Eur J Pediatr (1998) 157: 743±746 Ó Springer-Verlag 1998 METABOLIC DISEASES M. Huemer á A. Muehl á K. Wandl-Vergesslich á W. Strobl R. J. A. Wanders á S. Stoeckler-Ipsiroglu Stroke-like encephalopathy in an infant with 3-hydroxy-3-methylglutaryl-coenzyme A lyase de®ciency Received: 31 August 1997 and in revised form 30 January 1998 / Accepted: 31 January 1998 Abstract A 2.5-year-old boy presented with acute metabolic decompensation in whom 3hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) lyase de®ciency was diagnosed. Four days after metabolic decompensation, a stroke-like encephalopathy with tonic clonic convulsion of the left arm and leg and coma developed. Brain oedema and subsequent demarcation and atrophy were observed mainly within the supply areas of the right anterior and middle cerebral artery and to a lesser extent in various sites within the right hemisphere. Residual neurological de®cits included spastic paresis of the left arm and leg, and left supranuclear facial palsy and aphasia, indicating bilateral di€use brain a€ection. Conclusion In the presented patient with HMG-CoA lyase de®ciency, stroke-like encephalopathy occurred days after metabolic decompensation indicating ongoing (intracerebral) metabolic derangement. Monitoring of the intracerebral accumulation of toxic metabolites by magnetic resonance spectroscopy and of cerebral haemodynamics might be useful for a better understanding of the pathogenetic mechanisms of stroke-like encephalopathy and to identify patients at risk. Key words 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) lyase de®ciency á Organic aciduria á Stroke-like encephalopathy Abbreviation 3-HMG-CoA lyase á 3-hydroxy-3-methyl-glutaryl-coenzyme A lyase Introduction 3-Hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) lyase de®ciency (McKusick 246450) is an autosomal recessive inborn error of leucine catabolism, characterized by high urinary excretion of 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-hydroxyisovaleric and 3-methylglutaric acids. In a catobolic state, patients are prone to acute metabolic decompensation with coma, hepatomegaly, metabolic acidosis and non-ketotic hypoglycaemia [4, 5, 11]; they may, however, develop W. Strobl Department of Medical Chemistry, University of Vienna, Waehringer Strasse 10, A-1090 Vienna, Austria R. J. A. Wanders Academisch Medisch Centrum, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands normally, but recurrent metabolic decompensation may ®nally result in mental and neurological de®cits [9]. We report a patient with HMG-CoA lyase de®ciency who developed a stroke-like encephalopathy during clinical recovery from an acute metabolic crisis. Case report This male patient was born to healthy, consanguineous Arabian parents. Pregnancy and delivery were uneventful. Muscular S. Stoeckler-Ipsiroglu (&) á M. Huemer A. Muehl á K. Wandl-Vergesslich Department of Paediatrics, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria, Tel.: +43-1-40400-3210, Fax: +43-1-4063484 744 Table 1 Urinary excretion of organic acids during acute metabolic decompensation (day 1), onset of stroke-like encephalopathy (day 4) and 6 days (day 10) and 6 weeks after stroke-like encephalopathy Day 1 Day 4 Day 10 6 weeks Normal values [1] 3-OH-3-methyl-glutaric acid (mmol/mol creatinine) 3-methylglutaconic acid (mmol/mol creatinine) 3-OH-isovaleric acid (mmol/mol creatinine) 3-methylglutaric acid (mmol/mol creatinine) 4.100 9.100 460 320 11±36 24.200 21.400 1500 1.410 <9 9.600 5.800 310 290 <50 1.900 3.000 180 270 <7 hypotonia was not reported, but the boy required tube feeding during the 1st weeks of life. At the age of 9 months he had an unexplained episode of drowsiness, hypoglycaemia and hepatomegaly. He started walking at the age of 18 months, but otherwise his development was reportedly normal. At the age of 32 months, the patient was admitted to our hospital with a prolonged generalized febrile convulsion following a 36 h episode of diarrhoea and vomiting due to enterovirus infection. Pathological laboratory ®ndings included hyperglycaemia (13.9 mmol/l), metabolic acidosis (pH 7.16, BE ±10 mmol/l) and slightly elevated transaminases (GOT 101 U/l, GPT 95 U/l). Complete blood cell count, C-reactive protein, plasma ammonia and lactic acid concentrations were normal. Despite i.v. ¯uid and glucose supply, 12 h after the convulsion the boy was still lethargic and showed muscular hypotonia and hepatomegaly. The EEG revealed slow thetadelta background activity with predominance over the right hemisphere. Pathological ®ndings now included hypoglycaemia Fig. 1 MRI scan (T2-weighted) of the brain from a patient with HMG-CoA lyase de®ciency 48 h after febrile convulsion (50 h before stroke-like encephalopathy). Patchy high signal intensities within the supratentorial white matter (arrows) Fig. 2A, B CT scan of the brain from a patient with HMG-CoA lyase de®ciency. A 12 h after onset of stroke-like encephalopathy: marked increase of the volume of the right hemisphere with loss of sulci and compression of the right lateral ventricle indicating