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Two sisters with a complex clinical pattern, including microcephaly, microgenia, defects of skin pigmentation, anal stenosis/atresia, and combined immunodeficiency together with spontaneous chromosomal instability and cellular hypersensitivity to X-rays and bleomycin are described. Complementation studies on heterokaryons proved that the underlying genetic defect is non-allelic with that of patients with ataxia telangiectasia (complementation groups AB-E) and the Nijmegen breakage syndrome, but identical with the case described by Conley et al. (1986).

Das Levy-Hollister-Syndrom ist gekennzeichnet durch extrem variabel ausgepragte Dysplasien im Bereich verschiedener Organsysteme. Ein autosomal-dominanter Erbgang ist bekannt, die meisten Falle treten jedoch sporadisch auf. Auf dem Gebiet der Hals-, Nasen-, Ohrenheilkunde fallen neben einer Xerostomie, bedingt durch Aplasie der grosen Kopfspeicheldrusen und angeborener sensorineuraler, konduktiver oder kombinierter Schwerhorigkeit v. a. Ohrmuschelfehlbildungen auf, die zumeist als Tassenohrmalformation in Erscheinung treten. Berichtet wird uber einen 2 Jahre alten Jungen mit einer ausgepragten Xerostomie. Die Ursache hierfur ist eine beidseitige Aplasie der Glandula parotis und der Glandula submandibularis. Daruber hinaus zeigen sich geringgradige Dysmorphien beider Ohrmuscheln sowie beidseitige Innenohrfehlbildungen als Ursache einer sensorineuralen Schwerhorigkeit. Da die Abgrenzung zu anderen Erkrankungen und Syndromen aufgrund der extrem variablen Expressivitat schwierig ist, fuhrt oft nur eine facherubergreifende Zusammenarbeit zur Diagnose. Aufgrund des dominanten Erbganges ist Betroffenen eine humangenetische Beratung zu empfehlen. Ohrmuscheldysplasien und konduktive Horminderungen sind ggf. einer operativen Therapie zuganglich.

Objective We reevaluated 49 girls with either Rett syndrome (RTT) or features of RTT who had negative test results for mutations in the MECP2 gene and compared them with 49 girls who had positive test results. The girls with MECP2-positive results included 2 girls with forme fruste and 2 with congenital RTT. Study design Based on the original diagnostic criteria for RTT, we developed a 10-item checklist with a score ranging from 0 to 12. Results If only girls with a score of 8 or more had been tested, 46% of the girls without mutations would have been excluded from testing without missing a single girl with MECP2-positive results. Conclusions This checklist provides a simple aid for deciding whether or not a genetic test for RTT should be performed with only a minimal risk of missing girls with MECP2-positive results. (J Pediatr 2003;142:332-5)

Objectives The present study investigates the effect of topical injections of botulinum toxin A into the cephalic salivary glands of children with chronic hypersalivation due to neurodegenerative diseases. Methods Five children with hypersalivation due to severe neurological diseases received, under ultrasound guidance, a total of 50-65 units of botulinum toxin A (Botox) into the parotid and submandibular glands on both sides. All injections were tolerated without local anaesthesia. Before and 1, 2, 4, 8 and 12 weeks after toxin injection, salivary flow rates and the concentrations of total protein, alpha-amylase, acid phosphatase, kallikrein, and immunoglobulin A were measured in the secretions; simultaneously, the patients were clinically examined with regard to severity of symptoms, and their salivary glands were subjected to ultrasound study. Results A distinct improvement of symptoms within the first 2 weeks following toxin administration were reported by the parents. Sialometry revealed considerably reduced flow rates but sialochemistry showed an increase of amylase activity. Ultrasound examination did not reveal any changes of the salivary parenchyma, and side-effects were absent. Conclusion Treatment of drooling by topical injection of botulinum toxin A into the salivary glands is a reliable and also side-effect-free therapeutic option for children with neurological disorders. All children involved in our study experienced a distinct improvement of their quality of life.

Mutations in the MECP2 (Methyl-CpG-binding protein) gene recently have been reported to cause Rett syndrome (RTT), an X-linked dominant neurodevelopmental disease. We investigated 125 sporadic cases of Rett syndrome by direct sequencing. Thirty different mutations were found in 97 patients with Rett syndrome. Seventeen mutations have not been described previously. We provide evidence for the existence of several hot spot regions and of a deletion-prone region located at the 3′ most region of the gene. This latter region most probably forms secondary structures in vitro. Similar structures in vivo could explain the high frequency of deletions in this region. Nine of 10 recurrent mutations were located in either the methyl CpG binding domain (MBD) or in the transcriptional repression domain (TRD), and all missense mutations were located in one of these functionally important domains. There was a high frequency of more than 60% of truncating mutations (nonsense mutations along with frameshift mutations). One patient with a mild form of the disease and a normal head growth carries a novel c.27-6C>A mutation that causes a cryptic splice site in intron I resulting in a frameshift transcript. The detection rate in our collective was 77.6%. Our findings show that the majority of German Rett patients carry mutations in the MECP2 gene confirming the suggested locus homogeneity for the disease. Hum Mutat 17:183–190, 2001. © 2001 Wiley-Liss, Inc.

