Basic principles of genetics

What is a genetic disease?

EXPERTS: Did you know?

The GLA gene provides instructions for making an enzyme alpha-galactosidase A, which is necessary for the metabolism of a lipid called globotriaosylceramide or GL-3. GLA gene mutations prevent alpha-galactosidase A from effectively breaking down GL-3, leading to a buildup of GL-3 in most cells throughout the body. Progressive accumulation of GL-3 causes cell damage, leading to the wide range of symptoms of Fabry disease.23 The condition is a systemic disease that manifests as brain vascular disease, heart disease, and progressive kidney failure.24,26

What is a genetic disease?

­
Genetic diseases result, in whole or in part, by a change in the DNA sequence. Such diseases result when an error or a change in one or more genes leads to a mutant, missing, inactive, or partially active protein, all of which can cause disease. Often when we think about a genetic disease, we’re talking about an inherited disease.4   


Autosomal-dominant diseases

What is a genetic disease?

­Genetic diseases result, in whole or in part, by a change in the DNA sequence. Such diseases result when an error or a change in one or more genes leads to a mutant, missing, inactive, or partially active protein, all of which can cause disease. Often when we think about a genetic disease, we’re talking about an inherited disease.4  


Autosomal-dominant diseases

Autosomal-dominant diseases

In autosomal-dominant diseases, one copy of the defective gene is sufficient for a person to inherit the condition. In some cases, an affected child inherits the disease from an affected parent.5


Examples of autosomal-dominant diseases


Huntington’s disease (HD)


Huntington’s disease is a progressive neurodegenerative disease that is inherited in an autosomal-dominant pattern, which means that a person inherits one defective copy of the gene and can develop the disease.6-8 When a man or a woman with HD has children, each child has a 50% chance of inheriting the mutated gene and developing the disease. In the United States, approximately 30,000 people have HD and another 200,000 are at risk of developing the disease.9

  • What causes Huntington’s disease?

    Buildup of mutant huntingtin protein (mHTT) is thought to cause HD.#sup_10# The normal function of huntingtin protein is not known, but the mHTT buildup is toxic to brain cells.


    The HTT gene mutation involves a DNA segment known as CAG trinucleotide repeat. CAG is a segment made up of the 3 DNA base pairs, cytosine (C), adenine (A), and guanine (G). In people with HD, the CAG segment repeats 36 to more than 120 times. People with 40 or more CAG repeats will develop HD.#sup_7#


    Repeat expansion mutation


    #img1#


    #ssep#HD first affects the striatum, which is a core structure of the brain. This structure is critical for motor function and reward- and goal-orientated behavior.#sup_6# Loss of brain cells in the striatum leads to the following problems#sup_11-13#: 

    • Motor function issues 

    • Cognitive dysfunction 

    • Psychiatric disturbances#esep#


    Symptoms begin gradually and progress over many years until the death of the individual. The median survival from symptom onset to death is 30 to 40 years.#sup_14#

  • How is HD diagnosed?

    The course of HD can be divided into premanifest and manifest periods, which itself is described as stages of increasing severity. The premanifest period can be further subdivided into presymptomatic and prodromal categories. Initially, a period may occur when people show no subjective symptoms, measurable abnormalities, or clinical signs of HD and are therefore termed presymptomatic. This may occur up to 10 to 15 years before the onset of HD. People may then enter the prodromal period, where the gradual appearance of subtle motor, cognitive, and behavioral changes, which do not meet the current criteria for formal HD diagnosis based on motor abnormalities, may occur.#sup_15#


    The Unified Huntington’s Disease Rating Scale (UHDRS) is a standardized test that measures motor control, cognitive symptoms, behavioral symptoms, independence, and a person’s ability to function in everyday life. The UHDRS is used for both clinical and research purposes. It contains a motor diagnostic confidence level (DCL) subscale, which scores a person from 0 (no motor abnormalities indicating HD) to 4 (motor abnormalities ≥99% likely due to HD).#sup_16#

     

    A diagnosis of HD is made on the motor DCL, with a score of 4 indicating to a greater than 99% certainty that the motor abnormalities are due to HD.#sup_16# However, subtle motor dysfunction, cognitive changes, and behavioral alterations may be seen before a clinical diagnosis is made. HD is confirmed by molecular genetic testing that shows CAG segment repeats of 36 to more than 120 times of the HD gene.#sup_7# Let’s review the progression of HD in more detail below.

  • What is premanifest HD?

    The period before diagnosable signs and symptoms of HD appear is termed premanifest.#sup_15# Subtle but progressive changes in mood may occur during the premanifest phase and progress over the years before a definite clinical diagnosis of manifest HD is made.#sup_15-16# If the individual has a family history of HD, consider genetic testing to confirm if the CAG trinucleotide repeat mutation is present.#sup_17#

  • What is presymptomatic HD?

