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Biomedical subjects

J S Müller

Publications and source records attributed to J S Müller.

14 recordsLinked to original sources
PubMed2006

Impaired receptor clustering in congenital myasthenic syndrome with novel RAPSN mutations.

OBJECTIVE: Congenital myasthenic syndromes (CMS) with underlying RAPSN mutations turned out to be of high clinical relevance due to their worldwide frequency. To date, all reported patients with CMS with sequence variations in the translated region of RAPSN carry the mutation N88K on at least one allele. The authors report two patients lacking the common N88K allele but harboring differing novel mutations of the RAPSN gene on both alleles: one patient is homozygous for a missense mutation (R164C); the second patient is compound heterozygous for a splice (IVS1-15C>A) and another missense mutation (L283P). METHODS: The authors analyzed the RAPSN gene for sequence variations and carried out in vitro studies in order to delineate the potential pathogenicity of the three novel RAPSN mutations. RESULTS: For the putative splice mutation (IVS1-15C>A), the authors constructed wild-type and mutated RAPSN minigenes for transfection and subsequent RNA analysis. The mutation generates a novel acceptor splice site leading to retention of 13 nucleotides of intron 1 in the mature mRNA and subsequently to a frameshift transcript. Cotransfection of wild-type AChR subunits with RAPSN-constructs carrying R164C and L283P indicate that both mutations diminish coclustering of AChR with rapsyn. CONCLUSIONS: Screening for the common mutation RAPSN N88K facilitates targeted genetic analysis in congenital myasthenic syndromes. However, absence of a N88K allele does not exclude underlying RAPSN mutations as cause of the congenital myasthenic syndromes. Sequencing of the entire gene may be considered in patients with joint contractures and respiratory problems even in the absence of the mutation N88K.

Base Sequence↗
PubMed2006

Long-term improvement of slow-channel congenital myasthenic syndrome with fluoxetine.

We report on a 15-year-old patient who was diagnosed with congenital myasthenic syndrome (CMS) at the age of 7 months. At initial diagnosis, the CMS was not further characterized. The patient was treated for several years with the anticholinesterase drug (Mestinon), without clinical benefit. The patient deteriorated progressively and became dependent on home nocturnal ventilatory support, being unable to take part in daily life activities at age of 12 years. At age 14, the slow-channel syndrome mutation CHRNE L269F (805C>T) was detected and acetylcholinesterase inhibitor therapy was immediately stopped. Fluoxetine therapy was started and gradually increased over 2 months. The boy improved dramatically in strength and endurance and was taken off ventilatory support 1 month after the fluoxetine therapy was initiated. The clinical improvement was confirmed by functional respiratory and electrophysiological tests.

Adolescent↗
PubMed2005

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.

DNA Mutational Analysis↗
PubMed2005

An intronic base alteration of the CHRNE gene leading to a congenital myasthenic syndrome.

Reported is a patient with a congenital myasthenic syndrome due to two compound heterozygous mutations of the CHRNE gene. The molecular consequences of a novel intronic base alteration (CHRNE IVS5-16GA) remote from the splice acceptor site were investigated in vivo and in vitro. In conclusion, RNA analysis may be necessary to reveal unexpected splicing aberrations due to intronic mutations that are not part of the consensus splice site.

Adolescent↗
PubMed2004

Clinical variability of CMS-EA (congenital myasthenic syndrome with episodic apnea) due to identical CHAT mutations in two infants.

Congenital myasthenic syndromes (CMS) result from mutations in various synapse-associated genes. Mutations in the choline acetyltransferase (CHAT) gene cause a presynaptic CMS associated with episodic apnea (CMS-EA). We present two unrelated Croatian children affected by CMS-EA. Beside other clinical findings characteristic for CMS, both patients manifested intermittent apneas since early infancy. Whereas the course of disease is mild in the female patient (patient 2), the male patient (patient 1) experienced recurrent and severe episodes of apnea despite adequate treatment with AChE-inhibitors and shows a global developmental delay with delayed myelination and signs of hypoxic-ischemic injury in brain imaging. Interestingly, sequencing of the CHAT gene revealed identical, compound heterozygous mutations S694C and T354M in both children. These findings are in line with a remarkable clinical heterogeneity observed in patients with CHAT mutations and emphasize the potential role of apneic crises for the development of secondary hypoxic brain damage and psychomotor retardation.

Apnea↗
PubMed2004

Synaptic congenital myasthenic syndrome in three patients due to a novel missense mutation (T441A) of the COLQ gene.

Congenital myasthenic syndromes (CMS) with deficiency of endplate acetylcholinesterase (AChE) are caused by mutations in the synapse specific collagenic tail subunit gene (COLQ) of AChE. We identified a novel missense mutation (T441A) homozygously in three CMS patients from two unrelated German families. The mutation is located in the C-terminal region of the ColQ protein, which initiates assembly of the triple helix, and is essential for insertion of the tail subunit into the basal lamina. Density gradient analysis of AChE extracted from muscle of one of the patients revealed the absence of asymmetric AChE. All patients were characterized by an onset of disease in childhood, exercise-induced proximal weakness, absence of ptosis and ophthalmoparesis, a decremental EMG response, and deterioration in response to anticholinesterase drugs. However, age at onset, disease progression, disease severity, and functional impairment varied considerably among the three patients. As adults, two siblings from one family experience only mild impairment, while the third patient requires a wheelchair for most of the day and assisted ventilation at night.

