Fatal cerebral edema associated with serine deficiency in CSF
A 7-year old, normally developing girl was diagnosed with moderately severe asthma for which she used inhalation therapy with combination of salmeterol/fluticasone. The day before her death, she presented with a mild febrile condition, including malaise, headache, and nausea. Medical examination showed no abnormality, and domperidone was prescribed. The morning before her death, her mother found her unresponsive in bed, probably following a seizure. At that time, blood glucose, as measured by a bed-side apparatus, was 2.1 mmol/l. In the emergency room, the patient had convulsions, which responded to diazepam. Physical examination showed expiratory wheezing, normal blood pressure and capillary refill time, a relatively low heart rate (100/min), no hepatosplenomegaly, normal pupils, and no signs of trauma or bleeding. Hypoglycemia or electrolyte disturbances were excluded. Liver enzymes and bilirubin were slightly elevated, and blood ammonia was normal (15 µmol/l). She regained consciousness for 1.5 h but became progressively dyspneic and presented suddenly with apnea and desaturation, decortication rigidity, bilateral fixed mydriatic pupils, and deep coma. She was intubated and treated with dexamethasone and mannitol. A brain computed tomography (CT) scan showed bilateral central herniation and cerebral edema. There were indisputable signs of brain death, and she died 24 h after the first symptoms.\nAmino acid analysis of both plasma and CSF revealed strongly decreased serine concentrations (Tables , , ) comparable with levels observed in patients with 3-PGDH deficiency (de Koning et al. ). Enantiomer separation revealed D-serine to be 0.9 µmol/L (ref. 0.8–4.3 µmol/L) and L-serine 4.0 µmol/L (ref. 17.2–44.0 µmol/L), with slightly elevated D-serine/total serine ratio of 18% in CSF (Fuchs et al. ). Concentrations of the other amino acids were normal or decreased according to a nonspecific pattern (data not shown). A deficiency of 3-phosphoglycerate dehydrogenase was excluded in cultured fibroblasts (43 nmol/mg per min; normal 29.5 ± 2.7 nmol/mg per min). Further metabolic screening revealed increased ketone bodies and lactate in urine, plasma, and CSF (Table ). Plasma acylcarnitine profile showed an elevated concentration of OH-C4-carnitine. A fatty acid oxidation defect was excluded. Brain microscopy showed bilateral necrosis in the cerebral tonsils compatible with central herniation. No signs of encephalitis or meningitis were found, but diffuse interstitial edema was obviously present. Postmortem microbiology sampling yielded a parainfluenza type II virus in the lungs, probably explaining fever onset and asthmatic signs as her presenting condition. The clinical picture probably reflects a toxic encephalopathy.