Arch Dis Child: first published as 10.1136/adc.63.7.767 on 1 July 1988. Downloaded from Archives of Disease in Childhood, i988, 63, 767-770 Annotations Inherited peroxisomal disorders involving the nervous system For genetic reasons peroxisomes may be absent or defective. Because of the great importance of the lack one or more of their enzymes. The result may peroxisomal enzymes involved in the I oxidation of be subtle and long delayed, but is often catastrophic VLCFA and the use of measurements of VLCFA in and immediately recognisable as a serious disorder diagnosis, this group is itself subdivided. Group 3A at birth. The trouble for the clinician is that it is includes those conditions in which VLCFA oxidation often not possible to make a diagnosis unless the is impaired and thus VLCFA accumulates, and right tests are thought of: these tests are not part of group 3B those in which the single enzyme defect is routine 'metabolic screens.' It is first necessary to of another sort. frame the question 'could this be a peroxisomopathy?' The object of this annotation is to help with when GENERALISED PEROXISOMAL DISORDERS (GROUP 1) and how to answer this question. The now classical example is the cerebro-hepato- renal syndrome of Zellweger. l 2The typical neonate Peroxisomes is more dysmorphic than a baby with Down's syndrome with high forehead and huge fontanelle Peroxisomes are subcellular organelles with a single with metopic extension. Inactivity is even greater membrane which occur in every cell apart from the than in the Prader-Willi syndrome and hypotonia mature erythrocyte. They are seen best by appro- especially of the muscles of the neck is profound. priate preparation of a biopsied liver specimen Epileptic seizures commonly begin in the neonatal where they are about 0*5 i in diameter and round on period. Because of general unresponsiveness it is section. A high concentration is inferred in other difficult to tell that the infant is blind and deaf, but tissues including proximal renal tubules, adrenal the electroretinogram (ERG) and brainstem auditory http://adc.bmj.com/ cortex, brown fat (particularly in cold adaptation), evoked responses (BAER) are both flat. The liver is and myelin forming glia. Peroxisomes, in addition to firm and the renal cortex is echogenic. Calcification the peroxidation from which the name derives, are of the patellae and other cartilages may overshadow involved in numerous metabolic processes. For the considerable retardation of the bone age. Mal- clinical diagnostic purposes the most important formations of the heart or gut may be present and enzymatic actions to be aware of are the P oxidation dominate the clinical picture. After early death, of very long chain fatty acids (VLCFA), the synthesis general pathology shows hepatic fibrosis, renal of bile acids, and the synthesis of ether glycerolipids cysts, and small adrenals with striated inclusions on September 24, 2021 by guest. Protected copyright. (plasmalogens), the latter involving the enzyme acyl (the striations representing VLCFA). The brain CoA:dihydroxyacetone phosphate acyl transferase shows both malformation and degeneration. All the which is commonly known as DHAP-AT. Although features of Zellweger syndrome appear to stem from not conclusively proved at the time of writing, the a virtual lack of peroxisomes and their functions. location of the phytanic acid oxidase which is More difficult to recognise in group 1 are the deficient in Refsum disease must also be in the milder variants of Zellweger syndrome. Comple- peroxisome. mentation studies suggest that mild Zellweger syndrome, infantile Refsum disease, and hyperpipe- Classification of inherited peroxisomal disorders colicacidaemia may be the same disorder.3 Four recent publications include photographs of the faces Inherited peroxisomal disorders are classified into of these children up to age 13 and the similarities are three groups. In group 1 are conditions in which considerable.7 Characteristically the lobule of the peroxisomes are absent or greatly diminished, with a ear is unformed and the palate high arched. Pre- generalised impairment of peroxisomal functions. In sentation may not be with neurological problems but group 2 peroxisomes are present but there is an rather with failure to thrive and steatorrhoea, and impairment ofsome but not all peroxisomal functions. low plasma cholesterol and vitamin E concentrations. In group 3 only a single peroxisomal function is Clues to the peroxisomal aetiology come from the 767 Arch Dis Child: first published as 10.1136/adc.63.7.767 on 1 July 1988. Downloaded from 768 Stephenson palpable liver, the retarded bone development, and disease. A remarkable feature of this X linked the defects of vision (retinal) and hearing (sensori- disorder is extreme variability within pedigrees,'6 so neural) which become apparent. Dots of pigment on that later onset adrenomyeloneuropathy (presenting the retina are characteristic. With time, development with spastic paraparesis) or adult onset ALD may ceases and although these children may