An Overview of Common Genetic Disorders

Introduction

Genetic testing has been a popular trend lately due to the success of websites such as 23andMe, Ancestry, and many others; and the amount of information these testing services can provide by a simple swab or mouth rinse is amazing. While some use these services for learning about their ancestral background or most effective diet and exercise plans, many people use these services to learn if they have a genetic marker for major diseases such as Alzheimer’s disease or breast cancer. While these genetic markers often just show an increased likelihood of developing a disease later in life, the success of this form of testing has brought a lot of attention to genetic disorders, including those that are present at birth. This paper will discuss five different types of interesting and common genetic disorders, explaining the genetic origin, symptoms, diagnosis, and any other major details of each disorder.

Autosomal Dominant Polycystic Kidney Disease

Autosomal Dominant Polycystic Kidney Disease, also known as ADPKD, is a very common form of polycystic kidney disease due to the nature of its dominant genetic transmission. It is present in somewhere between 1 in 400 to 1 in 1,000 babies and affects approximately 400,000 people in the United States. As the name implies, PKD is a genetic disorder that involves the growth of fluid-filled cysts in both kidneys, which can eventually lead to kidney failure.

ADPKD for most people sets in as an adult, even though the disease is present from birth. While the disease tends to target the kidneys for most of the damage, this disease can also cause cysts to develop in other organs or complications associated with the circulatory system. According to the National Human Genome Research Institute, hypertension is the most common issue associated with ADPKD.

The diagnosis of ADPKD involves using ultrasounds, CT scans, or MRI studies of the kidneys. According to Torres et al., the most common form of testing for ADPKD is renal ultrasound because of the cost and safety of the procedure. Previously the criteria for diagnosis required fewer cysts than three, but these criteria were revised because of the younger age group tested. While the age groups older than thirty were not affected by the changes in criteria, “Requirement of three or more cysts (unilateral or bilateral) has a positive predictive value of 100% in the younger age group and minimizes false-positive diagnoses, as 2.1 and 0.7% of the genetically unaffected individuals younger than 30 years have one and two renal cysts, respectively.” (2009). Other than diagnostic testing, there is a genetic test available that checks for mutations of the PKD1 and PKD2 genes, so that perhaps people who are worried they have the disease can know for sure and adjust their lifestyle before onset. Also, there are prenatal tests available for prenatal diagnosis, but they are very rarely requested since the disease is not detectable at birth.

As mentioned previously, there are two different genes that can serve as genetic markers for ADPKD. What is similar about these genes is that mutations in either gene are highly variable and usually private, which means that each mutation is usually unique to the individual. In addition, at the time of the article written by Torres et al., “the ADPKD Mutation Database lists 333 truncating PKD1 mutations identified in 417 families with a total of 869 variants, including missense mutations and silent polymorphisms”. This article was written in 2009, and in 2019 the database now lists 2,323 different mutations, which shows the growth rate in the number of different mutations associated with these genes.

What is quite different about these genes is that while both genes do show markers for the same disease, according to the article by Torres et al., which gene has the marker for the disease has a huge impact on the severity of the symptoms. According to this article,” PKD1 is more severe than PKD2-associated disease (age at ESRD End-stage Renal Disease 54.3 versus 74.0 years for PKD1 and PKD2, respectively). The greater severity of PKD1 is due to the development of more cysts at an early age, not to faster cyst growth”.

Treatment for ADPKD is to target the symptoms rather than cure the disease, as there is no known cure for ADPKD. Pain in the area of the kidneys is treated with pain medications, and chronic pain is treated with antidepressants. When medication is no longer effective at treating pain, fluid is drained from the kidney cysts as a last resort. Blood pressure is tracked regularly, treating high blood pressure with anti-hypertensives. Once kidney function is starting to become affected, treatment becomes more aimed at slowing the decline into kidney failure. This can involve restricting protein in the patient’s diet, controlling blood pressure, and preventing acidosis and hyperphosphatemia. Following renal failure, the only options are dialysis or renal transplant, and the most successful tend to be dialysis.

Huntington Disease

Huntington's Disease, also referred to as HD, is an autosomal dominant neurodegenerative disorder and the onset is usually during the middle of life (around 35 to 44 years of age). This disease usually causes the death of the affected patient between twelve and fifteen years from the onset of symptoms. Down Syndrome affects around one in 10,000 people or approximately 30,000 people in the United States. Huntington's Disease causes some severe psychiatric, cognitive, and motor defects that are usually such as uncontrollable movements as well as emotional and intellectual issues.

