High cerebral guanidinoacetate and variable creatine concentrations in argininosuccinate synthetase and lyase deficiency: implications for treatment?

Cerebral creatine and guanidinoacetate and blood and urine metabolites were studied in four patients with argininosuccinate synthetase (ASS) or argininosuccinate lyase (ASL) deficiency receiving large doses of arginine. Urine and blood metabolites varied largely. Cerebral guanidinoacetate was increased in all patients, while cerebral creatine was low in ASS and high in ASL deficiency. Because high cerebral guanidinoacetate might be toxic, lowering the arginine supplementation with additional creatine supplementation might be important.

Cerebral 1H MR spectroscopy showing elevation of brain guanidinoacetate in argininosuccinate lyase deficiency.

MR spectroscopy in a patient with argininosuccinate lyase deficiency revealed elevated cerebral guanidinoacetate signals, indicating that the phenomenon of increased levels of this compound in brain tissue is not limited to creatine deficiencies.

1H chemical shift imaging of the brain in guanidino methyltransferase deficiency, a creatine deficiency syndrome; guanidinoacetate accumulation in the gray matter.

MR spectroscopy results in a mild case of guanidinoacetate methyltransferase (GAMT) deficiency are presented. The approach differs from previous MRS studies in the acquisition of a chemical shift imaging spectral map showing gray and white matter with the corresponding spectra in one overview. MR spectroscopy revealed guanidinoacetate (GAA) in the absence of creatine. New is that GAA signals are more prominent in gray matter than in white. In the prevailing view, that enzyme deficiency is localized in liver and pancreas and that all GAA is transported into the brain from the blood and the cerebrospinal fluid, this would be compatible with a more limited uptake and/or better clearance of GAA from the white matter compared to the grey matter.

Normal very-long-chain fatty acids in peroxisomal D-bifunctional protein deficiency: a diagnostic pitfall.

We present a relatively mild case of peroxisomal D-bifunctional protein deficiency with inconsistent screening results in plasma for peroxisomal disorders.

Neuroglycopenia in normoglycaemic patients, and the potential benefit of ketosis.

We report a patient with recurrent symptoms of neuroglycopenia due to a defective glucose transport into brain. The potential benefit of ketosis in neuroglycopenia is discussed from the therapeutic concept of a ketogenic diet in GLUT1-deficiency syndrome.

Neurobehavioural relationships after the onset of puberty.

The behavioural and cognitive development were studied of 68 children with and 259 without minor neurological function (MND) at 14 years, when the majority of children showed three or more physical signs of puberty. MND was differentiated into fine manipulative disability, co-ordination problems, choreiform dyskinesia and hypotonia. The normal group was subdivided into those who had been normal at 12 years and those who had had MND. All types of MND were related to cognitive and behavioural problems. Fine manipulative disability was related to behavioural and cognitive difficulties; co-ordination problems to learning difficulties; and choreiform dyskinesia and hypotonia were related to attention difficulties and school failure, notwithstanding normal IQ. Besides MND, socio-economic class, family adversities and female gender contributed to the development of behavioural and cognitive problems. The behaviour of children with MND at 12 years who were normal at 14 years did not differ from that of normal children.

Neurobehavioral relationships and puberty: another transformation?

In a follow-up study of the Groningen Perinatal Project (GPP) on minor neurological dysfunction (MND) at 12 and 14 years the onset of puberty appeared to play a role. The children were selected on the presence (n = 185) and absence (n = 185) of MND at 9 years. Puberty was defined by the presence of three or more physical puberty signs. With the onset of puberty the incidence of MND decreased. The neurobehavioral relationships became more explicit after the onset of puberty. All types of MND were related to behavioural and cognitive problems at this developmental stage. In normal children, boys showed an increase of strength during puberty whereas the movements of girls became more fluent. The apparent changes in neurological function during puberty were interpreted as a transformation of the central nervous system. The possible causes are discussed. The conclusion is that gonadal hormones and especially oestrogens, play a role. The fact that two-thirds of the children with MND and behavioural problems outgrow the problems during puberty, can be of great help. Finally, any longitudinal study of brain function, which includes the age of puberty, should pay attention to the pubescent stage.

Is minor neurological dysfunction at 12 years related to behaviour and cognition?

Behavioural and cognitive development at 12 years were studied in 172 children with and 174 children without minor neurological dysfunction (MND). MND could be differentiated into fine manipulative disability, co-ordination problems, hypotonia and choreiform dyskinesia. Fine manipulative disability related significantly to problems of cognition and behaviour; co-ordination problems to cognitive problems; and hypotonia and choreiform dyskinesia to behavioural problems, the former more than the latter. Socio-economic status and family adversity contributed to the risk for development of both cognitive and behavioural problems; gender did not. The onset of puberty seemed to change these relationships: follow-up is needed for definite conclusions.

Minor neurological dysfunction after the onset of puberty: association with perinatal events.

In order to study the hypotheses that puberty is related to a decrease of minor neurological dysfunction (MND) and that persisting MND is associated with perinatal factors, two groups (174 normal, 172 MND) of the Groningen Perinatal Project were followed from 12 to 14 years. At 14 years almost all the children had entered puberty (n = 329) defined as the presence of three or more puberty signs. In the MND group 55% of the children were normal at 14 years and in 45% MND signs were still present, though in a less extensive form. The latter phenomenon was most clear in children who had just begun puberty. The effect of puberty was similar in both sexes. MND which persisted into puberty was related to neonatal neurological deviancy, lower social class, lower obstetrical optimality score and male sex. After differentiation with specific MND clusters, it appeared that fine manipulative disability was associated with neonatal neurological deviancy, with minor physical anomalies and with lower social class; choreiform dyskinesia with asphyxia; hypotonia with constitutionally related factors; and coordination problems with pre-maturity (< 32 weeks).