Aminophylline is a respiratory stimulant commonly used for the treatment of central apnea. Experiences from clinical practice, however, revealed that aminophylline is not reliably effective in preterm infants, whereas it is normally effective in infants and mature patients. In an established animal model for postnatal development of respiratory control mechanisms, we therefore examined the hypothesis that the clinical observations reflect a developmental change in the sensitivity of the central respiratory network to methylxanthines. The medullary respiratory network was isolated at different postnatal ages ( postnatal days 1–13; P1–P13) in a transverse mouse brain stem slice preparation. This preparation contains the pre-Bötzinger complex (PBC), a region that is critical for generation of respiratory rhythm. Spontaneous rhythmic respiratory activity was recorded from the hypoglossal (XII) rootlets and from neurons in the PBC by using the whole cell patch clamp technique. Bath-applied aminophylline [20 μM] increased the frequency (+41%) in neonatal animals (P1–P6) without affecting the amplitude of respiratory burst activity in XII rootlets. The same concentration of aminophylline did not have any significant effect on the frequency of respiratory XII bursts but increased the amplitude (+31%) in juvenile animals (P7–P13). In the same age group, aminophylline also augmented the amplitude and the duration of respiratory synaptic drive currents in respiratory PBC neurons. The data demonstrate that augmentation of the respiratory output is due to direct enhancement of central respiratory network activity and increase of synaptic drive of hypoglossal motoneurons in juvenile, but not neonatal, animals. This indicates a developmental change in the efficacy of aminophylline to reinforce central respiratory network activity. Therefore, we believe that the variable success in treating respiratory disturbances in premature infants reflects maturational changes in the expression of receptors and/or intracellular signal pathways in the central respiratory network.

The lines of Blaschko represent one of the cutaneous patterns of mosaicism followed by various skin disorders. Developmental abnormalities affecting other tissues derived from the embryonic ectoderm and mesoderm are occasionally associated. We describe a 30-year-old man with depigmented, bilateral hypertrichosis and dilated follicular orifices following Blaschko’s lines associated with cerebral and ocular malformations. The findings suggest a previously unreported neurocutaneous, autosomal lethal gene syndrome from the group of epidermal naevus syndromes.

A whole X chromosome study of families in which Rett syndrome had been diagnosed in more than one member indicated that the region between Xq27 and Xqter was the most likely region to harbour a gene which may be involved in the aetiology of the disease. Further, more detailed studies of Xq28 detected weak linkage and a higher than expected sharing of maternally inherited alleles. It is suggested that there may be more than one gene involved in the aetiology of this syndrome, particularly as the very rare families in which more than one girl is affected often show variable clinical symptoms.

Medullary respiratory neurons are influenced by a variety of neuromodulators, but there is a lack of information about the specific intracellular signal pathways involved. In this report we describe the modulatory effects of the cyclic adenosine-triphosphate (cAMP)-dependent protein kinase and of protein kinase C pathways on voltage- and ligand-controlled ionic conductances and demonstrate their functional significance in regulating the excitability of medullary respiratory neurons of the vivo cat. Evidence is presented that PKA and PKC pathways are persistently activated. PKA regulates current flow through persistently activated and GABAB receptor-controlled potassium channels as well as GABAA receptor-controlled chloride channels. PKC also depresses persistent potassium currents but it potentiates excitatory and inhibitory synaptic currents. The clinical significance of these intracellular signal pathways is demonstrated in a case of a child suffering from apneustic breathing, who was successfully treated with a 5HT-1A receptor agonist.

Wahrend enorme Fortschritte in der Aufklarung von Atiologie und Pathogenese mitochondrialer Zytopathien (MC) erzielt wurden, sind die Moglichkeiten, die progredienten Multisystemerkrankungen therapeutisch zu beeinflussen, begrenzt. Eine kausalorientierte Therapie mus berucksichtigen, das die biochemischen Defekte heterogen sind (Pyruvatdehydrogenase, Pyruvatarboxylase, Atmungskettenkomplexe), gewebespezifische und/oder zeitabhangige Expression zeigen und kombiniert auftreten konnen. Therapieprinzipien sind 1. Reduktion der endogenen Produktion von toxischen Metaboliten (durch diatetische Masnahmen), 2. Erhohung der enzymatischen Restaktivitat (durch Kofaktoren bzw. Enzymaktivatoren), 3. Uberbruckung von Enzymdefekten (durch Elektronenakzeptoren bzw. -donatoren) und 4. antioxidative und membranoprotektive Masnahmen. Diese Ubersicht stellt die Wirkmechanismen verschiedener Substanzen vor und diskutiert ihre therapeutischen Wirksamkeiten anhand von Literaturdaten und eigenen Erfahrungen bei 26 Patienten. Patienten mit myopathischen Verlaufsformen von Komplex I-Defekten, Kearns-Sayre- Syndrom und mit auf sekundarem Karnitinmangel beruhenden Kardiomyopathien profitieren am starksten von Supplementationsmasnahmen. Bei Patienten mit enzephalopathischen Manifestationsformen (z. B. Leigh-Syndrom) werden zwar haufig Normalisierungstendenzen des gestorten Laktat-Pyruvat-Stoffwechsels beobachtet, doch wird die klinische Symptomatik allenfalls vorubergehend gebessert oder die Progredienz gemildert. Im Einzelfall sind die therapeutischen Effekte nicht vorhersagbar, sodas angesichts der geringen Nebenwirkungsraten Therapieversuche gerechtfertigt sind. Gentherapeutische Strategien lassen effektivere Behandlungsmasnahmen erwarten.

We report on monozygotic twins with different clinical phenotypes of X-linked adrenoleukodystrophy. At the age of 10 years both boys were neurologically asymptomatic. The first cranial magnetic resonance examination showed normal findings in the first twin and parietooccipital demyelination in the second. The latter developed behavioral problems 9 months later, followed by visual impairment and gait ataxia. His cranial magnetic resonance image at the age of 11 years showed progressive demyelination. In contrast, neurological status and magnetic resonance images remained normal in the first twin. The same point mutation in exon 8 of the adrenoleukodystrophy gene (C2203T) was detected in both boys. All genotype examinations were consistent with the diagnosis of monozygotic twins, suggesting that some nongenetic factors may be important for different adrenoleukodystrophy phenotypes.

