Clinical approach to inherited peroxisomal disorders

Abstract

At least 21 genetic disorders have now been found that are linked to peroxisomal dysfunction. Whatever the genetic defect might be, peroxisomal disorders should be considered in various clinical conditions, dependent on the age of onset. The prototype of peroxisomal disorders is represented by 'classical' Zellweger syndrome (ZS) which is the most severe disorder combining all the characteristic symptoms. ZS is characterized by the association of errors of morphogenesis, severe neurological dysfunction, neurosensory defects, regressive changes, hepatodigestive involvement with failure to thrive, usually early death, and absence of recognizable liver peroxisomes. Other peroxisomal disorders (pseudo-Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), pseudo-neonatal adrenoleukodystrophy, rhizomelic chondrodysplasia punctata (RCDP), and hyperpipecolic acidaemia) share some of these symptoms, but with varying organ involvement, severity of dysfunction, and duration of survival. The diagnosis should not cause difficulty when all the characteristic manifestations are present. Depending on the main presenting sign, peroxisomal disorders in neonates should be suspected in two categories of circumstances: polymalformative syndrome with craniofacial dysmorphism, and severe neurological dysfunction. During the first 6 months of life, the predominant symptoms may be hepatomegaly, prolonged jaundice, liver failure, anorexia, vomiting and diarrhoea leading to failure to thrive resembling a malabsorption syndrome; severe psychomotor retardation, hearing loss and ocular abnormalities become evident. Beyond 4 years of age, behavioural changes, intellectual deterioration, visual impairment and gait abnormalities may be the presenting symptoms. Independently of the clinical symptoms and age of onset, most peroxisomal disorders described so far can be clinically screened by recordings of electroretinogram, visual-evoked responses, and brain auditory-evoked responses, which are almost always abnormal. Nine of the 17 peroxisomal disorders with neurological involvement are associated with an accumulation of very long-chain fatty acids (VLCFA), which suggests that assay of plasma VLCFA should be used as a primary test. However, assays of plasma phytanic acid and plasma/urine bile acid intermediates should also be performed in view of the recent reports of atypical chondrodysplasia variants (without rhizomelic shortening) and isolated trihydroxycholestanoic aciduria. The differential diagnoses in various clinical conditions and age periods are discussed.

Diffusion-weighted MR imaging in leukodystrophies

“…Schematically, two types of peroxisomal disorders are known [22,23]. Peroxisome assembly deficiencies (or peroxisomal biogenesis disorders) are caused by the dysfunction of practically all or several peroxisomal enzymes.…”

Fast Diffusion of Very Long Chain Saturated Fatty Acids across a Bilayer Membrane and Their Rapid Extraction by Cyclodextrins

“…Several peroxisomal biogenesis disorders (Zellweger syndrome, neonatal ALD, and infantile Refsum disease) and deficiencies of peroxisomal fatty acid (FA) degradation enzymes are also marked by abnormally high levels of VLCFA (5,6). However, the clinical manifestations are quite different (1,7), and it is not clear whether there is a common underlying biophysical or biochemical mechanism. It is generally presumed that VLCFA accumulate mainly because of inefficient degradation (␤-oxidation), which normally takes place in the peroxisomes (8 -11), or possibly because of the combination of impaired ␤-oxidation and enhanced FA elongation (12).…”

Hepatic peroxisomes in isolated hyperpipecolic acidaemia: evidence supporting its classification as a single peroxisomal enzyme deficiency

“…In contrast, in isolated HPA with only one abnormal metabolite, as in the three patients we studied, peroxisomes were clearly present with some morphological alterations, which indicates a compensatory mechanism. We propose classifying isolated HPA as a single peroxisomal enzyme deficiency disease, as Poggi et al [20] have done.…”

“…We should ask, however, whether the term HPA, in particular isolated HPA, should be reserved for patients with elevated pipecolic acid only [20].…”