    In the presymptomatic category, patients do not exhibit symptoms and have no changes in function. Therefore, no relevant changes are seen in the UHDRS, and the DCL should be 0 or 1. If the individual has a family history of HD, consider genetic testing to confirm if the CAG trinucleotide repeat is present.#sup_15-17#

  • What is prodromal HD?

    Prodromal HD may possibly comprise up to 10 years or more, before a clear and unequivocal diagnosis of manifest HD can be made. Subtle or soft motor signs indicating the presence of a disease process prior to the development of the full clinical syndrome may appear before the onset of motor symptoms. People with prodromal HD may have a DCL of 2, that is, changes are attributable to HD but not clinically confidant.#sup_15# If a clinician strongly suspects an individual has HD and they have a family history of HD, consider genetic testing to confirm if the CAG trinucleotide repeat mutation is present.#sup_17#

  • What is manifest HD?

    #ssep#There are 5 stages of manifest HD that are broadly categorized into 3 groups, early-stage manifest HD, middle-stage manifest HD, and late-stage manifest HD. After the onset of motor abnormalities (DCL score of 4), it is function, rather than motor signs, that determines these disease stages. The UHDRS total functional capacity (TFC) scale is a tool to help assess how people with HD manage their capacity to work, ability to handle finances, perform domestic chores and activities of daily living (ADL), and arrange their care. The TFC scale ranges from 13 (normal) to 0 (severe disability).#sup_16#


    What is early-stage manifest HD?

    Stage 1 and stage 2 comprise early manifest HD. Generally, people still maintain typical pre-disease levels of independence in all other basic functions, such as financial management, domestic responsibilities, and ADLs (eg, eating, dressing, bathing) or perform satisfactorily in typical salaried employment (possibly at a lower level) and require slight assistance in only one basic function like finances, domestic chores, or ADLs. For stage 1, the TFC ranges between 11 to 13. For stage 2, the TFC ranges between 7 to 10.#sup_16##esep#


    What is middle-stage manifest HD?

    Stage 3 makes up middle-stage manifest HD. Typically, people may become unable to perform complex functions, such as working, driving, or shopping independently, but may still take care of their ADLs and simple household tasks. For stage 3, the TFC ranges between 3 to 6.#sup_16#


    What is late-stage manifest HD?

    Stage 4 and stage 5 comprise late-stage manifest HD. Usually, once people reach this stage, they can no longer take care of their ADLs without assistance. For stage 4, TFC ranges from 1 to 2. Patients who are diagnosed with stage 4 HD may require major assistance in financial affairs, domestic responsibilities, and most ADLs. Care may be provided at home, but the needs of patients may be better provided at an extended care facility. For Stage 5, TFC should be 0. Patients who are diagnosed with stage 5 HD may require major assistance in financial affairs, domestic responsibilities, and all ADLs. Typically, full-time skilled nursing care is required.#sup_16#

Spinocerebellar ataxias (SCAs)


Spinocerebellar ataxias (SCAs) are a group of inherited progressive neurodegenerative diseases that mainly affect the cerebellum. Currently, more than 40 types of SCAs have been identified. Not all SCAs are restricted to pure cerebellar degeneration; some types involve other areas of the central nervous system, including the pontine nuclei, spinal cord, cortex, peripheral nerves, and basal ganglia.18


The prevalence of SCAs, which are inherited in an autosomal-dominant fashion, is estimated to be about 1 to 5 in 100,000 individuals.19  Spinocerebellar ataxia 3 (SCA3) is the most common subtype of type 1 autosomal-dominant ataxias worldwide. The prevalence of SCA3 is estimated to be 1 to 2 in 100,000 people but varies significantly based on geography and ethnicity.20

  • What causes spinocerebellar ataxia 3?

    SCA3, also known as Machado-Joseph disease, is a progressive cerebellar disease that is inherited in an autosomal-dominant pattern.#sup_21,22# Mutations in the ATXN3 gene are thought to cause SCA3.#sup_21#

     

    The ATXN3 gene provides instructions for how to make ataxin-3, a protein involved in the ubiquitin-proteasome system. This system is responsible for destroying and removing excess or damaged proteins. The molecule ubiquitin attaches to damaged proteins, tagging them for degradation. Ataxin-3 removes ubiquitin from the proteins before they are broken down, so that ubiquitin may be reused. Nonfunctional ataxin-3 cannot remove ubiquitin for reuse, and as a result, ubiquitin, damaged proteins, and ataxin-3 build up and form aggregates within the nucleus of cells. It is not yet well understood how these aggregates affect cell function.#sup_21#