Isolated periodic dystonia in the arms and legs was the first manifestation in three siblings with Leigh's syndrome. The symptomatology is identical and progressive in both brothers, whereas the progressive, dystonic movements of the 14-year old sister have disappeared completely for the last three years. CSF lactate was increased in both brothers. All siblings showed MRI abnormalities of the globus pallidus with different pronounciation. Since the therapeutic use of alpha-liponic-acid the recurrent encephalopathic episodes disappeared in both boys without affecting the dystonic movements. The girl is asymptomatic without any therapy. Leigh's syndrome is a differential diagnosis in children with a first manifestation of periodic dystonic movements.

Summary: Since our last report on valproate (VPA)-related hepatotoxicity in 1988, 8 other children have died of VPA-associated liver failure in Germany and Switzerland. We compared the clinical course of these children with that of 6 children with a reversible outcome of severe hepatotoxicity related to VPA. Thirty-five percent of patients with fatal liver failure were normally developed, 23.5% were receiving VPA monotherapy, and 35·3% were aged s2 years. The initial clinical symptoms of VPA-related hepatotoxicity were nausea, vomiting, apathy or coma, and increasing seizures in more than 50% of patients, in combination with febrile infections at onset of symptoms. As compared with the series of German patients reported in 1988, one third of the fatalities occurred after the first 6 months of therapy as compared with 6% in the 1988 series. Clinical symptoms and laboratory findings were the same in patients with reversible and with fatal outcome. Early or immediate withdrawal of VPA after the first signs of VPA-associated hepatotoxicity may be responsible for the increased number of children who recovered after VPA-related severe liver failure. The pathogenesis of liver failure during VPA treatment remains unknown; metabolic defects and cofactors such as polypharmacy or infections have become increasingly likely to contribute by depleting intracellular CoA. Worldwide, 132 patients have died of VPA-associated liver failure and/or pancreatitis. Because a group at risk for fatalities with VPA cannot be defined precisely, patients treated with VPA and their families must be made well aware of the clinical symptoms of hepatotoxicity such as apathy, vomiting, or increased seizure frequency, especially in the presence of febrile infections. Laboratory tests and clinical controls during the first 6 months of therapy should not be neglected. ReSUMe On presente le cas de 8 enfants morts pendant le traitement a l'acide valproique (VPA) en Allemagne et en Suisse depuis 1988. Chez 2 enfants, le developpement psychomoteur a ete normal. Deux enfants etaient sous monotraitement au VPA, 2 enfants etaient âges de moins de trois ans. Deux enfants montraient les premiers symptomes apres les 6 premier mois du traitement, ce qui a ete le cas seulement chez 6% des patients presentes en 1988 (Scheffner et al., 1988). Les premiers symptdmes de l'hepatotoxicite menancante etaient nausee, vomissement et apathie, frequemment en combinaison avec une infection febrile, chez les 8 enfants morts comme chez 6 enfants dont l'hepatotoxicite etait reversible, qui sont egalement presentes en detail dans cette communication. Les paramteres de laboratoire correspondaient a la defaillance hepatique chez tous les enfants. L'interval entre les premiers symptomes jusqu'a la discontinuation du VPA s'est raccourci a quelques jours depuis 1988, ce qui pourrait expliquer l'augmentation relative des cas reversibles. Le metabolite anorma1 4-ene-VPA ne joue aucun role ni pour la detection ni pour le traitement de la defaillance hepatique. Les mecanismes pathogeniques decesifs restent obscurs, une depletion intracellulaire du CoA soit en combinaison avec des maladies metaboliques ou soit avec une polytherapie ou une infection febrile paraissent au centre du pathomechanism. Au total, 132 cas d'hepatotoxicite fatale en relation avec le traitement au VPA ont ete decrits dans le monde entier. Comme il est impossible de delimiter avec precision un groupe au risque majeur pendant le traitement au VPA, les symptomes cliniques de l'hepatotoxicite menancante doivent etre bien connus B chaque patient traite au VPA et a sa famille. Des controles cliniques et des examens de laboratoire au moins une fois par mois pendant le six premiers mois du traitement ne doivent pas etre negliges. L'augmentation du pourcentage de