Eur J Pediatr (2005) 164: 655–659 DOI 10.1007/s00431-005-1729-5 O R I GI N A L P A P E R Emma E. Hobson Æ Sumesh Thomas Patricia M. Crofton Æ Alison D. Murray John C. S. Dean Æ David Lloyd Isolated sulphite oxidase deficiency mimics the features of hypoxic ischaemic encephalopathy Received: 7 April 2005 / Accepted: 18 May 2005 / Published online: 16 July 2005 Ó Springer-Verlag 2005 Abstract Isolated sulphite oxidase deficiency (ISOD) is a rare autosomal recessive inborn error of metabolism, which may present at birth with intractable seizures (often of prenatal onset) and severe neurological abnormalities. In infants who survive, lens dislocation may occur from 8 weeks of age. The neuropathological findings in ISOD are similar to those seen in severe perinatal asphyxia. We describe two siblings with ISOD born to healthy non-consanguineous parents. The first child presented within 48 h of birth with poor feeding and seizures. He died from septicaemia on day 20 of life. The clinical presentation, neuroradiology and autopsy suggested a diagnosis of severe hypoxic ischaemic encephalopathy with a low recurrence risk. The second child presented with seizures within an hour of birth. She lived for 16 months during which time she failed to make developmental progress and continued to experience intractable seizures. Her neuroradiology was similar to her brother’s. A diagnosis of ISOD was suggested from high urinary S-sulphocysteine in the second child and confirmed by the absence of sulphite oxidase activity in skin fibroblast culture. The diagnosis has enabled the couple to access prenatal testing in a subsequent pregnancy. Conclusion: Isolated sulphite oxidase deficiency is an autosomal recessive condition which may mimic ischaemic encephalophathy. The disorder should be considered in all cases of intrauterine seizures, intractable seizures in the newborn period and infants with clinical and radiological features of ischaemic encephalophathy, especially when no obvious insult can be determined. Keywords Hypoxic ischaemic encephalopathy Æ Prenatal diagnosis Æ Seizures Æ Sulphite oxidase deficiency Abbreviation ISOD: isolated sulphite oxidase deficiency E. Hobson and S. Thomas contributed equally to this paper E. E. Hobson (&) Department of Clinical Genetics, St Mary’s Hospital, Hathersage Road, Manchester, M13 0JH, UK E-mail: emma.hobson@nhs.net Tel.: +44-161-2764150 Fax: +44-161-2766145 S. Thomas Æ D. Lloyd Department of Neonatology, Aberdeen Maternity Hospital, Aberdeen, Scotland A. D. Murray Department of Radiology, University Hospital Aberdeen, Aberdeen, Scotland J. C. S. Dean Clinical Genetics Centre, University Hospital Aberdeen, Aberdeen, Scotland P. M. Crofton Department of Paediatric Biochemistry, Royal Hospital for Sick Children, Edinburgh, Scotland Introduction Endogenous sulphite is an intermediate metabolite produced in the degradation of the sulphur-containing amino acids cysteine and methionine. Sulphite oxidase catalyses the oxidation of sulphite to sulphate in most tissues, including the brain. Disruption of this pathway occurs in the inborn error of metabolism isolated sulphite oxidase deficiency (ISOD), and results in progressive neurodegeneration. ISOD is a rare autosomal recessive disorder, which may present at birth with seizures and severe neurological abnormalities. Affected children often die in infancy. Lens dislocation (ectopia lentis) commonly occurs from 8 weeks of age [5]. There have been approximately 50 cases of sulphite oxidase deficiency reported worldwide. The number of affected children alive is fewer due to the lethal nature of the disease 656 process. The neuropathological findings in ISOD, of cortical necrosis and extensive cavitating leukoencephalopathy, are distinctive, but nonspecific. These changes are similar to those observed in severe perinatal asphyxia which may result in misdiagnosis [1,11]. We describe two siblings with ISOD born to healthy non-consanguineous Scottish parents. Fig. 1 Brain MRI, T1 ( a) and T2 ( b) weighted axial images at 5 days old showing normal appearances. Low intensity in the white matter on T1 weighted images is due to incomplete myelination and is normal in neonates Case report A female infant was born by elective caesarean section at 37 weeks gestation after an uneventful pregnancy. She was noted to