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Peter Huppke

Publications and source records attributed to Peter Huppke.

11 recordsLinked to original sources
PubMed2007

Breathing dysfunctions associated with impaired control of postinspiratory activity in Mecp2-/y knockout mice.

Rett syndrome (RTT) is an inborn neurodevelopmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 gene (MECP2). Besides mental retardation, most patients suffer from potentially life-threatening breathing arrhythmia. To study its pathophysiology, we performed comparative analyses of the breathing phenotype of Mecp2-/y knockout (KO) and C57BL/6J wild-type mice using the perfused working heart-brainstem preparation (WHBP). We simultaneously recorded phrenic and efferent vagal nerve activities to analyse the motor pattern of respiration, discriminating between inspiration, postinspiration and late expiration. Our results revealed respiratory disturbances in KO preparations that were similar to those reported from in vivo measurements in KO mice and also to those seen in RTT patients. The main finding was a highly variable postinspiratory activity in KO mice that correlated closely with breathing arrhythmias leading to repetitive apnoeas even under undisturbed control conditions. Analysis of the pontine and peripheral sensory regulation of postinspiratory activity in KO preparations revealed: (i) prolonged apnoeas associated with enhanced postinspiratory activity after glutamate-induced activation of the pontine Kölliker-Fuse nucleus; and (ii) prolonged apnoeas and lack of reflex desensitization in response to repetitive vagal stimulations. We conclude that impaired network and sensory mediated synaptic control of postinspiration induces severe breathing dysfunctions in Mecp2-/y KO preparations. As postinspiration is particularly important for the control of laryngeal adductors, the finding might explain the upper airway-related clinical problems of patients with RTT such as apnoeas, loss of speech and weak coordination of breathing and swallowing.

Animals↗
PubMed2006

Treatment of epilepsy in Rett syndrome.

INTRODUCTION: Epilepsy is very frequent in Rett syndrome (RTT) patients and often difficult to treat. Because most cases of RTT are caused by mutations in the MECP2 gene it is reasonable to assume that convulsions are based on common pathogenetic mechanisms and thus should have a similar response to antiepileptic drugs. PURPOSE: To find the optimal treatment for epilepsy in RTT. METHODS: We performed a retrospective study on 110 female patients with confirmed MECP2 mutations. RESULTS: The median age was 10 years, 58% had a history of epilepsy and 55% received antiepileptic drugs (AEDs). Only sulthiame, carbamazepine and valproate were administered in an adequate frequency to allow statistical analysis. The best anticonvulsive results were seen in the RTT group that was treated with carbamazepine. Sulthiame was slightly less effective while valproate was significantly less effective. The rate of side effects was equivalent in all groups. In conclusion, carbamazepine should be recommended as first choice AED in RTT. If carbamazepine is not effective or not well tolerated sulthiame ought to be taken as second choice AED.

Adolescent↗
PubMed2005

Mutation analysis of the HDAC 1, 2, 8 and CDKL5 genes in Rett syndrome patients without mutations in MECP2.

Mutations in the MECP2 gene are found in only 80% of patients with Rett syndrome (RTT). Therefore other genes have to be involved in the pathogenesis of RTT. By using our defined diagnostic criteria we first re-evaluated 50 girls with possible RTT in whom the sequencing of the MECP2 gene had not revealed any mutations. Only 15 of theses patients fulfilled all criteria for RTT and could be considered to have classical RTT. In eight of these, further molecular analyses revealed large deletions of the MECP2 gene. In the remaining seven girls we then analyzed the genes HDAC1, HDAC2, and HDAC8 that encode for the histone deacetylases 1, 2, and 8 which interact with MeCP2 and are essential for its function. Although these histone deacetylase genes have been considered as good candidate genes for RTT our molecular analysis of these genes did not detect any mutations. Because recently mutations in CDKL5 were reported in patients with RTT, we included this gene in our analysis but failed to detect any mutations. We conclude that only a subgroup of girls with possible RTT and no detectable mutation in the sequencing of the MECP2 gene do really have classical RTT. In many of those large MECP2 gene deletions can be detected by further analysis. The genes HDAC1, HDAC2, and HDAC8 do not seem to play a role in the pathogenesis of RTT and at least in our subgroup no mutations in the CDKL5 gene were detected.

Cell Cycle Proteins↗
PubMed2005

Visually self-induced seizures sensitive to round objects.

PURPOSE: To describe a previously unreported type of self-induced pattern-sensitive seizures in a child. METHODS: Evaluation of clinical and EEG features. RESULTS: An 18-month-old boy was initially seen with series of short focal tonic seizures self-induced by gazing intermittently at round objects. Self-induction of these seizures had an obvious relieving effect on the child. Covering the round object foiled further seizures but resulted in a tantrum. Later in the course, an increasing variety of patterns proved to be capable of inducing seizures, which occurred with increasing frequency and severity, including secondarily generalized tonic-clonic seizures. Interictal EEG revealed multifocal sharp-and-slow-waves. Ictal EEG showed no abnormalities during short focal seizures and rapidly generalizing epileptic discharges during a secondarily generalized seizure. No photosensitivity was noted. Motor and mental development of the boy stagnated over a period of 2 years. Behavioral therapy as well as medical treatment, consisting of various combinations of antiepileptic drugs (AEDs) together with a selective serotonin-reuptake inhibitor, were of merely transient benefit. Only combined pharmacotherapy, including valproate, sulthiame, and clobazam, resulted in seizure control at age 3 years 9 months. CONCLUSIONS: Visual capture of geometric patterns other than stripes or gratings may trigger focal seizures with secondary generalization. Synchronization of cortical neurons responsible for pattern recognition may account for epileptogenesis in this child.