    The ATXN3 gene mutation also involves CAG trinucleotide repeats, similar to other neurodegenerative diseases such as HD. In people with SCA3, the CAG segment repeats more than 50 to 80 times. Usually, a greater number of repeats is associated with earlier onset and faster progression of signs and symptoms, a phenomenon called anticipation.#sup_21#


    Repeat expansion mutation


    #img1#


    #ssep#Brain cells are most affected by mutations in the ATXN3 gene. SCA3 is associated with cell death in the brainstem and cerebellum, as well as the spinal cord. Progressive cell loss in the brain and spinal cord causes the signs and symptoms characteristic of SCA3.#sup_21 #Presenting features include the following#sup_22#:

    • Balance dysfunction

    • Eye muscle movement disorders

    • Gait problems

    • Clumsiness

    • Speech difficulties#esep# 

    Ten to fifteen years after disease onset, individuals usually need assistive devices to help with activities of daily living.#sup_18# The mean survival after disease onset is approximately 21 years.#sup_23#


X-linked recessive diseases

X-linked recessive diseases

X-linked recessive diseases are caused by mutations in genes on the X chromosome. Men only have one X chromosome, so only one defective copy of the gene is sufficient to cause disease. Women have two X chromosomes, so a mutation would have to occur in both copies of the gene to cause disease; although, women carriers can sometimes display some disease symptoms. It is less likely that women will have two defective copies of this gene. Men are affected by X-linked recessive diseases much more frequently than women. In fact, one characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.5


Examples of X-linked recessive diseases

 
Fabry disease


Fabry disease is caused by mutations in the GLA gene, which is located on the X chromosome, one of two sex chromosomes. Thus, Fabry is an X-linked disease, inherited in a recessive pattern. 

 
Fabry disease occurs in all populations and affects both males and females. It is estimated that there are about 3800 men with Fabry disease in the United States. It is not known how many women are affected by the disease.25 


Published data from the Fabry registry indicates that men with the disease are expected to live to an average age of 50 to 57 years. Women with Fabry disease are expected to live to an average age of 64 to 72 years.27 

EXPERTS: Did you know?

The GLA gene provides instructions for making an enzyme alpha-galactosidase A, which is necessary for the metabolism of a lipid called globotriaosylceramide or GL-3. GLA gene mutations prevent alpha-galactosidase A from effectively breaking down GL-3, leading to a buildup of GL-3 in most cells throughout the body. Progressive accumulation of GL-3 causes cell damage, leading to the wide range of symptoms of Fabry disease.20 The condition is a systemic disease that manifests as brain vascular disease, heart disease, and progressive kidney failure.21,23

Hemophilia


Hemophilia is a bleeding disorder that interferes with blood clotting. Hemophilia A and hemophilia B are inherited in an X-linked recessive pattern. This means that the genes associated with hemophilia are located on the X chromosome, one of two sex chromosomes.28

 

For all severities of hemophilia A, it is estimated that this disease occurs in 17.1 cases per 100,000 men. Hemophilia B is not as common. For all severities of hemophilia B, it is estimated that this disease occurs in 3.8 cases per 100,000 men.29 

  • What causes hemophilia?

    Mutations in the F8 gene cause hemophilia A; whereas mutations in the F9 gene cause hemophilia B. A defect or mutation in either of these genes can result in the inability or reduced ability to express blood clotting factor VIII or blood clotting factor IX, or the reduced functionality of one of these proteins. Hemophilia A or B can range from mild to moderate to severe, depending on the level of factor produced. People with mild hemophilia have factor VIII or factor IX levels between 5% to 40% of normal; those with moderate hemophilia have factor levels between 1% to 5% of normal, and those with severe hemophilia have factor levels less than 1% of normal.#sup_30,31#


    When the genes associated with the production of proteins required for blood clotting are missing or mutated, depending on the severity, the patient may bleed spontaneously or may not clot enough to stop bleeding, even after a minor trauma or surgery.#sup_28#

      

    Current treatment for hemophilia B consists of life-long prophylactic or on-demand injections of replacement factor IX.#sup_32# Despite treatment, people with moderate and severe hemophilia are at risk of bleeds, notably joint bleeds,#sup_33# which can cause chronic inflammation of the synovial membrane and disease of the joints. Intracranial bleeding affects around 2% of people with hemophilia and is potentially life-threatening.#sup_34,35# Appropriate prophylaxis may reduce the risk of bleeding events, including severe intracranial bleeding.#sup_36,37# Although the life expectancy for people with hemophilia has improved, premature mortality remains a challenge in severe hemophilia and/or where access to prophylaxis is limited.#sup_34-36# The average lifespan of people with hemophilia B (United Kingdom, non-HIV) depends on the severity of the disease: 63 years for severe hemophilia and 75 years for mild-to-moderate hemophilia. For comparison, the average lifespan of the general population is 78 years.#sup_35#

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