l'hepatotoxicite reversible indique la possibilite de diminuer les complications fatals en se toujours rendant compte du probleme de l'hepatotoxicite pendant le traitement au VPA. RESUMEN Se presenta 8 pacientes fallecidos durante el tratamiento con acido valproico (VPA) en Alemania y en Suiza desde 1988. En 2 de los ninos el desarollo psicomotor era normal, 2 estaban bajo monoterapia, 2 eran menores de 3 anos. Dos de los ninos mostraban sus primeros sintomas de la hepatotoxicidad amenazadora despues de los 6 primeros meses del tratamiento, un porcentaje mucho mas elevado que los 6% encontrados en 1988 (Scheffner et al., 1988). Los primeros sintomas eran nausea, vomito, y apatia, frequentemente juntos con una infecion febril, sin diferencia entre los ninos fallecidos y 6 otros pacientes con una hepatotoxicidad reversible, tambien descritos en esta communicacion. Los parametros de laboratorio patologicos correspondian a la insuficiencia del higado. El intervalo entre los primeros sintomas de la hepatotoxicidad y la dicontinuacion del VPA era solo algunos dias desde 1988, lo que podria explicar el aumento relativo de los casos reversibles. El metabolito anomal 4-en-VPA no tiene ningun valor ni por la diagnosis ni por el tratamiento de la hepatotoxicidad asociada con el VPA. Los mecanismos patogenicos no estan claros, la reduccion del CoA a1 nivel intracelular sea por causa de una politerapia o de una infecion febril o sea en el contexto con un defecto metabolico parece en el centro del patomechanismo. En total, estan descritos en la literatura 132 pacientes fallecidos por hepatotoxicidad durante el tratamiento con VPA. Como no se ha logrado definir con precision el grupo con riesgo mayor durante el tratamiento con VPA, los sintomas de la hepatotoxicidad amenazadora tienen que ser bien conecidos por los pacientes bajo terapia con el VPA y tambien por sus familias. Controles clinicos y de laboratorio al menos uns vez por mes durante los 6 primeros meses del tratamiento parecen perentorios. El aumento relativo de los casos reversibles indica la possibilidad de reducir los fallecimentos relacionados al VPA si la vigilancia por este problema quede constante. ZUSAMMENFASSUNG Die klinischen Verlaufe von 8 Kindern, die seit 1988 in Deutschland und der Schweiz an einem Valproat (VPA)-assoziiertem Leberversagen verstorben sind, werden 6 Patienten mit einem reversiblen Verlauf gegenubergestellt. Zwei der 8 verstorbenen Kinder waren normal entwickelt, 2 erhielten eine VPA-Monotherapie, und ebenfalls 2 waren unter 3 Jahre alt: Die ersten Zeichen eines drohenden Leberversagens waren Ubelkeit, Erbrechen, Apathie und Koma, oder eine Zunahme der Anfalls-frequenz, bei mehr als der Halfte der Patienten bei einem gleichzeitig bestehenden fieberhaften Infekt. Vergleicht man die seit 1988 aufgetretenen Todesfalle unter VPA mit den zuvor berichteten (Scheffner et al., 1988), fallt eine Zunahme der Komplikationen jenseits des 6.Behandlungsmonats auf (ein Drittel der neuen Patienten im Vergleich zu 6% der fruheren Serie). Im Hinblick auf die klinischen Symptome und die Laborveranderungen unterschieden sich die irreversiblen nicht von den reversiblen Krankheitsverlaufen. Ein sofortiges Absetzen des VPA bei Auftreten von verdachtigen Symptomen kannte seit 1988 zu einem hoheren Anteil von reversiblem Leberversagen gefuhrt haben. Der abnormale VPA-Metabolit 4-en-VPA erwies sich als nicht spezifisch fur die VPA-assozierte Hepatotoxizitat, die Bestimmung der VPA-Metabolite hat sich weder fur die Diagnostik noch fur das Verstandnis des Leberversagens unter VPA fur nutzlich erwiesen. Der Pathomechanismus der VPA-assozierten Hepatotoxozitat bleibt unklar, ein Absinken des intrazellularen CoAs entweder durch Co-Faktoren wie Polytherapie oder fieberhafte Infekte oder durch metabolische Defekte scheint jedoch eine zentrale Rolle zu spielen. Weltweit sind bisher insgesamt 132 Patienten an einem Leberversagen unter einer VPATherapie verstorben. Da eine Risikogruppe fur diese Komplikation nicht scharf abgegrenzt werden kann, mussen alle Patienten und deren Familien die klinischen Symptome der VPA-assozierten Hepatotoxizitat kennen, um so ein rasches Absetzen des VPA bei Auftreten solcher Symptome zu ermoglichen. Klinische Kontrollen sowie Laborkontrollen bleiben wahrend der ersten 6 Behandlungsmonate mindestens einmal monatlich erforderlich. Eine unverandert hohe Aufmerksamkeit fur das Problem der VPA-assozierten Leberkomplikationen kann moglichweise dazu beitragen, die Anzahl der Todesfalle in Verbindung mit einer VPA-Therapie zu vermindern.

