The congenital myasthenic syndromes: expanding genetic and phenotypic spectrums and refining treatment strategies.

PURPOSE OF REVIEW: Congenital myasthenic syndromes (CMS) are a group of heterogeneous inherited disorders caused by mutations in genes encoding proteins whose function is essential for the integrity of neuromuscular transmission. This review updates the reader on the expanding phenotypic spectrum and suggested improved treatment strategies. RECENT FINDINGS: As next-generation sequencing is taken into the clinic, its use is both continuing to unearth new causative genes in which mutations underlie CMS and also broadening the phenotypic spectrum for known CMS genes. The number of genes in which mutations may cause neuromuscular transmission defects has now passed 30. The defective transmission may be part of an overall more complex phenotype in which there may be muscle, central nervous system or other involvement. Notably, mutations in series of genes encoding proteins located in the presynatic motor bouton have been identified. Rare cases of mutations in basal laminar proteins of the synaptic cleft are coming to light and additional mutations/phenotypic features have been located in some of the larger neuromuscular junction proteins such as AGRN and MUSK, where previously mutation screening by sanger sequencing was time consuming and costly. Finally, there are more reports of the beneficial effects of treatment with β2-adrenergic receptor agonists in patients, and the study of their action in disease models. SUMMARY: Recent studies of the CMS illustrate the increasing complexity of the genetics and pathophysiological mechanisms involved. With therapy tailored for the underlying disease mechanism treatment, although incomplete, is usually life-transforming. However, treatment for newly identified conditions in which myasthenia is only one component within complex multisystem disorder will prove challenging.Welllcome trus

Megaoesofagus bij hond en kat

Megaoesofagus wordt gekarakteriseerd door een gedilateerde slokdarm met een verminderde peristaltiek. Het is de meest voorkomende oorzaak van regurgitatie bij de hond. De ziekte komt zelden voor bij de kat. De aandoening kan congenitaal zijn of verworven worden. Bij de aangeboren vorm komen de symptomen meestal pas tot uiting rond de speenleeftijd. Een erfelijke basis werd aangetoond bij bepaalde rassen. De verworven vorm ontstaat meestal op volwassen leeftijd, met een erg ruime leeftijdsmarge. Regurgitatie en ademhalingsproblemen zijn de meest voorkomende symptomen. De diagnose wordt gesteld door middel van radiografie of fluoroscopie. Bijkomende onderzoeken zijn doorgaans aangewezen om een onderliggende oorzaak op te sporen. In ongeveer de helft van de gevallen wordt geen onderliggende oorzaak gevonden en wordt de megaoesofagus beschouwd als zijnde idiopathisch. Patiënten met megaoesofagus worden meestal conservatief en symptomatisch behandeld. De onderliggende ziekte, slechte voeding en verslikkingspneumonie vereisen een directe en grondige aanpak. De prognose is vaak gereserveerd bij de hond. Bij congenitale megaoesofagus beschrijft men iets gunstigere vooruitzichten. Katten lijken beter te reageren op de ingestelde behandeling

Insulinoma bij de hond, deel 2: een retrospectieve studie van 23 gevallen (2002-2008)

Twenty-three dogs with insulinoma were included in this retrospective study. These tumors were mostly found in middle-aged to old dogs, weighing over 25 kg. The most important symptoms were weakness, seizures and collapse. The mean duration of clinical signs before referral was 5 months. Interestingly, the onset of clinical signs was reported more frequently during the summer months. Paired serum glucose and insulin concentrations were measured in all dogs. Fructosamine concentrations were measured in more than one third of the cases, all showing levels lower than normal (258 mu mol/l). In 50% of the dogs, abdominal ultrasound detected signs of an insulinoma, but only in one third of the cases nodules were visible. Scintigraphy, with the radiopharmaceutical drug Indium-111 pentetreotide, was performed in 6 dogs, with a detection rate of 83%. Electrophysiological examination of 3 dogs confirmed the clinical signs of an insulinoma-associated polyneuropathy. Histopathological examination of 5 dogs demonstrated the presence of an insulinoma. In one third of the dogs metastases were present at the time of diagnosis. The mean survival time after diagnosis was 10,3 months. There was no significant difference in survival between the medicinally and surgically treated group. However, it is difficult to make a definitive conclusion, because of the low number of surgically treated dogs

Retrospectieve studie van 20 honden en 1 kat met tetanus (2001-2008)

In 20 dogs and I cat a diagnosis of tetanus was made based on the typical clinical signs and a possible wound history. In 7 animals a tooth abnormality was considered as the entrance way of the bacteria. By means of radiography of the thorax several animals were evaluated for the presence of possible complications such as aspiration pneumonia, megaoesophagus or hiatal hernia. The treatment existed mainly of metronidazole as an antibiotic, acetylpromazine to control the muscle spasms and additional supportive therapy. The survival rate was 71%

Effect of salbutamol on neuromuscular junction function and structure in a mouse model of DOK7 congenital myasthenia.

