Sickle Cell Disease (SCD): Practice Essentials, Background, Genetics

Single Gene Disorders - Autosomal Recessive

There are several different patterns of inheritance of single gene disorders that we can study including:

autosomal recessive

autosomal dominant

incomplete dominance

sex-linked recessive

X and Y chromosomes = sex chromosomes

All other chromosomes = autosomescloseautosomesChromosomes that control the characteristics of an organism but do not determine its sex.

Autosomal recessive inheritance

Autosomal recessive traits are expressed rarely, sufferers require two recessive allelescloserecessive alleleAlternative form of a gene that is expressed only if a dominant allele of that gene is not present. An organism must have two copies of a recessive allele for that allele to be expressed. To be affected (homozygous recessive).

Recessive traits may skip generations and will affect both genders equally. An example of an autosomal recessive condition is cystic fibrosis.

Cystic fibrosisclosecystic fibrosisA disorder that mainly affects the lungs, pancreas, liver, and intestine. The main symptom is difficulty breathing. Is an inherited disorder of cell membranes that mainly affects the lungs and digestive system. They can become clogged with lots of thick, sticky mucus as too much is produced.

Over many years, the lungs become increasingly damaged and may eventually stop working properly. A number of treatments are available to help reduce the problems caused by the condition, but unfortunately average life expectancy is reduced for people who have it.

It is caused by a faulty recessive allelecloserecessive alleleAlternative form of a gene that is expressed only if a dominant allele of that gene is not present. An organism must have two copies of a recessive allele for that allele to be expressed. On chromosome 7. To be born with cystic fibrosis, a child has to inherit two copies of this faulty gene - one from each of their parents. Their parents will not usually have the condition themselves, because they will only carry one faulty gene and one that works normally.

In the diagram below cystic fibrosis involves:

the recessive allele (lower case), which can be shown as f

the dominant allele (capital letter), which can be shown as F

An individual who is homozygousclosehomozygousThis describes a genotype in which the two alleles for the characteristic are identical. (ff) with the recessive allele will develop cystic fibrosis. Someone who is heterozygouscloseheterozygousThis describes a genotype in which the two alleles for a particular characteristic are different. (Ff) will be a carrier of the recessive allele, but will not develop cystic fibrosis and have no symptoms.

Someone who is homozygous with the dominantclosedominantAn allele that always expresses itself whether it is partnered by a recessive allele or by another like itself. Allele (FF) will not develop cystic fibrosis, as you need two faulty alleles (ff) for the condition. In this combination, no faulty alleles are present.

Example 1

In example 1, both parents are heterozygous, Ff. The chance of them producing a child with cystic fibrosis is 1 in 4, or 25%. The parents are carriersclosecarrierSomeone who does not suffer from a condition but carries the allele and can pass it to his or her offspring. Of the disorder, and it is possible for them to produce a child with cystic fibrosis, without having it themselves. Carriers have no symptoms and are usually unaware they are carrying the recessive allele.

Example 2

In example 2, only one parent (the father) has a copy of the recessive allele (Ff). There is no chance of them producing a child with cystic fibrosis. However, half the possible offspring will be homozygous, FF, and be unaffected, and half will be heterozygous, Ff and carry the recessive allele. The ratio of FF to Ff is 1:1 or 50%.

This genetic diagram shows how cystic fibrosis is inherited.

Mendelian Genetics: Patterns Of Inheritance And Single-Gene Disorders

Autosomal recessive single-gene diseases occur only in individuals with two mutant alleles of the disease-associated gene. Remember, for any given gene, a person inherits one allele from his or her mother and one allele from his or her father. Therefore, individuals with an autosomal recessive single-gene disease inherit one mutant allele of the disease-associated gene from each of their parents. In pedigrees of families with multiple affected generations, autosomal recessive single-gene diseases often show a clear pattern in which the disease "skips" one or more generations.

Phenylketonuria (PKU) is a prominent example of a single-gene disease with an autosomal recessive inheritance pattern. PKU is associated with mutations in the gene that encodes the enzyme phenylalanine hydroxylase (PAH); when a person has these mutations, he or she cannot properly manufacture PAH, so he or she is subsequently unable to break down the amino acid phenylalanine, which is an essential building block of dietary proteins. As a result, individuals with PKU accumulate high levels of phenylalanine in their urine and blood, and this buildup eventually causes mental retardation and behavioral abnormalities.

