Question

Describe the mechanisms behind Huntingtons Disease and Sickle cell, connecting how the genetic anomalies relate to their phenotypes/observed symptoms.

Answer 1

Huntington disease (HD) is inherited in an autosomal dominant manner. This means that having a change (mutation) in only one of the 2 copies of the HTT gene is enough to cause the condition. When a person with HD has children, each child has a 50% (1 in 2) chance to inherit the mutated gene and develop the condition. Most people with HD have an affected parent. The family history can sometimes appear negative for various reasons even though a parent carries, or carried, a mutation in the HTT gene. In rare cases, HD is caused by a new (de novo) mutation in the HTT gene, in which case the disease occurs for the first time in the affected person and is not inherited from a parent.As HD is passed through generations, the size of the mutation in the HTT gene (called a trinucleotide repeat) often increases. A longer repeat in the HTT gene may cause earlier onset of symptoms. This phenomenon is called anticipation. HD symptoms typically manifest between 30 and 45 years of age, so the majority of HD patients have already had children before they are diagnosed, and they have thus passed the mutant HTT gene on to the next generation. Individuals carrying the mutated allele have a 50% chance of passing this allele to each of their children. In large families with a history of HD, the disease is likely to appear in every generation, because it is an autosomal dominant condition. Although HD phenotypes nearly always appear late in life, the dominant mutation in the HTT gene is present from birth.

Huntington disease (HD) is a progressive disorder that causes motor, cognitive, and psychiatric signs and symptoms. Signs and symptoms vary by stage and may include:

•Early stage:

Behavioral disturbances

Clumsiness

Moodiness

Irritability

Paranoia

Apathy

Anxiety

Hallucinations

Abnormal eye movements

Depression

Impaired ability to detect odors

•Middle stage:

Dystonia

Involuntary movements

Trouble with balance and walking

Chorea with twisting and writhing motions

Unsteady gait (style of walking)

Slow reaction time

General weakness

Weight loss

Speech difficulties

Stubbornness

•Late stage:

Rigidity (continual tension of the muscles)

Bradykinesia (difficulty initiating and continuing movements)

Severe chorea

Serious weight loss

Inability to speak

Inability to walk

Swallowing problems

Inability to care for oneself

Sickle-cell anemia is caused by a point mutation in the β-globin chain of hemoglobin, causing the hydrophilic amino acid glutamic acid to be replaced with the hydrophobic amino acid valine at the sixth position. The β-globin gene is found on the short arm of chromosome 11. Any combination of two of these alleles represents an individual's genotype. Individuals with genotype AS have the sickle cell trait phenotype, and individuals with SS genotype have the sickle cell disease phenotype. Among children and adults with sickle cell anemia (homozygous for sickle hemoglobin), the median age at death was 42 years for males and 48 years for females. Among those with sickle cell-hemoglobin C disease, the median age at death was 60 years for males and 68 years for females. Sickle cell anemia is a pleiotropic disease because the expression of a single mutated HBB gene produces numerous consequences throughout the body. The mutated hemoglobin forms polymers and clumps together causing the deoxygenated sickle red blood cells to assume the disfigured sickle shape.

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Sickle Cell Disease (Anemia) Symptoms, Genetics, Diagnosis, Treatment, and Life Expectancy

Medical Author: William C. Shiel Jr., MD, FACP, FACR

Medically Reviewed on 1/10/2020

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Table of Contents

Definition

Symptoms/Signs

Inherited

Tests/Diagnosis

Treatment/Symptoms

Pain Treatment

Cure

Sickle Cell Disease (Anemia) Center

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Sickle cell anemia (disease, SCD) facts

Illustration of misshapen red blood cells.

Sickle cell disease is a hereditary condition that causes red blood cells to be deformed.

Sickle cell anemia (SCD) is an inherited disorder of the hemoglobin in blood.

Sickle cell anemia requires the inheritance of two sickle cell genes.

Sickle cell trait, which is the inheritance of one sickle gene, almost never causes problems.

Virtually all of the major symptoms of sickle cell anemia are the direct result of the abnormally shaped sickled red blood cells blocking the flow of blood.

The current treatment of sickle cell anemia is directed primarily toward managing the individual features of the illness as they occur.

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What is sickle cell anemia?

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Sickle cell anemia (sickle cell disease) is a disorder of the blood caused by an inherited abnormal hemoglobin (the oxygen-carrying protein within the red blood cells). The abnormal hemoglobin causes distorted (sickled appearing under a microscope) red blood cells. The sickled red blood cells are fragile and prone to rupture. When the number of red blood cells decreases from rupture (hemolysis), anemia is the result. This condition is referred to as sickle cell anemia. The irregular sickled cells can also block blood vessels causing tissue and organ damage and pain.

Sickle cell anemia is one of the most common inherited blood anemias. The disease primarily affects Africans and African Americans. It is estimated that in the United States, some 90,000 to 100,000 Americans are afflicted with sickle cell anemia. Overall, current estimates are that one in 500 U.S. African American births is affected with sickle cell anemia.

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What are the symptoms and signs of sickle cell anemia?

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Virtually all of the major symptoms of sickle cell anemia are the direct result of the abnormally shaped, sickled red blood cells blocking the flow of blood that circulates through the tissues of the body. The tissues with impaired circulation suffer damage from lack of oxygen. Damage to tissues and organs of the body can cause severe disability in patients with sickle cell anemia. The patients endure episodes of intermittent "crises" of variable frequency and severity, depending on the degree of organ involvement.

The major features and symptoms of sickle cell anemia include:

Fatigue and anemia

Pain crises

Dactylitis (swelling and inflammation of the hands and/or feet) and arthritis

Bacterial infections

Sudden pooling of blood in the spleen and liver congestion

Lung and heart injury

Leg ulcers

Aseptic necrosis and bone infarcts (death of portions of bone)

Eye damage

Some features of sickle cell anemia that can occur at any age include:

Fatigue

Anemia

Pain crises

Bone infarcts

Many features typically occur in certain age groups.

Infants with sickle cell anemia do not develop symptoms in the first few months of life because the hemoglobin produced by the developing fetus (fetal hemoglobin) protects the red blood cells from sickling. This fetal hemoglobin is absent in the red blood cells that are produced after birth so that by 5 months of age, the sickling of the red blood cells is prominent and symptoms begin.

Infants and younger children can suffer signs and symptoms of;

fever,

abdominal pain,

pneumococcal bacterial infections,

painful swellings of the hands and feet (dactylitis), and

splenic sequestration.

Adolescents (preteens and teens) and young adults more commonly develop:

Leg ulcers

Aseptic necrosis

Eye damage

Symptoms in adult typically are intermittent pain episodes due to injury of bone, muscle, or internal organs.