Multi-system Genetic Diseases

Question 1

What are different modes of inheritance?

Answer 1

• Chromosomal
  
  • Numerical such as trisomy 21
  • Structural such as translocations, deletions and microdeletions
• Single gene disorders
  
  • Autosomal dominant such as TS, NF1, myotonic dystrophy
  • Autosomal recessive such as CF
  • X-linked such as Duchenne muscular dystrophy
• Multifactorial
  
  • Polygenic
  • Environmental factors such as in diabetes and haemochromatosis

Question 2

Why is there multi-system involvement due to mutations?

Answer 2

• Several genes with diverse functions are involved (chromosomal)
• Single genes widely expressed in different tissues
• Single gene tissue-specific expressions but tissue integral part of many systems

Question 3

What are some important multi-system genetic diseases?

Answer 3

• NF1
• Myotonic dystrophy
• Tuberous sclerosis

Question 4

What does NF1 stand for?

Answer 4

Neurofibromatosis type 1

Question 5

What is NF1 also called?

Answer 5

Von Recklinghausen disease

Question 6

Describe the genetics of NF1 (dominant/recessive, expression, location)?

Answer 6

• Autosomal dominant
• Variable expression – inter and intra-familial
• Gene is 17q, a tumour suppressor gene

Question 7

What is the prevalence of NF1?

Answer 7

1/2500

Question 8

What is the diagnostic criteria for NF1?

Answer 8

• café au lait spots - 6 or more
• neurofibromas - 2 or more
• axillary freckling
• Lisch nodules (specks in iris)
• optic glioma
• thinning of long bone cortex
• family history

Question 9

What are the clinical features of NF1?

Answer 9

• Macrocephaly
• Short stature
• Dysmorphic features – “noonan look”
• Learning difficulties
• Epilepsy
• Scoliosis
• Pseudoarthosis of tibia
• Hypertension
• Neoplasia
  
  • CNS (optic gliomas), endocrine

Question 10

Describe the management for NF1?

Answer 10

• Annual review of affected individuals until diagnosis can be excluded (5 years)
  
  • BP
  • Spine for scoliosis
  • Tibia for unusual angulation
  • Visual acuity and visual fields
  • Educational assessment

Question 11

Describe the genetics of NF2 (gene location)?

Answer 11

• Gene is on chromosome 22

Question 12

What are clinical features of NF2?

Answer 12

• Acoustic neuromas
  
  • Bilateral
• CNS and spinal tumours

Question 13

What does TS stand for?

Answer 13

Tuberous sclerosis

Question 14

What is the incidence of TS?

Answer 14

1/7000

Question 15

Describe the genetics of TS (dominant/recessive, expression, genes)?

Answer 15

• Autosomal dominant
• Variable expression – asymptomatic to severe mental and physical handicap
• 2 genes on different chromosomes both cause TS with identical phenotypes – TSC1 and TSC2

Question 16

What are the clinical features of TS?

Answer 16

• Classic triad
  
  • Epilepsy – infantile spasms, myoclonic seizures
  • Learning difficulties
  • Skin lesions – depigmented macules, angiofibromas, fibrous plaque forehead, shagreen patches, ungula fibromas
• Kidney problems
  
  • Cysts and angiomyolipomata
• Phakomas in eye
• Rhabdomyomas in heart

Question 17

What is the classic triad for TS?

Answer 17

• Epilepsy – infantile spasms, myoclonic seizures
• Learning difficulties
• Skin lesions – depigmented macules, angiofibromas, fibrous plaque forehead, shagreen patches, ungula fibromas

Question 18

What kind of epilepsy occurs in TS?

Answer 18

• Epilepsy – infantile spasms, myoclonic seizures

Question 19

What skin lesions are seen in TS?

Answer 19

• Skin lesions – depigmented macules, angiofibromas, fibrous plaque forehead, shagreen patches, ungula fibromas

Question 20

What investigations are done for TS?

Answer 20

• Cranial MR
• Renal USS
• Echocardiogram

Question 21

Describe the management of TS?

Answer 21

• Screening of at risk relatives
• Surveillance and genetic counselling

Question 22

Descibe the genetics of myotonic dystrophy (dominant/recessive)?

Answer 22

Autosomal dominant

Question 23

What are the clinical features of myotonic dystrophy?

Answer 23

• Cataract
  
  • Bilateral, late onset
• Muscle weakness, stiffness and myotonia
• Low motivation, bowel problems, diabetes
• Heart block
• Learning difficulties

Question 24

What are complications of myotonic dystrophy?

Answer 24

• Death post-anaesthetic a risk if not monitored