Serial trans-fontanellar sonographic examination in a patient with glutaric aciduria type I (GA I) demonstrated that the typical frontotemporal cerebral atrophy developed postnatally within three months paralleling the onset of dystonic symptoms. Pathogenesis of the accompanying macrocephaly remains unclear and can form a diagnostic pitfall. Diet low in lysine and tryptophan led to a dramatic fall in urinary glutaric acid (GA) excretion but as in other patients with GA I did not substantially influence clinical symptoms and course. We determined unchanged levels of GA in plasma and cerebrospinal fluid resulting from variable renal tubular secretion and reabsorption of GA. Monitoring urinary excretion of GA appears inappropriate to control dietary treatment in GA I. Substitutive correction of secondary carnitine depletion seems to protect from deleterious metabolic crises. Treatment with valproic acid resulted in a rise of GABA-concentration in cerebrospinal fluid but did not ameliorate clinical symptoms. This finding is in contrast with the hypothesis that inhibition of cerebral GABA-synthesis by GA is responsible for the development of dystonia in GA 1. Although we observed impressing fluctuation of dystonic symptoms, levodopa did not show therapeutic effects. The extreme variability in the severity of neurologic disease in metabolically identical individuals leads to a "two-hit"-hypothesis.

A novel disease of the metabolism of creatine and guanidinoacetate (GUAC) in a 22-month-old child has been reported recently from our department (Stockler et al 1994). Following an uneventful development in the first 3 months, the boy developed muscular hypotonia, weakness and a distinct extrapyramidal disorder with hemiballistic-dystonic movements. In magnetic resonance spectroscopy of the brain the absence of a creatine signal and a massively increased GUAC signal eventually led to the diagnosis of guanidinoacetate methyltransferase deficiency. The boy was successfully treated with oral creatine monohydrate. Standard laboratory results were not very specific, so that the need has arisen for a readily available method to screen for the elevated levels of guanidinoacetate seen in this disease. Presently HPLC is the established method (Marescau et al 1985). We have developed a simple mass fragmentographic method for the determination of GUAC in urine and plasma. The reaction of the guanidino group of GUAC with hexafluoroacetylacetone (Malcolm and Marten 1976) results in the formation of a bis(trifluoromethyl)pyrimidine derivative and the carboxyl group is then converted to the trimethylsilyl ester. 2-Phenylbutyrate is used as the internal standard since this has a suitable retention time and is widely available.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

The Levy-Hollister syndrome is characterized by a highly variable expression of dysplasia in different organ systems. Autosomal-dominant inheritance is recognised, but most cases are sporadic. In the field of otorhinolaryngology, xerostomia can be found due to aplasia of the major salivary glands, as well as congenital sensorineural, conductive or combined hearing loss and dysplasia of the auricles, mostly appearing as cup-shaped ears. Here we report on a 2-year-old boy with severe xerostomia. The disease was found to be caused by bilateral aplasia of the parotid and submandibular glands. There were also slight dysplasias of both auricles and a bilateral inner ear malformation as the origin of sensorineural hearing loss. Due to its highly variable expression, Levy-Hollister syndrome is often difficult to distinguish from other diseases and syndromes, so that the cooperation of different departments is necessary for an accurate diagnosis. Because of its dominant inheritance, a genetic consultation should be recommended to the patient. Auricular dysplasia and conductive hearing loss can possibly be treated surgically.

We looked for pathogenic MECP2 mutations in 11 families with an index case affected by Rett syndrome (RTT), together with a sib or other relative affected by RTT or a less specific developmental disturbance. In one family, we detected the same MECP2 mutation in two affected sisters and their unaffected mother, who was subsequently shown to have skewed X chromosome inactivation. In five families, one affected subject was found to have a MECP2 mutation, but the other relative in whom a diagnosis of RTT was suspected, did not carry this or any other detectable MECP2 mutation. In the remaining five families, no MECP2 mutation was detected in any subject. These results suggest that familial RTT is rare and may be overdiagnosed. Furthermore, and despite the small probability of recurrence, many relatives of females with the usual, sporadic RTT may seek genetic testing to clarify their situation. Rett syndrome (RTT) is a neurodevelopmental disorder that mostly affects females and is usually sporadic. It has therefore often been considered to be an X linked dominant condition with male lethality, although it is now recognised that de novo mutations in RTT occur predominantly on the paternally derived X chromosome and this could lead to similar observations.1–4 It is an important cause of profound mental handicap in girls, accounting for up to 10% of all cases. The diagnosis is currently based upon the clinical criteria proposed by the Rett Syndrome Working Group in 1988.5 The major criteria are: (1) normal pre- and perinatal period and apparently normal development for the first 6 months of life, (2) a period of regression occurring at 6 months to 3 years of age, (3) deceleration in head growth, (4) acquisition of stereotypical hand movements, and (5) eventual profound developmental delay. In addition, there are a …

Definition. Der Begriff Poliodystrophia cerebri progressiva (M. Alpers) umfasst eine Gruppe von Krankheiten der grauen Substanz, die basierend auf den Erstbeschreibungen von Alpers aus den Jahren 1931 und 1960 diese von den Leukodystrophien abgrenzen sollte. Es handelt sich also um akute Degenerationen der grauen Substanz, deren Atiologie sehr heterogen ist. Die primare Definition des Krankheitsbildes orientierte sich an der Degeneration der Neurone der grauen Substanz.

Rett syndrome (RTT) is one of the most frequent neurodevelopmental disorders affecting almost exclusively females. It is characterised by normal development until 6-18 months followed by a more or less rapid decline of acquired functions mainly of the higher brain functions, such as communicative speech and purposeful hand use. Mutations in the MECP2 gene have been described in RTT patients world wide.1–4 Along with classical RTT females, several RTT variants, like the preserved speech variant, congenital RTT, and a patient with an Angelman syndrome-like phenotype, have been reported to carry mutations in the MECP2 gene.4–8 RTT has been considered an X linked dominant disease lethal in males. This assumption was supported by the small number of affected RTT males and by a lethal knock out mouse model.9 Recently, however, two independent groups have shown that nullizygous male and heterozygous female knock out mice are viable.10,11 This finding strongly questions the hypothesis of male lethality of the RTT trait. Our recently published findings about a very high percentage of paternal origin of the mutation in the MECP2 gene in sporadic cases of RTT provide a simple explanation for the scarcity of affected males.12 Meanwhile, there has been a series of reports describing mutations in the MECP2 gene of males. The affected males can be divided into two groups according to the type of their mutation. The first group carries mutations in the MECP2 gene either already described in RTT females or mutations of unquestionable pathological value (frameshift mutations or nonsense mutations).5–16 All these patients are characterised by early onset of the disease and a severe encephalopathy. A subgroup are males with a 47,XXY karyotype who present with the typical RTT symptoms. The second group includes patients carrying mutations inherited from their …

Rett syndrome (RTT) is a neurodevelopmental disorder that almost exclusively affects girls. Recently mutations in MECP2, that encodes the methyl CpG binding protein 2 (MeCP2), have been found to cause RTT. MeCP2 has a role in gene silencing. It binds to methylated cytosine in the DNA and recruits histone deacetylases. We studied the methylation pattern of the promoters of two X chromosomal genes, G6 PD and SYBL1, in patients with RTT and in a control group. Both genes undergo X inactivation which correlates with promoter methylation. A 1 : 1 ratio of methylated versus non-methylated alleles was expected. In the control group a median ratio of 47 : 53 of methylated to non-methylated alleles was found at the G6 PD promoter locus. In 22 patients with RTT the median ratio was significantly different, 33 : 67 (p < 0.0001). Analysis of the SYBL1 promoter revealed an almost identical median ratio of methylated versus non-methylated alleles (RTT 47 : 53; control 49 : 51), however, the range was wider in the RTT group (RTT 23 : 77 to 56 : 44; control 43 : 57 to 55 : 45). There was no apparent correlation between G6 PD promoter methylation status and mutations in the MeCP2 gene or the severity of the clinical phenotype in our patient group. The finding of reduced methylation at the G6 PD promoter is an interesting finding and suggests that there could be widespread dysregulation of X chromosomal genes in Rett syndrome.

