Smith-Lemli-Opitz syndrome/RSH (SLOS) is

The authors describe four unrelated girls with a distinctive neurologic disorder with early-onset progressive ataxia and hypodontia with a characteristic pattern of delayed dentition. Cerebral MRI shows hypomyelinated white matter and cerebellar atrophy; 1H-MRS of white matter reveals a marked elevation of myo-inositol.

Two distinct disorders with elevated urinary excretion of 2-hydroxyglutaric acid are known: L-2-hydroxyglutaric aciduria and D-2-hydroxyglutaric aciduria. This paper presents clinical and biochemical studies in three patients and unsuccessful prenatal diagnosis in one case with combined D-2- and L-2-hydroxyglutaric aciduria. We suggest that these patients, who displayed a phenotype of neonatal onset metabolic encephalopathy, present a third variant of 2-hydroxyglutaric aciduria. Prenatal diagnosis is not reliable in this disorder.

Pyridox(am)ine-5'-phosphate oxidase converts pyridoxine phosphate and pyridoxamine phosphate to pyridoxal phosphate, a cofactor in many metabolic reactions, including neurotransmitter synthesis. A family with a mutation in the pyridox(am)ine-5'-phosphate oxidase gene presenting with neonatal seizures unresponsive to pyridoxine and anticonvulsant treatment but responsive to pyridoxal phosphate is described. Pyridoxal phosphate should be considered in neonatal epileptic encephalopathy unresponsive to pyridoxine.

Pyridox(am)ine-5'-phosphate oxidase converts pyridoxine phosphate and pyridoxamine phosphate to pyridoxal phosphate, a cofactor in many metabolic reactions, including neurotransmitter synthesis. A family with a mutation in the pyridox(am)ine-5'-phosphate oxidase gene presenting with neonatal seizures unresponsive to pyridoxine and anticonvulsant treatment but responsive to pyridoxal phosphate is described. Pyridoxal phosphate should be considered in neonatal epileptic encephalopathy unresponsive to pyridoxine.

The biochemical hallmark of glutaric aciduria type I (GA I) due to glutaryl-CoA dehydrogenase deficiency is the accumulation of glutaric acid, and to a lesser degree of 3-hydroxyglutaric and glutaconic acids. Abnormal metabolites vary from gross organic aciduria to only slightly or intermittently elevated or even normal excretion of glutaric acid, making the diagnosis sometimes difficult. Close to 100 pathogenic mutations have been identified in the gene encoding glutaryl-CoA dehydrogenase. Specific mutations correlate with low or no excretion of glutaric acid, but there appears to be no correlation between genotype and clinical phenotype. GA I causes unique age- and location-specific neuropathological sequelae. Starting in the second half of gestation, maturation of the frontal and temporal cortex is hindered, leading to the characteristic appearance of frontotemporal atrophy. Between 6 and 18 months of age, relatively mild neurological symptoms may become exacerbated by fever or a catabolic state in the course of common infections or routine immunizations, by fasts required for surgery, or by minor head injuries. Putamen and caudate are destroyed, resulting in a permanent movement disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spasticity. Recently, the underlying pathophysiology could be delineated to an environmentally triggered age- and location-specific overstimulation of the NMDA 2B receptor subtype. Current therapy prevents brain degeneration in more than 90% of affected infants who are treated prospectively. Without treatment, more than 90% of affected children will develop severe neurological disabilities. Recognition of this disorder before the brain has been injured is essential to treatment. GA I may be recognized in routine neonatal screening performed with tandem mass spectrometry by an elevation of glutarylcarnitine. Where this is not done, timely diagnosis depends on the recognition of relatively nonspecific physical findings such as hypotonia, irritability, macrocephaly, on the detection of suggestive abnormalities in neuroimaging and on quantitative urinary organic acid analysis by gas chromatography--mass spectrometry.

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Careful clinical delineation and advances in analytical methods have opened new possibilities for the detection of inherited neurometabolic disorders, some of which require specific CSF analyses for diagnosis. Although patients suffering from these disorders have recognizable phenotypes, there are strong indications that remain many undiagnosed, leading to a continuation of futile diagnostic searches and, for most disorders, withholding of available rational therapy. As there is still widespread uncertainty about when to perform specialist CSF investigations, it is the aim of this paper to define the place for CSF investigations in the diagnostic work-up of a child with an encephalopathy of unknown origin. Most neurometabolic disorders can be identified through serum, plasma and urine analyses in conjunction with neuroradiological investigations. Whenever CSF investigations are performed, the analysis should include quantitative determination of lactate, pyruvate and amino acids, the latter by methods especially suited for CSF, in addition to cells, glucose, protein, immunoglobulin classes, specific immunoglobulins, and an evaluation of the blood-brain barrier. If the disease course is non-progressive or if extracerebral symptoms are present in addition to an encephalopathy, e.g. endocrinological, hepatic, muscular or renal symptoms, investigations of metabolites in CSF over and above lactate, pyruvate and amino acids are generally noncontributary. Specific CSF investigations, which are discussed in detail, test metabolic pathways of brain metabolism, especially of neurotransmission. For a successful diagnosis of these defects, analyses must be planned individually, before CSF samples are taken, based on family history, clinical findings and disease course. Different determinations require different logistics from taking of the sample to shipment. One indication for specialized CSF analyses including biogenic monoamines and GABA is severe neonatal/infantile epileptic encephalopathy. In addition to a therapeutic trial of B6, folinic acid should be tried empirically for two to three days as the emerging syndrome of folinic acid responsive seizures appears to be the underlying cause in a sizable proportion of patients. In later infancy and childhood, defects in the metabolism of the biogenic monoamines may be suspected in patients with (fluctuating) extrapyramidal disorders, in particular Parkinsonism dystonia or more general "athetoid cerebral palsy", and vegetative disturbances. A severe epileptic encephalopathy and progressive mental retardation may be present. Neuroimaging findings do not show specific lesions. Determinations of folates and organic acids in CSF appear at present only warrantable individually in special constellations, e.g. classical clinical findings and disease course suggestive of glutaryl-CoA dehydrogenase deficiency with repeated negative quantitative analyses of organic acids in urine. The diagnosis of disorders, which require specific analyses of CSF, can only be achieved by conscious diag...