nephronophtise type I, or the predominant mutations of nephrin in congenital nephrotic syndrome in the Finnish population, or mutations localized preferentially in some exons such as in the UMOD gene (which encodes uromodulin or Tamm-Horsfall protein) etc.

In spite of the progress of the techniques, the detection of the mutations in certain diseases remains long, expensive, of difficult application or especially not very relevant for the current diagnosis, for example in the ADPKD (ultrasound) or the syndrome of Alport (cutaneous biopsy or kidney biopsy). The technical limitations and reasons for the methodological difficulties go beyond the scope of this introduction.

Two other examples illustrate the genetic complexity in kidney disease. In addition to the mutations of nuclear DNA, that of mitochondrial DNA (mtDNA). Mitochondrial cytopathies are the consequence and sometimes include glomerular or tubulointerstitial renal disease with Fanconi syndrome, often diabetes mellitus, deafness and neuromuscular manifestations. But many mitochondrial molecules are encoded by nuclear genes and meet the rules of classical Mendelian inheritance (whereas mtDNA mutation diseases are maternally transmitted). Other cases of non-Mendelian inheritance are known: for example triallelic inheritance in certain autosomal recessive diseases such as Bardet-Biedl syndrome or nephronophtise with neurological involvement where there is a homozygous mutation of a gene and a heterozygous mutation another gene; examples of bi- (or di-) genic diseases have been described in some families of hereditary nephrotic syndrome where a nephrin mutation and a podocin mutation coexist.

“Transition” between pediatrics and adult medicine:

Hereditary (or non-inherited) kidney disease, such as cystic fibrosis, congenital heart disease, and hereditary metabolic diseases, are excellent examples where the transition from pediatrics to adult medicine is a necessity. This transition must be prepared, organized and coordinated. She still faces many obstacles: reluctance of teenagers and their families to leave the pediatric teams who have followed them since the first years of life, reluctance of the pediatric teams to “separate” from these adolescents, poorly prepared teams treating children adults to welcome these “new” patients who have diseases often poorly known to adult doctors, and finally lack of material resources specifically dedicated to this transition. Collaboration between pediatric and adult medicine teams for care and research is one of the elements of a successful transition. The training of all nephrologists in so-called pediatric diseases is also a prerequisite.

The knowledge of pediatric nephrology teaches us to recognize the late-onset and atypical forms of certain genetic diseases first described in children.

Two examples:

• The autosomal dominant disease by mutation of TCF2 / HNF1- b was first observed in children with early renal impairment and then by diabetologists in the form of MODY (maturity-onset diabetes of the young) type 5. In fact , the nephrological presentation of the adult is quite common: slowly progressive renal disease, with glomerular or non-glomerular cysts, or morphological abnormalities of the upper urinary tract, associated with an early drop, genital and / or hepatic abnormalities. Diabetes mellitus may be absent or appear only several years after renal impairment;

• Mutations in the NPHS2 gene (coding for podocine) result in the autosomal recessive kidney-negative nephrotic syndrome of the very young child. The disease can occur in adulthood with the same phenotype but the genotype is different: a polymorphism or variant R229Q (found in 4-5% of the population) on one allele and an inactivating mutation on the other allele.

Genetic counseling:

Genetic counseling is first and foremost about informing a patient (and their family) of the inheritance of their disease, its mode of transmission and its evolution. To do this, it is necessary that the hereditary character be well demonstrated, that the family tree is well established and that the information is given by an informed doctor, knowing the disease and its future. The nephrologist must therefore be at the origin of genetic counseling and be associated with it. Molecular testing for mutation may be valuable in establishing the genetic status of some members of the family, for example potential female carriers in X-linked diseases.

Informed and written consent to these tests must be acquired according to the rules recalled above. The information of all family members via the proposal is also required.

Genetic counseling can also include information on the possibilities of prenatal diagnosis (or even preimplantation diagnosis) according to the request of a couple but this is the domain of the geneticist and is therefore not discussed here.

Treatment of renal genetic diseases:

First, renal inherited diseases have benefited from more general advances in medicine, such as advances in hepatic surgery or embolization of cerebral artery aneurysms in dominant polycystic disease; or the use of ACE inhibitors / angiotensin II receptor antagonists (ACE inhibitors) in hereditary diseases with proteinuria, including Alport syndrome and Fabry disease. Organ transplantation (apart from kidney transplantation) has also been an improvement in the treatment of certain inherited renal diseases: firstly, by correcting certain extra-renal abnormalities, by liver transplantation in case of massive polycystic liver disease or by heart transplantation in case of heart failure in Fabry disease; on the other hand, by correcting the very deficit of the disease by means of liver transplantation in type I primary hyperoxaluria or certain hereditary amyloses (for example by transthyretin or α- chain deficiency of fibrinogen).

