8. IEMS and 9. lysosomal storage disorders

Question 1

Which 6 IEMs are screened for in newborns in the UK?

Answer 1

1. PKU
2. MCADD
3. Maple syrup urine disease
4. Homocystinuria
5. Glutaric acidaemia 1
6. Isovaleric acidaemia

Question 2

What type of IEM is Zellweger spectrum disorder?

Answer 2

Peroxisome biogenesis disorder

Question 3

What is the role of peroxisomes?

Answer 3

Site of oxidative reactions, important for metabolism

Question 4

What are the 3 phenotypes associated with ZSD?

Answer 4

Zellweger syndrome

Neonatal ALD

Infantile Refum disease

Question 5

What is the phenotype of ZSD?

Answer 5

ZS most severe, IRD least severe

Hypotonia, failure to thrive, seizures, liver dysfunction, SNHL, retinal dystrophy

Question 6

What genes are associated with ZSD? What inheritance pattern?

Answer 6

13 PEX genes - encode peroxins, required for peroxisome assembly

All AR

PEX1 most commonly mutated (60% of cases)

Question 7

What type of IEM is Smith-Lemli-Opitz syndrome?

Answer 7

Cholesterol biosynthesis disorder

Question 8

What is the clinical phenotype of SLO syndrome

Answer 8

Wide clinical spectrum

Multiple congenital anomalies - growth retardation, microcephaly, ID, cleft palate, distinctive facies, polydactyly

Question 9

What causes SLO?

Answer 9

DHCR7 (AR)

Question 10

What type of IEM is Wilson disease?

Answer 10

Copper transport disorder

Question 11

What causes Wilson disease?

Answer 11

Biallelic mutations in ATP7B - exports copper out of cell

Question 12

What is the phenotype of Wilson disease?

Answer 12

Liver disease, jaundice, autoimmune hepatitis

Tremor, chorea, dystonia

Kayser-Fleischer rings due to copper deposits in cornea

Question 13

What type of IEM is Pompe disease?

Answer 13

Glycogen storage disease type II

Question 14

What is the classic phenotype of Pompe disease?

Answer 14

Onset in utero/neonatal

Hypotonia, muscle weakness, cardiomegaly, HCM

Death in first year from left ventricular outflow obstruction without treatment with enzyme replacement therapy

Question 15

What causes Pompe disease?

Answer 15

GAA mutations - accumulation of glycogen

Question 16

What are lysosomes and what is their role?

Answer 16

Membrane bound organelles in all nucleated cells

Break down biological polymers

Maintain acidic environment optimal for hydrolytic enzymes

Question 17

What causes lysosomal storage diseases?

Answer 17

Accumulation of toxic material due to inhibited lysosome function

Question 18

What type of IEM is Gaucher disease and what causes it?

Answer 18

Lysosomal storage disease

GBA mutations

Question 19

What type of IEM is Niemann Pick types A, B and C, and what cause them ?

Answer 19

Lysosomal storage disease

A & B = SMPD1 (AR)
C = NPC1 & NPC2

Question 20

What is the difference between Niemann Pick types A, B & C?

Answer 20

Type A = Classic infantile, onset at 3 months. Failure to thrive, psychomotor regression, cherry red spot

Type B = Milder phenotype - hepatosplenomegaly, recurrent lung infections, thrombocytopenia

Type C = Classical presentation in mid-late childhood - ataxia, dystonia

Question 21

What causes Fabry disease?

Answer 21

Alpha-galactosidase deficiency

GLA gene

Question 22

How is Fabry disease treated?

Answer 22

ERT with Fabrazyme & Replagal

Question 23

What is the clinical phenotype of metachromatic leukodystrophy?

Answer 23

Mostly late-infantile onset

Muscle weakness, hypotonia, clumsiness, frequent falls, toe walking, dysarthria, seizures

Language and cognitive decline

Question 24

What causes MLD?

Answer 24

Biallelic ARSA mutations - arylsulfatase A enzyme deficiency

Failure to break down sulphatides - sulphates build up in myelin sheath

Question 25

How is MLD treated?

Answer 25

Libmeldy approved by NICE in 2022 - gene therapy using modified HSC