be mobile coexist. People with the gene defect may even be they show considerable mental handicap perhaps asymptomatic beyond middle age. The similarity of with autistic features. Originally some of these the neuropathology to aggressive multiple sclerosis children were regarded as having a variant of and the presence of oligoclonal bands in the cere- Refsum disease (see below) but it is now clear that brospinal fluid has supported the idea that for when there is a generalised peroxisomal deficienc, childhood ALD to occur an autoimmune mechanism phytanic acid from the diet accumulates with age. is necessary in addition to the genetic defect in The last of the current members of group 1 goes VLCFA metabolism. That defect has now been by the title of neonatal adrenoleukodystrophy identified as of a specific peroxisomal acyl-CoA (NALD). It got this name because of its patho- synthetase. 17 The site of the gene on Xq28 is logical resemblance to X linked adrenoleuko- adjacent to the genes for red and green colour dystrophy the first member of group 3A. Comple- blindness which may be simultaneously deleted.'8 mentation studies indicate that it is genetically distinct from the others.3 Affected infants may be Defects of,B oxidation: 'pseudo-Zellweger syndrome', hypotonic and have neonatal seizures but early 'pseudo-NALD', etc disorder of development may be mild. Dysmorphic In normal VLCFA metabolism the acyl-CoA syn- features are also slight-facial photographs are thesised by the enzyme deficient in ALD is oxidised included in three recent reports.91 Retinal blind- by three peroxisomal enzymes in sequence: acyl- ness may be the over-riding early feature so that the CoA oxidase ('oxidase'), bifunctional protein, and infant is regarded as having Leber's amaurosis.12 3-oxoacyl-CoA thiolase ('thiolase'). Later, neuropathy is common.9 13 The most charac- The first disorder now known to lack one of these teristic part of the history, however, is that after enzymes was originally labelled pseudo-Zellweger even a few years of progress there is regression, syndrome19: it was later discovered that the child in often abruptly after a febrile illness, with loss of question lacked only the protein of the thiolase skills and neurological functions and fatal outcome. enzyme.20 The clinical and pathological features resembled Zellweger syndrome except that dys- IMPAIRMENT OF SOME PEROXISOMAL FUNCTIONS morphic features were not so appreciable and there http://adc.bmj.com/ (GROUP 2) was no calcific stippling. A further family has been Rhizomelic chondrodysplasia punctata (RCDP) is described21 in which although the thiolase protein the only certain disorder having a defect in a was present as shown by immunoblot, the duodenal selected number of peroxisomal functions,14 but it bile acid pattern indicated thiolase deficiency and may be that the Conradi-Hunermann form15 will was identical to that of the infant with pseudo- also become included. Infants with RCDP should be Zellweger syndrome (PT Clayton, personal com- of munication). Except for the huge fontanelle (in easily recognisable by the proximal shortening on September 24, 2021 by guest. Protected copyright. their limbs and epiphyseal calcifications, cataracts, keeping with a severely delayed bone age), dys- and (if survival is sufficiently long) evidence of morphic signs were slight in this family (figure). In a mental handicap. further child with evidence of thiolase inactivity, calcific stippling of the patellae was present DEFECTS OF A SINGLE PEROXISOMAL ENZYME (GROUP 3) (MD King, personal communication). All of these Our knowledge of disorders of a single peroxisomal infants had neonatal onset seizures and profound function (group 3) is expanding at a great rate. This hypotonia (figure). is primarily so in group 3A which now contains four Isolated deficiency of the oxidase protein leads to conditions having a primary defect in VLCFA a clinical course like NALD, entitled pseudo- metabolism. The identity of the respective enzyme NALD.22 Pseudo-NALD was also the name given deficiencies has been established in little over a to the condition of a similar patient in whom the year. pathology also resembled NALD.23 Later, the oxidase protein was found to be present,24 but Disorders with accumulation of VLCFA (group 3A) presumably it is present in an inactive form. Adrenoleukodystrophy (ALD) presents in boys as The last of the three selective fi oxidation dis- either school failure due to central demyelination orders, bifunctional protein deficiency, has now (visible on a computed tomogram) or as adrenal been discovered (HW Moser, personal communica- insufficiency, hence the old name Addison-Schilder tion) in a patient with 'clinical clues' (see below). Arch Dis Child: first published as 10.1136/adc.63.7.767 on 1 July 1988. Downloaded from Inherited peroxisomal disorders involving the nervous system 769 :I Figure Siblings with defective thiolase: (a) fontanelle and high forehead aged 3 months; (b) extreme neck hypotonia (same day as (a)); and (c) brotheragedI week; dysmorphism minimal.