14 - Pathophysiology of Genetic Neuronal Diseases

Question 1

what is Fabry Disease?

Answer 1

an inherited disorder that results from the buildup of a particular type of fat in the body’s cells

Question 2

what are the characteristics of Fabry Disease?

Answer 2

• episodes of pain, particularly in the hands and feet (acroparesthesias) umbilicus too;
• clusters of small, dark red spots on the skin called angiokeratomas;
• a decreased ability to sweat (hypohidrosis);
• cloudiness of the front part of the eye (corneal opacity);
• hearing loss.

Question 3

what are the life threatening complications of Fabry Disease?

Answer 3

progressive kidney damage, heart attack, and stroke. Milder forms of the disorder may appear later in life and affect only the heart or kidneys

Question 4

what is a notable sign/symptom of Fabry Disease?

Answer 4

Angiokeratomas

Question 5

what are Angiokeratomas?

Answer 5

the red-purple maculopapular skin lesions characteristic of the disorder

Question 6

T/F, ocular manifestations can occur with someone who has Fabry Disease? if so, describe it?

Answer 6

T; “spoke-like” pattern on cornea, visible through slit lamp ophthalmoscopy (does not affect vision), also conjunctival involvement

Question 7

what genes are related to Fabry Disease?

Answer 7

GLA Gene, which codes for alpha-galactosidase A

Question 8

what is significant about galactosidase A?

Answer 8

This enzyme is active in lysosomes. Alpha-galactosidase A normally breaks down fatty substance called globotriaosylceramide.

Question 9

what is the effect of the mutation in the GLA gene?

Answer 9

Mutations in the GLA gene alter the structure and function of the enzyme, preventing it from breaking down this substance effectively. As a result, globotriaosylceramide builds up in cells throughout the body, particularly cells lining blood vessels in the skin and cells in the kidneys, heart, and nervous system.

Question 10

what is the effect of the mutations that decrease but do not eliminate galactosidase A enzyme activity?

Answer 10

usually a milder, late onset form of Fabry disease develops that affect only the heart and kidney

Question 11

how do people inherit Fabry Disease?

Answer 11

inherited via x-linked pattern;

A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition.

Because females have two copies of the X chromosome, one altered copy of the gene in each cell usually leads to less severe symptoms in females than in males, or may cause no symptoms at all.

Question 12

what is the effect of Fabry Disease in females who have the form with one altered copy of the GLA gene and how does it compare to other x-linked disorders?

Answer 12

it is more severe compared to other x-linked disorders and causes many medical problems

These women may experience many of the classic features of the disorder, including nervous system abnormalities, kidney problems, chronic pain, and fatigue.

They also have an increased risk of developing high blood pressure, heart disease, stroke, and kidney failure. The signs and symptoms of Fabry disease usually begin later in life and are milder in females than in their affected male relatives.

Some females who carry a mutation in one copy of the GLA gene never have any of the signs and symptoms of Fabry disease.

Question 13

what Lesch Nyhan Syndrome?

Answer 13

Lesch-Nyhan syndrome is a condition characterized by the overproduction and accumulation of uric acid, a waste product of normal chemical processes that is found in blood and urine.

Question 14

what is the effect of the overproduction of uric acid in Lesch Nyhan Syndrome?

Answer 14

can cause gouty arthritis (arthritis caused by an accumulation of uric acid in the joints), kidney stones, and bladder stones.

Question 15

what are the medical problems associated with Lesch Nyhan Syndrome?

Answer 15

Problems with the nervous system and behavioral disturbances

Question 16

what are the associated abnormal muscle movements of Lesch Nyhan Syndrome?

Answer 16

Abnormal involuntary muscle movements such as flexing, jerking, and flailing are often displayed by people affected with this disorder.

Question 17

what are the typical characteristics of people who have Lesch Nyhan Syndrome?

Answer 17

usually cannot walk, require assistance sitting, and are generally wheelchair-bound.