Age Factors↗
PubMed2005

Molecular diagnosis of Rett syndrome.

In 1999, mutations in the MECP2 gene were identified as the primary cause of Rett syndrome. MECP2 mutations can be found in 70% to 80% of all clinically defined Rett syndrome cases; in classic Rett syndrome, this frequency is even higher. In most cases, missense and nonsense mutations affecting functionally important domains can be found. Additionally, a hot spot for small deletions has been defined, and several gross rearrangements have also been described. Among female individuals with Rett syndrome, the spectrum of clinical phenotypes is broad, but most fulfill the diagnostic criteria. In contrast, male individuals with mutations in the MECP2 gene are rare, and only a minority have clinical symptoms resembling Rett syndrome.

Female↗
PubMed2004

Large deletions of the MECP2 gene detected by gene dosage analysis in patients with Rett syndrome.

MECP2 mutations are responsible for Rett syndrome (RTT). Approximately a quarter of classic RTT cases, however, do not have an identifiable mutation of the MECP2 gene. We hypothesized that larger deletions arising from a deletion prone region (DPR) occur commonly and are not being routinely detected by the current PCR-mediated screening strategies. We developed and applied a quantitative PCR strategy (qPCR) to samples referred for diagnostic assessment from 140 patients among whom RTT was strongly suspected and from a second selected group of 31 girls with classical RTT. Earlier MECP2 mutation screening in both groups of patients had yielded a wild-type result. We identified 10 large deletions (7.1%) within the first group and five deletions in the second group (16.1%). Sequencing of the breakpoints in 11 cases revealed that eight cases had one breakpoint within the DPR. Among seven cases, the breakpoint distant to the DPR involved one of several Alu repeats. Sequence analysis of the junction sequences revealed that eight cases had complex rearrangements. Examination of the MECP2 genomic sequence reveals that it is highly enriched for repeat elements, with the content of Alu repeats rising to 27.8% in intron 2, in which there was an abundance of breakpoints among our patients. Furthermore, a perfect chi sequence, known to be recombinogenic in E. coli, is located in the DPR. We propose that the chi sequence and Alu repeats are potent factors contributing to genomic rearrangement. We suggest that routine mutation screening in MECP2 should include quantitative analysis of the genomic sequences flanking the DPR.

Base Sequence↗
PubMed2003

The spectrum of phenotypes in females with Rett Syndrome.

Since the discovery of mutations in the methyl-CpG binding protein-2 (MECP2) gene in Rett Syndrome (RTT) a large number of females have been diagnosed worldwide. In this article we present the clinical and developmental data of 120 RTT females with mutations in the MECP2 gene and individually describe typical and atypical cases. We found a broad spectrum of phenotypes in females. At the severest end we have females with primary developmental delay who never learned to turn, sit or walk and who developed severe epilepsy. At the mildest end of the spectrum, there are females with only minor neurological symptoms who have good gross motor function, speak and have relatively well-preserved hand function. A number of girls either do not fulfil all the necessary diagnostic criteria or present with symptoms that have not been described in RTT before. Comparing our data with the normal population we found that girls with RTT have a smaller occipito-frontal circumference, shorter length and lower weight at birth. As a result of molecular genetic analysis a broad spectrum of phenotypes in RTT females has evolved. We found evidence that the defect in MeCP2 influences the somatic growth before birth.

Adolescent↗
PubMed2003

Indication for genetic testing: a checklist for Rett syndrome.

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.

Child↗
PubMed2002

Eosinophilic fasciitis leading to painless contractures.

UNLABELLED: We report on an 11-year-old girl who developed multiple joint contractures over a period of 3 months. The disease presented with progressive involvement of the fingers, elbows, shoulders, knees and feet and was not accompanied by other symptoms. Laboratory investigations showed eosinophilia and hypergammaglobulinaemia. Muscle ultrasound and magnetic resonance imaging of the right forearm revealed thickened fascia and a full thickness biopsy confirmed the diagnosis of eosinophilic fasciitis. Following treatment with pulsed steroids, the contractures resolved. CONCLUSION: our case shows that eosinophilic fasciitis can present without skin involvement and arthritis and therefore has to be regarded as a differential diagnosis of contractures in childhood. Pulsed steroid treatment was effective and without side-effects.

Biopsy↗
PubMed2002

EEG features of glut-1 deficiency syndrome.

PURPOSE: Glut-1 deficiency syndrome (Glut-1 DS) is caused by the deficiency of the major glucose transporter in cerebral microvessels. METHODS: We performed pre- and postprandial EEG recordings in two unrelated children with Glut-1 DS with developmental delay and seizures predominantly in the morning before breakfast. RESULTS: Extensive epileptiform discharges observed in the fasting state were improved markedly by food intake, as documented in EEG recordings 1 and 2 h after a meal. The ratio of cerebrospinal fluid glucose to blood glucose was decreased in both children. Glut-1 deficiency was confirmed by biochemical and molecular genetic investigations. CONCLUSIONS: Pre- and postprandial EEG recordings offer a simple screening test for Glut-1 DS.

Adolescent↗