To determine whether primary or secondary growth hormone (GH) deficiency has a causative role in linear growth retardation, a key feature in Rett syndrome (RTT).In 38 patients with Rett syndrome a variable set of investigations was performed including assays of growth and thyroid hormones, gonadotropins, gonadal and adrenal steroids and determination of bone age. Not all measurements were attainable from all patients. In three patients the 24-h growth hormone secretion profile was evaluated using the pulsar method.The bone age determined in 24 patients was found to be normal in 8, retarded in 9 and accelerated in 7 patients. Insulin-like growth factor (IGF)-1 was low in 8 out of 23 patients. IGF-binding protein (IGFBP)-3 and insulin and arginine-stimulated growth hormone secretion were both normal, indicating normal GH secretion in the majority of patients. The 24-h GH secretion profile in the first patient showed a normal day/night rhythm and a normal increase in nocturnal GH secretion. The second patient's overall GH secretion was normal but there was no day/night rhythm. The third patient showed borderline low GH secretion. Normal age-appropriate plasma values were found for the thyroid hormones (T4, TSH), TSH-night rhythm, oestradiol, prolactin and cortisol (08.00, 18.00).Our study provides no evidence that growth retardation in RTT is caused by growth hormone deficiency. A disturbed hypothalamic control cannot be excluded but it is unlikely that this is the major cause of growth retardation in RTT.

We describe histopathological changes in a 2-year-old boy who died from myelinopathia centralis diffusa. Despite extensive white matter destruction, surprisingly high numbers of oligodendrocytes expressing proteolipid protein mRNA were detected. In an active demyelinating lesion in the brainstem, oligodendrocytes showed typical signs of apoptosis. We suggest that death of mature oligodendrocytes is the critical event in the disease.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that apparently is lethal in male embryos. RTT almost exclusively affects female offspring and, in 99.5% of all cases, is sporadic and due to de novo mutations in the MECP2 gene. Familial cases of RTT are rare and are due to X-chromosomal inheritance from a carrier mother. We analyzed the parental origin of MECP2 mutations in sporadic cases of RTT, by analysis of linkage between the mutation in the MECP2 gene and intronic polymorphisms in 27 families with 15 different mutations, and we found a high predominance of mutations of paternal origin in 26 of 27 cases (P

Fehlbildungen (Misbildungen, Anomalien) sind pranatal durch Anlagefehler entstandene Formabweichungen von Organen oder Korperteilen bei sonst normalen Geweben. Als Dysplasien werden morphologische Anomalien bezeichnet, die durch fehlerhafte Organisation und/oder Funktion von Gewebe oder Gewebekomponenten zustande kommen Von primaren Fehlbildungen sind sekundare Formabweichungen zu unterscheiden: Disruptionen (Defekte eines ursprunglich sich normal entwickelnden Organs, Organ- oder Korperteils), Deformitaten (durch mechanische Einflusse hervorgerufene Form- oder Lageanomalien eines Organs, Organ- oder Korperteils), Degeneration oder Deterioration. Kombinierte Anomalien (multiple Defekte) treten auf, wenn ein Entwicklungsfeld betroffen ist (polytope Felddefekte) oder pathogenetische Sequenzen entstehen (z.B. Potter-Sequenz bei Oligohydramnion). Fehlbildungssyndrome sind Muster angeborener Anomalien, die in ihrer Pathogenese sicher oder vermutlich zusammenhangen und nicht auf einen einzelnen morphologischen Defekt zuruckgefuhrt werden konnen, auch nicht Teil eines embryonalen Entwicklungsfeldes sind. Sie konnen Ausdruck pleiotroper Wirkung von Genmutationen sein und durch Chromosomenanomalien oder Teratogene hervorgerufen werden. Man unterscheidet sie von Assoziationen, die durch eine Storung in der fruhen Blastogenese entstehen, sowie von einem zufalligen Zusammentreffen verschiedener Anomalien, die sich in ihrer Pathogenese (noch) nicht verbinden lassen (Syntropie).

UNLABELLED Only recently have mutations in MECP2 been found to be a cause of Rett Syndrome (RTT), a neuro-developmental disorder characterized by mental retardation, loss of expressive speech, deceleration of head growth and loss of acquired skills that almost exclusively affects females. We analysed the MECP2 gene in 31 patients diagnosed with RTT. Sequencing of the coding region and the splice sites revealed mutations in 24 females (77.40%). However, no abnormalities were detected in any of the parents that were available for investigation. Eleven mutations have not been described previously. Confirming two earlier studies, we found that most mutations are truncating and only a few of them are missense mutations. Several females carrying the same mutation display different phenotypes indicating that factors other than the type or position of mutations influence the severity of RTT. Four females with RTT variants were included in the study. Three of these presented with preserved speech while the fourth patient with congenital RTT lacked the initial period of normal development. Detection of mutations in these cases reveals that they are indeed variants of RTT. They represent the mild and the severe extremes of RTT. CONCLUSIONS mutations in MECP2 seem to be the main cause for RTT and can be expected to be found in approximately 77% of patients that fulfil the criteria for RTT. Therefore analysis of MECP2 should be performed if RTT is suspected. Three mutation hotspots (T158M, R168X and R255X) were confirmed and a further one (R270X) newly identified. We recommend screening for these mutations before analysing the coding region.

