[Transition from neuropediatrics to neurology in neuromuscular diseases]. / Transition von der Neuropädiatrie zur Neurologie bei neuromuskulären Erkrankungen.

BACKGROUND: Neuromuscular diseases in childhood, adolescence and adulthood are rare or very rare diseases and for many of them the prevalence and incidence are unknown. Causal therapies are currently used for individual disease entities only. Nevertheless, new genetic methods, a better understanding of the pathophysiology and multidisciplinary treatment concepts help to improve patient life expectancy and quality of life. As a result, more and more patients with an early disease onset reach adulthood and further care in adult medicine is necessary. This imposes new challenges particularly on neurology and the requirements for interdisciplinary cooperation in adult medicine are increased. OBJECTIVE: How can transition be made meaningful? Where do structural and content problems stand out? MATERIAL AND METHOD: Using the example of Duchenne muscular dystrophy, the content and structural requirements for transition are presented and important aspects and possible problems are pointed out. CONCLUSION: The transition process is complex and requires time and personnel resources. If carried out sensibly, it can lead to a better and more efficient care of patients in the long term and thus can also become economically more effective.

Facing the genetic heterogeneity in neuromuscular disorders: linkage analysis as an economic diagnostic approach towards the molecular diagnosis.

The identification of an ever increasing number of gene defects in patients with neuromuscular disorders has disclosed both marked phenotype and genotype variability and considerable disease overlap. In order to offer an economic strategy to characterise the molecular defect in patients with unclassified neuromuscular disorders, we designed DNA marker sets for linkage analysis of 62 distinct neuromuscular disorders gene loci, including all known muscular dystrophies, congenital myopathies, congenital myasthenic syndromes and myotonias. Genotyping of marker loci of 140 clinically well-characterised families with unclassified neuromuscular disorders reduced the number of candidates to one or two genes in 49 % of the families. Subsequent mutation analysis and genome-wide scans enabled the determination of the genetic defect in 31 % of the families including the identification of a new gene and a new mutation in an unexpected candidate gene. This highlights the effective application of this approach both for diagnostic strategies as well as for the identification of new loci and genes.

Elevated p21 mRNA level in skeletal muscle of DMD patients and mdx mice indicates either an exhausted satellite cell pool or a higher p21 expression in dystrophin-deficient cells per se.

Abnormalities in proliferation and differentiation of the dystrophin-deficient muscle are a controversial aspect of the pathogenesis of Duchenne muscular dystrophy (DMD). Analyses of molecules involved in cell cycle modulation do not exist in this context. Cells withdrawn from the cell cycle permanently express p21. The fact that p2 1, in contrast to other cell cycle proteins, is not diminished when myotubes are reexposed to growth media, allocates this cyclin-dependent kinase inhibitor a special function. Here we report for the first time statistically increased p21 mRNA levels in dystrophin-deficient muscle tissue. Only 42% of conventional RT-PCRs from six muscle samples of human controls yielded positive results but almost all skeletal muscle biopsy samples (87%) from DMD patients (n=5). For p21 mRNA quantification in murine muscle samples we were able to use the exact real-time TaqMan PCR method due to generally higher p21 mRNA levels than in human muscles. In addition, contamination with fibroblasts can be excluded for the murine samples because they do not demonstrate fibrosis at the age of 350 days but start to lose their regenerative capacity. In accord with the results in humans, we observed p21 mRNA levels in mdx mice that were approx. four times as high as those in control mice. Elevated p21 mRNA level may indicate a shift in cell composition towards differentiated p21 expressing cells as a result of an exhausted pool of undifferentiated, non-p21-expressing satellite cells due to previous cycles of de- and regeneration. Alternatively, dystrophin-deficient cells per se may express higher p21 levels for unknown reasons. Although we cannot distinguish between these possibilities, the eventual transfec tion of a patient's own satellite cells with p21 antisense oligonucleotides may enable the dystrophic process to be influenced.

Ataxia with vitamin E deficiency: biochemical effects of malcompliance with vitamin E therapy.

To prevent neuronal damage, patients with ataxia with isolated vitamin E deficiency need lifelong supplementation with high doses of vitamin E. Short interruptions of therapy, such as occur in malcompliance, do not lead to clinical symptoms. However, the authors show that even short withdrawals may cause a prolonged decrease of the total radical trapping capacity of plasma; its major contributors, such as urate and sulfhydryl groups, fail to compensate for the missing vitamin E.

Heterozygous myogenic factor 6 mutation associated with myopathy and severe course of Becker muscular dystrophy.

