8. IEMS and 9. lysosomal storage disorders Flashcards
Which 6 IEMs are screened for in newborns in the UK?
- PKU
- MCADD
- Maple syrup urine disease
- Homocystinuria
- Glutaric acidaemia 1
- Isovaleric acidaemia
What type of IEM is Zellweger spectrum disorder?
Peroxisome biogenesis disorder
What is the role of peroxisomes?
Site of oxidative reactions, important for metabolism
What are the 3 phenotypes associated with ZSD?
Zellweger syndrome
Neonatal ALD
Infantile Refum disease
What is the phenotype of ZSD?
ZS most severe, IRD least severe
Hypotonia, failure to thrive, seizures, liver dysfunction, SNHL, retinal dystrophy
What genes are associated with ZSD? What inheritance pattern?
13 PEX genes - encode peroxins, required for peroxisome assembly
All AR
PEX1 most commonly mutated (60% of cases)
What type of IEM is Smith-Lemli-Opitz syndrome?
Cholesterol biosynthesis disorder
What is the clinical phenotype of SLO syndrome
Wide clinical spectrum
Multiple congenital anomalies - growth retardation, microcephaly, ID, cleft palate, distinctive facies, polydactyly
What causes SLO?
DHCR7 (AR)
What type of IEM is Wilson disease?
Copper transport disorder
What causes Wilson disease?
Biallelic mutations in ATP7B - exports copper out of cell
What is the phenotype of Wilson disease?
Liver disease, jaundice, autoimmune hepatitis
Tremor, chorea, dystonia
Kayser-Fleischer rings due to copper deposits in cornea
What type of IEM is Pompe disease?
Glycogen storage disease type II
What is the classic phenotype of Pompe disease?
Onset in utero/neonatal
Hypotonia, muscle weakness, cardiomegaly, HCM
Death in first year from left ventricular outflow obstruction without treatment with enzyme replacement therapy
What causes Pompe disease?
GAA mutations - accumulation of glycogen
What are lysosomes and what is their role?
Membrane bound organelles in all nucleated cells
Break down biological polymers
Maintain acidic environment optimal for hydrolytic enzymes
What causes lysosomal storage diseases?
Accumulation of toxic material due to inhibited lysosome function
What type of IEM is Gaucher disease and what causes it?
Lysosomal storage disease
GBA mutations
What type of IEM is Niemann Pick types A, B and C, and what cause them ?
Lysosomal storage disease
A & B = SMPD1 (AR)
C = NPC1 & NPC2
What is the difference between Niemann Pick types A, B & C?
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
What causes Fabry disease?
Alpha-galactosidase deficiency
GLA gene
How is Fabry disease treated?
ERT with Fabrazyme & Replagal
What is the clinical phenotype of metachromatic leukodystrophy?
Mostly late-infantile onset
Muscle weakness, hypotonia, clumsiness, frequent falls, toe walking, dysarthria, seizures
Language and cognitive decline
What causes MLD?
Biallelic ARSA mutations - arylsulfatase A enzyme deficiency
Failure to break down sulphatides - sulphates build up in myelin sheath
How is MLD treated?
Libmeldy approved by NICE in 2022 - gene therapy using modified HSC
