- Alport Syndrome (Hereditary nephritis).

Alport Syndrome (Hereditary nephritis)

AS, or hereditary nephritis, is a genetically heterogeneous disease caused by mutations in the genes coding for type IV collagen, a major component of basement membranes which is present in kidney, ear, and ocular lens.

GENETICS

• The most common form of hereditary nephritis.
• Approximately 85% of patients have X-linked inheritance caused by a mutation in the COL4A5 gene encoding the α5 chain of type IV collagen.
• Autosomal recessive forms of AS (10%)are caused by mutations in the COL4A3 and COL4A4 genes on chromosome 2 encoding the α3 and α4 chains, respectively, of type IV collagen.
• An autosomal dominant form of AS linked to the COL4A3-COL4A4 gene locus occurs in 5% of cases.

PATHOLOGY
- Light microscopy:

• Kidney biopsy specimens during the 1st decade of life show few changes
• Later, the glomeruli may develop mesangial proliferation and capillary wall thickening, leading to progressive glomerular sclerosis. Tubular atrophy, interstitial inflammation and fibrosis, and lipid-containing tubular or interstitial cells, called foam cells, develop as the disease progresses.

- Multifactorial inheritance (polygenic inheritance).

Multifactorial inheritance (polygenic inheritance)

 

Result from the interplay of genetic and environmental factors.

There is a similar rate of recurrence among all 1st-degree relatives (parents, siblings, offspring of the affected child). It is unusual to find a substantial increase in risk for relatives related more distantly than 2nd degree to the index case.

The magnitude of the trait is determined by number of genes (each adding a small amount to the quantity of the trait or subtracting a small from it)

Also number of environmental factors each act by adding or subtracting an amount to final result. 

Conditions often associated with multifactorial inheritance:

Congenital malformations:

•      neural tube defects

•      congenital heart disease

•      cleft lip and palate

•      pyloric stenosis

•      developmental dysplasia of the hip (DDH)

•      talipes equinovarus

•      hypospadias

- Factors affecting gene expression (in AD disorders)

Factors affecting gene expression

 

 (in Autosomal dominant disorders)

1.     Pleiotropy

2.     Variable expressivity

3.     Reduced penetrance

4.     New mutations

5.     Homozygosity

6.     Knudson two-hit hypothesis

Pleiotropy

·        A single gene (AD) that may give rise to ≥ 2 apparently unrelated effects.

·        In tuberous scelerosis, some affected individuals may have all features (learning difficulties, epilepsy, facial rashes,…)

·        Pleiotropy can result from different mutations in the same gene

·        AD traits may involve only one organ of the body i.e. the eye in congenital cataract. 

Variable expressivity  

·        Striking variation in the clinical features of AD disordes from person to person , even in the same family.

·        In AD polycystic kidney disease, some affected individuals develop renal failure in early adulthood whilst others have just a few renal cysts without affection of renal function.

Reduced Penetrance

·        Penetrance describes the frequency with which phenotypic manifestation of a gene are expressed.

·        A highly penetrant gene (100% penetrance) will express itself almost regardless of the effect of the environment or other interacting gene.

·        This phenomenon explains apparent skipped generations in certain pedigrees.

·        Reduced penetrance when the gene produces characteristic features much less often.

Factors Affecting Penetrance:

1.     Modifier genes.

2.     Hormonal/ reproductive factors.

3.     Response to DNA damage.

4.     Carcinogens (Not everyone with an altered gene develops cancer).

- Cystinosis (liginac Syndrome).

Cystinosis (liginac Syndrome)

A/E:  defect in the metabolism of cysteine that results in accumulation of cystine crystals in most of the major organs of the body, notably the kidney, liver, eye, and brain.

Incidence:

-       It occurs at an incidence of 1 : 100,000 to 1 : 200,000.

-       Is the most common cause of Fanconi syndrome in children.

-       In certain populations, such as French Canadians, the incidence is much higher.

clinical patterns:

1.    Infantile or nephropathic cystinosis: the most severe form present in the 1st 2 yr of life with severe tubular dysfunction and growth failure. If the disease is not treated, the children develop end-stage renal disease by the end of their 1^st decade.

2.    A milder form of the disease manifests in adolescents and is characterized by less-severe tubular abnormalities and a slower progression to renal failure.

