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Pseudo Infantile Refsum's Disease: Catalase- Deficient Peroxisomal Particles with Partial Deficiency of Plasmalogen Synthesis and Oxidation of Fatty Acids

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Pseudo Infantile Refsum's Disease: Catalase- Deficient Peroxisomal Particles with Partial Deficiency of Plasmalogen Synthesis and Oxidation of Fatty Acids 003 I-3998/93/3403-0270$03.00/0 PEDIATRIC RESEARCH Vol. 34. No. 3. 1993 Copyright 8 1993 International Pediatric Research Foundation. Inc I'ritrrid in U S :I. Pseudo Infantile Refsum's Disease: Catalase- Deficient Peroxisomal Particles with Partial Deficiency of Plasmalogen Synthesis and Oxidation of Fatty Acids P. AUBOURG, K. KREMSER, M. 0. ROLAND. F. ROCCHICCIOLI. AND I. SlNGH ABSTRACT. Zellweger syndrome, neonatal adrenoleuko- RCDP, rhizomelic chondrodysplasia punctata dystrophy, and infantile Refsum's disease are genetic dis- IRD, infantile Refsum's disease orders characterized by the virtual absence of catalase- positive perosisomes and a general impairment of perosi- somal functions. Recent studies in these three disorders have provided morphologic evidence of perosisomal Peroxisomes are subcellular organelles that participate in the "ghosts" of density 1.10 g/cd that contain membrane @-oxidation of long-chain fatty acids and VLCFA (1-3), the proteins but lack a majority of the matrix enzyme activities. synthesis of plasmalogens (4), the oxidation of L-pipecolic acid We report here the biochemical studies in a female infant (5, 6). and bile acid synthesis (7). In addition, peroxisomes with clinical features of infantile Refsum's disease whose contain catalase that degrades the Hz02 produced by various liver and fibroblasts contained cytosolic catalase but no oxidases (8). Peroxisomes, like mitochondria. arise by growth catalase-positive peroxisomes. Oxidation of phytanic and and division of preexisting peroxisomes (9). All peroxisomal pipecolic acids was severely impaired, whereas osidation proteins studied so far are synthesized on free polyribosomes, of very-long-chain fatty acids and dihydrosyacetone phos- then translocated into preexisting peroxisomes. Peroxisomal pro- phate acyltransferase activity were only partially teins are generally synthesized in their final size with two excep- decreased. Immunoblot analysis showed that the three tions. The (I-ketothiolase is synthesized as a 44-kD precursor peroxisomal &oxidation enzymes (acyl-CoA oxidase, converted into a 41-kD mature enzyme, and the acyl-CoA oxi- enoyl-CoA hydratasel3-hydrosyacyl-CoA dehydrogenase, dase is synthesized as a 72-kD precursor converted into two and 3-ketoacyl-CoA thiolase) were detectable in liver tis- subunits of 52 and 20 kD. In both cases, the proteolytic cleavage sues. The 3-ketoacyl-CoA thiolase was of the mature form occurs inside peroxisomes (10). (41 kD). in contrast with other perosisomal disorders with The term "disorders of peroxisome biogenesis" refers to a multipl'i enzyme deficiencies. The majority of these per- group of inherited neurodegenerative disorders in which the oxisomal enzvme activities were associated with two sub- structure and metabolic function(s) of peroxisomes are defective cellular membrane vesicle fractions lacking catalase: one (reviewed in 9). Tissues from infants with cerebrohepatorenal had the density of normal peroxisomes (1.17 g/cm"), the syndrome (Zellweger syndrome), n-ALD, or IRD contain none other, yet undescribed, a lower density (1.137 g/cm"). This or few catalase-containing peroxisomes with a normal morphol- suggests that perosisomes (density = 1.17 g/cm") and ogy (1 1, 12). In these disorders, peroxisomes fail to be formed structures with lower density (density = 1.137 g/cm") found normally, leading to a generalized defect of the peroxisomal in this patient's cultured skin fibroblasts, although lacking enzymes (9). RCDP differs from these disorders because peroxi- catalase, contained functional perosisomal enzymes. This somes are grossly normal in this disease and contain catalase. distinguishes this disorder from other disorders of perosi- Moreover, only three peroxisomal functions are impaired (plas- some biogenesis. (Pediatr Res 34: 270-276, 1993) malogen synthesis, oxidation of phytanic acid, and processing of @-ketothiolase)(1 3- 15). This article reports a study of peroxisomal enzyme activities Abbreviations in a patient with clinical features of IRD and absence of catalase- n-ALD, neonatal adrenoleukodystrophy containing peroxisomes in liver and fibroblasts. Western blot @-ketothiolaseor thiolase, 3-ketoacyl-CoA thiolase analysis demonstrated the presence of peroxisomal @-oxidation bifunctional enzyme, enoyl-CoA hydratasel3-hydrosyacyl- enzymes in the liver. The activities for oxidation of VLCFA and CoA dehydrogenase DHAP-AT were partially defective in fibroblasts. The peroxi- VLCFA, very-long-chain fatty acid somes from cultured skin fibroblasts had a bimodal distribution DAB, diaminobenzidine in the Nycodenz gradient: a small population with normal den- DHAP-AT, dihydroxyacetone phosphate acyltransferase sity (1.17 g/cm3) and a major population of peroxisome-like structures with lighter density (1.137 g/cm7). These two peroxi- somal populations showed varying degrees of peroxisomal en- zyme activities but lacked catalase. These lighter density peroxi- Received February 4. 