Classification of Peroxisomal Disorders 

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Peroxisomes: peroxisomes are ubiquitous membrane bound subcellular organes that participate in multiple metabolic processes. They are biochemically defined by the presence of a catalase and several oxidases, which can also be recognized by immunohistochemistry. They are more numerous in cells that specialize in the metabolism of complex lipids and in the developing nervous system than in other mature cells.

Principal biochemical pathways: Head

• Peroxisomal b-oxidation: the main substrates are very-long-chain-fatty acid (VLCFAs) and trihydroxycholestanoic acids (THCA) which are intermediate substrate in bile acid synthesis from cholesterol, pristanic acid and long-chain dicarboxylic acids.

• Plasmalogen biosynthesis: Plasmalogens belong to a special class of phospholipids. Their role is unknown, but they are especially abundant in the CNS.

• Phytanic oxidation: Phytanic acid is a branched-chain fatty acid derived from dietary sources. It is degraded into pristinic acid through a-oxidation. Pristinic acid is further metabolized via the peroxisomal b-oxidation pathway.

• Pipecolic catabolism: L-pipecolate oxidase is a peroximal enzyme which catalyses the hydrogenation of L-pipecolate.

Classification of peroxisomal disorders:

Group I (Assembly deficiencies):  Head

• Pathogenesis: The salient pathologic features of this group is failure in the biogenesis (assembly) of peroxisomes. Loss of multiple peroxisomal enzyme activities often associated with morphological abnormalities of the organelle. Trilaminar inclusions within lysosomes can be seen under electron microscope.

• Biochemistry: Many of the disorders in this group are due to defects in importing the protein into the peroxisomes resulting in defective peroxisomal biogenesis or defects in maintaining peroxisomal intergrity. 

• Genetics: This group constitutes the generalized peroxisomal disorders and are inherited as autosomal recessive traits. The incidence in newborn is about 1:50,000 live births.

    Entities include:

• Zellweger syndrome *  

• Infantile Refsum's disease *

• Hyperpipecolic acidemia

• Rhizomelic chondrodysplasia punctata (classical type)

• Neonatal adrenoleukodystrophy *

• Pseudo-infantile Refsum’s disease

• Zellweger-like syndrome  

Group II (Single enzyme deficiency): The structure of peroxisomes is intact and only one defective enzyme is involved. Head

    Group IIa: Single peroxisomal enzyme deficiency involving b-oxidation pathway

• X-linked adrenoleukodystrophy (ALD protein)

• Pseudo-neonatal adrenoleukodystrophy (Acyl-CoA oxidase)*

• Pseudo-Zellweger (Thiolase)

• Bifuctional enzyme deficiency (Bifunctional protein) *

    Group IIb: Single peroxisomal enzyme deficiency without involving b-oxidation pathway

• Refsum’s disease (Phytanic acid oxidase)

• Pseudo-rhizomelic chondrodysplasia (Plasmalogen synthesis)

• Di-(tri)-hydrocholestanoic acidemia (Bile acid synthesis)

• Mevalonic aciduria (Cholesterol synthesis)

* Neonatal onset: These peroxisomal disorders have neonatal onset (connatal peroxisomal disorders). They are autosomal recessive disorders with typical clinical features including multiple dysplastic features, and pathological features including neuronal migration defects combined with degenerative changes.

Short note: Head

Infantile Refsum’s disease: They present as mild Zellweger’s syndrome and have increase in serum phytanic acid. Hepatic cells contain no peroxisomes; stacks of angulated trilaminar inclusions can be seen in lysosomes under electron microscope. Micronodular cirrhosis is also a feature of this this disease.  Adrenal glands are small but contain no ballooned cells and have no abnormal lipid profiles on electron microscope. No renal cyst. Optic nerves show no demyelination.

Hyperpipecolic acidemia: It has close resemblance to the Zellweger’s syndrome, neonatal adrenoleukidystrophy and infantile Refsum’s disease and may represent a variant of one of these entities. Serum pipecolic acid level is increased. Increases in pipecolic acid in liver and brain have also been documented. 

Rhizomelic chondrodysplasia punctata (RCDP): This is a bone dysplasia with rhizomelic dwarfism, facial dysmorphism, congential cataract, joint contractures, severe epiphyseal and extraepiphyseal calcification, mental retardation, hepatomegaly, and ichthyosis. Peroxisomes may be intact in fibroblasts but abnormally shaped or totally absent in liver. This entity is clinically heterogenous and has variants.

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