Peroxisomal disorders

Question 1

What is peroxisomal biogenesis?

Answer 1

peroxisomes bud off of the ER and are formed and main tend by peroxisomal membrane proteins (PMPs) encoded by PEX genes

Question 2

What are the basic functions of peroxisomes?

Answer 2

• have overlapping and shared functions with mitochondria
• carry out oxidation reactions leading to the production of hydrogen peroxide and then decompose the hydrogen peroxide
• break down uric acid, amino acids, and fatty acids (major source of metabolic energy)
• involved in lipid biosynthesis

Question 3

What is an inborn error of metabolism?

Answer 3

Inborn error - heritable and genetic, usually autosomal recessive ( consanguinity effects). Affects a single gene (usually coding for an enzyme)
Of metabolism - affects energy, waste, storage, synthesis, transport (e.g. PKU)

Question 4

Systems affected by peroxisomal disorders:

Answer 4

• CNS (hypotonia, seizures, spasticity, etc)
• PNS (sensorimotor polyneuropathy)
• Ophtho (cataracts, retinopathy, glaucoma)
• ENT (craniofacial dysmorphisms)
• GI (liver disfunction, cholestasis, hepatomegaly)
• Endo (adrenal insufficiency/ Addison’s hypothyroid, hypogonadism)
• Skeletal (bone stippling, limb malformations, etc)
• Renal (cysts, renal insufficiency)
• Skin

Question 5

What is the genetic defect in Zellweger Spectrum Disorders?

Answer 5

PEX - inhibited formation of peroxisomes (PEX encodes for PMP)

Question 6

What are the clinical features of Zellweger Spectrum Disorders?

Answer 6

Severe hypotonia, large anterior fontanelle, characteristic facial features, hepatosplenomegaly, seizures and global delay, elevated very long chain fatty acids (VLCFA) severe leukodystrophy (destruction of brain white matter)

Question 7

What is the treatment for Zellweger Spectrum Disorders?

Answer 7

There isn’t one

Question 8

What is the genetic defect in Rhizomelic Chondrodysplasia Punctate, Type 1 (RCDP 1)?

Answer 8

PEX7 - codes for PMP, formation of peroxisome hindered
- causes ACAA1 (mito/TCA energy metabolism), PhyH (processes phytanic acid), and AGPS (plasmalogen synthesis) are abnormal

Question 9

What are the clinical features of Rhizomelic Chondrodysplasia Punctate, Type 1 (RCDP 1)?

Answer 9

short (rhino long bones (Melia), epiphyseal (chondrodysplasia) stippling (punctate), facial dysmorphisms, cataracts, intellectual disability, low plasmalogens

Question 10

What is the treatment for Rhizomelic Chondrodysplasia Punctate, Type 1 (RCDP 1)?

Answer 10

Phytanic acid restricted diet

60% of children survive the first year and 39% the second

Question 11

What is the genetic defect in X-Linked Adrenoleukodystrophy?

Answer 11

ABCD1 (straight chain VLCFA transporter) - affects 100% males from birth and 80% of female carriers have elevated VLCFA

Question 12

What are the clinical features in X-Linked Adrenoleukodystrophy?

Answer 12

elevated VLCFA

Childhood cerebral (males only, 35% affected) - Addison’s (adrenal failure), psychomotor deterioration (4-12 yo), behavioral changes, vision and hearing loss, loss of motor function, MRI with T2 hyper intensity and leading edge of enhancement, rapid progression (2 yr average from onset to death)

Adrenomyeloneuropathy (40-45% affected) - late 20’s males, progressive paparesis (stiff gait), >35 yo in 20% carrier females have milder symptoms

Question 13

What is the treatment for X-Linked Adrenoleukodystrophy?

Answer 13

• Bone marrow transplant - good treatment when MRI shows changes but before clinically symptomatic (80%, 5 year survival)
• Lorenzo’s oil (substrate replacement therapy) - not harmful but has not shown a benefit