Peroxisomes are spherical 1pm diameter organelles with a multitude of oxidative and other enzymes packed within a single-layered membrane (http://www.peroxisomedb.org)

• global' peroxisomal disorders with impaired peroxisomal biogenesis (fewer or even no peroxisomes), together with those single peroxisomal enzyme defects that induce a similar phenotype (in particular, D-bifunctional protein deficiency)
• adrenoleukodystrophy, due to an X-linked defect of the peroxisomal ABCD1 gene that codes for the peroxisomal membrane protein ABCD1, a member of the ATP-hmding cassette transporters.

While estimation of very long chain fatty acids (VLCFA) may detect many peroxisomal isomers there is no 'metabolic screen' that will detect them all. 

CLINICAL CLUES TO PEROXISOMAL DISORDERS

• Neonatal hypotonia (especially extreme hypotonia of the neck) Neonatal seizures (refractory or phenytoin-responsive in a hypotonic baby)
• Neonatal unresponsiveness (except reflex crying)
• Non-development
• Retinal blindness ('Leber amaurosis')
• Sensorineural deafness
• Gross dysmorphic features of Zellweger syndrome type (high forehead, flat face, simian creases, simple genitalia)
• Mild dysmorphism (large fontanelle with open metopic suture, absent ear lobules)
• Leukodystrophy, neuronal migration defects especially perisylvian polymicrogyria
• Hepatomegaly (± hepatic insufficiency)
• Developmental delay with malabsorption features, retinopathy and sensorineural deafness
• Development delay with seizures and areflexia (peripheral neuropathy).
• School-age regression in a boy with previously normal development (+ Addison disease)
• Spastic paraplegia in older females.

Investigation results found in peroxisomal disorders

In neonatal and early manifesting peroxisomal disorders

• EEG trains of repetitive spikes shifting from side to side
• Slow nerve conduction (± EMG denervation)
• Low or absent ERG
• Brainstem auditory evoked potentials (BAEP) - gross abnormalities
  • High threshold
  • Delayed wave V latency
  • Lack of response
• MRI evidence of migration disorder
• MRI white matter altered signal
• Patellar or other chondral calcification
• Bone age retardation
• Echogenic renal cortex on ultrasound
• Increased CSF protein
• Liver biopsy: hepatic fibrosis
• Clotting defect of hepatic type
• Increased AST and ALT
• Low cholesterol
• Low vitamin E
• Increased phytanic acid
• Increased pipecolic acid
• Urinary excretion: amino acids, glycosaminoglycans, dicarboxylic acids.

In the regressing school child:

• Visual evoked potential (VEP) - latency increasem
• BAEP increased latency of wave V
• MRI increased signal in posterior central white matter on T2 images usually but not always

Special peroxisomal investigations

• Once sufficient clinical and investigational clues have been assembled, special tests for peroxisomal disorders may be sought at specialized laboratories. These primarily test

• The size of the peroxisomal compartment - simply, are peroxisomes missing and all functions depressed?
• The integrity of the peroxisomal beta-oxidation pathway, which metabolizes VLCFAs and also, in pan, bile acids

The tests of most direct help are as follows.

• VLCFAs in plasma

VLCFAs are increased in all disorders with absent or grossly diminished peroxisomes, and in most disorders of the VLCFA metabolic pathway (but not in all defects of isolated peroxisomal enzymes). This is the only test necessary for confirmation of the diagnosis of adrenoleukodystrophy in the regressing schoolchild.

• VLCFAs in fibroblasts

If a peroxisomopathy is suspected - as when there is characteristic dysmorphism, non-development and retinal and sensorineural hearing defects, then normal plasma studies (including normal plasma VLCFA) do not exclude D-bifunctional protein (DBP) deficiency. In this clinical situation, request full fibroblast studies including fibroblast C26:0 beta-oxidation rate and VLCFA ratios.

Bile acids

Abnormal bile acids are found in the urine, plasma and duodenal juice in infants with a lack of peroxisomes, and in those with peroxisomal DBP deficiency.

Dihydroxyacetone phosphate acyl transferase (DHAP-AT)

This is estimated in fibroblasts (and in Platelets). It is reduced in all cases of general lack of peroxisomes.

Liver biopsy with special studies.

It is possible to demonstrate lack of peroxisomes by special histochemistry and electronmicroscopy, and enlarged peroxisomes in biochemical lesions of the beta-oxidation pathway, but such studies are no longer essential for diagnosis, lmmunoblot methods allow determination of the individual beta-oxidation enzymes, but as these enzymes may be totally inactive despite demonstrable protein, it cannot at present be said that liver biopsy is a necessary investigation.