In 1993, it was discovered that an unstable expansion of CAG (trinucleotide) repeats within the coding region of the gene HTT was the mutation responsible for causing HD. The HTT gene, or “IT15” as it was known in early Huntington's Disease research, is located on chromosome four and encodes for the protein huntingtin. This mutation causes an expanded glutamine residue attached to the amine group terminal. The exact biological function of this protein is unknown, so it is hard to determine the link between this protein, the HTT mutation, and the disease.

The symptoms of HD vary depending on what stage the patient can be classified as during the course of the disease. In the early stages of the disease, common symptoms include behavioral disturbances such as moodiness, anxiety, depression, and paranoia, as well as an impaired ability to detect odors. As the disease progresses to the middle stage, the patient can start to experience motor problems involuntary movements and muscle contractions, problems with balance, a slow reaction time, speech difficulties, and can become more stubborn than before. Finally, in the late stages of the disease the patient can be noticeably rigid (constant tension of muscles), struggle with bradykinesia (difficulty initiating or continuing movements), weight loss, and an inability to speak, walk, or properly care for themselves.

A diagnosis of HD is suspected when a patient has signs and symptoms of Huntington's Disease as well as a family history that is consistent with autosomal dominant inheritance. This means that a parent must be affected by the disease in order for the patient to be able to have a diagnosis of HD. There are cases of random mutations, but there are few such cases. After establishing the diagnosis possibility by confirming that the signs and symptoms are present as well as family history, a genetic test can be done that identifies the exact mutation in the HTT gene that is a marker for Huntington's Disease.

There is currently no treatment available that can cure HD, so the best option available for patients facing the disease are treatments that can slow down the course of the disease and manage the symptoms. This treatment is aimed at keeping the patient living happily for as long as possible. At this time there are two FDA-approved treatments, both of the same drug class. The first is Deutetrabenazine (brand name: Austedo), and the other is Tetrabenazine (brand name: Xenazine). Both of these medications are used to manage the chorea or involuntary movements associated with HD.

Sickle Cell Anemia

Sickle cell anemia is a red blood cell disorder characterized by the presence of an abnormal protein in the red blood cells. This protein is hemoglobin and in a patient that has sickle cell anemia, it is known as hemoglobin S. This change in hemoglobin affects the red blood cell’s ability to carry oxygen and greatly shortens life expectancy. Sickle cell anemia is the most common inherited blood disorder in the United States, affecting around 70,000 to 80,000 Americans. The disease is also estimated to occur in approximately one in 500 African Americans and one in 1,000 to 1,400 Hispanic Americans.

Sickle cell anemia is an autosomal recessive disease, which means that both parents must at least be carriers for the offspring to inherit the disease. While it would seem uncommon for this recessive disease to be passed down, there is a major reason that it is actually very common for African Americans in particular to be carriers of the disease: malaria. Malaria was very prevalent along the equator, particularly in Africa when Sickle Cell Anemia started to become a major disease. Many Africans were dying from the disease, particularly children. It is believed that the mutation occurred due to selective pressure, as the life expectancy of a young child was greater if they were a carrier of the sickle cell trait. The exact mutation involved in sickle cell anemia is in the HBB gene (NHLBI). According to an article by Lucio Luzzatto, the life expectancy for a child without a mutation in either allele was very low due to malaria. As a carrier for sickle cell, known as sickle cell trait the life expectancy for a child in Africa was slightly higher, which is why it is believed that this mutation became prominent due to those with the mutation surviving longer. However, if a child has two alleles for sickle cell, the life expectancy is far shorter than if the child were left to fend malaria off without the trait.

Early signs that an infant has sickle cell anemia include jaundice, fatigue, and dactylitis (painful swelling of the hands and feet). There are many complications associated with the disease such as acute and chronic pain, severe anemia, damage to the spleen causing an increased risk of infection, strokes, and many more. If these signs occur in an infant a doctor will then order a Complete Blood Count (CBC) with mean corpuscular volume (MCV) as well as a reticulocyte count. Alongside this there will also be a hemoglobin profile analysis, which is usually performed by electrophoresis and the infant will be given penicillin VK (250 mg per day) as a prophylactic treatment.

