Accidental natalizumab administration to the third trimester of pregnancy in an adolescent patient with multiple sclerosis.

BACKGROUND: Natalizumab is neither licensed for the use in adolescents nor during pregnancy. There are no reports of accidental natalizumab exposure during pregnancy continued as long as to the third trimester of pregnancy. AIMS: We report the outcome of pregnancy in a 17-year-old adolescent patient with multiple sclerosis (MS) treated with natalizumab from the age of 16, who was diagnosed to be pregnant in the 31st gestational week (gw) of pregnancy. To our knowledge, this report describes the first patient receiving natalizumab to the third trimester of pregnancy. CASE REPORT: Because of high relapse activity, natalizumab treatment was administered in an adolescent patient with MS. Pregnancy was diagnosed in the 31st gw after 17 natalizumab infusions, seven of them accidentally during pregnancy. RESULTS: Pre- and postnatal development of the child was normal. CONCLUSIONS: The case reported indicates that accidentally continued natalizumab treatment until few weeks before delivery may have no negative impact on the developing foetus.

Successful treatment of anti-N-methyl-D-aspartate receptor encephalitis presenting with catatonia.

The case of a 12-year-old girl with the typical clinical symptoms of the recently described anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is reported. Within 6 weeks the full clinical spectrum of this condition presented with seizures, agitation, stupor, autonomic instability, dysphagia and hypoventilation leading to a diagnosis of pernicious catatonia. MRI and CSF glucose, protein and lactate were repeatedly normal. EEG revealed rhythmical slowing. No teratoma was detected. Recognition of the unique pattern of the clinical symptoms led to early consideration of this disease which was confirmed by detection of anti-NMDAR antibodies. After high dose prednisolone without clinical improvement, plasmapheresis was followed by a rapid reduction in antibodies and recovery within a few weeks. To our knowledge this is the youngest patient with anti-NMDAR encephalitis to have been described to date. We speculate that NMDAR antibodies may be directly involved in the pathogenesis of this disease.

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.

Novel truncating and missense mutations of the KCC3 gene associated with Andermann syndrome.

BACKGROUND: Andermann syndrome (OMIM 218000) is an autosomal recessive motor-sensory neuropathy associated with developmental and neurodegenerative defects. The cerebral MRI reveals a variable degree of agenesis of the corpus callosum. Recently, truncating mutations of the KCC3 gene (also known as SLC12A6) have been associated with Andermann syndrome. METHODS: The authors assessed clinically and genetically three isolated cases from Germany and Turkey with symptoms consistent with Andermann syndrome. RESULTS: The authors detected four novel mutations within the KCC3 gene in their patients: two different truncating mutations in the first patient, a homozygous truncating mutation in the second, and a homozygous missense mutation in the third patient. In contrast to the classic phenotype of the Andermann syndrome linked to truncating KCC3 mutations the phenotype and the course of the disease linked to the missense mutation appeared to be different (i.e., showing additional features like diffuse and widespread white matter abnormalities). CONCLUSIONS: Not only truncating but also missense mutations of the KCC3 gene are associated with Andermann syndrome. Different types of KCC3 mutations may determine different clinical phenotypes.

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.

Molecular and functional characterisation of mild MCAD deficiency.

We report a novel mild variant of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) diagnosed in four infants who, in neonatal screening, showed abnormal acylcarnitine profiles indicative of MCADD. Three patients showed completely normal urinary organic acids and phenylpropionic acid loading tests were normal in all four patients. Enzyme studies showed residual MCAD activities between "classical" MCADD and heterozygotes. ACADM gene analysis revealed compound heterozygosity for the common mutation K329E and a novel mutation, Y67H, in two cases, and homozygosity for mutation G267R and the novel mutation S245L, respectively, in two children of consanguineous parents. As in other metabolic disorders, the distinction between "normal" and "disease" in MCAD deficiency is blurring into a spectrum of enzyme deficiency states caused by different mutations in the ACADM gene potentially influenced by factors affecting intracellular protein processing.

Characterization of four arylsulfatase A missense mutations G86D, Y201C, D255H, and E312D causing metachromatic leukodystrophy.

Metachromatic leukodystrophy is a lysosomal storage disease caused by the deficiency of arylsulfatase A. Here we describe a hitherto unknown arylsulfatase A allele carrying a E312D missense mutation and characterize the effects of this and three previously described missense mutations, G86D, Y201C, and D255H, on arylsulfatase A. In transfection experiments no enzyme activity can be expressed from arylsulfatase A cDNAs coding for the D255H substituted enzyme, whereas Y201C and E312D mutations were associated with low amounts of residual enzyme activity. All amino acid substitutions lead to a decreased stability of the mutant enzyme, and metabolic labeling experiments indicated that except for the E312D substitution the mutations cause arrest of the mutant arylsulfatase A polypeptides in a prelysosomal compartment.

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.

The dynamics of brain concentrations of phenylalanine and its clinical significance in patients with phenylketonuria determined by in vivo 1H magnetic resonance spectroscopy.

Cerebral concentrations of phenylalanine (PHE) were measured by means of quantitative in vivo 1H MR spectroscopy in 8 adult patients treated early for phenylketonuria type I. A 1.5-Tesla routine magnetic resonance scanner, localization sequence with short echo time (20 ms), and a fully automated data processing scheme were used. Baseline plasma PHE concentrations were 1.04 (0.70-1.39) mmol/L PHE with concurrent brain PHE concentrations of 0.27 (0.13-0.41) mmol/kg of wet weight resulting in a plasma/brain ratio of 4.12. Plasma and brain concentrations correlated significantly (Kendall tau b = 0.91, p < 0.01). During an oral load with a single dose of 100 mg L-PHE per kg of body weight in four patients, plasma levels steeply increased. Concurrent brain PHE increase was less steep, was significantly delayed, and still continued up to 20 h postload. Despite the proven rise in plasma and brain concentrations of PHE, neuropsychologic examinations revealed no impairment of attentional and fine motor abilities from preload up to 20 h postload.

Identification and quantitation of phenylalanine in the brain of patients with phenylketonuria by means of localized in vivo 1H magnetic-resonance spectroscopy.

Localized proton MR spectroscopy was used to identify phenylalanine (PHE) and to quantitate its cerebral concentration in patients with type I phenylketonuria (PKU). Data acquisition was optimized for the detection of low-concentration metabolites, using a short TE (20 ms) double Hahn-echo localization sequence for large volumes within the head coil and for smaller volumes using a surface coil. Previously described methods to quantitate localized MR spectra were extended to cover the case of low-concentration metabolites, unevenly distributed in three brain compartments and measured in difference spectra only. PHE content was determined in difference spectra of four PKU patients with respect to normals and in one patient before and after an oral load of L-PHE. PHE concentrations of 0.3 to 0.6 mmol/kg brain tissue were obtained, resulting in a concentration gradient for PHE between blood and brain tissue of 2.4 to 3.0. No significant changes were found for the abundant metabolites in gray or white matter. Previously reported MRI changes were confirmed to be due to increased cerebro-spinal-fluid-like spaces.

[Clinical results with sodium valproate in childhood and in adolescence]. / Klinische Erfahrungen mit Natriumvalproat im Kindesalter und in der Adoleszenz.

This is a review of own experiences and from the literature concerning efficacy and side effects of valproate in the treatment of generalized and partial epilepsies of childhood and adolescence.

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.