hemispheric brain oedema (arrows). Focal oedema within the posterior part of the left hemisphere (arrows). B 6 weeks after stroke-like encephalopathy: demarcation and atrophy of the right hemisphere and focal residual changes in the frontal, temporal and parietal regions of the left hemisphere indicating di€use liqui®cation after infarction (arrows) (1.7 mmol/l) in the absence of urinary ketone bodies, lactic acidaemia (4.4 mmol/l) and highly elevated urinary excretion of 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-hydroxyisovaleric, and 3-methylglutaric acids (Table 1) suggestive of HMG-CoA lyase de®ciency. Serum and urinary carnitine were not measured. A skin biopsy was performed in order to assess HMG-CoA lyase activity in cultured ®broblasts. Under treatment with glucose (7 mg/kg/min) and carnitine (100 mg/kg/d), hypoglycaemia and lactic acidaemia resolved and the patient's clinical status improved signi®cantly. The EEG 48 h after the febrile convulsion still revealed slow theta-delta activity on both hemispheres. MRI scan of the brain showed symmetrical di€use pathological signal intensities within the supratentorial white cerebral matter with low signal intensity on T1- and high signal intensity on T2-weighted images (Fig. 1). Ninety-eight hours after the initial febrile convulsion, the boy deteriorated unexpectedly with tonic clonic convulsion and paresis of left arm and leg and gaze deviation. He was unresponsive to external stimuli and had to be mechanically ventilated. White blood cell count was 12.000/ll in plasma and 155/3 lymphoid cells in CSF with normal protein and glucose concentrations. Treatment with ceftriaxon and acyclovir was initiated until bacterial cultures and viral antibody tests in CSF showed negative results ruling out bacterial or viral meningo-encephalitis. During this episode, blood glucose, lactic acid and ammonia concentrations were normal, but urinary excretion of characteristic organic acids was still highly elevated (Table 1). The CT scan of the brain performed 12 h after clinical deterioration showed marked oedema with blurring of cortical sulci and loss of white/grey matter differentiation in the right hemisphere. Similar but less pronounced ®ndings were also seen within the posterior part of the left hemisphere (Fig. 2A). Due to recurrent convulsions and respiratory insuciency the boy required respirator therapy for 3 weeks. His metabolic state 745 remained stable and the excretion of characteristic urinary organic acids became signi®cantly lower than during the metabolic crisis (Table 1). Follow up CT scan of the brain showed a gradual decrease in supratentorial oedema followed by demarcation and atrophy in the territory of the right anterior and middle cerebral artery. Less prominently, focal residual changes were also found in the frontal, temporal and parietal regions of the left hemisphere (Fig. 2B). Other conditions predisposing to cerebral thrombosis and embolism were excluded by the following normal results: global clotting tests, clotting factors, protein C, activated protein C resistance, protein S, antithrombin III, plasma and urinary amino acids including free homocysteine, electrocardiogram, cardiac ultrasound, extracranial and transcranial Doppler sonography of the carotid artery and basal cerebral arteries and measurement of arterial blood pressure. Antiphospholipid antibody tests were negative. Neurological examination 6 weeks later demonstrated spasticdystonic paresis of the left arm and leg, left-sided supranuclear facial palsy and aphasia. The patient was discharged with a proteinrestricted low fat diet and frequent carbohydrate-rich meals. He returned to his home country and was lost to subsequent follow up. HMG-Co A lyase de®ciency was con®rmed by the lack of enzyme activity in the patient's cultured skin ®broblasts (patient Al: 0 nmol/min/mg protein; normal range: 22.0 ‹ 4.8 nmol/min/mg protein) whereas normal activities were found for reference enzymes such as glutamate dehydrogenase. Parental ®broblasts were not studied. Discussion In this patient with HMG-CoA lyase de®ciency, strokelike encephalopathy developed 4 days after an acute metabolic crisis during clinical recovery and normalization of biochemical parameters. The symmetrical white matter lesions demonstrated by MRI prior to the onset of stroke-like encephalopathy are characteristic for HMG-CoA lyase de®ciency [2, 6, 8, 9] and possibly re¯ect a pre-existing chronic metabolic encephalopathy. At that time, no signi®cant focal brain oedema (as a possible result of the initial metabolic decompensation and status epilepticus) was observed and primary clotting abnormalities and vascular malformations as possible causes for cerebral stroke were absent. The diagnosis of stroke-like encephalopathy was based on the unpredictable, acute onset of focal neurological symptoms and the development of signi®cant brain oedema and residual atrophy. Whereas major changes within the territories of the right anterior and middle cerebral artery are substrate for contralateral spastic hemiparesis and supranuclear facial