Myogenic factors (MYF) belong to the basic helix-loop-helix (bHLH) transcription factor family and regulate myogenesis and muscle regeneration. The physiological importance of both functions was demonstrated in homozygous Myf knockout mice and mdx mice. Myf5 and Myod are predominantly expressed in proliferating myoblasts while Myf4 and Myf6 are involved in differentiation of myotubes. In a boy with myopathy and an increase of muscle fibres with central nuclei we detected a heterozygous 387G-->T nucleotide transversion in the MYF6 gene (MIM*159991). Protein-protein interaction of mutant MYF6 was reduced, and DNA-binding potential and transactivation capacity were abolished, thus demonstrating MYF6 haploinsufficiency. The boy's father carried the identical mutation and, in addition, an in-frame deletion of exons 45-47 in his dystrophin gene. This mutation is normally associated with a mild to moderate course of Becker muscular dystrophy but the father suffered from a severe course of Becker muscular dystrophy suggesting MYF6 as a modifier.

Dystrophinopathy in a boy with Chediak-Higashi syndrome.

Chediak-Higashi syndrome (CHS) is a hereditary, biphasic immunodeficiency syndrome which usually leads to early death, during the first decade. The second phase is characterized by a lymphoproliferative syndrome with histiocytic infiltrations in various tissues. Recently the gene has been identified on chromosome 1q43. In the patient presented here, a mutation within codon 3197 was found, resulting in a frame-shift. Additionally, Duchenne muscular dystrophy (DMD) was diagnosed by immunostaining of the muscle. Unusual for both CHS and DMD muscle weakness and hypotonia became evident during the first months of life. Compared to typical DMD cases we found an increased histiocytic infiltration in the muscle. The underlying muscular dystrophy probably predisposes to the affection of muscle in the second phase of CHS. This patient is presented as an example of modification of the phenotype by a second genetic disease.

[BiPAP therapy of respiratory disorders in patients with congenital neuromuscular diseases]. / BiPAP-Therapie von Atmungsstörungen bei Patienten mit angeborenen neuromuskulären Erkrankungen.

BACKGROUND: Patients with hereditary generalized neuromuscular diseases develop respiratory failure and decreased maximal inspiratory pressure (Pi max) due to both, involvement of respiratory muscles in the disease and secondary spine- and thorax-deformity. In recent years mechanical respiratory support was done mostly by hyperbaric pressure ventilation when the patients become hypercapnic during daytime. However, polysomnographic investigations have shown that despite normal ventilation during daytime, severe respiratory failure might be detectable only during sleep. PATIENTS AND METHODS: Fourty patients with hereditary generalized neuromuscular diseases were analyzed using polysomnographic analyses and lung function tests (4-channel-ECG,2-channel-ECG, EOG, respiratory parameters, continuous oxygen saturation measurement and capillary blood gas analyses during sleep). Patients with need of ventilatory support during sleep were treated using bilevel positive airway pressure ventilation (BiPAP). RESULTS: Twenty patients revealed severe sleep related breathing disorders and were therefore treated by BiPAP. All showed normalisation or substantial improvement during BiPAP-therapy except two patients with persistent daytime symptoms. During follow-up (6 to 38 months) 3 patients died (cardiomyopathy, pulmonary embolism, pneumonia). The most important side effect of BiPAP-therapy was pressure marks due to the masks. CONCLUSIONS: BiPAP is useful for treatment of sleep related respiratory failure in patients with hereditary generalized neuromuscular diseases.

Serum levels of carboxyterminal propeptide of type I procollagen, aminoterminal propeptide of type III procollagen and laminin P1 in Duchenne muscular dystrophy.

The striking proliferation of connective tissue in Duchenne muscular dystrophy is attributed, besides other components of the extracellular matrix, to an increase of endomysial and perimysial type III and type I collagen. We investigated if muscle fibrosis correlates to an increased serum concentration of procollagen I or III. Therefore, we measured the serum levels of carboxyterminal propeptide of type I procollagen, aminoterminal propeptide of type III procollagen and laminin P1 in 20 boys with progressive muscular dystrophy (16 definite Duchenne muscular dystrophy, 2 suspected of Duchenne muscular dystrophy, 2 Becker muscular dystrophy). In contrast to collagen I and III the expression of laminin in the basement membrane is known to be normal in Duchenne muscular dystrophy. There was no significant alteration of serum concentration of procollagen III N-peptide, procollagen I C-peptide and laminin P1 in boys with Duchenne muscular dystrophy. Measuring these parameters is not useful for investigating the extent of muscle fibrosis or for monitoring the effect of therapeutic trials such as steroid treatment.

Large cerebral vessel occlusive disease in Lyme neuroborreliosis.

