Autosomal Dominant

  Autosomal Dominant:

 

Autosomal dominant or dominance is a pattern of genetic inheritance that occurs within autosomes (non-sex chromosomes). Their appearance and function are mostly the results of the dominance of one parental gene over the other.

In the context of genetic disorders, the term "autosomal" specifically means that the gene in question is located on one of the numbered chromosomes, which are distinct from the sex chromosomes. These autosomes carry the majority of an individual’s genetic material, playing a crucial role in determining inherited traits and potential disorders.

Understanding whether a disorder is linked to autosomal chromosomes helps in predicting inheritance patterns and potential risks. This knowledge is essential for genetic counseling and making informed health decisions."  From a medical point of view, autosomal dominant disorders represent disorders caused by a single copy of a mutated gene. Scientists refer to a mutated gene as an allele. Alleles are carried by both parents and affect both male and female offspring.

Each child of a parent with an autosomal dominant disorder has a 50% chance of inheriting the mutated gene. This means that the presence of just one copy of the mutation from one parent is enough to cause an autosomal dominant inherited disorder.

Understanding this pattern of inheritance is crucial for predicting the likelihood of passing on genetic conditions. By focusing on the probability of inheritance and the role of alleles, we can better appreciate how these disorders manifest across generations, affecting family health dynamics.

Autosomal Dominant vs. Recessive

For a geneticist, the concept of autosomal dominant vs autosomal recessive gene inheritance can easily be understood. The likelihood that a gene will be expressed defines whether a gene is recessive or dominant. A gene is only located on the non-sex chromosomes when it is autosomal. The millions of alleles that make up human DNA’s twenty-two autosomal chromosomal pairs can mutate everywhere. Our chromosomes come paired and we inherit one set from our biological father and one set from our biological mother.

In the realm of genetics, understanding the inheritance pattern is crucial. A child of a person affected by an autosomal dominant condition has a 50% chance of inheriting the condition via a dominant allele. This means that only one copy of the altered gene, inherited from one affected parent, is enough to cause the disorder. In contrast, an autosomal recessive disorder requires the inheritance of two copies of a mutated gene, one from each parent, to manifest the disorder. This necessitates both parents being carriers, even if they are unaffected themselves.

This combination, in which some portions of the genetic code from one parent take priority over the identical genetic information from the other, determines how we appear and how we behave. Our genotype, or genetic makeup, appears incredibly intricate. For instance, there are many distinct alleles involved in determining eye color rather than just one. Our dominant genes, which are typically the outcome of smaller dominant alleles, determine whether the genetic information from our mother or father is expressed. Even if they don’t have a direct impact while dominant alleles exist, recessive alleles can impact subsequent generations.

By understanding these inheritance patterns, we can better predict and comprehend the transmission of genetic disorders across generations, enhancing our grasp of human genetics overall.

Fully Dominant vs. Partially Dominant Disorders

Autosomal dominant disorders can be divided into two types: fully dominant and partially dominant. In fully dominant disorders, the mutated gene completely masks the normal gene, causing all individuals carrying the mutated gene to display the characteristics of the disease. This means every carrier exhibits the illness without exception.

In contrast, incomplete dominance, or partially dominant disorders, involves a degree of interaction between the mutated gene and the normal gene. As a result, individuals carrying the mutated gene display varying degrees or types of disease characteristics. This variance can lead to different symptoms or severity levels in individuals, making it a more complex pattern of inheritance.

In fully dominant cases, the mutated gene’s influence is absolute, leaving no room for variability in how the disease manifests. Every carrier will show the traits associated with the disorder uniformly.

Conversely, partially dominant disorders introduce an element of unpredictability. The interaction between the mutated and normal genes means that the expression of the disorder can differ significantly from one individual to another. This can include variations in severity, onset age, and specific symptoms, adding layers of complexity to diagnosing and managing these conditions.

The Definitions to Fully Understand

Let’s quickly examine the distinctions between a gene, an allele, and a chromosome to make autosomal dominance more understandable. Chromosomes contain an organism’s entire genetic blueprint, made up of information shared by parents. We have exact copies of our parents’ DNA, and our DNA contains a mixture of them.

A gene is a length of DNA that determines a genetic trait, such as a propensity to develop a particular type of cancer. We were born with these traits, or damage to our DNA can cause certain traits to form over time. Our genotype is responsible for the characteristics of our DNA. Dominant and recessive genes determine whether these traits are pronounced. The expressed genes (usually dominant genes) give rise to phenotypes (functional or visual traits).

