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München, Germany

Limbrock J.G.,Kinderzentrum Munich
Journal fur Neurologie, Neurochirurgie und Psychiatrie

Sucking and swallowing problems may already arise in the first year of life in a child with ICP, but mostly the typical oral motor problems develop later: openmouth posture, tongue thrust, drooling, choking on lumpy or solid food, or on liquids (dysphagia), dysarthria etc. This review article highlights the corresponding areas of posture, respiration, lip seal, tongue, mucosa, dental and maxillary position, drinking and eating, and articulation - based on up-todate literature. Drooling has many implications for social participation (International Classification of Functioning [ICF]), and is highlighted with pathogenetic and therapeutic reasoning. Reduction of saliva - by drugs or surgery - does not touch the root of the problem - the effectiveness and frequency of swallowing - and often leads to long-term consequences for teeth, oral hygiene, and swallowing. Therefore, improvement of functions is preferred, and such therapies are discussed. Two are specially depicted: The Castillo Morales® concept, including stimulating palatal plates, and the Pörnbacher therapy (NEPA). They approach whole-body motricity and indirectly and directly also oral motricity and perception. Finally, the indication for gastrostomy feeding is reflected, considering new findings on the neuroplasticity of swallowing. Source

Steffen A.,University of Lubeck | Beutner D.,Klinik und Poliklinik fur HNO Heilkunde | Hakim S.,University of Lubeck | Jost W.,Fachbereich Neurologie | And 14 more authors.
Laryngo- Rhino- Otologie

Hypersalivation describes a relatively excessive salivary flow, which wets the patient himself and his surroundings. It may result because of insufficient oro-motor function, dysphagia, decreased central control and coordination. This reduces social interaction chances and burdens daily care. Multidisciplinary diagnostic and treatment evaluation is recommended already at early stage and focus on dysphagia, and saliva aspiration. Therefore, a multidisciplinary S2k guideline was developed. Diagnostic tools such as fiberoptic endoscopic evaluation of swallowing and videofluoroscopic swallowing studies generate important data on therapy selection and control. Especially traumatic and oncologic cases profit from swallowing therapy programmes in order to activate compensation mechanisms. In children with hypotonic oral muscles, oralstimulation plates can induce a relevant symptom release because of the improved lip closure. In acute hypersalivation, the pharmacologic treatment with glycopyrrolate and scopolamine in various applications is useful but its value in long-term usage critical. The injection of botulinum toxin into the salivary glands has shown safe and effective results with long lasting saliva reduction. Surgical treatment should be reserved for isolated cases. External radiation is judged as ultima ratio. Therapy effects and symptom severity has to be followed, especially in neurodegenerative cases. The resulting xerostomia should be critically evaluated by the responsible physician regarding oral and dental hygiene. © Georg Thieme Verlag KG Stuttgart · New York. Source

Sommer A.,University Hospital Freiburg | Christensen E.,Juliane Marie Center | Schwenger S.,Kinderzentrum Munich | Seul R.,Marien Hospital Witten | And 4 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease

Aminoacylase 1 is a zinc-binding enzyme which hydrolyzes N-acetyl amino acids into the free amino acid and acetic acid. Deficiency of aminoacylase 1 due to mutations in the aminoacylase 1 (ACY1) gene follows an autosomal-recessive trait of inheritance and is characterized by accumulation of N-acetyl amino acids in the urine. In affected individuals neurological findings such as febrile seizures, delay of psychomotor development and moderate mental retardation have been reported. Except for one missense mutation which has been studied in Escherichia coli, mutations underlying aminoacylase 1 deficiency have not been characterized so far. This has prompted us to approach expression studies of all mutations known to occur in aminoacylase 1 deficient individuals in a human cell line (HEK293), thus providing the authentic human machinery for posttranslational modifications. Mutations were inserted using site directed mutagenesis and aminoacylase 1 enzyme activity was assessed in cells overexpressing aminoacylase 1, using mainly the natural high affinity substrate N-acetyl methionine. Overexpression of the wild type enzyme in HEK293 cells resulted in an approximately 50-fold increase of the aminoacylase 1 activity of homogenized cells. Most mutations resulted in a nearly complete loss of enzyme function. Notably, the two newly discovered mutations p.Arg378Trp, p.Arg378Gln and the mutation p.Arg393His yielded considerable residual activity of the enzyme, which is tentatively explained by their intramolecular localization and molecular characteristics. In contrast to aminoacylase 1 variants which showed no detectable aminoacylase 1 activity, aminoacylase 1 proteins with the mutations p.Arg378Trp, p.Arg378Gln and p.Arg393His were also detected in Western blot analysis. Investigations of the molecular bases of additional cases of aminoacylase 1 deficiency contribute to a better understanding of this inborn error of metabolism whose clinical significance and long-term consequences remain to be elucidated. © 2011 Elsevier B.V. Source

Steenweg M.E.,VU University Amsterdam | Van Berge L.,VU University Amsterdam | Van Berkel C.G.M.,VU University Amsterdam | De Coo I.F.M.,Erasmus Medical Center | And 12 more authors.

AimLeukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is known as a relatively mild leukoencephalopathy. We investigated the occurrence of severe variants of LBSL with extensive brain magnetic resonance imaging (MRI) abnormalities. MethodMRIs of approximately 3,000 patients with an unknown leukoencephalopathy were retrospectively reviewed for extensive signal abnormalities of the cerebral and cerebellar white matter, posterior limb of the internal capsule, cerebellar peduncles, pyramids, and medial lemniscus. Clinical data were retrospectively collected. ResultsEleven patients fulfilled the MRI criteria (six males); six had DARS2 mutations. Clinical and laboratory findings did not distinguish between patients with and without DARS2 mutations, but MRI did. Patients with DARS2 mutations more often had involvement of structures typically affected in LBSL, including decussatio of the medial lemniscus, anterior spinocerebellar tracts, and superior and inferior cerebellar peduncles. Also, involvement of the globus pallidus was associated with DARS2 mutations. Earliest disease onset was neonatal; earliest death at 20 months. InterpretationThis study confirms the occurrence of early infantile, severe LBSL, extending the known phenotypic range of LBSL. Abnormality of specific brainstem tracts and cerebellar peduncles are MRI findings that point to the correct diagnosis. Copyright © 2012 by Thieme Medical Publishers, Inc. Source

van de Kamp J.M.,VU University Amsterdam | Betsalel O.T.,VU University Amsterdam | Mercimek-Mahmutoglu S.,The Hospital for Sick Children | Abulhoul L.,University College London | And 49 more authors.
Journal of Medical Genetics

Background: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype-genotype correlation has been lacking. Methods: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). Results and conclusions: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 30 end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones. Source

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