Mbbs help multifactorial diseases

1. Multifactorial disorders
LECTURE 8

2. Multifactorial genetic disorders, or complex traits, result from
several genes in combination with lifestyle and environmental
influences.

4. 1. Alzheimer’s disease
Alzheimer's is a disease that causes dementia, or loss of brain
function. It affects the parts of the brain that are important for
memory, thought, and language.
The brain of a person with Alzheimer's contains abnormal
clumps of cellular debris and protein (plaques) and collapsed
microtubules (support structures inside the cell).

5. Microtubule collapse is caused by a malfunctioning protein
called tau, which normally stabalizes the microtubules. In
Alzheimer's patients, tau proteins instead cluster together to
form disabling plaques and tangles. These plaques and tangles
damage the healthy cells around them, leading to cell death.
The brain also produces smaller amounts of neurotransmitters
(acetylcholine, serotonin, and norepinephrine), chemicals that
allow nerve cells to talk to one another.

6. The most common form of the disease, which strikes after age
65, is linked to the apolipoprotein E (apoE) gene on
chromosome 19.
Scientists don't know how apoE4 increases the risk of
developing Alzheimer's. Everyone has apoE, which comes in
three forms.

8. One of the forms (apoE4) increases a person's risk of
developing Alzheimer's.
The other two forms seem to protect against the disease.
While people who inherit the apoE4 form of the gene are at
increased risk for the disease, they will not necessarily
develop it.
Mutations in genes found on chromosomes 1, 14, and 21 are
linked to rarer forms of the disease, which strike earlier in life.

9. How do people get Alzheimer's disease?
Scientists don't know exactly how people develop
Alzheimer's, but they believe it is caused by a combination of
genes and environmental factors. It is a multifactorial disorder.
The early-onset forms of Alzheimer's are inherited in an
autosomal dominant pattern, which means that only one parent
has to pass down a defective copy of the gene for their child to
develop the disorder.

11. 2. Breast cancer and ovarian cancer
Cells normally grow and divide just enough to grow or to
replace damaged tissue. But sometimes the mechanisms that
regulate cell growth stop working and cells divide out of
control. This out-of-control growth is called cancer. Cancer
that develops in breast or ovarian tissue is called breast or
ovarian cancer, respectively.

13. Most people who develop breast or ovarian cancer have no
history of the disease in their family.
In fact, only 5 to 10 percent of all breast and ovarian cancers
are caused by inherited genetic factors.
These rare cases typically result from inherited mutations in
either the BRCA1 or BRCA2 gene.

15. BRCA1 and BRCA2 are called tumor suppressor genes,
because they control cell growth. BRCA1 is located on
chromosome 17, and BRCA2 on chromosome 13.
Scientists believe BRCA1 and BRCA2 work by fixing
damaged or broken DNA.

16. Women who inherit a mutated copy of the BRCA1 or BRCA2
gene accumulate broken and deformed chromosomes, and
therefore have a greater chance of accumulating mutations that
will lead to uncontrolled cell growth and cancer.
Men who inherit the defective genes are also more likely to
develop prostrate cancer.

17. High-risk families include those whose members carry a
mutation in either the BRCA1 or BRCA2 gene. The mutated
BRCA1 and BRCA2 genes are inherited in an autosomal
dominant pattern. A child needs to inherit just one copy of the
mutated gene to have an increased cancer risk. Children who
have a parent with a BRCA1 or BRCA2 mutation have a 1 in
2 chance of inheriting the mutation.

18. Just because a person inherits the defective gene does not
mean he or she will develop cancer, but inheritance greatly
increases the risk. Out of every 100 women who inherit a
mutated BRCA1 or BRCA2 gene, as many as 60 will develop
breast cancer by age 50; by age 70, approximately 80 will
develop breast cancer.

19. Williams syndrome is a rare genetic disorder characterized by
growth delays before and after birth (prenatal and postnatal
growth retardation), short stature, mental deficiency, and
distinctive facial features that typically become more
pronounced with age. Such characteristic facial features may
include a round face, full cheeks, thick lips, a large mouth that
is usually held open, and a broad nasal bridge with nostrils
that flare forward (anteverted nares).

20. Affected individuals may also have unusually short eyelid
folds (palpebral fissures), flared eyebrows, a small lower jaw
(mandible), and prominent ears. Dental abnormalities may
also occur including abnormally small, underdeveloped teeth
(hypodontia) with small, slender roots.

21. Williams syndrome may also be associated with cardiac
defects, abnormally increased levels of calcium in the blood
during infancy (infantile hypercalcemia), musculoskeletal
defects.