Allele

An extremely particular portion of a gene or chromosome that is located at the same position is known as an allele. Every gene has 2 alleles, one from each parent. While an eye color gene may exist, different alleles will determine the precise color. The alleles determine the blood type you have if one of your genes has the blood type characteristic. Given that several alleles make up a single gene in the case of autosomal dominance, we should speak of dominant alleles. It can impact the entire gene, even if just one of tens of thousands of alleles appears damaged.

The afflicted gene is frequently the name of an autosomal dominant (or recessive) ailment. As such, the gene’s related alleles cause the condition. One allele has prevailed over another, according to the definition of the word dominant. A phenotype can occur by a gene with only one copy from one biological parent. But a recessive mutation must pass by both parents. When up against a dominant allele, a recessive allele cannot prevail. The dominant gene in your dark hair originates from your father if both of your parents have brown hair. The brown hair allele is also dominant over a blonde allele in your DNA.

If the male does not have a dominant gene for brown hair, and the female is blond, then the children will have blonde hair. When both parents carry the recessive gene, the child will also have blonde hair. This child will have brown hair if it receives a dominant and recessive gene or a group of alleles. Since so many distinct alleles may impact hair color, scientists can rarely anticipate the precise shade of brown.

Understanding Genetic Spelling Changes

Understanding how a genetic spelling change affects the inheritance of a dominant disorder is crucial to grasping why these conditions appear consistently in families.

When we talk about an autosomal dominant disorder, we’re referring to a scenario where a single alteration in the DNA sequence of just one gene can lead to the disorder. This change, often likened to a “spelling error” in the genetic code, is enough to cause the disorder because the dominant gene essentially overrules the normal gene counterpart.

Inheritance Pattern

• Single Gene Alteration: Only one copy of the gene needs to carry the mutation for the disorder to manifest. This means it doesn’t matter whether the other gene copy is normal; the altered gene takes precedence.
• 50% Transmission Risk: With each child having a 50% risk of inheriting the altered gene from an affected parent, the disorder often appears in each generation. You can visualize this as a coin toss for each offspring, where each child has an equal chance of inheriting the dominant gene.
• Family Tree Manifestation: Due to this straightforward inheritance pattern, these disorders typically show up prominently across generations, appearing in a vertical pattern through family trees.

This genetic mechanism highlights the impactful role of dominant genes and how even a minor spelling change can lead to a significant hereditary condition. Understanding these principles is key to predicting and managing such genetic disorders.

Carriers

An adult can carry a recessive gene, but it will not result in an identifiable trait (phenotype). Two recessive exact genes will result in the related phenotype when combined with a recessive gene from the other parent. The recessive gene is suppressed when a dominant gene is present. Blonde hair is recessive and dominant in the autosomal dominance scenario from above. Blonde hair gene expression is prevented by the presence of a dominant dark hair gene.

Temporary concealment of an autosomal dominant disease is possible in some circumstances. This means that before we learned about genetic fingerprinting, we believed that some diseases were not genetically caused but rather brought on by the environment. For instance, Huntington’s disease is a progressive autosomal dominant brain condition that impairs cognition, emotion, and movement.  However, this only happens when the gene undergoes a certain stage of mutation. Because Huntington’s gene has not reached the threshold that triggers the symptoms, a parent can pass on the gene without ever having been officially diagnosed with the condition.

Although it is now feasible to detect the presence of a gene long before symptoms show, it is still impossible to forecast whether a person would experience the symptoms or the ailment. We now understand that Huntington’s is a unique form of autosomal dominant illness. One diseased parent will pass on a faulty gene to the affected child, although this parent may not have manifested any symptoms of the illness. Parents cannot carry an autosomal dominant gene.

Symptoms don’t begin to manifest until a specific number of mutations occur. A condition can occur by our surroundings just as much as by the existence of a dominant gene.

Autosomal Dominant Examples

Examples of autosomal dominance can relate to genetic behaviors. For example, it relates to skin, hair, and eye color, the risk of developing certain diseases, and even neurological traits. It shows the odds of inheriting brown, blue, or green eyes from either parent. However, eye color results from a myriad of alleles and is not always predictable. As an example, we recommend focusing on individual mutant alleles. This aids in the ability to eliminate the influence of other genetic factors.