There are many factors involved when trying to treat sickle cell anemia, many of which are just monitoring and treating symptoms as they appear. A blood and bone marrow transplant can be used as a treatment option for some sickle cell anemia patients, but most do not have this option and must live with the disease. Doctors will monitor the height, weight, blood pressure, and oxygen saturation of the blood, and will use frequent lab testing to monitor the disease in order to effectively treat patients. The most important steps in treatment are used for preventing major infections, so sickle cell patients must routinely take penicillin VK as a prophylactic treatment and stay up to date on all their vaccines, such as influenza and meningococcus vaccines.

It is also important to manage the large amounts of pain these patients live with, so doctors will always have pain medicines available to the patient. There are many complications associated with sickle cell, and many of them do require immediate attention by doctors or medical professionals, so many patients spend a lot of time at a hospital. This disease requires a lot of monitoring and quick treatment of symptoms, and the severe anemia caused by sickle cell often leads to a very short life expectancy. Sickle cell can cause acute chest syndrome and strokes, which often lead to the death of the patient. There are treatments available that can reduce the risk of acute chest syndromes, such as hydroxyurea and L-glutamine, but for most, even on these medications, these events are inevitable.

Hemophilia

Hemophilia is a bleeding disorder that slows down the process of blood clotting. This disease is far more common in males than females due to its inheritance pattern as an X-linked recessive disease. There are two different types of hemophilia: type A and type B. Hemophilia A is caused by a lack or decrease of clotting factor VIII, and this is the classic case of Hemophilia. Hemophilia B is caused by a lack or decrease in clotting factor IX, and this disease is also known as Christmas disease after the first patient recorded to have the disorder. Hemophilia occurs in approximately one out of every 5,000 male births, and hemophilia A is about four times as common as hemophilia B.

Hemophilia A and hemophilia B are caused by mutations on different genes that are responsible for two different coagulation factors. Hemophilia A is caused by mutations in the F8 gene which is responsible for Coagulation Factor VIII. Conversely, hemophilia B is caused by mutations in the F9 gene which is responsible for Coagulation Factor IX. There are multiple mutations that occur in these genes that cause hemophilia, and the number as well as which mutations occur greatly impact the severity of the disease. Some mutations only mildly impair the activity of the coagulation factors, and some mutations completely eliminate the coagulation factor function.

Warning signs associated with a patient that has no family history of hemophilia are all related to excess bleeding shortly after birth. A doctor will check for hemophilia in the case of prolonged bleeding in a male newborn following circumcision, after drawing blood and heel sticks, after a difficult delivery, or after unusual bruising.

Diagnosis of hemophilia is usually accomplished soon after birth, as many people who have a family history of hemophilia request that their baby boys get tested. Screening tests for hemophilia are the Complete Blood Count (CBC), Activated Partial Thromboplastin Time Test (APTT), Prothrombin Time Test (PT), and Fibrinogen Test. The CBC usually just shows prolonged bleeding after the needle stick, so it is an indirect test for hemophilia. The APTT test measures the clotting ability of factors VIII, IX, XI, and XII, which indicates a patient with hemophilia. The PT test measures the time it takes for blood to clot, which is essential in recognizing a clotting deficiency. Finally, the Fibrinogen test is another way a doctor assesses the ability of a patient to form a blood clot. The Coagulation Factor Test is a final test that is required to diagnose any bleeding disorder, including hemophilia. This test requires the patient’s blood to be drawn and check for the presence and function of coagulation factors in the blood. If any factors are not present or working correctly, it leads to uncontrolled bleeding that is most often diagnosed as hemophilia.

The best option for treating patients with hemophilia is replacing blood clotting factors that are missing so that the blood can clot properly. This process is performed by an intravenous blood infusion of prepared concentrated clotting factors. Many patients with hemophilia learn how to perform these infusions on their own and stop bleeding episodes by performing an infusion. Performing these infusions on a regular basis acts as a preventative, so perhaps bleeding episodes will rarely occur if they ever do.

In rare cases, some people with hemophilia developed autoantibodies called inhibitors that stop coagulation factors from functioning properly. While this disease is not considered to be genetic like the other forms of hemophilia, it is unclear if there are markers that may make a person more likely to develop inhibitors.

