Effects of cholesterol and simvastatin treatment in patients with Smith-Lemli-Opitz syndrome (SLOS).

Smith-Lemli-Opitz syndrome (SLOS) is a malformation syndrome caused by deficiency of 7-dehydrocholesterol reductase catalysing the last step of cholesterol biosynthesis. This results in an accumulation of 7- and 8-dehydrocholesterol (7 + 8-DHC) and, in most patients, a deficiency of cholesterol. Current therapy consists of dietary cholesterol supplementation, which raises plasma cholesterol levels, but clinical effects have been reported in only a few patients. Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors were shown to reduce 7 + 8-DHC levels and increase cholesterol concentrations in two small trials with divergent clinical outcome. This retrolective study evaluates the effects of cholesterol only and of cholesterol plus the HMG-CoA reductase inhibitor simvastatin on plasma sterols in 39 SLOS patients and on anthropometric measures in 20 SLOS patients. Cholesterol as well as additional simvastatin decreased the plasma (7 + 8-DHC)/cholesterol ratio. However, the mechanism leading to the decreasing ratio was different. Whereas it was due to an increasing cholesterol concentration in the cholesterol-only cohort, a decreasing 7 + 8-DHC concentration was demonstrated in the cohort receiving additional simvastatin. We could not confirm a positive effect of simvastatin treatment on anthropometric measures or behaviour, as previously reported.

Congenital disorder of glycosylation IId (CDG-IId) -- a new entity: clinical presentation with Dandy-Walker malformation and myopathy.

A 1.5-year-old boy with macrocephaly due to a Dandy-Walker malformation presented with progressive hydrocephalus, extensive muscular hypotonia, transient cholestatic syndrome, extensive coagulation abnormalities and elevated creatine kinase indicating myopathy. Diagnostic work-up indicated a congenital disorder of glycosylation (CDG, formerly carbohydrate deficient glycoprotein syndrome). The serum transferrin pattern obtained by automated isoelectric focusing (IEF) showed an hitherto unreported pattern with strongly elevated tri-, di-, mono- and asialotransferrin bands, increasing in this order together with markedly decreased tetrasialotransferrin. Investigation of two additional glycoproteins, alpha(1)-antitrypsin and alpha(1)-antichymotrypsin, confirmed a generalised defect of glycosylation. All known glycosylation defects could be ruled out by enzymatic analyses in either leukocytes or fibroblasts or by the results obtained by IEF. SDS-electrophoresis demonstrated a marked difference in the molecular weight of transferrin, suggesting the lack of parts or of all oligosaccharide chains. The defect could be delineated to a deficiency of beta-1,4-galactosyltransferase (E.C.2.4.1.38) due to a homozygous insertion (1031 - 1032 insC). Details of the biochemical and molecular findings will be described elsewhere.

Cranial MRI changes may precede symptoms in Hallervorden-Spatz syndrome.

Two families are presented in which siblings of children affected with Hallervorden-Spatz syndrome exhibited characteristic cranial magnetic resonance imaging changes before developing clinical features of the disease. Linkage to a major locus on chromosome 20p supported the diagnosis of Hallervorden-Spatz syndrome. In some patients with Hallervorden-Spatz syndrome, iron is radiographically evident before the onset of clinical symptoms.

Mutations in the sepiapterin reductase gene cause a novel tetrahydrobiopterin-dependent monoamine-neurotransmitter deficiency without hyperphenylalaninemia.

Classic tetrahydrobiopterin (BH(4)) deficiencies are characterized by hyperphenylalaninemia and deficiency of monoamine neurotransmitters. In this article, we report two patients with progressive psychomotor retardation, dystonia, severe dopamine and serotonin deficiencies (low levels of 5-hydroxyindoleacetic and homovanillic acids), and abnormal pterin pattern (high levels of biopterin and dihydrobiopterin) in cerebrospinal fluid. Furthermore, they presented with normal urinary pterins and without hyperphenylalaninemia. Investigation of skin fibroblasts revealed inactive sepiapterin reductase (SR), the enzyme catalyzing the final two-step reaction in the biosynthesis of BH(4). Mutations in the SPR gene were detected in both patients and their family members. One patient was homozygous for a TC-->CT dinucleotide exchange, predicting a truncated SR (Q119X). The other patient was a compound heterozygote for a genomic 5-bp deletion (1397-1401delAGAAC) resulting in abolished SPR-gene expression and an A-->G transition leading to an R150G amino acid substitution and to inactive SR as confirmed by recombinant expression. The absence of hyperphenylalaninemia and the presence of normal urinary pterin metabolites and of normal SR-like activity in red blood cells may be explained by alternative pathways for the final two-step reaction of BH(4) biosynthesis in peripheral and neuronal tissues. We propose that, for the biosynthesis of BH(4) in peripheral tissues, SR activity may be substituted by aldose reductase (AR), carbonyl reductase (CR), and dihydrofolate reductase, whereas, in the brain, only AR and CR are fully present. Thus, autosomal recessive SR deficiency leads to BH(4) and to neurotransmitter deficiencies without hyperphenylalaninemia and may not be detected by neonatal screening for phenylketonuria.

Novel splice site mutation of aspartoacylase gene in a Turkish patient with Canavan disease.

Canavan disease is a severe, progressive autosomal recessive neurodegenerative leukodystrophy. Canavan disease occurs more frequently among Ashkenazi Jewish individuals with two predominant mutations in the aspartoacylase (ASPA) gene. The disease is less frequent in non-Jewish individuals and the mutations randomly reside on the ASPA gene, with one mutation seen more frequently among patients of European extraction. In the present study we report a novel homozygous donor splice site mutation of intron 4 in a child with first-cousin parents of Turkish extraction.

