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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.

Adult-onset type II citrullinaemia, caused by deficiency of the citrin protein encoded by the SLC25A13 gene, is characterised by a liver-specific argininosuccinate synthetase deficiency. DNA analysis for citrin deficiency revealed that SLC25A13 mutations are the cause of a particular type of neonatal intrahepatic cholestasis. We retrospectively investigated nine infants with cholestatic jaundice of unknown origin, detected by newborn screening over a period of 17 years, to determine the role of SLC25A13 defects in children. The results of the newborn screening were varied; four neonates were positive for hypermethioninaemia, two for hyperphenylalaninaemia, one for hypergalactosaemia and two for both hypermethioninaemia and hypergalactosaemia. Clinical characteristics of the patients were severe intrahepatic cholestasis, hypercitrullinaemia, and fatty liver. The symptoms resolved in all patients by 12 months of age without special treatment other than nutritional management. Although five patients were lost to follow-up, we detected SLC25A13 mutations in the remaining four patients examined. Conclusion: the differential diagnosis of cholestatic jaundice of unknown origin in infants should therefore include citrin deficiency. In this paper, we stress the importance of newborn screening to detect infants with neonatal intrahepatic cholestasis caused by citrin deficiency.

A 6-year-old male with partial ornithine transcarbamylase (OTC) deficiency had acute and rapidly progressive symmetrical swelling of the head of the caudate nuclei and putamina. Clinical presentation was ataxia and dysarthria progressing to seizures and coma; these symptoms gradually resolved with supportive management. Although he had been recently treated for mild hyperammonemia, there was no evidence of acute metabolic decompensation prior to presentation, and plasma ammonia and amino acids were consistent with good metabolic control. This case is novel in that the neurological insult affected the neostriatum of the basal ganglia and the episode occurred in the absence of an apparent metabolic abnormality, unique observations in a patient with OTC deficiency. Conclusion: This case suggests that the pathophysiology of metabolic stroke is complicated. It also argues for an evaluation for metabolic stroke in patients with known inborn errors of metabolism who present with unusual neurological symptoms in the absence of biochemical abnormalities. Similarly, this case suggests that patients presenting with unexplained neurological insults might benefit from an evaluation for an inborn error of metabolism.

In patients with defects in the synthesis, breakdown and metabolism of glutathione (GSH), like glutathione synthetase deficiency (GSD) and 5-oxoprolinase deficiency, urinary excretion of 5-oxoproline, an intermediate of the gamma-glutamyl cycle, is increased. We identified 20 patients with significantly elevated urinary excretion of 5-oxoproline (or =150 mmol/mol creatinine) during 5 years of selective screening for organic acidurias. In 6 of them, 5-oxoprolinuria was a constant finding including three patients with GSD and one with 5-oxoprolinase deficiency. One patient with constant 5-oxoprolinuria had GM2 gangliosidosis and one was clinically unaffected. In 14 patients, 5-oxoprolinuria was a transient abnormality and most often associated with an inborn error of metabolism outside the gamma-glutamyl cycle. In 9 of them 5-oxoprolinuria was associated with a neonatal urea cycle defect, with tyrosinaemia type I or occurred during metabolic decompensation in propionic acidaemia or methylmalonic acidaemia. Additionally, transient 5-oxoprolinuria was associated with homocystinuria, Stevens-Johnson syndrome, paracetamol intoxication, vigabatrin medication or extreme prematurity.5-Oxoprolinuria is a more common condition than hitherto thought and is primarily associated with defects in the gamma-glutamyl cycle. However, several other inborn errors of metabolism and pathophysiological conditions must be taken into account when discovering 5-oxoprolinuria.

The ornithine transcarbamylase (OTC) gene is located on the short arm of the X-chromosome and encodes the second enzyme of the urea cycle. OTC deficiency is an X-linked disorder that causes hyperammonemia leading to brain damage, mental retardation and death. The clinical and biochemical phenotype is extremely variable and can only partially be explained by the genotype. We identified mutations in the OTC gene of more than 150 patients with OTC deficiency. The "neonatal onset" group of patients has mutations that abolish enzyme activity, whereas the "late onset group" shows partial enzyme deficiency to variable degree. Of the mutations, 60% are associated exclusively with acute neonatal hyperammonemic coma while the remaining cause "late onset" disease. Several symptomatic and asymptomatic adults have now been identified to have deleterious mutations in the OTC gene leading to predisposition to hyperammonemia.The enlarging clinical, biochemical and molecular spectrum observed in patients with ornithine transcarbamylase deficiency suggests that this disorder behaves like a single gene disorder at one end of the spectrum and as a multi-factorial disease at the other.

