Folker Hanefeld

Succinic semialdehyde dehydrogenase deficiency: an inborn error of gamma-aminobutyric acid metabolism.

Gamma-hydroxybutyric aciduria is a disorder of gamma-aminobutyric acid metabolism in which a compound of known neuropharmacologic activity accumulates. We have studied two patients in whom high levels of gamma-hydroxybutyric acid were found in blood, urine and cerebrospinal fluid. A coupled assay has been developed which estimates succinic semialdehyde dehydrogenase activity in isolated human lymphocytes. The mean activity of succinic semialdehyde dehydrogenase in a control and the four parents and two healthy siblings of these patients was 8.8 +/- 1.9 pmol . min-1 . mg-1 protein. In the patients the activities were 0.8 and 1.1 pmol . min-1 . mg-1 protein, approximately 9-13% of control. In the presence of saturating amounts of NAD+, lymphocyte sonicates, derived from the patients accumulated a significant amount of 14C-succinic semialdehyde from 14C-gamma aminobutyric acid, whereas none could be detected in controls. The data suggest a deficiency of succinic semialdehyde dehydrogenase in these patients, the first documented defect of the metabolism of gamma-aminobutyric acid in man.

4-Hydroxybutyric aciduria: A new inborn error of metabolism. I. Clinical review

Atactic syndromes in childhood are difficult to classify and only few conditions are well defined and characterized by specific biochemical abnormalities e.g. IgA deficiency in Louis Bar syndrome (McKusick 20890), elevated serum levels of phytanic acid in Refsum’s disease (McKusick 26650) or a s-lipoproteinaemia in Bassen-Kornzweig syndrome (McKusick 20010). In 1981 we observed a Turkish boy who suffered from a non-progressive ataxia with muscular hypotonia. He excreted large amounts of 4-hydroxybutyric acid (GHB) in his urine. The biochemical findings in this boy led us to postulate a deficiency of succinic semialdehyde (SSA) dehydrogenase, as the first recognized inborn error of GABA metabolism (Jakobs et al., 1981).

Congenital muscular dystrophy with cerebral and ocular malformations (Cerebro-oculo-muscular syndrome)

Two children with the features of the Muscle, Eye and Brain (MEB) Disease (SANTAVUORI 1977), i.e. congenital muscular dystrophy (CMD), cerebral malformations and ocular abnormalities are reported and correlations with other inherited autosomal recessive syndromes of CMD, Fukuyama type of CMD and the Walker-Warburg syndrome discussed. The association of CMD and cerebral lesions indicate an unfavourable clinical prognosis.

The prognostic value of eeg patterns in epilepsies with infantile spasms

By scoring EEG patterns (hypsarrhythmia = 10, absence of sleeping patterns = 10, focal epileptic discharge = 5, general-treatment or in whom infantile spasms never disappeared even during ACTH. A low voltage EEG did not have any ending ACTH therapy free of seizures showed lower scores compared to those infants relapsing after the end of ACTH treatment or in whom infantile spasms never disappeared even during ACTH. A low voltage EED did not have any prognostic significance. Using EEG scores it might be possible to separate non-responders and responders after 3 weeks of ACTH therapy, thus shortening ACTH treatment in non-responding infants.

Infantile spasms: CSF proteins before and during treatment with ACTH

SIR-The early treatment of infantile spasms with steroids, in particular with corticotrophin, often results in a dramatic reduction of seizures and the disappearance of the characteristic EEC pattern of hypsarrhythmia. The sudden onset of the disease and the effect of steroids has led to speculation about the possible r81e of unrecognized inflammatory or immunological reaction as a cause of the disease. There are also several reports on transient, reversible brain-shrinkage detected on CT scans of children with infantile spasms during treatment with ACTH* . Variousexplanations have been discussed to account for the ACTH effect on the brain: loss of water, disappearance of cerebral swelling that superimposes cerebral atrophy, the occurrence of hydrocephalus, and interference with brain growth by loss of neurons and proliferation of glia. Our results of CSF-protein analysis in children with infantile spasms before and during treatment with ACTH point against the loss of brain tissue. CSF-protein was investigated by agarose gel electrophoresis, using an analogue computer for quantitative analysis of the phoretograms. 23 children in whom lumbar puncture was performed to exclude meningitis served as controls. The protein profiles of CNS-barrier disturbance was demonstrated by 15 children with diagnosed acute meningoencephalitis. Before treatment with corticotrophin (60 to 120 rudaily), all 20children suffering from infantile spasms had a CSF-protein pattern of abnormally increased cerebrovascular permeability for proteins, especially for albumin (Table I ) . In contrast to the children with acute meningoencephalitis, they showed no increased gammaglobulin, pointing against acute or chronic CS infections. The CSF-protein pattern of cases classified as cryptogenic or symptomatic showed no difference. After receiving ACTH for two to three weeks, seven children with infantile spasms had a nearly normal CSF-protein pattern. Apparently the period of brain shrinkage is associated with the occurrence of normal cerebrovascular permeability. According to FISHMAN, an albumin-rich transudate characterizes vasogenic brain oedema. The composition of the brain extracellular fluid is reflected by the CSF. As ACTH is a potent drug for reducing vasogenic brain oedema, the resulting changes in CT scans and CSI; could be partially explained by reduction of cerebral swelling. The cause of the disturbed blood-brain barrier function demonstrated in our study remains unexplained. The anti-convulsive effect of ACTH cannot be explained by the tightening of the blood-brain barrier alone. I n order to understand these findings better, we need further studies of patients who remain free of seizures compared with those whose spasms recur after withdrawal of steroids.