The PKU-associated enzyme deficiency was determined biochemically in the 1950s—long before the PAH-encoding gene was mapped to human chromosome 12 and cloned in 1983. Specifically, Dr. Willard Centerwall, whose child was mentally handicapped, developed the first diagnostic test for PKU in 1957. Called the "wet diaper" test, Centerwall's test involved adding a drop of ferric chloride to a wet diaper; if the diaper turned green, the infant was diagnosed with PKU. The wet diaper test was used to reliably test infants at eight weeks after birth; by this time, however, infants who were affected by PKU had already often suffered irreversible brain damage.

Thus, in 1960, Dr. Robert Guthrie, whose niece suffered from PKU and whose son was also mentally handicapped, established a more sensitive method for detecting elevated phenylalanine levels in blood, which permitted a diagnosis of PKU within three days after birth. Guthrie's test used bacteria that were unable to make their own phenylalanine as messengers to report high blood levels of phenylalanine in an infant's blood sample obtained via heel prick. With Guthrie's method, the phenylalanine-deficient bacteria were grown in media together with a paper disk spotted with a drop of the infant's blood. If the phenylalanine levels in the blood were high, the bacteria would grow robustly, and a diagnosis of PKU could be made. Through the ability to discover that their child had PKU at such an early age, parents became able to respond immediately by feeding their child a modified diet low in proteins and phenylalanine, thereby allowing more normal cognitive development. Guthrie's test continues to be used today, and the practice of obtaining an infant's blood sample via heel prick is now used in numerous additional diagnostic tests.

Several other human diseases, including cystic fibrosis, sickle-cell anemia, and oculocutaneous albinism, also exhibit an autosomal recessive inheritance pattern. Cystic fibrosis is associated with recessive mutations in the CFTR gene, whereas sickle-cell anemia is associated with recessive mutations in the beta hemoglobin (HBB) gene. Interestingly, although individuals homozygous for the mutant HBB gene suffer from sickle-cell anemia, heterozygous carriers are resistant to malaria. This fact explains the higher frequency of sickle-cell anemia in today's African Americans, who are descendants of a group that had an advantage against endemic malaria if they carried HBB mutations. Finally, oculocutaneous albinism is associated with autosomal recessive mutations in the OCA2 gene. This gene is involved in biosynthesis of the pigment melanin, which gives color to a person's hair, skin, and eyes.

Autosomal Dominant Polycystic Kidney Disease

Researchers from Belgium found that overall survival and kidney transplant survival was better in patients with ADPKD vs non-ADPKD, but data were not conclusive on the association between WBC and outcomes.

Mayo Clinic researchers recently studied an algorithm based on artificial intelligence (AI) for measuring magnetic resonance-derived total kidney volume in autosomal dominant polycystic kidney disease against manually edited segmentations.

Patients with autosomal dominant polycystic kidney disease have their own regrets about how they've managed their disease, but they also blame healthcare providers for not opening their eyes to ways of improving their physical and psychological well-being, say the results of this report.

A Japanese study examined differences in total kidney volume and total liver volume in patients with autosomal dominant polycystic kidney disease receiving either peritoneal dialysis or hemodialysis. Some findings were unexpected.

This study demonstrated substantial genetic and phenotype variability in ADPKD among patients, which researchers propose could be used as a tool for ADPKD diagnosis.

A deep-learning model for fully automated joint kidney and liver segmentation was recently shown to be a robust and accurate tool for rapid estimation of kidney and liver volume. But is it feasible to implement it into routine clinical care?

According to a new study from Tokyo, decline in kidney function and increased kidney volume may be risk factors for intracranial aneurysm in patients with autosomal dominant polycystic kidney disease.

Korean investigators sought to identify risk factors associated with ADPKD progression. A standard therapy for slowing the advance to end stage renal disease is lacking.

The Polycystic Kidney Disease Foundation established the first national ADPKD Registry to facilitate therapeutic research on ADPKD, which has been limited by lack of an organized patient database.

---