Autosomal dominant disorders encompass a wide array of diseases, categorized broadly into several types:

• Neurological Diseases: These include conditions such as Huntington’s disease, which is discussed in detail below. Other related conditions are Charcot-Marie-Tooth disease, Machado-Joseph disease, and Neurofibromatosis.
• Musculoskeletal Diseases: Examples include Spondylocostal Dysostosis and Spondyloepiphyseal Dysplasia. Additional conditions in this category include Marfan’s syndrome, Cleidocranial dysostosis, and Osteogenesis imperfecta types I and IV.
• Metabolic Diseases: Disorders like metabolic syndrome, which can have genetic components, are part of this group. Familial hypocalciuric hypercalcaemia and Gilbert’s disease also fall under this category.
• Tumor Syndromes: Conditions such as Neurofibromatosis Tumors and Marfan Syndrome are included. Other syndromes include Familial medullary thyroid carcinoma, Retinoblastoma, and Von Hippel-Lindau syndrome.

Beyond these categories, there are numerous other conditions associated with autosomal dominant inheritance:
Syndromes and Other Disorders:

• Achondroplasia
• Adult polycystic kidney disease
• Hereditary haemorrhagic telangiectasia
• Ehlers-Danlos syndrome (EDS)
• Tuberous sclerosis
• Peutz-Jegher’s syndrome
• Von Willebrand’s disease

These conditions, among others, highlight the diverse manifestations of autosomal dominant inheritance, affecting a variety of bodily systems and functions. By understanding the breadth of these disorders, healthcare professionals can better diagnose and manage these conditions in patients.

Huntington’s Disease

The Huntington protein gene (HTT gene), which appears on chromosome 4, has between 10 and 35 instances of a particular section of code called the CAG trinucleotide repeat. These repeats take place 40 or more times in people with Huntington’s disease. Although it has recently been revealed that repeat expansions can fluctuate in size throughout one or more generations, this may be inherited. Huntington’s disease does not automatically occur in those who carry the HTT gene.

It has previously been noted that this condition appears as an autosomal dominant disorder with a twist; if the cause of greater repeat expansions is identified, researchers will treat or even eradicate the diseases linked to it. Multiple genetic abnormalities are brought on by repeat expansions. Being an autosomal dominant condition, all it takes for a characteristic to pass along to the next generation is for one parent to have it.

An uppercase letter H in the above figure stands in for the mother’s Huntingtin gene. The unshaded squares show that there is no HTT gene (hh) mutation, whereas the gray-shaded boxes signify HTT gene mutation (Hh). The parent with the mutant HTT may not exhibit Huntington’s symptoms and have fewer CAG trinucleotide repeats. This gene is dynamic, so greater repetitions might develop later in life or over the lifetime of any children this parent has.

What causes Huntington’s Disease

Huntington’s disease is a progressive autosomal dominant brain condition that impairs cognition, emotion, and movement. However, this only happens when the gene undergoes a certain stage of mutation. Because Huntington’s gene has not reached the threshold that triggers the symptoms, a parent can pass on the gene without ever having been officially diagnosed with the condition.

Causes of Huntington’s Disease

Huntington’s disease is caused by a mutation in the HTT gene located on chromosome 4. This mutation results in an elongated sequence of the Huntingtin protein. Over time, these abnormal proteins accumulate inside nerve cells, disrupting their normal function and eventually leading to cell death through a process called apoptosis.

Symptoms of Huntington’s Disease

The symptoms of Huntington’s disease usually appear in middle age and progressively worsen. They can be broadly categorized into motor, cognitive, and emotional symptoms:

Motor Symptoms:

• Chorea: Involuntary, dance-like movements involving rapid and unpredictable motions of the fingers, extremities, face, or trunk.
• Stiffness and Tremors: Known as catalepsy and tremor, these symptoms can significantly impact movement.
• Coordination Issues: Problems with balance, coordination, and muscle control can make daily activities challenging.
• Difficulty Swallowing and Speaking: As the disease progresses, these symptoms become more pronounced.

Cognitive Symptoms:

• Decreased Concentration and Impaired Judgment: These issues can interfere with daily tasks and decision-making.
• Memory Loss and Learning Difficulties: Affected individuals may struggle with retaining information and learning new skills.
• Dementia: Severe cognitive impairment can lead to an inability to function independently, drive, or take care of oneself.

