Seassion 4

Question 1

What 6 metabolic disorders are included in NBS?

Answer 1

1. phenylketonuria (PKU)
2. medium-chain acyl-CoA dehydrogenase deficiency (MCADD)
3. maple syrup urine disease (MSUD)
4. isovaleric acidaemia (IVA)
5. glutaric aciduria type 1 (GA1)
6. homocystinuria (pyridoxine unresponsive) (HCU)

Question 2

What are the four pathogenic mechanisms for Inborn errors of metabolism?

Answer 2

A - Toxic substrate accumulation

B - Product deficiency

C - Activation of alternate pathway

D - diversion of metabolic flux to secondary pathways and alternative metabolite production

Question 3

What are benefits of genetics testing for Inborn errors of metabolism?

Answer 3

Biochem has diagnose most of them however not always disease specific

Genetics allows:
· reproductive options
· determine carrier status
· an exact diagnosis
· prevents the need for invasive procedures
· can decrease the length of time it takes to obtain a diagnosis
· the use of specific therapies: e.g. nonsense mutation suppression
· can provide prognostic information for the patient

Question 4

What is the phenotype of Peroxisome Biogenesis Disorders?

What are the three types?

Answer 4

Hypotonic, feed poorly, and have distinctive facies, seizures, and liver cysts with hepatic dysfunction

Zellweger syndrome (ZS) - most severe

neonatal adrenoleukodystrophy (NALD)

Infantile Refsum disease (IRD) - least severe

Question 5

What metabolite is affected in Peroxisome Biogenesis Disorders?

Answer 5

plasma very-long-chain fatty acid (VLCFA)

Question 6

Variants in which genes are associated with Peroxisome Biogenesis Disorders?

Answer 6

The PEX genes (13 in total). Most commonly PEX1

Question 7

Name an X linked Inborn error of metabolism?

Answer 7

Ornithine Transcarbamylase Deficiency: Urea cycle deficiency disorder

Question 8

What is Smith-Lemli-Opitz Syndrome?

How can effect sexual development?

Answer 8

Cholesterol biosynthetic disorder

AR condition - DHCR7 gene

Cholesterol needed for testosterone synthesis

Question 9

What is Wilson Disease?

What is phenotype?

Answer 9

Copper transport disorder - AR variants in ATP7B

Liver disease includes recurrent jaundice, autoimmune-type hepatitis, chronic liver disease.

movement disorders
rigid dystonia

Kayser-Fleischer rings in cornea

Question 10

Where do ovaries/testes arise from?

Answer 10

The gonodal ridge

Question 11

What gene in an XY embryo drives testes differentiation?

Answer 11

SRY

Question 12

What happens in genital differentiation?

Answer 12

Female - regression of Wolffian ducts and development of Mullerian ducts to make fallopian tubes, uterus and upper vagina. happens independently

Male - Testosterone drives Wolffian ducts to create seminal vesicles and vasa defentia. DHT droves external genitalia. AMH binding causes regression of Mullerian ducts

Question 13

What is the most common cause of a 46,XX phenotypic male?

Answer 13

80-90% of cases are due to an XY translocation with SRY being on top of an X chromosome

Question 14

What is Swyer syndrome?

Answer 14

Complete XY gonadal dysgenesis caused by variants in SRY

*‘streak’ gonads
*Female external genitalia
*Failure of pubertal development
*Infertile
*High risk (~30%) of developing gonadoblastoma

Question 15

What is Complete androgen insensitivity syndrome?

Answer 15

XY by female phenotype
caused by variants in AR gene

*Female external genitalis, Normal development of breasts and female characteristics at puberty, Primary amenorrhea. Infertility, Intra-abdominal testes, Low risk (2-5%) of gonadoblastoma

Question 16

What phenotypes are associated with Androgen resistance syndromes/defects in androgen biosynthesis?

Answer 16

• 46,XY
• Bilateral testes and normal secretion of testosterone
• Female external genitalia
• Virilisation (development of a male pattern) of external genitalia at puberty
• Male breasts
• Reduced spermatogenesis

Question 17

What is Congenital adrenal hyperplasia (CAH)?

Answer 17

Group of disorders caused by by enzyme deficiencies affecting steroidogenesis most commonly caused by 21-hydroxylase deficiency. Reduced cortisol biosynthesis results in accumulation of its precursors which are also in the androgen synthesis pathway – and increased androgen synthesis;

In 46,XX foetuses it causes masculinisation of external genitalia

Question 18

What treatment is needed for CAH?

Answer 18

Treat the mother with dexamethosone (a corticosteroid) during the pregnancy - otherwsie babies are born “salt-waster” and die in neonatal period

Hormone treatment after birth

Question 19

What gene dels and dups are involved in DSDs?

Answer 19

o Deletion of SOX9, NF5A1 or WT1 can lead to 46XY gonadal dysgenesis
o Duplication of DAX1 or WNT4 can lead to 46XY gonadal dysgenesis
o Duplication of SOX9 or SOX3 in 46XX can lead to testicular DSD

Question 20

What are the four terms for sperm quality?

Answer 20

Azoospermia - Absent sperm in ejaculate

Oligozoospermia - Reduced sperm count < 15x106/ml

Asthenozoospermia - Reduced sperm motility (<40% motile)

Teratozoospermia - Morphologically abnormal sperm