Medium-chain acyl-CoA dehydrogenase deficiency does not correlate with apparent life-threatening events and the sudden infant death syndrome: results from phenylpropionate loading tests and DNA analysis.

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of fatty acid metabolism and typically presents in early childhood as potentially fatal hypoketotic, hypoglycaemic crisis often associated with Reye-like symptoms. Re-investigations of cases of sudden infant death syndrome (SIDS) have revealed in some instances a deficiency of MCAD, suggesting that this metabolic disorder may lead to sudden infant death without prior clinical symptoms. In the present study, we examined 142 infants who had suffered from an apparent life-threatening event (ALTE) or were otherwise considered at risk for SIDS for MCAD deficiency by phenylpropionate loading. In no case excretion of phenylpropionylglycine, the hallmark of MCAD deficiency, was increased. In contrast, 3 out of 55 children with symptoms of metabolic disorders showed increased phenylpropionylglycine excretion, and in all three cases MCAD deficiency was confirmed by DNA analysis. In addition, we investigated 142 cases of sudden unexplained child death and 100 control subjects for the A985G mutation in the MCAD gene which is associated with about 98% of enzyme deficiencies. We found one case of heterozygosity each in the patient and control group. Our data indicate that MCAD deficiency is not a major cause of ALTE and, in agreement with results from similar studies in other countries, its frequency is not increased in children who died of SIDS.

Compound heterozygosity for metachromatic leukodystrophy and arylsulfatase A pseudodeficiency alleles is not associated with progressive neurological disease.

Several allelic mutations at the arylsulfatase A (ASA) locus cause substantial deficiencies of this lysosomal enzyme. Depending on the genetically determined degree of the deficiency, the clinical outcome may be very different--either metachromatic leukodystrophy (MLD), a lethal lysosomal storage disorder affecting the nervous system, or, more frequently, the so-called pseudodeficiency (PD), which has no apparent clinical consequence. Because of compound heterozygosity for MLD and PD, 1/1,000 individuals in the population have low residual enzyme activities, which are intermediate between those of MLD patients and those of PD homozygous normal individuals. In order to assess whether PD/MLD compound heterozygotes bear a health risk, we examined clinically and biochemically 16 individuals with this genotype. Of these subjects, two had neurological symptoms and two showed lesions, without clinical symptoms, in magnetic resonance imaging of the brain. None of these symptoms was progressive, nor did they resemble those of MLD. Nerve conduction velocities were normal in these probands, and they secreted only low amounts of sulfatide in the urine. We conclude that the observed neurological symptoms are unrelated to the ASA genotype and that PD/MLD compound heterozygotes are not at an increased risk for developing progressive nervous system diseases.

[Glomerulonephritis with transient C3 hypoclompimentemia and endotheliomesangial glomerulonephritis in childhood. A long-term experience]. / Glomerulonephritis mit transitorischer C3-Hypokomplementämie und endotheliomesangiale Glomerulonephritis im Kindesalter. Eine Langzeiterfahrung.

62 children (20 girls and 42 boys, ranging in age between 3 and 15 years), presenting with acute hypocomplementemic glomerulonephritis or morphologically confirmed endotheliomesangial glomerulonephritis, were admitted to the University Children's Hospital, Berne from 1970 to 1991. The annual incidence of cases of acute hypocomplementemic glomerulonephritis was stable during the study period. The site of the antecedent infection was the throat in 26 patients, upper respiratory tract in 15, the skin in 9, and unknown in 10. The latent period ranged from 0.5 to 3.5 weeks. 41 patients developed hypertension and 17 renal failure. Hypertensive complications were observed in 6 patients and remitted completely in 5 cases. A nephrotic syndrome (edema, proteinuria of 40 mg/[m2.h], albuminemia < 25 g/l) was observed in 11 patients. Microscopic hematuria persisted in many patients for one year or more. Proteinuria remitted in all but one patient, who was found to have Alport syndrome. This study shows the stable frequency of hypocomplementemic glomerulonephritis since 1970, its good prognosis, and the importance of the measurement of C3-complementemia in children presenting with acute glomerulonephritis.

[Variability of epileptic seizure phenomenology in infants and children]. / Variabilität der epileptischen Anfallsphänomenologie bei Säuglingen und Kindern.

It is well known that some patients may have two or more different types of seizures. Partial epilepsies and more than 15 different epileptic syndromes (e.g. West or Lennox-Gastaut syndrome or epilepsies with absences) can lead to the intraindividual manifestation of two or more seizure types. Among 728 children with epilepsy seen at the outpatient department 9.1% had two different types of seizures and 1.5% had more than two types of seizures. The most common association observed was between tonic-clonic seizures and absences. The most frequently observed epileptic syndromes were in decreasing order: multifocal epilepsies, epilepsies with absences, Lennox-Gastaut syndrome and West syndrome. The association of two or more different seizure types in the same patient seems to be a negative prognostic factor.

Does migraine-related stroke occur in childhood?

This report concerns seven children who had at least one episode of infarct, possibly during an attack of migraine. They fulfilled the following criteria: presence of acute neurological deficit associated with headache or other symptoms characteristic of migraine attacks; a history of migraine; evidence of infarct on CT scan; and no other evident cause of the stroke. CT showed that the area of infarction was in the distribution of the posterior cerebral artery in three cases. Four of the children have been followed for at least 23 months and none has severe residual deficit. An aetiological relationship between migraine and stroke could not be demonstrated. However, epidemiological data suggest that childhood migraine can be a contributory risk-factor for strokes.