Emotional and Behavioral Symptoms:

• Mood Swings and Personality Changes: These can include impulsiveness, compulsive behavior, anxiety, and depression.
• Lack of Motivation and Initiative: Individuals may show decreased personal hygiene and empathy.
• Aggressive and Irritable Behavior: Such changes can strain relationships and social interactions.

Huntington’s disease remains a challenging condition, as symptoms intensify over time, profoundly affecting both the individual and their loved ones. Understanding both its genetic basis and symptomatic progression is crucial for managing the disease effectively.

Are There Treatments Available for Huntington’s Disease?

Yes, there are treatments available for managing Huntington’s disease, although a complete cure has yet to be found. The main focus of current therapies is to alleviate symptoms and enhance the quality of life for those affected.

Drug Treatments

Medications are central to managing symptoms of Huntington’s disease. They primarily address movement disorders and psychiatric symptoms. Key drug categories include:

• Nerve blockers: These help in reducing movements known as chorea by blocking dopamine activity.
• NMDA receptor antagonists: These drugs target glutamate activity, which can help in managing overexcitement in the brain.
• Anticholinergics: They work by limiting the action of acetylcholine, aiding in controlling muscle coordination.
• Alpha-adrenoceptor antagonists: These drugs decrease norepinephrine activity, helping to manage anxiety issues.
• SSRIs (Selective Serotonin Reuptake Inhibitors): These are often prescribed for mood stabilization, reducing depression and anxiety.

Non-Drug Therapies

Managing the disease also involves non-drug interventions:

• Physical Therapy Aims to improve coordination and maintain mobility.
• Speech Therapy: Focuses on enhancing communication skills as speech can become affected.
• Occupational Therapy: This helps patients adapt to daily challenges, maintaining independence.
• Psychotherapy: Provides emotional support, addressing behavioral changes and mental health issues.

Experimental Treatments

Gene therapy is an exciting area of research currently in clinical trials. This innovative approach targets the root cause by attempting to alter or replace the mutated HTT gene responsible for the disease. The goal is to slow or prevent nerve cell damage.

In conclusion, while a definitive cure is still in development, various treatments are available to help manage symptoms effectively and improve the lives of those living with Huntington’s disease.

Polycystic Kidney Disease

Half of a Hh and hh parent’s kids are susceptible to the mutant characteristic (Hh). Punnet squares and pedigree charts are terms used to describe diagrams that display hereditary qualities.

Another common example of autosomal dominance is polycystic kidney disease. In this disorder, multiple cysts develop in the kidneys and reduce their ability to filter waste products from the blood. Similar to Huntington’s Disease, autosomal dominant polycystic kidney disease (ADPKD) is the product of transmission of the disease from one parent. In this case, a single mutated copy of the PKD1 or PKD2 gene causes the disease. PKD1 appears on chromosome 16, while PKD2 is found on chromosome 4. A relatively newly discovered gene on chromosome 11 can cause combined polycystic kidney disease and liver disease. Similar to HD, some cases of ADPKD result in new mutations. Contrary to Huntington’s disease, polycystic kidney disease can also be classified as autosomal recessive (ARPKD).

What is Polycystic Kidney Disease (PKD) and How is it Inherited?

Polycystic kidney disease (PKD) is an inherited disorder caused by mutations in specific genes. These mutations, such as those in PKD1, PKD2, and PKHD1, lead to abnormal sequences encoding polycystin—a crucial protein for maintaining the structure and function of renal tubules. When gene mutations occur, they result in defects or insufficient quantities of polycystin, impairing the normal development and operation of renal tubules.

There are two main types of PKD:

1. Autosomal Dominant PKD (ADPKD): Typically diagnosed in adulthood, this form requires only one mutated gene from an affected parent to cause the disease.
2. Autosomal Recessive PKD (ARPKD): This type can be identified in utero or during infancy and requires two copies of the mutated gene, one from each parent, to manifest.

By understanding the genetic basis and types of PKD, we gain insight into how this complex disorder is inherited and affects kidney functionality.

Additional Autosomal Dominant Conditions include:

• Spondylothoracic Dysostosis
• Goldenhar Syndrome
• Cleidocranial Dysplasia
• Charcot-Marie-Tooth Disease

What Causes Polycystic Kidney Disease

Another common example of autosomal dominance is polycystic kidney disease. In this disorder, multiple cysts develop in the kidneys and reduce their ability to filter waste products from the blood. Similar to Huntington’s Disease, autosomal dominant polycystic kidney disease (ADPKD) is the product of transmission of the disease from one parent. In this case, a single mutated copy of the PKD1 or PKD2 gene causes the disease. PKD1 appears on chromosome 16. PDK2 on chromosome 4. A relatively newly discovered gene on chromosome 11 can cause combined polycystic kidney disease and liver disease. Similar to HD, some cases of ADPKD result in new mutations. Contrary to Huntington’s Disease, polycystic kidney disease can also be classified as autosomal recessive (ARPKD).