have jerking movements 40 min after delivery and was admitted to the neonatal unit at 90 min of age. Her seizures were generalised and difficult to control. Cranial ultrasound performed on the day of birth demonstrated an immature gyral pattern with no other significant abnormalities. CT of the brain performed the following day revealed extensive low attenuation in the white matter of both hemispheres, more than would be expected due to non-myelination. The corpus callosum was abnormal. Brain MRI on day 5 was normal (Fig. 1); however, a repeat MRI scan on day 18 showed dramatic changes with cystic encephalomalacia involving the frontal, parietal and, to a lesser extent, temporal lobes (Fig. 2). A further MRI scan at 3 months of age demonstrated the ongoing progressive nature of the neurodegeneration (Fig. 3). These changes were evident on serial cranial ultrasound. An EEG performed on day 28 showed a discontinuous trace with interhemispheric asynchrony and prolonged periods of absent cortical activity. The infant remained hypotonic and obtunded with episodes of short-lived seizures. Enteral feeding was established using high calorie milk feeds via a nasogastric tube. She showed little awareness of her surround- Fig. 2 Brain MRI, T1 weighted axial image on day 20 showing a marked change with extensive cystic encephalomalacia involving the frontal and parietal lobes. There is ventricular dilatation secondary to atrophy. T2 weighted images were degraded by movement artifact 657 she became microcephalic and hypertonic. She had subtle dysmorphic features, including sunken eyes and a prominent forehead, which were similar to those seen in her brother, who had died 2 years previously (see below). Regular ophthalmological examinations until her hospital discharge were normal. There was a progressive decline in her ability to bottle feed, with total reliance on tube feeding. At the age of 8 months she responded to tactile stimuli and appeared to have areas of hyperaesthesia. She died at 16 months of age following a viral respiratory infection. The diagnosis of ISOD was made following biochemical analysis of urine and plasma. On day 3, urinary S-sulphocysteine excretion was 134 lmol/mmol creatinine (reference range <10 lmol/mmol). Urinary thiosulphate excretion was slightly elevated at 0.057 mmol/ mmol creatinine (reference range <0.043 mmol/mmol creatinine). Plasma S-sulphocysteine was just detectable at 4 lmol/l. Plasma and urinary uric acid levels were normal, excluding molybdenum cofactor deficiency. These findings were consistent with ISOD and the diagnosis was confirmed by the absence of sulphite oxidase activity in skin fibroblast culture. This infant was the 3rd child of non-consanguineous parents. Their first pregnancy resulted in a healthy son. Their second child was a male infant born at 38 weeks gestation. The mother had experienced unusual fetal movements in the third trimester of the pregnancy, which in retrospect may have been fetal seizures. The infant was admitted to the neonatal unit on day 2 of life because of poor feeding, irritability, seizures and abnormal posturing. He died from Gram-negative septicaemia on day 20. At that time, the clinical presentation, cranial ultrasound images, brain MRI and EEG findings were thought to be strongly suggestive of severe hypoxic ischaemic encephalopathy. Autopsy showed severe white matter loss with astrogliosis affecting the cortex and cerebellum with neuronal loss affecting the basal ganglia and thalami. There was also evidence of cerebellar hypoplasia, cystic encephalomalacia and a thin corpus callosum. A diagnosis of hypoxic ischaemic encephalopathy was made based on the clinical and post mortem findings. Urinary S-sulphocysteine excretion was not measured in this infant. Following the diagnosis of ISOD in the second affected infant, neuroradiological investigations and histopathology samples from the first affected infant were reviewed and found to be wholly consistent with a diagnosis of ISOD. Once the diagnosis of ISOD was made in the family, the couple proceeded, after prenatal counselling and chorionic villus sampling biochemical testing, to have an unaffected male infant. Fig. 3 Brain MRI, T1 ( a) and T2 ( b) weighted axial images at 3 months of age showing progressive atrophy, dilated peripheral CSF spaces and