Hereditary Diseases: How Do They Work?
In 1819, Queen Victoria was born with what scientists currently believe was a spontaneous mutation in her genome. Though unaffected herself, some of her children and then her grandchildren began to show signs of a bleeding disease. Her great-grandson, Alexei Romanov, would go on to seek the consultation of Grigori Rasputin to treat this condition. In time, the “royal disease” would go on to become one of the most famous examples of a hereditary disease, known more commonly today as hemophilia. However, it wasn’t until 1902 when Archibald Garrod’s observations of alkaptoneuria, highlighted the relevance of Mendel’s principles in the study of hereditary diseases (Urban, 1999). With today’s advancements in medicine, the focus naturally turns to conditions that are inherited, and whether or not a cure could ever be possible.
This article assumes a basic understanding of genetics. Readers who require a refresher can explore my article on gene editing linked here.
Inheritance: Important terms to remember
Germ cells (the cells responsible for the creation of a new organism via reproduction) contain half of the genome from the parent; in other words, half of an organism’s genes are obtained from each parent. By this measure, diseases too can be passed on, even if from a single parent. Whether or not the disease manifests depends on the nature of the gene.
Before expounding on this, one must acquaint oneself with basic terms related to genetics. A gene is well understood as a unit of inheritance, but that unit may undergo changes on account of a spontaneous mutation in the sequence of DNA that comprises it or any modifications that occur after the transcription or translation process. Such a variant is known as an “allele.” In gene studies, the “normal” gene, which does not code for a condition but rather an ordinary feature, is called the wild type. We will use these terms extensively throughout the article.
Genes mainly occur in pairs within the human genome; therefore, the presence of an allele that corresponds to a particular disease could possibly lead to the manifestation of that disease. This is determined by whether or not the allele is dominant or recessive.
A dominant allele requires only one copy of the allele to be present in a pair for the corresponding trait to manifest, while a recessive allele requires both copies to be present. To take a somewhat simplified example, the allele that codes for brown eyes in a person is dominant over the allele that codes for blue eyes; therefore, it is likely that a person inheriting one of each allele will manifest brown eyes, but if that person inherited both alleles for blue eyes, they would manifest blue eyes. Note that even in dominant gene expression, the person will still have a pair of genes, but only one will have the mutation corresponding to the respective trait.
A person carrying one wild-type gene and one allele, the condition for which is recessive, would not manifest symptoms, but instead be considered a “carrier,” as that gene may pass on to their progeny.
This is not the sole factor in determining the manifestation of a gene; there are two other significant factors. Penetrance is the proportion of people with a particular allele expressing the signs or symptoms the allele would generally cause. An allele that always causes its symptoms to appear in the person carrying it is said to have a 100% penetrance. In contrast, some alleles have reduced penetrance, which means not every person carrying that variant will necessarily show signs of having it. There is also the factor of expressivity, which determines the range of symptoms that can be shown for a particular condition, e.g two people with the same condition could have a vast range of symptoms between them, from benign to harmful ("What are reduced penetrance and variable expressivity?: MedlinePlus genetics," n.d.).
Interestingly, these two primary factors are not isolated purely based on genetics; environment and lifestyle are thought to affect penetrance and expressivity, though the extent of these influences are unknown.
Hereditary Diseases
As its name suggests, a hereditary disease is a condition that can be passed down from generation to generation. The nature of these diseases is variable, with symptoms ranging from mild fatigue to organ damage. This article will summarize a few that are well-known and have a hereditary factor.
Red-Green Color Blindness
A very familiar hereditary condition is color blindness, the most prominent of which is red-green color blindness. This condition manifests in two forms: protanopia (inability to perceive any reds) or deuteranopia (inability to perceive any greens). Despite that, the alleles for these conditions, though distinct, are both located on the X-chromosome, which makes the condition X-linked. Additionally, the condition is considered X-linked recessive but displays an interesting inheritance pattern (Cherney, 2020)
It is well understood in elementary biology that humans also have a pair of sex chromosomes: females have a pair of X chromosomes, while males have a single X chromosome and a single Y chromosome to make up that pair. We’ve discussed earlier in the article that recessive conditions require two copies of the relevant allele to manifest; therefore, a female with two of these alleles on their X chromosomes would display the symptoms. A woman with only a single mutant copy would not express color blindness but be a carrier instead. However, since males only carry one X chromosome, if they were to inherit a copy with the mutant for color blindness, they would express the symptoms and consequently be rendered “color-blind.” Worldwide, around 5-8% of men suffer from it, as opposed to 0.5-1% of women (Cherney, 2020).
There is also tritanopia, which is the inability to perceive blues or yellows, but this has a prevalence of 0.01%, making it incredibly rare. This condition is dominant, which means it has a 50% chance of being inherited, and unlike its related conditions, it is autosomal or not located on a sex chromosome (Neimark, 2021).
