Peroxisomal Disorders

Question 1

What are features of Peroxisomes?

Answer 1

• Peroxisomes are complex single membrane cell organelles found in all cell types except erythrocytes
• Generally, appear as spherical bodies of 0.1 – 1.0mm in diameter
• The number/cell varies depending on demand - most numerous in liver and kidney
• Peroxisomes have both catabolic and anabolic functions

Question 2

What are the metabolic functions of Peroxisomes?

Answer 2

Biosynthesis

• Bile acids
• Plasmalogens (etherphospholipids)
• Cholesterol (first steps), leading to the synthesis of farnesylpyrophosphate from acetyl-CoA
• Docosahexaenoic acid (C22:6ω3 or DHA) : essential FA

Catabolism

• α-oxidation of phytanic acid
• β-oxidation of very-long-chain fatty acids, and pristanic acid
• Detoxification of glyoxylate (alanine glyoxalate-aminotransferase : AGT)
• Oxidation of pipecolic acid (pipecolate oxidase in cerebral tissue)
• H2O2 (catalase, peroxidase, …)
• D-amino acids, polyamines, some leukotrienes and prostaglandins

Question 3

How is Peroxisomal biogenesis conducted?

Answer 3

Peroxisomes multiply by division of existing peroxisomes

Peroxisomal membranes are assembled and peroxisomal matrix proteins targeted from the cytosol and imported into the organelle

Transportation of proteins is highly selective and requires the presence of specific peroxisomal targeting sequences (PTSs). PTSs are recognised by receptors which direct the peroxisomal proteins to the peroxisomal membrane

This process is dependent on specialised proteins termed peroxins which are encoded by PEX genes

Question 4

How is Peroxisomal biogenesis genetically controlled?

Answer 4

• 16 PEX genes have been identified as essential for human peroxisomal formation
• Also, a large number of single enzyme functions within the peroxisome encoded by non- PEX genes

Question 5

What are the main categories of peroxisomal disorders?

Answer 5

Peroxisomal Biogenesis Disorders (PBD)

• Peroxisome biogenesis disorders are inherited in an autosomal recessive manner. These disorders occur in all populations around the world although the incidence of specific disorders varies with populations

Single Enzyme Defects

• These result in the loss of a single protein and subsequently the loss of a single peroxisomal function
• Peroxisomes are present in the cells. Phenotype varies but some disorders can be as severe as a PBD depending on the specific enzyme affected.

Question 6

What are examples of Peroxisomal biogenesis disorders?

Answer 6

• Zellweger spectrum (80% of PBDs)
• Rhizomelic chondropysplasia punctata type 1 (RCDP type 1)

Question 7

What are overlapping phenotypes of Zellweger spectrum?

Answer 7

Consists of 3 overlapping phenotypes:

• Zellweger syndrome (most severe)
• Neonatal adrenoleukodystrophy
• Infantile Refsum disease (mildest form)

Question 8

What are signs and symptoms of Zellweger spectrum?

Answer 8

Characteristic craniofacial features:

• Large anterior fontanelle
• Full forehead
• Broad nasal bridge
• High arched palate
• Small nose with anteverted nares

Ocular abnormalities

• Cataracts
• Glaucoma
• Corneal clouding

Question 9

What are the outcomes associated with Zellweger syndrome?

Answer 9

• Patients with Zellweger syndrome usually succumb to the disorder within the first few months of life.
• Patients with the milder forms of the Zellweger spectrum have similar but less severe symptoms. Survival varies from 4 months to several decades.
• Most IRD patients learn to walk but their gait is ataxic and their mental function is in the severely retarded range.
• Treatment is symptomatic and supportive

Question 10

How does Rhizomelic chondropysplasia punctata Type 1 present?

Answer 10

• Characteristic proximal shortening of the limbs (rhizomelia)
• Punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata
• Facial dysmorphism
• Microcephaly
• Small stature
• Cataracts
• Psychomotor retardation
• Severe intellectual disability.

Question 11

What leads to Rhizomelic chondropysplasia punctata Type 1?

Answer 11

• Peroxisome biogenesis is partially impaired due to PEX7 mutations
• Plasmalogen biosynthesis and phytanic α-oxidation are impaired (low plasmalogens, increased phytanate)

Question 12

What is the outcome of Rhizomelic chondropysplasia punctata Type 1?