We report the 9-year follow-up of a patient suffering from N-acetylglutamate synthetase deficiency, an urea cycle disorder leading to severe neonatal hyperammonaemia. Hitherto two patients from two families with this inborn error of metabolism had been observed. Our management consisted mainly of a protein-restricted diet and oral treatment with N-carbamylglutamate, an activator of carbamylphosphate synthetase, together with arginine or citrulline. The somatic development was normal whereas a moderate psychomotor retardation was diagnosed. The patient died after an episode of coma and prolonged generalized convulsions at the age of 9.5 years.

Inherited metabolic disorders are the cause of a small but significant number of sudden unexpected deaths in infancy. We report a girl who suddenly died at 11 months of age, during an intercurrent illness. Autopsy showed spongiform lesions in the subcortical white matter, in the basal ganglia, and in the dentate nuclei. Investigations in an older sister with developmental delay, ataxia, and tremor revealed L-2-hydroxyglutaric aciduria and subcortical white matter changes with hyperintensity of the basal ganglia and dentate nuclei at brain magnetic resonance imaging. Both children were homozygous for a splice site mutation in the L2HGDH gene. Sudden death has not been reported in association with L-2-hydroxyglutaric aciduria so far, but since this inborn error of metabolism is potentially treatable, early diagnosis may be important.

Four children, from two families, suffered from fatal degeneration of the cerebral grey matter. Their disease was characterised by intractable epilepsy, epilepsia partialis continua, progressive deterioration, and terminal hepatic dysfunction. EEG showed marked and distinctive slow wave abnormality, visual evoked responses were diminished, and cerebral atrophy was seen on CT scan. Pathological findings were of neuronal loss and hepatic cirrhosis. The combination of cerebral degeneration, hepatic disease and familial occurrence suggests an inborn error of metabolism with autosomal recessive inheritance. The features described are those of Alpers syndrome, especially the recently delineated subgroup with progressive neuronal degeneration and liver disease.

Choreoathetosis, spastic parapareses, dementia and optic atrophy were the main clinical features in a sibship with progressive encephalopathy of late onset. The urine contained constantly elevated amounts of 3-methylglutaric and 3-methylglutaconic acids. The identity of these metabolites was confirmed by synthesis and mass spectrometry. On leucine loading, the excretion of the metabolites was elevated.

Myophosphorylase deficiency (McArdle's syndrome) is an uncommon condition characterized by exercise intolerance, muscle cramps and myoglobinuria. The present report describes the clinical, histochemical, electronmicroscopic and biochemical findings in a 12-year-old boy with myophosphorylase deficiency. The diagnosis should have been suspected when the boy was 6 years old. Most index cases have not been diagnosed until adult life, but this syndrome has to be considered in the differential diagnosis of exercise intolerance in childhood.

Acrodermatitis enteropathica is an inborn error of metabolism resulting in zinc malabsorption and severe zinc deficiency. From personal experience and a literature review the following conclusions were drawn: 1. Symptoms other than dermatitis, vary with age. Diarrhoea, mood changes, anorexia, and neurological disturbance were reported most frequently in infancy. Growth retardation, alopecia, weight loss and recurrent infections were prevalent in toddlers and schoolchildren. Spontaneous remission may occur at adolescence. 2. The severity of symptoms also varies. Intermittent or mild cases of the disease and those presenting with uncommon features such as ophthalmic, cerebral or hepatic involvement, are easily overlooked. In the severe cases this may result in a fatal outcome. If untreated, the overall mortality rate is 20%, being higher in males. 3. The laboratory diagnosis is hazardous. In patients, mean zinc values in serum, urine and hair were ca. 50% of normal levels. There is a 15% overlap with healthy controls; moreover, low zinc levels in serum, urine or hair are also found in other diseases. A more specific test is required. 4. In cases of doubt, in vitro or in vivo zinc absorption tests using radioisotopes (65Zn or 69mZn) may be performed. These appear not to be influenced by other conditions and show less overlap with controls. If such tests are unavailable, the clinical response to 3-30 mumol zinc/kg per day for 5 days may be awaited. This is recommended in infants or children with one or more symptoms of acrodermatitis enteropathica.

A very unusual pattern of organic acid excretion was established in the urine of two premature newborns with severe respiratory distress and cerebral haemorrhages. By combined gas chromatography/mass spectrometry the following acids were identified: lactic acid, alpha-hydroxy-butyric acid, beta-hydroxy-butyric acid, alpha-hydroxy-isovaleric acid, and p-hydroxy-phenyllactic acid. Calculation of the concentration revealed an excessive excretion of lactic acid and also very high excretion of the other acids. A postmortem blood sample from one of the patients revealed a comparable pattern. The abnormal urinary organic acid excretion pattern was most probably caused by severe tissue hypoxia.