In the peroxisomal disorders there is either a failure to form intact peroxisomes, resulting in multiple metabolic abnormalities (generalised peroxisomal disorders), or there is deficiency of a single peroxisomal enzyme. In total there are about 20 of these disorders, and the overall frequency is estimated to be 1 in 25,000 to 1 in 33,000. Many metabolic processes occur in peroxisomes, both catabolic and anabolic, including peroxisomal ß-oxidation, plasmalogen biosynthesis, pipecolic acid oxidation, phytanic acid oxidation and reduction of H2O2 by catalase. The prototype of the peroxisomal assembly defects is Zellweger syndrome, which has a severe neonatal presentation and multiple clinical and biochemical abnormalities. Neonatal adrenoleucodystrophy and infantile Refsum disease are variant forms of Zellweger syndrome in which there are similar biochemical abnormalities but somewhat milder clinical phenotypes. In rhizomelic chondrodysplasia punctata (RCDP), characterised by proximal limb shortening and mental retardation, peroxisomes are present but of abnormal structure and there are defects of import of some proteins into the organelles. The single peroxisomal enzyme deficiencies include X-linked adrenoleucodystrophy X-ALD), its later onset adult form adrenomyeloneuropathy (AMN), other single defects of peroxisomal ß-oxidation, and single defects of plasmalogen biosynthesis. Other single peroxisomal enzyme deficiency diseases have phenotypes similar to patients with peroxisome assembly defects, when the defect is in a step in â-oxidation, or similar to RCDP when the defect is in a step in plasmalogen biosynthesis.
Important initial investigations for these patients include measurement of plasma very long chain fatty acids, phytanic acid and pipecolic acid. These assays are available in the Clinical Biochemistry Department at Guy’s Hospital. The service offered by the SAS laboratory is to perform follow-up enzymology using blood or cultured fibroblasts for further characterisation of the disorders, or for clarifying the diagnosis where initial metabolite results are inconclusive. Prenatal diagnosis for some of the disorders is also available.
A list of disorders for which tests are available is given below. In practice several tests may be required for evaluation of these patients because a single assay may not be diagnostic, and in some later-onset patients metabolite abnormalities can be quite subtle. The range of phenotypes for peroxisomal disorders is wide and there are likely to be new disorders still to be discovered. Some features that indicate testing for a peroxisomal disorder include the following:
- dysmorphia, including high forehead, low, broad nasal bridge and external ear deformities;
- hypotonia;
- cataracts or cloudy cornea;
- hepatomegaly and liver disease;
- renal cysts;
- psychomotor retardation;
- retinitis pigmentosum;
- impaired hearing;
- adrenal insufficiency;
- peripheral neuropathy;
- ataxia.
|
Disorder |
Enzyme Or Test |
|
| Zellweger syndrome* | Dihydroxyacetone phosphate acyl transferase | |
| neonatal adrenoleucodystrophy* and Catalase latency | Catalase latency | |
| infantile Refsum disease* | Plasmalogen biosynthesis | |
| Rhizomelic chondrodysplasia punctata)* | Plasmalogen biosynthesis | |
| Zellweger syndrome neonatal adrenoleucodystrophy infantile Refsum disease X-ALD and other single a-oxidation defects |
Very long chain fatty acids | |
(* = prenatal diagnosis available)