1993; accepted April 19, 1993. some-like structures are physically and functionally distinct from Correspondence: P. Aubourg. Inserm U342, Hbpital Saint Vincent de Paul. 82 avenue Denfert Rochereau. 75014 Paris, France. the recently described peroxisomal membrane "ghosts" (16, 17) Supported by National Institutes of Health Grant NS-22576 (1,s.) and by the and w-particles (18). The disorder reported here is therefore Association Fran~aisecontre la Myopathie (P.A.). different from other disorders of peroxisomal biogenesis. -7 70 PSEUDO INFANTILE REFSUM'S DISEASE 27 1 MATERIALS AND METHODS fractions and homogenates was 52 and 57 mCi/mmol. respec- Case report. The patient was a female infant born after an tively. uneventful 42 wk of gestation. The parents were not related. She The peroxisomal steps of plasmalogen biosynthesis were as- weighed 3620 g at birth and no facial dysmorphism was noted. sayed in fibroblasts by the double label. double substrate method Cholestasis was present during the neonatal period. Bilateral (28), and the activity of DHAP-AT was measured according to hearing loss was noted at 2 y. The patient walked at 2% y and the procedure described previously (29, 30). For substrate (di- could speak several words at 3 y. At 3% y, clinical evaluation hydroxyacetone phosphate) synthesis, the reaction mixture con- showed cerebellar ataxia, retinitis pigmentosa with extinguished tained 10 pCi [U-"C]glycerol 3-phosphate (sp act 156 mCi/ electroretinogram, and peripheral neuropathy. Brain-stem audi- mmol). 0.6 mM glycerol-3-phosphate, 5 mM pyruvate, 1 mM tory evoked responses showed severe dysfunction of central NAD', lactate dehydrogenase (10 units), cu-glycerol-3-phosphate auditory pathways. Hepatomegaly was detected. Between 3I/z and dehydrogenase (10 units), and 50 mM triethanolamine buffer. 8 y, she deteriorated slowly and lost most of her motor and pH 7.6. After 60 min of incubation at 25"C, the reaction was language abilities. At 8l/2 y, weight was 30 kg and head circum- stopped by the addition of an equal volume of chloroform ference 54 cm (98th percentile). The patient had few spontaneous and, after mixing vigorously, the upper phase containing movements, brief visual fixation, and could still respond to her [U-14C]dihydroxyacetone phosphate was transferred to an- surroundings. She was not able to walk or to sit up. Other findings other set of tubes. Under these conditions, the conversion of included quadriparesis with Babinski signs and ankle clonus, [U-14C]glycerol 3-phosphate to [U-"C]dihydroxyacetone phos- generalized hypotonia, severe pigmentary retinopathy, and hep- phate was quantitative (30). For assay of DHAP-AT activity, a atomegaly. A skeletal survey was normal. Aspartate transaminase reaction mixture containing 0.1 mM [U-14C]dihydroxyacetone and alanine transaminase were 0.55 and 0.43 pkat/L. respectively phosphate, 8 mM MgCI2, 8 mM sodium fluoride, 0.4 mg albu- (normal <0.60 pkat/L). A morning ACTH concentration was 18 min, 0.15 mM palmitoyl-CoA, and 75 mM acetate buffer. pH nmol/L (normal 40). Visual and brain-stem auditory evoked 5.4, in 0.12 mL was incubated at 37°C for 2 h. The reaction was responses were normal. A computed tomography scan showed stopped with 0.45 mL of chloroform:methanol (1:2), 150 pL of chloroform, and 150 pL 2 M KC1/0.2 M HjP04. The lower moderate cortical atrophy without demyelination. At 15 y of age, her neurologic status has remained unchanged. phase (200 pL) was applied to filter papers (Whatman 3MM). hfatc~rialsand gctlcral r~cthods.The sources of reagents were which were dried at room temperature and then washed with 20 as follows: cell culture reagents were from Gibco Laboratories. mL of 1076, 10 mL of 5%. and 10 mL of 1% trichloroacetic Grand Island, NY; [I-14C]phytanic acids (55 mCi/mmol), [""I] acid, respectively. Filter papers were dried overnight and the radioactivity was counted. sodium iodide (100 mCi/mL), and [U-14C]glycerol3-phosphate (159 mCi/mmol) were from Amersham Corp., Arlington Plasma levels of phytanic acid were measured by gas-liquid Heights, IL; perdeuterated DL-pipecolic acid was from MSD chromatography-mass spectrometry (26) and tu-oxidation of Isotopes Div., Montreal, Quebec, Canada; molecular weight phytanic acid by fibroblasts was determined by the method of markers for electrophoresis and protein A were from Sigma Poulos cr ul. (31). The concentrations of the bile acid interme- Chemical Co., St Louis, MO; Nycodenz was from Accurate diates, trihydroxycoprostanoic acid and dihydroxycoprostanoic Chemical and Scientific Corp., Westbury,
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