BRCA-related Breast Cancer
Perhaps unsurprisingly, genetics play a role in developing certain types of cancer, which includes BRCA-related breast cancer. This particular form arises from mutations in the BRCA1 and BRCA2 genes, which in their wild-type forms are universally present in our bodies. When DNA is synthesized and replicated in the human body, the BRCA1 and BRCA2 genes encode proteins that ensure that any damaged DNA is repaired, effectively acting as tumor suppressors. Mutations that cause these functions to fail eventually lead to the development of breast cancer. The condition is autosomal dominant, requiring only a single copy of the mutant allele to manifest ("BRCA gene mutations: Cancer risk and genetic testing fact sheet," 2024).
Though the mutation only occurs in around 0.2-0.3% of the population, up to 60% of women who inherited deleterious mutations in either BRCA gene will develop breast cancer in their lifetime, as compared to 13% of the general population. This is an example of a condition that displays reduced penetrance, as not every woman who inherits these mutations will necessarily develop breast cancer, but those who do constitute a large percentage. The numbers amongst this population account for 57-65% of women with BRCA1 mutations and 49-55% of women with BRCA2 mutations. However, it has been noted that less than 10% of women worldwide diagnosed with breast cancer have BRCA mutations. Additionally, BRCA1 mutations account for around 58% of ovarian cancer cases. In comparison, BRCA2 mutations account for up to 29%, with additional studies showing that additional cancers, such as prostate or pancreas, are attributed to BRCA mutations (Kryzak, 2023) ("Cancer and heredity," 2019).
Studies have shown that estrogen and progesterone receptor pathways interact with mutations in BRCA1 that correspond to the development of cancer in estrogen-responsive tissue, while other studies have shown similar links between these hormonal pathways and BRCA2. This indicates that these hormones are a large portion of the reason that BRCA mutations affect women, despite the fact that the genes and subsequent mutations are not specific to women (Katiyar et al, 2006) (Wang & Di, 2014). Despite that, around 1% of men with BRCA1 mutations and around 7% with BRCA2 mutations develop breast cancer, which is an incredibly small but very real likelihood (Kryzak, 2023).
Sickle Cell Disease
Named quite aptly for its phenotype, sickle cell disease is an inherited blood disorder that causes the development of abnormal hemoglobin, resulting in some of the body’s red blood cells becoming misshapen, resembling a sickle. These stiffer blood cells often burst when entering blood vessels and do not last as long as typical red blood cells, which are round and flexible. As a result, the affected would suffer from a deficiency in their red blood cells, or anemia. Additionally, the sickle cells can block smaller blood vessels and obstruct blood flow, leading to pain and potential organ damage ("Sickle cell disease | Sickle cell anemia | MedlinePlus," n.d.). The disease manifests as three types depending on the hemoglobin gene mutated: HbSS, which is known as sickle cell anemia; HbSC, a slightly less severe variant; and HbS beta thalassemia, which is combined with a condition where a low amount of hemoglobin is produced ("Sickle cell disease," 2019).
Sickle cell disease is an autosomal recessive trait, which means it requires two copies, and is a disease with variable expressivity; a large number of patients are afflicted by anemia, jaundice, or immense pain, but there have been cases of patients living a vast majority of their lives without observing symptoms(Raval & Rathod, 2023). Moreover, despite being recessive, it is possible for carriers of the trait (who would not manifest the full range of symptoms) to still produce sickle cells under conditions of stress. However, these are highly unlikely to affect the quality of their lives (Aime, 2024). Current studies show that close to 300,000 babies are born every year with some form of blood disorder, including sickle cell disease (Thomson et al, 2023).
However, the sickle cell trait is known to confer a unique immunity against malaria. Patients carrying only a single copy of the sickle cell trait were shown to be protected against the lethal effects of malaria. However, they are not immune to contracting the parasite. Currently, it is thought that a large majority of blood cells that the parasite binds in the carrier patient are sickled cells, which are then destroyed in the body, thereby destroying the parasite. Several studies in African countries have validated this fact, and it has even been suggested that the carriers encourage the development of acquired immunity in the otherwise unprotected population. However, this does not apply to patients who carry two copies and have sickle cell disease; in patients with HbSS, their anemia is exacerbated by malaria, and they are far more likely to suffer lethal symptoms (Luzzatto, 2012).
How are hereditary diseases treated?
Seeing how widely hereditary diseases can differ, it naturally follows that the treatment of each disease is vastly different. The fact that they are hereditary raises yet another concern: is it possible to eradicate the disease at its source? Conditions that arise from such things as bacterial infections, which are external sources that enter the body, can be treated by removing the source altogether. Still, for diseases that arise from within our very genome, the question of treating it at its origin is a greater journey into the unknown.