BACKGROUND—Sufficient ATP concentrations maintain physiological processes and protect tissue from hypoxic damage. With decreasing oxygen concentration, ATP synthesis relies increasingly on the presence of phosphocreatine. AIM—The effect of exogenously applied creatine on phosphocreatine and ATP concentrations was studied under control and anoxic conditions. METHODS—Pregnant mice were fed orally with creatine monohydrate (2 g/kg body weight/day). Brainstem slices from these mice pups were compared with those from pups of non-creatine supplemented pregnant mice. Measurements were performed under normoxic and anoxic conditions. In addition, brainstem slices from non-creatine treated mice pups were incubated for 3 hours in control artificial cerebrospinal fluid (CSF) (n = 10) or in artificial CSF containing 200 µM creatine (n = 10). ATP and phosphocreatine contents were determined enzymatically in single brainstem slices. RESULTS—ATP concentrations were in the same range in all preparations. However, there was a significant increase of phosphocreatine in the brainstems from pups of creatine fed mice when compared with the brainstems of pups from non-creatine treated mice or in non-incubated brainstems of control animals. After 30 minutes anoxia, ATP as well as phosphocreatine concentrations remained significantly higher in creatine pretreated slices compared with controls. CONCLUSION—The data indicate that exogenous application of creatine is effective in neuroprotection.

The occurrence of mitochondrial mutations with primary pathogenic significance for Leber's hereditary optic neuropathy in patients with a multiple sclerosis-like phenotype and the preferential maternal transmission points to an involvement of the mitochondrial genome in conferring increased susceptibility to MS. To evaluate the link between MS and mtDNA variations we investigated a total of thirteen children with MS as well as twenty controls by sequencing eight mitochondrial encoded genes which are known to be the loci for LHON-associated mutations. Numerous synonymous nucleotide substitutions and common polymorphisms were excluded from comparative analyses. No primary LHON mutations were found. Secondary LHON mutations were identified more frequently in control subjects than in the children with MS. The remaining eight discrete missense mutations were chosen for further characterization. Only two of them were found in more than one patient. Our results suggest that nucleotide substitutions within the ND1, ND2, ND4, ND5, ND6, COI, COIII or cytochrome b genes of mtDNA do not contribute to the etiology of typical MS. However, the association of LHON mutations with visual impairment in MS as well as the relationship between phenotypic diversity in certain subgroups of patients with individual mtDNA genotypes merits further investigations.

The higher maternal transmission of multiple sclerosis in familial cases and the coincidence of a MS-like phenotype with mitochondrial point mutations in patients with Leber's hereditary optic neuropathy has inspired a detailed assessment of the mitochondrial genome as an etiological factor in the pathogenesis of MS. To further elucidate the contribution of maternally transmitted mutations to MS susceptibility, we sequenced five protein- and all RNA-coding genes of the mtDNA from thirteen children with MS and twenty unaffected individuals. After excluding several synonymous mutations and common polymorphisms, a total of ten ambiguous missense or protein synthesis mutations were selected and analysed. By defining minimal criteria for pathogenity--incidence, location and degree of evolutionary conservation--we conclude that sequence variations in COII, ATPase6 and 8, ND3, or ND4L subunits of oxidative phosphorylation as well as in rRNA and tRNA genes are unlikely to increase susceptibility for the development of MS.

Deficiency of dolichyl-P-Glc:Man9GlcNAc2-PP-dolichyl glucosyltransferase is the cause of an additional type of carbohydrate-deficient glycoprotein syndrome (CDGS type V). Clinically this type resembles the classical type Ia of CDGS caused by the deficiency of phosphomannomutase. As a result of the glucosyltransferase deficiency in CDGS type V nonglucosylated lipid-linked oligosaccharides accumulate. The defect is leaky and glucosylated oligosaccharides are found on nascent glycoproteins. The limited availability of glucosylated lipid-linked oligosaccharides explains the incomplete usage of N-glycosylation sites in glycoproteins. This finding is reflected in the presence of transferrin forms in serum that lack one or both of the two N-linked oligosaccharides and the reduction of mannose incorporation to about one-third of control in glycoproteins of fibroblasts.

The effect of creatine (Cr) on the response of the respiratory center to anoxia was analyzed at different postnatal stages in a brainstem slice preparation of mice. Spontaneous rhythmic activity was recorded from hypoglossal rootlets (XII) and from identified neurons within the preBötzinger complex using the whole cell patch clamp technique. The hypoxic response was evaluated in slices from animals (n = 46), which received normal nutrition (controls, n = 16), from litters of animals fed with Cr (2 g/kg/day; nutrition group, n = 8), or after incubating slices for 3 h in Cr (200 microM) (incubation group, n = 22). ATP was measured in slices from controls and Cr-incubated slices which underwent 30-min anoxia. In neonatal animals (P0-5), amplitudes of hypoglossal bursts increased initially during anoxia by 14% in controls and by 41% in Cr-supplemented animals when compared with preanoxic values. Hypoglossal burst duration increased by 3% in controls, but by 18% in the Cr-nutrition group. In brainstem slices, the initial increase of amplitudes changed from 14% (controls) to 59% (Cr incubation) and prolongation of bursts from 3% (controls) to 37% (Cr incubation) compared with preanoxic values. In juvenile controls (P6-13), burst amplitude and duration increased by 12 and 14% during early anoxia when referred to preanoxic values. In slices from Cr-pretreated animals, increases of 48% (amplitude) and 21% (burst duration) occurred. The ATP levels remained constant during a 30-min anoxic period in the Cr-pretreated group compared with a decrease of 44% in slices from controls. Our data suggest that Cr can ameliorate hypoxic energy failure. Further studies will examine the neuroprotective potential in humans.