Acetylcholinesterase↗
PubMed2003

Rapsyn N88K is a frequent cause of congenital myasthenic syndromes in European patients.

BACKGROUND: Mutations in various genes of the neuromuscular junction may cause congenital myasthenic syndromes (CMS). Most mutations identified to date affect the epsilon-subunit gene of the acetylcholine receptor (AChR), leading to end-plate AChR deficiency. Recently, three different mutations in the RAPSN gene have been identified in four CMS patients with AChR deficiency. OBJECTIVE: To perform mutation analysis of the RAPSN gene in patients with sporadic or autosomal recessive CMS. METHODS: One hundred twenty CMS patients from 110 unrelated families were analyzed for the RAPSN mutation N88K by restriction fragment length polymorphism and sequence analysis. RESULTS: In 12 CMS patients from 10 independent families, RAPSN N88K was identified either homozygous or heteroallelic to another missense mutation. Symptoms usually started perinatally or in the first years of life. However, one patient did not show any myasthenic symptoms before the third decade. Clinical symptoms typically included bilateral ptosis, weakness of facial, bulbar, and limb muscles, and a favorable response to anticholinesterase treatment. Crisis-like exacerbations with respiratory insufficiency provoked by stress, fever, or infections in early childhood were frequent. All RAPSN N88K families originate from Central or Western European countries. Genotype analysis indicated that they derive from a common ancestor (founder). CONCLUSIONS: The RAPSN mutation N88K is a frequent cause of rapsyn-related CMS in European patients. In general, patients (RAPSN N88K) were characterized by mild to moderate myasthenic symptoms with favorable response to anticholinesterase treatment. However, severity and onset of symptoms may vary to a great extent.

Adolescent↗
PubMed2002

[Experiences with ambulatory arteriovenous shunt surgery. A cost-benefit analysis].

Placement of arteriovenous (av) fistulas has been executed at the reporting surgical department for 3 years. Calculation of the reimbursement by the insurance companies is based on the so-called "Unique Evaluation Table" (Einheitlicher Bewertungsmassstab). The aim of the study was to evaluate the efficiency of the placement of av fistulas in an out-patient setting and the acceptance of this approach in the patients. The costs based on an average of the duration of the intervention and treatment at the out-patient clinic per time unit for surgeon, nurse and operating room, as well as costs for use of specific materials were listed, summarized, and compared with the amount of money which was reimbursed by the insurance companies according to the "Unique Evaluation Table". During the 3-year time period, 67 patients underwent 70 placements of av fistulas in an out-patient setting (in total, 532 interventions). Patients answered a questionnaire, and procedures were evaluated for average costs. Based on the table-dependent reimbursement of DM 274.00 (according to the "Unique Evaluation Table"), costs of DM 497.94 (DM 445.50 for 54 min of mean duration of surgical procedure plus DM 52.44 for materials) were determined, indicating that no full reimbursement was found despite the fact that there was only a minimal rate of early complications (thrombosis, n = 2 [3%]) (infection, n = 1 [1.5%]). The expenses were 81.7% on average above the level of the reimbursement. In conclusion, despite high acceptance of an out-patient setting for placement of av fistulas in patients (82%), it is not efficient from an economic point of view and can be only provided for specifically selected cases. Therefore, it is not advisable at present to place av fistulas at German out-patient clinics with no following admission of the patients, to avoid financial disadvantages for the surgical department. New negotiations between the medical profession and the insurance companies are urgently needed to ensure an improved financial outcome for the clinics.

Ambulatory Surgical Procedures↗
PubMed2002

[Fistula Banding - Success-promoting Approach in Peripheral Steal Syndrome].

AIM: Evaluation of the diagnostic and therapeutic management of peripheral steal syndrome after placement of an autologous arteriovenous (av-) fistula and presentation of treatment results after its surgical correction. METHODS: During a time period from 1994 to 1999, 1 253 av-fistulas for hemodialysis were placed in our surgical department. Twenty-one patients (1.68 %) underwent service operations because of considerable lower perfusion of the hand. In 14 patients the av-fistula was ligated, whereas in 7 patients, a polytetrafluorethylene (PTFE) sleeve was implanted at the venous site for fistula "banding" to diminish blood flow. In addition to the clinical finding, pre-, intra- and postoperative blood flow rates were determined using Duplex ultrasonography. RESULTS: In patients showing flow rates of < 250 ml (carefully disclosed empiric value) ligation was chosen, whereas in cases with distinctly increased flow rates, banding of the arterialized vein was performed (authors' individually selected borderline flow). The extension of the banding was specified according to the intraoperatively determined flow rates. Recurrent steal syndrome was not observed over the entire postoperative observation period of 1-3 years. CONCLUSION: Arterial steal syndrome is a rare complication after placement of an av-fistula. In the majority of cases, surgical therapy is necessary. Pre- and intraoperative analysis of flow rates using Duplex ultrasonography may help to select the appropriate surgical approach and may, thus, determine the success rate of service operation.

Adult↗
PubMed1988

[Subcutaneous vascular access].

Experiences with 246 subcutaneous vascular access operations and general principles of these techniques are presented. After exclusion of early cases of fistula thrombosis an average patency time of 28.6 months was obtained.

Arteriovenous Shunt, Surgical↗