We report on a 12-year-old, previously healthy girl with an acute hemiparesis as the predominant clinical manifestation of Lyme neuroborreliosis (LNB). The diagnosis of LNB was based on cerebrospinal fluid (CSF) studies, laboratory findings and the clinical course whereas the patient's history and the lack of characteristic skin lesions obscured the diagnosis in the beginning. After four weeks of antibiotic and physiotherapeutic treatment, the hemiparetic symptoms had completely resolved. Although evidence of vasculitic and perivascular inflammation in LNB has been described in the literature, large cerebral vessel occlusive disease represents a rare finding. Appropriate treatment strategies can lead to good clinical rehabilitation, as shown in this case, making the timely diagnosis a crucial issue. We conclude that LNB should be considered in every stroke-like episode of unknown origin in children, even in the absence of a history of a tick bite or typical skin lesions.

Variable course of Canavan disease in two boys with early infantile aspartoacylase deficiency.

This is a report of two patients with Canavan disease from the Federal Republic of Germany. One is a severely retarded, macrocephalic boy, who had the characteristic laboratory findings of Canavan disease and progressive leucodystrophy on neuro-imaging. The other is retarded, with signs of a cerebral movement disorder showing no deterioration during the first 15 months. The significance of aspartoacylase deficiency in Canavan disease for differential diagnosis, genetic counselling and prenatal diagnosis of leucodystrophy is discussed.

Neuropathy with lysosomal changes in Marinesco-Sjögren syndrome: fine structural findings in skeletal muscle and conjunctiva.

The light- and electron-microscopical findings in the skeletal muscle and conjunctiva of 6 patients with Marinesco-Sjögren syndrome (MSS) were presented. All patients were related and showed the cardinal clinical symptoms of the syndrome: congenital cataracts, mental retardation, delayed statomotor development, and cerebellar ataxia. The most prominent alteration found in the skeletal muscle of four patients was extensive neurogenic atrophy with conspicuous groups of atrophic muscle fibers. Additional findings were vacuolar degeneration and secondary, unspecific changes like slight mitochondrial alterations and increased variability in muscle fiber calibers. The ultrastructural examination revealed double-membrane structures near to, but not in direct contact with the nucleus. The nuclear changes described earlier (7, 20) were not found in any of the cases. Conjunctival biopsies revealed a marked increase in the number of lysosomes in fibroblasts. In summary, to the well known myopathic damage of muscles in MSS a neurogenic component should be added. Disturbed lysosomal function is to be considered as the basic abnormality, though the enzyme defect has not yet been identified. In cases of clinically suspected MSS, examination of a conjunctival biopsy is highly recommended.

Epilepsia partialis continua associated with a homoplasmic mitochondrial tRNA(Ser(UCN)) mutation.

Epilepsia partialis continua (EPC) is a rare epileptic syndrome characterized by continuous focal seizures. We report on a 16-year-old girl who died of prolonged pharmacoresistant EPC in whom we identified a 7472insC mutation within the mitochondrial transfer ribonucleic acid (tRNA)(ser(UCN)). Additional symptoms included ataxia, lactic acidosis, myopathy, sensorineural hearing loss, severe headaches, and mental retardation. Quantification revealed 100% mutant mitochondrial DNA (mtDNA) in the patient, 4% in her mother, and none in her half-sister. This highly skewed mtDNA distribution is most improbable (approximately 3 x 10(-30)) if only explained by random genetic drift. Clustering of dysfunctional mitochondria and replicatory advantage of mutant mtDNA may play a role in the rapid segregation towards homoplasmy within one generation.

X-chromosomal (p21) muscular dystrophy and left ventricular diastolic and systolic function.

In order to screen for cardiac abnormalities, we prospectively studied 15 patients (age 8-25 years, mean 15.5 years) with Duchenne's (DMD) (n = 9) and Becker's (BMD) (n = 6) muscular dystrophy using the echocardiogram. Data were compared to a control group of 92 healthy individuals (age 7.9-25 years, mean 14.3 years). Left ventricular filling in diastole showed a different pattern when comparing echocardiographic Doppler results in patients and controls: Patients had lower peak velocity of early left ventricular diastolic filling (E-vmax)(P < 0.0001) and smaller time velocity integral of the E-wave (E-tvi)(P < 0.0001). In contrast, the atrial component (A-vmax, A-tvi) of diastolic filling in DMD/ BMD showed no significant difference to controls. The mean area of the mitral valve orifice was significantly larger in patients (P < 0.0001) without presence of mitral regurgitation. Systolic left ventricular function was significantly impaired in the DMD/BMD group; we found lower heart rate corrected fiber shortening velocity VCFc (P < 0.001) and higher peak systolic wall stress (P < 0.001) in DMD/BMD. In 8 of 15 patients, peak systolic wall stress was above 95th percentile of controls. In 6 of 15 patients, VCFc was lower than the 5th percentile of controls. Systolic and diastolic myocardial impairment was found even in young patients and at low stages of disability--equally among patients with DMD or BMD. Diastolic left ventricular impairment predominantly affected the early diastolic filling, but atrial compensation was poor. Peak systolic wall stress measurements were particularly useful in patients with CMP, reflecting the left ventricular afterload.