Question 18

what is the most common and distinctive behavioral problem in those with Lesch-Nyhan syndrome.

Answer 18

Self-injury, including biting and head banging

Question 19

what genes are related to Lesch-Nyhan syndrome?

Answer 19

Mutations in the HPRT1 cause a severe deficiency of the enzyme hypoxanthine phosphoribosyltransferase 1

Question 20

what is the enzyme hypoxanthine phosphoribosyltransferase 1 responsible for?

Answer 20

recycling purines, a type of building block of DNA and RNA.

Question 21

what is the effect of phosphoribosyltransferase 1 deficiency?

Answer 21

it results in the breakdown of purines which results in abnormally high levels of uric acid in the body.

It is unclear how a shortage of this enzyme causes the neurological and behavioral problems characteristic of Lesch-Nyhan syndrome.

Question 22

How do people inherit Lesch-Nyhan syndrome?

Answer 22

an X-linked recessive pattern

Question 23

where is the gene associated with Lesch-Nyhan syndrome located?

Answer 23

on the X chromosome

Question 24

which sex is more likely to be affected by Lesch-Nyhan syndrome?

Answer 24

Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females.

Question 25

what is a characteristic of X-linked inheritance?

Answer 25

fathers cannot pass X-linked traits to their sons

Question 26

What is Niemann-Pick disease?

Answer 26

an inherited condition involving lipid metabolism, which is the breakdown, transport, and use of fats and cholesterol in the body.

Question 27

what is the effect of lipid metabolism in people with Niemann-Pick disease?

Answer 27

its abnormal and so abnormal lipid metabolism causes harmful amounts of lipids to accumulate in the spleen, liver, lungs, bone marrow, and brain.

Question 28

Niemann-Pick disease is divided into four main types based on the genetic cause and the signs and symptoms, what are they?

Answer 28

Niemann-Pick disease type A
Niemann-Pick disease type B
Niemann-Pick disease type C, sub divided into types C1 and C2

Question 29

describe Niemann-Pick disease type A?

Answer 29

appears during infancy and is characterized by an enlarged liver and spleen (hepatosplenomegaly), failure to gain weight and grow at the expected rate (failure to thrive), and progressive deterioration of the nervous system.

Question 30

describe Niemann-Pick disease type B?

Answer 30

it has a range of features that may include hepatosplenomegaly, growth retardation, and problems with lung function including frequent lung infections. Other signs include blood abnormalities such as elevated levels of cholesterol and other lipids (fats), and decreased numbers of blood cells involved in clotting (platelets).

Question 31

describe Niemann-Pick disease type C?

Answer 31

usually appears in childhood, although infant and adult onsets are possible. Signs of Niemann-Pick disease type C include severe liver disease, breathing difficulties, developmental delay, seizures, poor muscle tone (dystonia), lack of coordination, problems with feeding, and an inability to move the eyes vertically.

Question 32

what is Niemann-Pick disease type A also known as?

Answer 32

the neurological type and so children affected by this condition generally do not survive past early childhood.

Question 33

what is Niemann-Pick disease type B also known as?

Answer 33

the non-neurological type because the nervous system is not usually affected. People with Niemann-Pick disease type B usually survive into adulthood.

Question 34

what is the survival rate for people who have Niemann-Pick disease type C?

Answer 34

People with this disorder can survive into adulthood. Niemann-Pick disease type C is further subdivided into types C1 and C2, each caused by a different gene mutation.

Question 35

what are the genes related to Niemann-Pick disease?

Answer 35

NPC1, NPC2, and SMPD1

Question 36

which genes cause Niemann-Pick disease types A and B?

Answer 36

Mutations in the SMPD1 gene, this gene provides instructions for producing an enzyme called acid sphingomyelinase

Question 37

what is the function of sphingomyelinase?

Answer 37

This enzyme is found in the lysosomes, where it processes lipids such as sphingomyelin

Question 38

what is the effect of a mutation in the SMD1 gene responsible for the enzyme sphingomyelinase?