palsy, aphasia seems to result from the minor residual changes within the left hemisphere (we have no evidence that the patient was left-handed before this episode). Stroke-like encephalopathy has been reported in a number of inherited metabolic disorders. In organic (propionic, methylmalonic, glutaric) acidurias, urea cycle defects and mitochondriopathies, stroke-like events occur during acute metabolic decompensation [7, 10]. As in our patient, these events are usually associated with severe encephalopathy and focal neurological symptoms do not necessarily correlate with de®nite vascular territories. For these conditions, the terms ``metabolic stroke'' and ``stroke-like episode'' are commonly used. Possible pathogenetic mechanisms include both vascular constriction due to acidosis and presence of toxic metabolites as well as endothelial oedema and cell damage due to intracellular accumulation of toxic metabolites with consequent breakdown of mitochondrial energy metabolism [7, 10]. Reduced cerebral perfusion due to exsiccosis has also been discussed [7]. Interestingly, in our patient stroke-like encephalopathy occurred days after the acute metabolic crisis when acidosis and hypoglycaemia had already resolved. Only persisting slow background activity in the EEG and extremly high urinary organic acid excretion indicated ongoing metabolic derangement. In a patient with maple syrup urine disease and ongoing encephalopathy despite recovery from metabolic decompensation, selective accumulation of lactic acid in the brain has been demonstrated by in vivo proton magnetic resonance spectroscopy [3]. Accordingly in our patient, organic acids, mainly lactic acid, might still have been selectively elevated in brain tissue during the manifestation of stroke-like encephalopathy. Therefore monitoring of the intracerebral accumulation of toxic metabolites by magnetic resonance spectroscopy and of cerebral haemodynamics might be useful for a better understanding of the pathogenetic mechanisms of stroke-like encephalopathy and to identify patients at risk. References 1. Blau N, Duran M, Blaskovics ME (1996) Physician's guide to the laboratory diagnosis of metabolic diseases. 1st edn. Chapman & Hall, London 2. Brismar J, Ozand PT (1994) CT and MR of the brain in the diagnosis of organic acidemias:experiences from 107 patients. Brain Dev [suppl] 16:104±124 3. Felber SR, Sperl W, Chemelli A, Murr C, Wendl U (1993) Maple syrup urine disease:metabolic decompensation monitored by proton magnetic resonance imaging and spectroscopy. Ann Neurol 33:396±401 4. Gibson KM, Breuer J, Nyhan WL (1988) 3-Hydroxy-3-methylglutaryl-coenzyme A lyase de®ciency: review of 18 reported patients. Eur J Pediatr 148:180±186 5. Gibson KM, Breuer J, Kaiser K, Nyhan WL, McCoy EE, Ferreira P, Greene CL, Blitzer MG, Shapira E, Reverte F, Conde C, Bagnell P, Cole DEC (1988) 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase de®ciency: report of ®ve new patients. J Inherit Metab Dis 11:76±87 6. Gordon K, Riding M, Cam®eld P, Bawden H, Ludman M, Bagnell P (1994) CT and MRI of 3-hydroxy-3-methylglutarylcoenzyme A lyase de®ciency. AJNR 15:1474±1476 7. Heidenreich R, Natowicz M, Hainline B, Berman P, Kelley RI, Hillman RE, Berry GT (1988) Acute extrapyramidal syndrome in methylmalonic acidemia: ``metabolic stroke'' involving the globus pallidus. J Pediatr 113:1022±1027 8. Lisson G, Leupold D, Bechinger D, Wallesch C (1981) CT ®ndings in a case of de®ciency of 3-hydroxy-3-methylglutarylCoA-lyase. Neuroradiology 22:99±101 9. Ozand PT, Al Aqueel A, Gascon G, Brismar J, Thomas E, Gleispach H (1991) 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase de®ciency in Saudi Arabia. J Inherit Metab Dis 14:174±188 746 10. Sperl W, Felber S, Skladal D, Wermuth B (1997) Metabolic stroke in carbamyl phosphate synthetase de®ciency. Neuropediatrics 28:229±234 11. Sweetmann L, Williams JC (1995) Branched chain organic acidurias. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. 7th edn. McGraw Hill, New York, pp 1387±1422 ANNOUNCEMENTS Hot Topics '98 in Neonatology December 6±8, 1998 Hyatt Regency, Capitol Hill Washington, DC Jerold F. Lucey, MD Conference Chairmain Preliminary program (5/98) Brain Hypothermia ± Research Progress 97±98 John Wyatt, MD ± Moderator ± England Peter Gluckmann, MD ± New Zealand Alistair Gunn, MD ± New Zealand David Edwards, MD ± England · Apoptosis Karen Nelson Jeffrey Perlman ± USA · Epidemiology of Hypoxic Ischemic Encephalopathy Neonatal Skin Steven Hoath, MD ± USA Alfred Lane, MD ± USA Necrotizing Enterocolitis ± Review What's New Robert Kliegman, MD ± USA ``Useless Therapies'' ± Discussion Pro & Con Mary Ellen Avery, MD ± USA The 4th International Skeletal Dysplasia Meeting 1st Announcement The 1999 International Skeletal Dysplasia Meeting will be held in Baden-Baden, Germany, July 29 to August 1, 1999. Attendance will be limited. A key topic will be the mechanisms and errors of skeletal morphogenesis. The abstract deadline will be April 30, 1999 and the estimated comprehensive fee is US $ 600. 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