Cranial ultrasound findings in aspartoacylase deficiency (Canavan disease).

Canavan disease (CD) is a rare leukodystrophy which is lethal in infancy or early childhood. The underlying biochemical abnormality in CD is a hereditary deficiency of N-aspartoacylase transmitted in an autosomal recessive fashion. We report on the ultrasound (US), CT, and MRI findings of three unrelated boys with biochemically confirmed CD. At 6 and 9 months of age, two CD patients with rapid neurological deterioration showed markedly enhanced acoustic attenuation of the white matter with the exception of the corpus callosum, giving the appearance of a reversed pattern of echogenicity of cortical gray and subcortical white matter. While gyri and sulci had an almost normal US appearance, the periventricular gray matter featured prominently with increased echogenicity. In contrast another CD patient with a more protracted course had ventricular enlargement when examined by US at 5 and 9 months but no alteration in white matter echogenicity. MRI showed impaired myelinization in all three patients with Canavan disease.

Comparison of three immunoassays for diagnosing sensitization to latex in children with spina bifida.

As natural rubber latex (latex) has become more widespread in our environment, physicians have become increasingly aware of the problem of possible allergic reactions. Many fatal and near-fatal incidents have been reported (mainly during surgery) (1-3) and data has been published on groups frequently exposed to latex, such as patients with spina bifida (4-9), healthcare professionals (10-12) and occupationally exposed persons (13). The incidence of latex allergy in children seems to be increasing (14). Tests are therefore needed which can reliably detect sensitization to latex. Our aim was to compare the diagnostic accuracy of three commercial immunoassays for measuring specific IgE in serum to latex.

Clinical and genetic heterogeneity in megalencephalic leukoencephalopathy with subcortical cysts (MLC).

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) was recently localized on chromosome 22q (tel) and 26 different mutations of the gene MLC1 have been found. We report three siblings of non-consanguineous parents who presented with characteristic features of MLC, but did not have MLC1 mutations. MEYHODS: Clinical, laboratory and neuro-imaging findings of the siblings are described and similar patients with MLC are reviewed. RESULTS: All three siblings suffered from ataxia, progressive severe tetraparesis, dysarthria, dysphagia and epilepsy. Generalized dystonia occurred in one patient. Mental deterioration progressed more slowly than motor deterioration. The youngest male was the most severely affected and died at the age of 23 years. The two older females are now 34 and 35 years old. Our patients are among the oldest described with this clinical entity. No mutation of the MLC1 gene was found in our siblings and linkage with the MLC1 locus was excluded. CONCLUSIONS: The genetic findings in our patients suggest at least a second gene locus for MLC.

Autosomal dominant glut-1 deficiency syndrome and familial epilepsy.

Glut-1 deficiency syndrome was first described in 1991 as a sporadic clinical condition, later shown to be the result of haploinsufficiency. We now report a family with Glut-1 deficiency syndrome affecting 5 members over 3 generations. The syndrome behaves as an autosomal dominant condition. Affected family members manifested mild to severe seizures, developmental delay, ataxia, hypoglycorrhachia, and decreased erythrocyte 3-O-methyl-D-glucose uptake. Seizure frequency and severity were aggravated by fasting, and responded to a carbohydrate load. Glut-1 immunoreactivity in erythrocyte membranes was normal. A heterozygous R126H missense mutation was identified in the 3 patients available for testing, 2 brothers (Generation 3) and their mother (Generation 2). The sister and her father were clinically and genotypically normal. In vitro mutagenesis studies in Xenopus laevis oocytes demonstrated significant decreases in the transport of 3-O-methyl-D-glucose and dehydroascorbic acid. Xenopus oocyte membranes expressed high amounts of the R126H mutant Glut-1. Kinetic analysis indicated that replacement of arginine-126 by histidine in the mutant Glut-1 resulted in a lower Vmax. These studies demonstrate the pathogenicity of the R126H missense mutation and transmission of Glut-1 deficiency syndrome as an autosomal dominant trait.