Finally, progress has been or will be made in the specific treatment of certain genetic diseases. Hereditary metabolic diseases have benefited first. It has long been known that the administration of allopurinol prevents the formation and renal and urinary deposition of 2,8 dihydroxyadenine in APRTase deficiency or that of vitamin B 6 may partially or completely improve certain type I primary hyperoxaluria. recently, cysteamine, ocularly and orally, delays the progression of certain complications in cystinosis. Biotechnology-derived human α- galactosidase corrects enzyme deficiency and should prevent most manifestations of Fabry disease. In these rare diseases, performing therapeutic trials is not easy because it is difficult to collect large numbers of “eligible” patients. In primary hyperoxaluria, the administration of Oxalobacter formigenes may reduce the production of oxalate in the intestine and thus the precipitation of calcium oxalate in the kidney.

Therapeutic advances for other diseases should come from a better knowledge of the mechanism (s) of genetic diseases and the design of molecules able to oppose these dysfunctions. In this physiopathological and pharmacological approach are the current trials in ADPKD using a vasopressin V2 receptor antagonist (tolvaptan), octreotide, a somatostatin analogue, or rapamycin or analogues (sirolimus, éverolimus). in polycystic kidney but also hepatic. Other products will likely follow in order to stop or slow cyst progression (assessed by magnetic resonance imaging [MRI]) and to protect kidney function.

The cellular therapy of certain renal genetic diseases (Alport, Fabry) has already been tested in animals. It is the same for the gene therapy of mice with an equivalent of Fabry disease, but the application to humans of gene therapy still poses many difficulties.

The advances made by genetics have consequences far beyond genetics:

The contribution of genetics goes far beyond genetic diseases.

Three examples:

• Genetic diseases of kidney development have identified mutated genes. These same non-mutated genes govern the normal development of the kidney: PAX2 (reincolobome), EYA (branchio-oto-renal syndrome [BOR]), TCF2 / HNF1- b , etc. ;

• familial nephrotic syndromes have made known podocytic molecules hitherto unknown, controlling glomerular permeability: nephrin, podocin (components of the slit diaphragm located between two podocytes), a -actinin 4 (cytoskeleton component), TRPC6 ( calcium channel), etc. For a long time, it was thought that the selective permeability of the glomerular capillary wall was determined by physicochemical factors (the pressure balance, the negative charges of the wall); the discovery of the mechanisms of these nephrotic syndromes, congenital or not, has demonstrated the major role of these molecules, coded by identified genes;

• autosomal dominant von Hippel-Lindau disease (VHL) includes retinal and central nervous system hemangioblastomas, pancreatic cysts or tumors, pheochromocytomas, endolymphatic sac tumors, and renal involvement, cysts or especially multifocal and bilateral renal carcinomas. These last tumors are exemplary of hereditary cancers where two molecular events occur: on the one hand, the VHL germline mutation affecting an allele, and on the other hand a somatic VHL mutation affecting the other allele. Remarkably, in most sporadic renal cell carcinomas, two somatic mutations of the VHL protein are associated.

From a rare hereditary disease, we have moved to a more general mechanism, renal carcinogenesis. Other hereditary renal cancers associated with other systemic manifestations have subsequently been recognized. VHL protein is involved in an even more general mechanism, the “sensitivity” of cells to oxygen (oxygen sensing). In this phenomenon, the inducible factor hypoxia (HIF) plays a central role activating various genes that stimulate angiogenesis or the production of erythropoietin (in the kidney). VHL protein provides cellular regulation of HIF- a by allowing its degradation in the proteasome. The consequences of this discovery, schematically described, lead to the design of new molecules that oppose angiogenesis or stimulate the production of erythropoietin.

The advances generated by the study of genetic diseases, which are often rare, have consequences far beyond genetics.

Monogenic diseases still unknown to the polygenic predisposition to renal diseases:

So far, monogenic diseases have been discussed (although a few rare examples of digenic diseases have been presented). In addition, the same clinical phenotype may be due to mutations of several genes (this is genetic heterogeneity) but each family is characterized by a mutation of a single gene.

All genetic renal diseases have not been identified.

In some families, several subjects have nephropathy without apparent specificity, without recognized extrarenal manifestations. These “gene-seeking” diseases are not exceptional. The same is true for primary IgA nephropathy (or Berger’s disease), which is often sporadic, occasionally familial, or for vesico-ureteric reflux and the resulting nephropathy, often familial (sometimes “syndromic”), associated with extrarenal manifestations. as in BOR or kidney-coloboma syndrome, often isolated). For two decades, a familial predisposition has been demonstrated to develop nephropathy in type I diabetes mellitus; a predisposition locus has been recently located on chromosome 3.

Finally, in many populations, particularly in the black population in the United States, many families have been identified where several members are dialysed or transplanted.

This predisposition to renal failure is probably polygenic and dependent on unknown environmental factors.

loading...
«
»

Share This Post

Related Articles

Powered by WordPress · Designed by Theme Junkie