In an infant with progressive, severe extrapyramidal movement disorder and extremely. low urinary creatinine excretion, in vivo proton magnetic resonance spectroscopy of the brain showed a depletion of creatine and an accumulation of guanidinoacetate, the immediate precursor of creatine. The suggested defect in creatine biosynthesis at the level of guanidinoacetate methyltransferase was confirmed by the demonstration of defective activity of this enzyme in liver tissue and by identification of the underlying genetic defect. Creatine substitution by means of oral creatine monohydrate at high dosage (4-8 g per day) resulted in a striking improvement of the extrapyramidal movement disorder, normalisation of abnormal slow background activity in the EEG, and disappearance of bilateral abnormal signal intensities in the globus pallidus. The low urinary creatine excretion normalized and brain creatine and creatine phosphate, as measured by in vivo magnetic resonance spectroscopy, increased significantly. Guanidinoacetate methyltransferase deficiency is a new, treatable inborn error of metabolism. Screening methods and non-invasive diagnosis of the enzyme defect are needed for the early detection and treatment of patients with this effect.

Aromatic L-amino acid decarboxylase (AADC) deficiency results in an impaired synthesis of catecholamines and serotonin, and has been reported only in two middle eastern families. We report on a European family with an affected child. The child showed the characteristic clinical picture of an extrapyramidal movement disorder, oculogyric crises and vegetative symptoms seen in the three patients described previously. Treatment with a combination of the AADC cofactor pyridoxine, the monoamine oxidase B inhibitor selegiline and bromocriptine was started during the fifth year of life and showed only a moderate clinical improvement in contrast to patients who have been treated since the first year of life.

Apneusis is a disturbance of respiratory rhythm characterized by severely prolonged inspiratory effort. It may occur after damage to the respiratory network within the lower brain stem and pons from an overdose of central nervous system depressants, blockade of glutamate receptors, asphyxia, hypoxia, or ischemia. Experimental studies conducted on laboratory mammals, such as anesthetized cats and rats, suggest that apneusis results mostly from depression of glutamatergic synaptic processes that are necessary for activation of inhibitory mechanisms that terminate inspiration. The impairment of synaptic transmission leads to prolonged inspiratory efforts and apneustic discharges of brainstem respiratory neurons. Apneustic patterns can be consistently converted to normal by administration of serotonin type 1A (5-HT1A) receptor agonists. This observation encouraged a treatment of severe apneusis with buspirone, an agonist for 5-HT1A receptors, in a child after neurosurgery for an astrocytoma in the pons and medulla oblongata. Oral administration of buspirone produced a prompt and highly effective remission of apneusis without side effects. Treatment with 5-HT1A agonists, therefore, might offer a novel and effective pharmacotherapy against apneustic disturbances of breathing.

Two patients with reinfection of Borrelia burgdorferi are presented. An 11-year-old girl developed recurrent acute peripheral facial palsy at an interval of five years. A 64-year-old woman showed paraesthesia in the leg and effusion in the knee. Three years later, an erythema migrans developed at the thigh. In both patients tick bites, corresponding clinical manifestations, and detection of specific antibodies proved the reinfections. The course of the humoral immune responses showed basic differences between the patients. At the interval between the first and second infection, the specific antibodies of the girl decreased beyond the cut-off level. On the other hand, the titer of specific IgG antibodies of the other patient remained at a constant level. Reasons for the failure of immune protection are discussed.

Jaeken's syndrome or the carbohydrate-deficient glycoprotein (CDG) syndrome, is a newly recognized metabolic syndrome with poor weight gain in children, and multisystematic abnormalities, mainly due to defective carbohydrate entities in many glycoproteins, leading to neurologic dysfunction. Using the standardized method of phenotype evaluation with computer assistance according to the Munich Dysmorphologic Database, two sisters with CDGs were examined to decide if this metabolic entity contains dysmorphic features characterising dysmorphic syndromes. Diagnosis was based on clinical symptomatology and transferrin isoforms which showed tetrasialotransferrin deficiency and increased disialotransferrin in serum. Dysmorphic studies can be helpful in recognition of this syndrome, now described for the first time in Poland.

Monocyte/macrophage differentiation was studied in biopsy samples of multiple sclerosis (MS) lesions obtained in the early course of the disease. Macrophages were identified by immunocytochemistry using a panel of antibodies recognizing different macrophage-activation antigens. The number of cells stained with each antibody was related to the demyelinating activity of the lesions as detected by the presence of myelin degradation products. The pan-macrophage marker Ki-M1P revealed the highest numbers of macrophages in early and late active lesions. Lower numbers were encountered in inactive, demyelinated, or remyelinated lesions. The acute stage inflammatory macrophage markers MRP14 and 27E10 were expressed in either only early active (MRP14) or early and late active (27E10) lesions, thus allowing the identification of actively demyelinating lesions. The chronic stage inflammatory macrophage marker 25F9, in contrast, showed increasing expression with decreasing lesional activity. These findings indicate a differentiated pattern of macrophage activation in MS lesions and allow the staging of demyelinating lesions in routinely fixed and paraffin-embedded tissue.