Genetic conditions

Question 1

Lysosomal storage disorders - name 3

Answer 1

Tay Sachs
Gaucher’s
Fabry

Question 2

Fabry disease

a) What is it?
b) Inheritance and gene affected
c) Presentation
d) Diagnosis
e) Treatment

Answer 2

a) Lysosomal storage disease, affecting the heart, nervous system, and kidneys

b) X-linked recessive:
- Mutations in the GLA gene
- Leads to deficiency in the alpha-galactosidase A (Gal A) enzyme, which is responsible for breaking down fatty molecules, mainly globotriaosylceramide (Gb3 or Gl-3) - deficiency leads to accumulation of these

c) Classical (child-adolescent onset)
- Episodes of severe pain, and burning and tingling sensations in the hands and feet — which may be triggered by exercise, fever, fatigue, and stress
- Clusters of small, dark spots in several locations on the skin that become larger and more abundant with age
- Clouding appearance of the eyes without visual disturbance
- Later, causes CKD and LVH/heart failure

Atypical (adult-onset)

• Around age 30-40, may present with LV hypertrophy, CKD and white matter lesions on the brain, or cramp-fasciculation syndrome
• Classical symptoms as above

d) Enzyme assay for Gal-A levels or GLA gene
e) Gal-A enzyme replacement

Question 3

HNPCC vs FAP

Answer 3

HNPCC:

• AD-inherited condition causing polyps that are NOT diffuse
• 6 different genetic causes
• Presents with cancer often in 40s
• Lynch 1 - not associated with cancer in the family
• Lynch 2 - associated with FHx colorectal/ ovarian/ pancreatic /endometrial cancer
• Requires colonoscopic surveillance

FAP:

• AD-inherited condition from defective APC gene on Ch 5
• Causes >100 colon polyps and 100% risk of colorectal cancer if untreated
• Presents in 20s - 30s usually
• Also may have extra-colonic polyps
• Requires prophylactic colectomy

Question 4

X-linked dominant conditions

a) Examples
b) Difference in phenotype male vs female

Answer 4

a) Fragile X syndrome
Vitamin-D resistant rickets

Rarely, Alport syndrome (usually X-linked recessive)

b) - Roughly equal prevalence male vs female
- Females generally have less severe symptoms due to having two X chromosomes

Question 5

NF-1

a) Gene and inheritance
b) Presentation - mnemonic: CAFE SPOT

Answer 5

a) NF-1 gene on Chromosome 17 - codes for neurofibromin
AD-inheritance (though 50% sporadic)

b) CAFE SPOT:
C: café-au-lait spots (>6)
A: axillary or inguinal freckling
F: fibromas - neurofibroma (two or more) or plexiform neurofibroma (one)
E: eye hamartomas (Lisch nodules)
S: skeletal abnormalities, e.g. sphenoid wing dysplasia, leg bowing
P: phaeochromocytoma
OT: optic tumour (optic nerve glioma)

Question 6

NF-2

a) Gene and inheritance
b) Presentation

Answer 6

a) NF-2 gene on Chromosome 22 - codes for schwannomin
- AD-inheritance (50% sporadic)

b) - Bilateral vestibular schwannomas by age 30: tinnitus, hearing loss, etc.
- Other CNS cancers may present (e.g. glioma, meningioma, ependymoma)
- Cataracts
- Seizures, LD, etc.

Question 7

Mitochondrial disorders

a) Inheritance
b) Common clinical features
c) Examples

Answer 7

a) - Those caused by mutations in mitochondrial DNA are transmitted by maternal inheritance (all offspring of affected mother will inherit the disease)
- Those caused by mutations in nuclear DNA may be AD, AR or X-linked inheritance

b) Neuromuscular weakness, growth failure, sensorineural hearing loss, retinitis pigmentosa, ataxia, cardiomyopathy, heart block, lactic acidosis, IDDM

c) - Kearns-Sayre
- Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS)
- Leber’s hereditary optic neuropathy (LHON)

Question 8

Usher syndrome

Answer 8

Sensorineural deafness + retinitis pigmentosa

3 types, all AR-inheritance

Question 9

Friedrich ataxia

Answer 9

?

Question 10

Triple repeat expansion diseases

Answer 10

Huntington
Fragile X
Myotonic dystrophy
Friedreich's ataxia
Spinocerebellar ataxia
Kennedy's disease

Question 11

Dubin-Johnson

a) Inheritance and epidemiology
b) Gene mutation, protein affected
c) Presentation

Answer 11

a) AR inheritance
1: 3000 Iranian Jews

b) cMOAT gene mutation - causing defective MRP2 protein
c) Failure of conjugated bilirubin excretion, causing jaundice, but otherwise asymptomatic

Question 12

Familial high lipid diseases

a) Types and lipid profile

Answer 12

a) Homozygous familial hypercholesterolaemia
- Total cholesterol 12-15, raised LDL cholesterol
- Tendon xanthomata, MI in 20s/30s

Heterozygous familial hypercholesterolaemia:

• Total cholesterol ~ 8, raised LDL cholesterol
• Tendon xanthomata, MI in 40s/50s

Familial mixed hyperlipidaemia
- Raised + LDL + triglycerides

Familial hypertriglyceridaemia-

• Raised triglycerides, normal LDL
• High VLDL

Familial HDL deficiency
- Normal LDL, reduced HDL

Question 13

Homocystinuria vs Marfans

Answer 13

Marfans

• Autosomal dominant
• Fibrillin-1 on Ch 15
• Upwards lens dislocation (look up as they are so tall)

Homocystinuria

• Autosomal recessive
• Mutation in cystathionine beta-synthase (CBS) gene on Ch 21
• Causes methionine build up
• Downwards lens dislocation (look down towards their urine)
• Marfanoid habitus, venous thrombosis, learning difficulties
• Rx: pyridoxine, low protein diet

Question 14

Primary ciliary dyskinesia

Answer 14

Dynien absence

Question 15

Y-linked diseases

Answer 15

Incredibly rare

Non-obstructive spermatogenic failure

Not hairy ears

Question 16

Tuberous sclerosis

a) Cause
b) Clinical features (mnemonic: ASH LEAF)

Answer 16

a) - Mutations in the TSC1 or TSC2 genes
- 1/3 inherited (AD), 2/3 de novo
- Leads to development of hamartomas in multiple organs

b) Ash leaf macules
Shagreen patches
Heart rhabdomyomas
Lung lymphangeoleiomyomatosis (LAM)
Epilepsy and astrocytoma
Angiomyolipomas and renal cysts
Fibromas - periungual fibroma, facial angiofibroma

Question 17

Single nucleotide polymorphisms

a) What are they?
b) Which are most significant?

Answer 17

a) Substitution of a nucleotide for any other nucleotide

b) Those in regulatory or coding areas of the DNA sequence