Conditions such as sickle cell disease are treated with bone marrow transplants, several drugs, and/or blood transfusions, all of which are long-standing remedies ("Sickle cell disease," 2019). However, in December 2023 the United States FDA approved the use of two treatments, Casgevy and Lyfgenia, the former being among the first FDA-approved treatments to use genome editing technology. Targeted at people over the age of 12, Casgevy utilizes CRISPR/Cas9 gene editing technology, which in layman’s terms acts like “Find and Replace” in MS Word: it is capable of replacing the DNA, and by extension, the gene, associated with the deformed hemoglobin with DNA that codes for wild type hemoglobin. Similarly, Lyfgenia uses a harmless virus as a vector to deliver healthy genes to the patient’s stem cells ("FDA approves first gene therapies to treat patients with sickle cell disease," 2023).
However, with gene therapy treatments comes a high price tag, as well as many regulatory hurdles before these treatments can become more commonplace, which often means that far more patient data is required, even if the treatment has FDA approval (Herzog et al., 2010).
Cancers such as breast cancer are conventionally treated through surgery, radiation therapy, chemotherapy, as well as a number of other therapies depending on the patient ("BRCA gene mutations: Cancer risk and genetic testing fact sheet," 2024). However, more recent research suggests using the CRISPR/Cas9 technology, as well as other methods, as targeted gene therapies to repair the BRCA genes responsible and potentially treat it at the source. Additionally, the Alliance for Cancer Gene Therapy has been conducting clinical trials for various gene therapies (Lavery, 2024), and in 2024, the NHS announced that it would soon deploy Talazoparib, an inhibitor drug targeting the symptoms brought about by BRCA mutations (Gunn, 2024).
As for red-green color blindness, there are technologies such as color-corrective lenses, and there have been studies carried out on achromatopsia, a different form of color blindness, in animals treated via gene therapy through adenovirus vectors (Hassall et al., 2017). Though this certainly paves the way for a cure for deuteranopia, the condition is not known to cause significant harm, and as such, any immediate cure might be a faraway hope.
This is compounded by the fact that many gene therapies are experimental, with only a handful having made it to market. With ongoing research and the rigor of regulatory processes, alongside the widespread debate regarding the ethicality of genetic modification, these cures have several hurdles to cross before they might accompany or replace existing therapies ("What are the ethical issues surrounding gene therapy?: MedlinePlus genetics," n.d.).
Genetic disorders that are not hereditary
There are still many genetic conditions in their provenance, but they are not hereditary. Perhaps the best known amongst these is trisomy 21, better known as Down Syndrome, which occurs due to a cell division error known as nondisjunction, where the fetal cells inherit an extra copy of a parent’s chromosome ("Down syndrome - Symptoms and causes," 2018). Similarly, Klinefelter Syndrome (or 47, XXY) occurs when the fetal cells that inherit the XY chromosomal pairing also inherit an added X chromosome, leading to the development of female secondary sexual characteristics, such as breast tissue or reduced body hair, alongside a number of health conditions ("Klinefelter syndrome: MedlinePlus genetics," n.d.). For conditions such as Klinefelter, hormone therapies are known to help, while Down Syndrome cannot be treated, but no known gene therapies exist at present.
Conclusion
With rapid advancements in modern biotechnology, our insights into the field of heredity only continue to grow. However, regulatory and ethical concerns, as well as a need for public awareness campaigns, must be addressed before their potential applications can be understood and applied on a large scale.
Glossary of Terms Used:
Allele: A variant of a gene
Autosomal:Relating to chromosomes that are not sex chromosomes
Carrier: A person carrying a single copy of a recessive allele, therefore not expressing its corresponding phenotype
Dominant: When only a single copy of a particular allele is required for its corresponding phenotype to be expressed
Expressivity: The range of symptoms shown for a particular condition
Germ cell: A cell that develops into a reproductive cell
Penetrance: The proportion of people with a particular allele that expresses its corresponding symptoms
Phenotype: The observable characteristics that arise from genes
Recessive: When two copies of a particular allele are required for its corresponding phenotype to be expressed
Wildtype: A gene in its non-mutated form, often expressing the most common phenotype associated with it.
Works Cited
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Additional Resources
https://medlineplus.gov/genetics/understanding/inheritance/penetranceexpressivity/
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(99)90364-1/fulltext
https://www.allaboutvision.com/conditions/color-blindness/tritanopia/
https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/cancer-and-heredity
https://www.nationalbreastcancer.org/what-is-brca/
https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet
https://pmc.ncbi.nlm.nih.gov/articles/PMC4046883
https://pmc.ncbi.nlm.nih.gov/articles/PMC1472667/
https://www.mjhid.org/mjhid/article/view/2012.065/477
https://www.health.com/sickle-cell-disease-8679127?utm_source=chatgpt.com
https://pmc.ncbi.nlm.nih.gov/articles/PMC3586794/
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https://www.mayoclinic.org/diseases-conditions/down-syndrome/symptoms-causes/syc-20355977
https://medlineplus.gov/genetics/condition/klinefelter-syndrome/