22. Musculoskeletal abnormalities associated with Williams
syndrome may include depression of the breastbone (pectus
excavatum), scoliosis or kyphosis, or an awkward gait.
In addition, most affected individuals have mild to moderate
mental retardation; poor visual-motor integration skills; a
friendly, outgoing, talkative manner of speech; a short
attention span; and are easily distracted.

23. Children with Williams syndrome are extremely sensitive to
sound and may overreact to unusually loud or high-pitched
sounds (hyperacusis). Chronic middle ear infections (otitis
media) are often present.

24. Motor development, (e.g., sitting and walking) and/or gross
and fine motor skills (e.g., picking up an object) may be
delayed. The development of secondary sexual characteristics
(e.g., pubic hair and underarm hair) may occur prematurely
(precocious puberty) in children with this disorder. Individuals
with this disorder may also have an unusually hoarse voice.

25. Ongoing research indicates that sporadic and familial
Williams syndrome result from deletions of genetic material
from genes located on the long arm (q) of chromosome 7
(7q11.23).

26. Alport syndrome is a genetic condition characterized by kidney disease, loss of
hearing, and eye abnormalities.
Alport syndrome, also known as hereditary nephritis is a genetic disorder arising
from the mutations in the genes encoding alpha-3, alpha-4, and alpha-5 of type 4
collagen (COL4A3, COL4A4, COL4A5) or collagen 4 α345 network
It takes place due to an abnormality of a gene that codes for type 4 collagen and
usually presents in patients with hematuria, edema, and hypertension.

27. Alport syndrome affects about 1 in 50,000 newborns and
males are more likely to be symptomatic than females. It is
estimated that approximately 30,000 to 60,000 people in the
United States (US) have this disorder.

28. A detailed history and physical examination must be obtained
along with family history. Laboratory evaluation should
include urinalysis (UA), urine microscopy, and renal function
panel. Individuals with Alport syndrome may develop
symptoms of hematuria, proteinuria, edema, hypertension, and
progressive decline in renal functions.

29. Over time, the symptoms worsen, and the patients experience
worsening proteinuria, hypertension. They can also present
with gross hematuria following an upper respiratory tract
infection.

31. During late childhood, people with Alport syndrome
frequently develop bilateral sensorineural hearing loss caused
by abnormalities of type 4 collagen in the inner ear.Hearing
loss becomes apparent in late childhood or early adolescence,
usually before the onset of kidney failure, and starts with high-
frequency loss.

32. Multiple ocular findings can be seen in patients with Alport
syndrome.
Affected individuals may have a cone-shaped lens (anterior
lenticonus), leading to abnormal refraction and a decreased
visual acuity.

33. Other abnormalities include subcapsular cataracts, abnormal
pigmentary changes in the retina with yellow or white flecks
(dot-and-fleck retinopathy), posterior polymorphous
dystrophy, and corneal erosions.

34. Patients typically present with persistent microscopic
hematuria before the age of ten years. This is due to the
defective glomerular basement membrane (GBM) permitting
the passage of red blood cells.
The clinical suspicion for Alport syndrome should be high in a
patient with hematuria, proteinuria, abnormal renal indices
along with ear and eye manifestations.

36. UA would reveal blood and protein, and urine microscopy
should be performed to evaluate for acanthocytes. Renal
biopsy is indicated in the setting of abnormal UA, presence of
acanthocytes, red blood cell casts, or abnormal renal indices.

37. Any patient with suspected Alport syndrome should be
referred to otorhinolaryngology for high-frequency hearing
loss and ophthalmology for the eye examination. Due to the
defective collagen, the lens lacks the integrity to maintain the
normal shape leading to anterior lenticonus into the anterior
chamber

38. Genetic testing can help establish the diagnosis and determine
the inheritance pattern of an individual and their family
members. Molecular Genetic testing is non-invasive, accurate,
and gives the prognosis as the underlying mutation can be
revealed. Next-generation sequencing (NGS) analyses of
COL4A3, COL4A4, COL4A5 are recommended in patients
with no family history of Alport syndrome.

39. For patients with positive family history, testing of the target
gene is recommended. If the genetic defect does not match the
family genetic mutation, a renal biopsy is preferred.

40. Unfortunately, there is no specific treatment for Alport
syndrome. Treatment is focused on limiting the progression of
proteinuria and kidney disease. Options include angiotensin-
converting enzyme inhibitors (ACEi), angiotensin receptor
blockers (ARBs) for the management of proteinuria,
hypertension