3.    A benign adult form with no renal involvement also exists.

-  Patients with nephropathic cystinosis present with clinical manifestations reflecting their pronounced tubular dysfunction and Fanconi syndrome…?

-  Patients are typically fair skinned and blond because of diminished pigmentation.

-  Ocular presentations include photophobia, retinopathy, and impaired visual acuity.

-  Patients also can develop hypothyroidism, HSM, and delayed sexual maturation.

-  With progressive tubulointerstitial fibrosis, renal insufficiency is invariant.

- Lowe Syndrome.

Lowe Syndrome

Lowe syndrome (oculocerebrorenal syndrome of Lowe) is a rare X-linked disorder characterized by:

-       congenital cataracts , glaucoma and blindness often develop.

-       mental retardation, hypotonia and hyporeflexia,

-       The renal abnormalities are tubular and include: hypophosphatemic rickets with ↓ serum phosphorus levels, low to normal serum calcium Levels,↑ serum alkaline phosphatase levels,pRTA, and aminoaciduria.

-  Significant proteinuria is common.

-  The disease is caused by mutations in the OCRL1 gene, which codes for a Golgi aparatus phosphatase.

-  There is no specific therapy for the renal disease or neurologic deficits.

-  Renal treatment may include alkali therapy, phosphate replacement, and vitamin D support.

-  Cataract removal is generally required.

-  Genetic counselling.

Death occur during childhood.

- Bartter syndrome.

 Bartter syndrome

The pathogenesis:

Failure of chloride reabsorption in the thick ascending limb of the loop of Henlé,thus resembling the pharmacological effect of furosemide (frusemide)

Bartter syndrome has been associated with 5 distinct genetic defects in loop of Henle transporters:

CCD, cortisol collecting duct; DCT, descending convoluted tubule; PGE2, prostaglandin E2; TAL, thick ascending loop of Henle.

- Wolf-Hirschhorn Syndrome.

Wolf-Hirschhorn Syndrome

*Pathophysiology:-
results from deletion of the distal short arm of chromosome no 4 (1).

* Clinically, the minimal diagnostic criteria for Wolf-Hirschhorn syndrome (ie, ‘‘core’’ phenotype) consists of typical facial appearance , mental retardation, growth delay, hypotonia and seizures (or EEG anomalies)(2).

* Different categories of the Wolf-Hirschhorn syndrome phenotype are defined according to the extent of the chromosome.4 deletion(2):-

• 1st category :- caused by small deletion that is usually associated with a mild phenotype, lacking major malformations. This category is likely under-diagnosed.
• 2nd category :- caused by large deletions that cause the widely recognizable Wolf-Hirschhorn syndrome phenotype.
• 3rd category :- caused by very large deletions that cause a severe phenotype that can hardly be defined as typical Wolf-Hirschhorn syndrome.

- Down Syndrome.

Down Syndrome.

-History:-
English physician John Down first characterized Down  syndrome as a distinct form of mental disability in 1862 due to  his perception that children with Down syndrome shared physical  facial similarities (epicanthal folds) with those of Mongolian race.

-Incidence:-

• In general population 1:660.
• It is the most common Autosomal abnormalities.
• It has equal sex distribution.

-Causes (cytogenic types):-

1-Complete Trisomy 21 (non disjunction):-

• Incidence:- 95%.
• Due to non-disjunction of chromosome 21 during meiotic division (  (i.e failure of a chromosome 21 pair to separate) so an ovum with 24 chromosomes when fertilized by a sperm carrying 23 chromosomes lead to formation of a fertilized ovum with 47 chromosome.
• It occur during oogenesis more than spermatgenesis.
• The risk increases with age of the pregnant mother especially  over 40years as the primary oocytes of the mother have satyed in the prophase for a long time ( 40 years or more).
• Karyotyping:- 

47,xx+21(female down).
47,xy+21(male down).
(+ means that an extra chromosome is present).

- Paediatric syndromes.

A Medical syndrome is defined as :- 
A group of symptoms and signs that collectively indicate or characterize a disease, psychological disorder, or other abnormal condition. There are a lot of medical syndromes and we try to list some of them:-

1. Down syndrome (click here).
2. Wolf-Hirschhorn Syndrome (click here).
3. Bartter syndrome (click here).
4. Liginac syndrome (click here) 
5. Lowe syndrome (click here)
6. Alport syndrome (click here)