Answer 38

Mutations in this gene lead to a deficiency of acid sphingomyelinase and the accumulation of sphingomyelin, cholesterol, and other kinds of lipids within the cells and tissues of affected individuals.

Question 39

mutations in what genes cause Niemann-Pick disease type C.

Answer 39

the NPC1 or NPC2 gene

Question 40

What is the NPC1 gene responsible for?

Answer 40

producing a protein that is involved in the movement of cholesterol and lipids within cells.

Question 41

what is the effect of in a deficiency of the protein produced by NPC1 gene?

Answer 41

A deficiency of this protein leads to the abnormal storage of lipids within cells as seen in people with Niemann-Pick disease type C1.

Question 42

What is the NPC2 gene responsible for?

Answer 42

provides instructions to produce a protein that binds and transports cholesterol.

Question 43

what is the effect of in a deficiency or absent levels of the protein produced by NPC2 gene?

Answer 43

Reduced or absent levels of this protein lead to the abnormal accumulation of lipids and cholesterol in the cells as seen in people with Niemann-Pick disease type C2

Question 44

T/F, The exact functions of the NPC1 and NPC2 proteins are not fully understood.

Answer 44

T

Question 45

How do people inherit Niemann-Pick disease?

Answer 45

its inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations.

The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition

Question 46

on a histological slide, what is of special note for the Niemann-Pick disease?

Answer 46

Foamy cytoplasm

Question 47

what are the common S/S of Niemann-Pick disease?

Answer 47

Protruding abdomen

Macular cherry red spots

Question 48

What is maple syrup urine disease?

Answer 48

is an inherited disorder in which the body is unable to process certain protein building blocks (amino acids) properly.

Question 49

where does maple syrup urine disease get its name from?

Answer 49

from the distinctive sweet odor of affected infants’ urine.

Question 50

how is maple syrup urine disease characterized in early infancy?

Answer 50

poor feeding, vomiting, lack of energy (lethargy), and developmental delay

If untreated, maple syrup urine disease can lead to seizures, coma, and death

Question 51

what is the most common and severe form the maple syrup urine disease?

Answer 51

the classic type and this becomes apparent soon after birth

Variant forms of the disorder become apparent later in infancy or childhood and are typically milder, but they still involve developmental delay and other medical problems if not treated.

Question 52

What genes are related to maple syrup urine disease?

Answer 52

BCKDHA, BCKDHB, DBT, and DLD genes

Question 53

what is the function of the BCKDHA, BCKDHB, DBT, and DLD genes?

Answer 53

provide instructions for making proteins that work together as a complex

The protein complex is essential for breaking down the amino acids leucine, isoleucine, and valine present in many kinds of food (particularly protein-rich foods such as milk, meat, and eggs)

Question 54

what is the effect in the mutations of the BCKDHA, BCKDHB, DBT, and DLD genes?

Answer 54

Mutations in any of these four genes reduce or eliminate the function of the protein complex, preventing the normal breakdown of leucine, isoleucine, and valine

As a result, these amino acids and their byproducts build up in the body.

Because high levels of these substances are toxic to the brain and other organs, their accumulation leads to the serious medical problems associated with maple syrup urine disease.

Question 55

How do people inherit maple syrup urine disease?

Answer 55

autosomal recessive pattern, which means both copies of the gene in each cell have mutations.

The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Question 56

what disease is associated with nail biting and head banging?

Answer 56

Lesch-Nyhan Syndrome

Question 57

what amino acid is included to be found in excess in maple syrup urine disease?

Answer 57

isoleucine

Question 58

what disease is associated with sausage like dilated vessels of the eye?

Answer 58

Fabry disease

Question 59

what disease is associated with red spots and decreased sweating, and pain/numbness in hands and feet?

Answer 59

Fabry disease

Question 60

which type of Niemann pick disease is characterized by a failure to thrive and neurological issues (usually results in death) of infants?

Answer 60

Type A