The influence of various aminoglycoside preparations on bilirubin/albumin binding

The effect of antibiotics of aminoglycoside structure on the albumin binding of bilirubin has been tested in homozygous (jaundiced) Gunn rats aged 3-5 days. The following drugs were investigated: different preparations of gentamycin, kanamycin, tobramycin and sisomicin. The animals received 50-75% of the LD50 of heterozygous (non-jaundiced) Gunn rats. Mortality, weight gain and changes in the plasma bilirubin concentration were recorded. It was found that the displacement of bilirubin from albumin is caused by the different stabilizers used and not by the antibiotic itself. With the exception of lyophilized preparations of gentamycin for intrathecal application all vials contain different amounts of these preservatives. Special preparations used during the newborn period contain relatively more of these stabilizers. The toxicity of the additives has already a negative influence on the LD50 for heterozygous Gunn rats when the low dosed Refobacin and Sulmicin vials are given. For Refobacin (production 1973/74) the tolerance is reduced by nearly 50%. The toxicity caused by the stabilizer alone is even more marked when given to homozygous (jaundiced) Gunn rats. It becomes evident that benzylalcohol is the substance responsible for the displacement of bilirubin from albumin. The serum concentration of bilirubin decreases for 3-24 hrs depending on the doses given to the animal. This offers the opportunity to measure the competitive displacement of bilirubin easily and exactly. The free unbound, unconjugated bilirubin tends to diffuse into the lipid of the brain with resultant kernicterus. This was shown in histochemical preparations of the cerebellum of young homozygous Gunn rats. Using enzyme reactions for lactic acid dehydrogenase and NADH2-tetrazolium reductase the cytotoxic effect of bilirubin on PURKINJE cells could be demonstrated. The effect of the stabilizers used in the other antibiotic drugs tested can be neglected under clinical conditions. Finally the steepness and duration of the decrease of plasma bilirubin after injection of the dangerous stabilizers was studied in animals of different age (3-5 days; 3-4 weeks). Different results observed can be explained by the more rapid metabolism of benzoates in older animals. However, it remains an open question at what age Gunn rats reflect most precisely the human situation in premature and newborn babies.

The Gunn Rat — A Model for Phototherapy

For more than 15 years, neonatologists, a pediatric neurologist, illumination engineers as consultants and later on a pediatrician, formerly trained in mathematics and chemistry — are using in our hospital the Gunn rat strain as a model. phototherapv (PT) was one of the main topics. Today, the succeeding steps of research shall be listed in short and completed by new data.*

Lyme Borreliosis in Children

Lyme borreliosis is a common infectious disorder in children. The daily life and play routines in particular make them more likely than adults to be bitten by ticks and thus more likely to be infected by Borrelia burgdorferi. Lyme borreliosis as a clinical entity was first recognized in children suffering from arthritis (1). In the meantime, research in this field has mainly been focused on the disease in adults. Epidemiological data about the true incidence of Lyme borreliosis in childhood are still sparce. The whole clinical spectrum of Lyme borreliosis described in adults is also found in children, but age-specific differences in the relative frequency of certain manifestations, in the course of the disease as well as in diagnostic pecularities are evident (2–9).

Acute and long-term side effects of antineoplastic treatment in children

27% of patients in CCR of ALL showed widening of cortical sulci but no enlargement of ventricular size or intracranial calcifications. These findings could be correlated to the single radiation dose (>170 rad) the duration of maintenance therapy (>24 months), pretherapeutic neurological and or neuro developmental abnormalities and the age at diagnosis (older children showing more frequently abnormal widening of sulci). Neuropsychological assessment using non-speed related methods revealed a profile of clearly normal IQs with reduced psychomotor speed.