Down Syndrome

Down syndrome is a genetic condition that is sometimes referred to as trisomy 21. This term means that there are three copies of chromosome 21. Down syndrome affects approximately one in 800 to one in 1,000 live-born infants. Patients with Down syndrome have learning disabilities, are mentally retarded, have a characteristic facial appearance, and have poor muscle tone in infancy.

Unlike other diseases mentioned in this paper, most cases of Down syndrome are not inherited. Down syndrome usually occurs as a random event while the reproductive cells are being formed. Nondisjunction during cell division results in an abnormal number of chromosomes in the reproductive cell, and in this case, the reproductive cell has an extra copy of chromosome 21. This reproductive cell, when join with the opposite reproductive cell, passes on this extra copy of chromosome 21 to the offspring.

Patients with Down syndrome will often experience other effects of the disease other than the mental and physical signs that are externally evident. A patient with Down syndrome is also at an increased risk for heart defects, with an astounding 40-60 percent of babies born with Down syndrome having a heart problem at birth. Along with these heart defects digestive problems such as gastroesophageal reflux or celiac disease, hearing loss, and hypothyroidism plague Down syndrome patients.

The treatment process for a patient with Down syndrome is unique from person to person. The treatment plan is adapted to fit each individual’s physical problems and intellectual weaknesses. Some babies have a hard time rolling over and beginning to walk, and physical therapy is a common treatment to accelerate the process of walking. All babies born with Down syndrome are checked for heart defects due to the high rate of association between the two. All newborns with Down syndrome are subjected to electrocardiograms and echocardiograms to try to prevent major problems from appearing due to these risks.

In some cases, infants with Down syndrome will have trouble swallowing or may have obstructions in their bowel. Surgery is an option and is usually performed to remedy these issues. Down Syndrome patients will also have frequent sinus and ear infections, and these must be treated aggressively to prevent hearing loss and chronic infections. There are many other scenarios that must be treated in patients with Down syndrome, but many adults with this condition live happily and independently as well as have successful careers. Early educational therapies and exercises to help control their muscle tone will help Down syndrome patients to stay on track to living normal, unassisted lives.

Works Cited

1. “About Autosomal Dominant Polycystic Kidney Disease.” NHGRI, www.genome.gov/GeneticDisorders/Autosomal-Polycystic-Kidney-Disease.
2. “About Down Syndrome.” NHGRI, www.genome.gov/Genetic-Disorders/Down-Syndrome.
3. “Autosomal Dominant Polycystic Kidney Disease: Mutation Database”. http://pkdb.mayo.edu/cgi-bin/v2_display_mutations.cgi?apkd_mode=PROD
4. “Coagulation Factor Tests: MedlinePlus Lab Test Information.” MedlinePlus, U.S. National Library of Medicine, 15 Apr. 2019, medlineplus.gov/lab-tests/coagulation-factor-tests/.
5. “Hemophilia - Genetics Home Reference - NIH.” U.S. National Library of Medicine, National Institutes of Health, ghr.nlm.nih.gov/condition/hemophilia#.
6. “Huntington Disease.” Genetic and Rare Diseases Information Center, U.S. Department of Health and Human Services, rarediseases.info.nih.gov/diseases/6677/huntington-disease.
7. Luzzatto, Lucio. “Sickle Cell Anaemia and Malaria.” Mediterranean Journal of Hematology and Infectious Diseases, Università Cattolica Del Sacro Cuore, www.ncbi.nlm.nih.gov/pmc/articles/PMC3499995/.
8. “Sickle Cell Disease.” National Heart Lung and Blood Institute, U.S. Department of Health and Human Services, www.nhlbi.nih.gov/health-topics/sickle-cell-disease.
9. Torres, Vicente E., and Peter C. Harris. “Autosomal Dominant Polycystic Kidney Disease: The Last 3 Years.” Kidney International, vol. 76, no. 2, 2009, pp. 149–168., doi:10.1038/ki.2009.128.
10. Vonsattel, Jean Paul G., and Marian Difiglia. “Huntington Disease.” Journal of Neuropathology and Experimental Neurology, vol. 57, no. 5, 1998, pp. 369–384., doi:10.1097/00005072-199805000-00001.
11. “What Is Hemophilia | CDC.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, www.cdc.gov/ncbddd/hemophilia/facts.html.