Understanding the Genetic Basis

Polycystic kidney disease (PKD) arises from mutations in one or more genes, notably PKD1, PKD2, and PKHD1. These mutations lead to an abnormal sequence encoding polycystin, a crucial component for maintaining the structure and function of renal tubules. When gene mutations occur, polycystin may be defective or insufficient, impairing normal renal tubule development and operation.

Types and Diagnosis

There are two primary types of PKD:

• Autosomal Dominant PKD (ADPKD): Typically diagnosed in adulthood.
• Autosomal Recessive PKD (ARPKD): Can be diagnosed in utero or during infancy.

Symptoms and Complications

Polycystic kidney disease (PKD) is an inherited condition characterized by the growth of numerous fluid-filled cysts on the kidneys. These cysts arise due to mutations in certain genes, such as PKD1, PKD2, and PKHD1, which are crucial for producing polycystin—a protein essential for the proper function and structure of renal tubules. The mutation leads to defects or insufficient quantities of polycystin, disrupting normal kidney development and function.

There are two primary forms of PKD:

1. Autosomal Dominant PKD (ADPKD): Typically diagnosed in adulthood.
2. Autosomal Recessive PKD (ARPKD): Can be diagnosed in utero or during infancy.

If these cysts become too large or numerous, they can damage the kidneys, reducing their function and potentially leading to kidney failure. Alongside impaired kidney function, PKD can also cause:

• High Blood Pressure: A common complication.
• Liver Cysts: Additional cyst formations can occur.
• Vascular Issues: Problems may arise in the brain and heart.

This extensive impact on the body underscores the importance of understanding both the genetic and symptomatic aspects of PKD. Beyond the kidneys, PKD’s influence extends to other organs, highlighting the need for comprehensive management and awareness of the disease’s potential complications.

How is Polycystic Kidney Disease Treated and Managed?

Polycystic Kidney Disease (PKD) management encompasses several key treatment strategies. Each approach focuses on alleviating symptoms, preventing complications, and improving quality of life.

Drug Therapy

One of the primary objectives is to manage high blood pressure, as it exacerbates kidney damage. Medications such as ACE inhibitors and ARBs are often prescribed to maintain blood pressure levels and manage infections when they occur.

Surgical Interventions

Surgical procedures may become necessary to address larger cysts, which can impair kidney function or impact appearance. Additionally, surgery might be required to deal with malignant tumors or to repair aneurysms and dissections. The timing for surgery is typically determined by the cyst’s size, location, and overall impact.

Dialysis and Kidney Transplantation

For patients whose kidney function has declined significantly, dialysis serves as an essential treatment to remove excess water and waste from the bloodstream, effectively acting as an artificial kidney. Kidney transplantation is another option, providing a more permanent solution by replacing the failing kidney. Both treatments necessitate ongoing monitoring and the use of medications to prevent infection or rejection.

Gene Therapy

Gene therapy is an innovative approach under clinical evaluation. It aims to correct the underlying genetic mutations associated with PKD, thereby restoring normal kidney function. This therapy focuses on altering or replacing defective genes to regulate the development and function of renal tubules effectively.

In conclusion, managing PKD involves a comprehensive approach tailored to individual patient needs, utilizing medical, surgical, and potentially groundbreaking genetic therapies to enhance patient outcomes. Regular check-ups and adherence to treatment regimens play a crucial role in effectively managing this condition.

Why choose the Medical City Children’s Orthopedics and Spine Specialists

The Medical City Children’s Orthopedics and Spine Specialists doctors only treat children. With offices in Arlington, Dallas, Flower Mound, Frisco, and McKinney, Texas, Doctors Shyam Kishan, Richard Hostin, and Kathryn Wiesman have spent years studying children’s health and have devoted their lives to treating them. We can help patients with Autosomal Dominant conditions because we have the greatest medical professionals and cutting-edge facilities. Get in touch with Medical City Children’s Orthopedics and Spine Specialists as soon as you can and make an appointment for your child.

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National Human Genome Research Institute: Autosomal Dominant Inheritance