Peroxisomal Disorders Flashcards
- Understand the basic functions of the peroxisome.
Peroxisome Function:
- VLCFA Catabolism (b-ox; C22 and higher)*
- BCFA Catabolism (a-ox and b-ox; eg Pristanic)
- De novo lipogenesis
- Ether phospholipid (plasmalogen) synthesis
- Bile acid synthesis
- DHA synthesis (brain and retina)
- ROS, RNS, H2O2 metabolism*
- Glyoxylate detoxification
- Alcohol detoxification
*Shared functions with mitochondria
Peroxisome where do you come from?
- From the ER
- Complex process of formation and maintenance (PEX genes)
- Import their own functional proteins
- Process: Peroxisomal Biogenesis
- Understand the concept of an inborn error of metabolism, and in particular how a single genetic defect may manifest as a multi-systemic disorder of peroxisomal metabolism.
“Inborn Error”: -Heritable, genetic -Single Gene (which codes for enzyme) Autosomal Recessive (usually) -Consanguinity effects
“of Metabolism”:
- Energy
- waste
- storage
- synthesis
- transport
Ex) Classic PKU
- Identify clinical features, causative genes, and potential therapies of several common Peroxisomal disorders, which include:
- Zellweger spectrum disorders
- Rhizomelic Chondrodysplasia Punctata Type 1
- X-linked Adrenoleukodystrophy
Zellweger spectrum disorders
Genes: PEX (~13 genes):
- Inhibited formation of peroxisomes
- Gene and mutation determine severity and phenotype
- Classification: Zellweger Syndrome > Neonatal Adrenoleukodystrophy > Infantile Refsume
- Now considered one disorder with a broad continuum of phenotypes
Combines incidence: 1/50,000
Syndromes:
- Severe hypotonia
- Large anterior fontanelle
- Characteristic facial features (tall forehead, hypertelorism, broad nasal root, anteverted nares, long flat philtrum)
- Cataracts, corneal opacity, nystagmus, optic nerve atrophy
- Hepatosplenomegaly, liver dysfunction, jaundice
- Congenital heart defects
- Bony stippling
- Adrenal insufficiency
- Seizures and global delay
- Vision and hearing impairment
Biochemical Dx:
-Elevated VLCFA, BCFA, BA
MRI: Severe leukodystrophy
Rx: Cholic acid (+/-)
Rhizomelic Chondrodysplasia Punctata Type 1
RCDP 1
Gene: PEX7
Only certain proteins imported- Primarily AGPS (plasmalogen synthesis) and PhyH (phytanic acid to pristaninc)- overlap with RCDP and a-ox
-<1/100,000
Clinical Sx:
- Short (Rhizo) long bones (melia)
- Epiphyseal (chondrodysplasia) stippling (punctata)
- Vertebral clefting
- Facial dysmoprhisms
- Cataracts (from birth through infancy)
- Intellectual disability (DQ<30)
- Seizures
- Variable in severity with milder forms known (less common)
Biochemical Dx:
-Low Plasmalogens, VLCFA normal, BCFA elevated (phytanic)
Px: 60% of children survived the first year and 39% the second; a few survived beyond age ten(poor)- Pulmonary causes
RCDP Type 5: similar but due to PEX5
X-linked Adrenoleukodystrophy
ALD
Gene:
- ABCD1 (straight VLCFA transporter)
- Most common peroxisomal disorder
- Only disorder on NBS (some states, not here)
- One of few disorders with proven effective treatment: -Not Lorenzo’s Oil
- Biochemical Dx: Elevated straight VLCFA (C24 and C26)
- X-linked: 80% of female carriers have elevated VLCFA (100% males from birth)
X-ALD Clinical Presentations:
Childhood Cerebral (males only*, 35% of affected):
-Addison’s (adrenal failure) onset at any age
-Psychomotor deterioration 4-12yo
-Behavioral changes (aggression, ADHD) and changes in handwriting (fine motor) sz, vision and hearing loss, loss of motor function
-MRI with T2 hyperintensity and leading edge of enhancement
-Rapid progression (2 years average from onset to death)
Adrenomyeloneuropathy (AMN 40-45% of affected): Late 20’s in males -Progressive paraparesis -Sphincter disturbances -Sexual dysfunction -Impaired adrenocortical function -All symptoms are progressive over decades >35yo in 20% carrier females- milder sx
Addison disease only (10% of affected):
- Primary adrenocortical insufficiency 2yr thru adulthood (most by 7.5yo)
- No neurologic abnormality (AMN sx may develops later)
Surveillance and Treatment:
Lorenzo’s Oil: Substrate replacement therapy
Mix of monounsaturated FA (4:1 Oleic:Erucic)
-Replaces C24:0 and C26:0 with C24:1 and C26:1 (which are not harmful)
-Lorenzo Odone lived to 30yo (22yrs longer than expected) in 2008
Large trials have not shown great benefit; ongoing
-Treatment: BMT
Initiated when MRI changes but before clinically symptomatic: time is crucial
Cannot reverse sx with this
MRI in asymptomatic males q6mo
Success of BMT excellent (~80% 5 year survival, Miller et al, 2011)
-Treat adrenal insufficiency as needed
-NBS for X-ALD is beginning