Answer 12

• Most do not survive past the first decade of life
• Treatment is largely symptomatic and supportive

Sometimes: clinical spectrum less severe

Question 13

What are types of Single Peroxisimal Enzyme Deficiencies?

Answer 13

• Peroxisomal β-oxidation deficiencies – diagnosed by measuring VLCFA
• Plasmalogen biosynthesis deficiencies – diagnosed by measuring plasmalogens
• Phytanic α-oxidation deficiencies
• Glyoxalate detoxification deficiencies

Question 14

What are examples of Peroxisomal β-oxidation deficiencies?

Answer 14

• X-linked adrenoleukodystrophy (X-ALD) = ALDP protein deficiency
• Acyl-CoA oxidase 1 (ACOX1) deficiency
• D-bifunctional protein (DBP) deficiency
• Sterol carrier protein (SCPx) deficiency
• 2-methyl acyl-CoA racemase (AMACR) deficiency

Question 15

What are features of Peroxisomal β-oxidation deficiencies?

Answer 15

• These have a severe phenotype similar to PBD disorders.
• Usually present in first months/year of life

Question 16

What are examples of Plasmalogen biosynthesis deficiencies?

Answer 16

• Rhizomelic chondrodysplasia punctata (RDCP) type 2 = DHAP-AT deficiency
• Rhizomelic chondrodysplasia punctata (RDCP) type 3 = Alkyl-DHAP synthetase deficiency

Question 17

What are examples of Phytanic α-oxidation deficiencies and Glyoxalate detoxification deficiencies?

Answer 17

Phytanic α-oxidation deficiencies

• Refsum disease = phytanoyl-CoA-2-hydroxylase deficiency

Glyoxalate detoxification deficiencies

• Hyperoxaluria type I = alanine glyoxalate-aminotransferase deficiency

Question 18

What are features of X-linked adrenoleucodystophy (X-ALD)?

Answer 18

• The most common single enzyme defect (prevalence is 1:20,000 to 1:50,000 births)
• X-linked inheritance – although approx. 50% of female carriers eventually present with symptoms
• N.B. VLCFAs can be normal in carriers. Mutation analysis required
• X-ALD has been included in some newborn screening programmes (not the UK)

Question 19

What causes X-linked adrenoleucodystophy (X-ALD)?

Answer 19

• Caused by mutations in ABCD1 gene which codes for a transporter protein which transports VLCFAs across the peroxisomal membrane

Question 20

What are the phenotypic traits of X-linked adrenoleucodystophy (X-ALD)?

Answer 20

• Clinical phenotype varies from severe childhood presentation to a mild adult form (adrenomyeloneuropathy).
• There is a form which can present at any age solely with Addison Disease (isolated adrenal insufficiency).
• Severe childhood disease takes the form of a progressive demyelination of the cerebral neurones and adrenal insufficiency
• Usually presents in boys between ages 3 to 10 years with behavioural abnormalities
• Further progression to dementia, speech difficulty, loss of hearing and vision and finally to decorticate spastic quadriparesis

Question 21

What are some family studies used in X-linked adrenoleucodystophy (X-ALD)?

Answer 21

• Once the mutation is known both male and female siblings can be tested
• Female carriers can show symptoms in later life and are at risk of passing disease to male offspring
• Male siblings are at risk of disease and can be treated by bone marrow transplant if diagnosed before significant neurological deterioration
• Extended family testing needed

Question 22

What is Refsum disease?

Answer 22

DO NOT confuse with Infantile Refsum Disease!

• Single enzyme defect of phytanoyl CoA hydrolase
• Enzyme is required for the ɑ oxidation of phytanic acid to pristanic acid
• Patients accumulate large amounts of phytanic acid in their plasma and tissues

Question 23

What are clinical features and the management for Refsum Disease?

Answer 23

• Clinical features include pigmentary degeneration, peripheral neuropathy and cerebella ataxia
• Effective treatment can be achieved by avoiding dietary phytanate and plasmapheresis

Question 24

What are some biochemical investigations of Peroxisomal Disorders?

Answer 24

In Plasma

• Very long chain fatty acids (VLCFAs): C22, C24, C26. C26:C22 and C24:C22 ratios
• Pristanate and phytanate
• Pipecolic acid
• Bile acids

In Red Blood Cells

• Plasmologens

In Urine

• Bile Acids
• Pipecolic Acid

In Cultured Fibroblasts

• DHAP-AT (dihydroxyacetone phosphate acyltransferase)