white matter ischaemic lesions (that are dark on T1 and bright on T2) with overlapping cranial sutures ings with an increase in seizure activity and screaming episodes that were improved with the use of triclofos sodium. Over the course of her 4-month hospital stay, Discussion ISOD is an autosomal recessive inborn error of metabolism caused by mutations in the sulphite oxidase gene (SUOX, OMIM 606887), which is located on the long 658 arm of chromosome 12. The clinical presentation of this rare and probably under-diagnosed condition is similar to that of molybdenum cofactor deficiency. Molybdenum cofactor deficiency is a more frequently diagnosed inborn error of metabolism that affects not only sulphite oxidase activity but also xanthine dehydrogenase and aldehyde oxidase activities [13]. Both disorders usually present shortly after birth with intractable seizures (which may be prenatal in onset), feeding and respiratory difficulties, although presentation later in childhood has been described [12,13]. Lens dislocation may be observed as early as 8 weeks but is usually a later finding. Sulphite oxidase deficiency, either isolated or as a consequence of molybdenum cofactor deficiency, should be considered in an infant or child with seizures, diffuse neurological disease and MRI findings suggestive of white matter loss or cystic encephalomalacia, especially if accompanied by lens dislocation [5]. When sulphite oxidase is deficient, alternative metabolic pathways for cysteine degradation are augmented, resulting in accumulation of the metabolites S-sulphocysteine and thiosulphate [11]. Dipstick analysis for urinary sulphite is unreliable owing to rapid oxidation of sulphite to sulphate at room temperature [15], and falsepositive results have also been reported [4]. Urinary thiosulphate measurement may be associated with both false-positives [8] and false-negatives [2]. A more reliable screening test is the identification of S-sulphocysteine on an aminoacid analyser profile by a centre with experience of this disorder. Careful interpretation is required as other substances may co-elute. Elevated S-sulphocysteine strongly suggests either molybdenum cofactor or ISOD. These two disorders are differentiated by the detection of low plasma and urinary urate levels in molybdenum cofactor deficiency (due to xanthine dehydrogenase deficiency) compared with normal levels in ISOD. In both conditions, deficient sulphite oxidase activity, measured in cultured skin fibroblasts by a single centre in Europe (Hôpital Debrosse, Lyon, France), confirms the diagnosis. Prenatal diagnosis may be carried out by assay of sulphite oxidase activity or DNA mutation analysis on uncultured chorionic villus samples collected at 11–14 weeks gestation. The use of DNA analysis is only possible if the index case has been previously characterised by those means [6,7]. These techniques avoid the delays inherent in enzyme analysis on cultured amniocytes, a method that has also been used in this condition [9]. The neuropathogenesis of ISOD is unclear; however, rodent neuronal cell culture experiments suggest that high levels of sulphite are neurotoxic [10]. Neuronal migration abnormalities noted on postnatal neuroimaging suggest that the severe mental retardation associated with ISOD is initiated prenatally. It has been postulated that the lens dislocation may arise as a consequence of either reduced levels of cysteine, weakening the zonule of the lens, or secondary to disruption of cysteine disulphide bonds due to excess sulphite [5]. The prognosis is poor. Infants presenting in the neonatal period appear to demonstrate a more aggressive form of the disorder with intractable seizures, disordered autonomic function, progressive cerebral palsy and death in early childhood from intercurrent infections. Dietary manipulation aimed at reducing the intake of methionine and cysteine has been attempted but current evidence does not show any consistent benefit in patients presenting in the neonatal period. Cases presenting in late childhood often have milder forms of the disease and may respond to specific dietary therapy [3,14]. ISOD is a rare autosomal recessive condition which may be mistaken for ischaemic encephalophathy and therefore is possibly under-diagnosed. 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