Congenital myasthenic syndromes (CMS) are characterized by fatigable muscle weakness resulting from impaired neuromuscular transmission. β2-adrenergic agonists are an effective treatment for DOK7-CMS. DOK7 is a component within the AGRN-LRP4-MUSK-DOK7 signalling pathway that is key for the formation and maintenance of the synaptic structure of the neuromuscular junction (NMJ). The precise mechanism of action of β2-adrenergic agonists at the NMJ is not fully understood. In this study, we investigated whether β2-adrenergic agonists improve both neurotransmission and structural integrity of the NMJ in a mouse model of DOK7-CMS. Ex-vivo electrophysiological techniques and microscopy of the NMJ were used to study the effect of salbutamol, a β2-adrenergic agonist, on synaptic structure and function. DOK7-CMS model mice displayed a severe phenotype with reduced weight gain and perinatal lethality. Salbutamol treatment improved weight gain and survival in DOK7 myasthenic mice. Model animals had fewer active NMJs, detectable by endplate recordings, compared with age-matched wild-type littermates. Salbutamol treatment increased the number of detectable NMJs during endplate recording. Correspondingly, model mice had fewer acetylcholine receptor-stained NMJs detected by fluorescent labelling, but following salbutamol treatment an increased number were detectable. The data demonstrate that salbutamol can prolong survival and increase NMJ number in a severe model of DOK7-CMS

Effect of radiotherapy on freedom from seizures in dogs with brain tumors.

BACKGROUND: Seizures are a common presenting sign in dogs with brain tumors. HYPOTHESIS/OBJECTIVES: To investigate the effect of radiotherapy on freedom from brain tumor-associated seizures and survival time in dogs. ANIMALS: Thirty-two client-owned dogs with brain tumor-associated seizures; 18 received medical treatment and radiotherapy, 14 received medical treatment alone. METHODS: Multicenter retrospective study. Baseline characteristics (seizure semiology, magnetic resonance imaging [MRI] characteristics, and treatment) and duration of seizure freedom were recorded for the 2 treatment groups. Duration of seizure freedom between groups was compared (log-rank test) using Cox's proportional hazard analysis, with baseline characteristics entered as covariates. RESULTS: The duration of seizure freedom and survival time were significantly longer in the radiotherapy group (P < .001), with a mean of 24 months (95% confidence interval [CI], 14.3-33.8) versus 1.7 months in the control group (95% CI, 0.5-2.9) and a mean of 34.6 months (95% CI: 25.2-44.1) versus 6.2 months in the control group (95% CI, 2.6-9.7) respectively. Baseline characteristics were not associated with duration of seizure freedom after the start of treatment. In the radiotherapy group, 5 dogs were euthanized during the study period because of causes other than seizures. In the control group, recurrence of seizures was observed before death in all dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: A longer period of seizure freedom and longer survival time was observed in dogs with brain tumors after radiotherapy compared to medical treatment only. The pathophysiological mechanisms of epileptogenesis and the effect of radiation therapy on seizure control are unclear to date. Further prospective studies are needed

Discospondylitis bij de hond: een retrospectieve studie van 18 gevallen

In a retrospective study (1997-2007) of 35 patients suspected of discospondylitis (DS), the diagnosis of discospondylitis was confirmed in 18 dogs. The signalment, the appearance and the clinical presentation of the dogs were comparable to those earlier reported in the literature. Radiography was the most important diagnostic technique, but in some cases further diagnostic investigation was necessary to confirm the diagnosis. Blood- and urine culture was important to identify a possible underlying cause. Medical therapy is the treatment of choice. Most of the dogs (76%) recovered very well after treatment. The results confirm that discospondylitis has a rather favorable prognosis when medical therapy is used

Rapsyn facilitates recovery from desensitization in fetal and adult acetylcholine receptors expressed in a muscle cell line.

KEY POINTS: The physiological significance of the developmental switch from fetal to adult acetylcholine receptors in muscle (AChRs) and the functional impact of AChR clustering by rapsyn are not well studied. Using patch clamp experiments, we show that recovery from desensitization is faster in the adult AChR isoform. Recovery from desensitization is determined by the AChR isoform-specific cytoplasmic M3-M4 domain. The co-expression of rapsyn in muscle cells induced AChR clustering and facilitated recovery from desensitization in both fetal and adult AChRs. In fetal AChRs, facilitation of recovery kinetics by rapsyn was independent of AChR clustering. These effects could be crucial adaptations to motor neuron firing rates, which, in rodents, have been shown to increase around the time of birth when AChRs cluster at the developing neuromuscular junctions. ABSTRACT: The neuromuscular junction (NMJ) is the site of a number of autoimmune and genetic disorders, many involving the muscle-type nicotinic acetylcholine receptor (AChR), although there are aspects of normal NMJ development and function that need to be better understood. In particular, there are still questions regarding the implications of the developmental switch from fetal to adult AChRs, as well as how their functions might be modified by rapsyn that clusters the AChRs. Desensitization of human muscle AChRs was investigated using the patch clamp technique to measure whole-cell currents in muscle-type (TE671/CN21) and non-muscle (HEK293) cell lines expressing either fetal or adult AChRs. Desensitization time constants were similar with both AChR isoforms but recovery time constants were shorter in cells expressing adult compared to fetal AChRs (P < 0.0001). Chimeric experiments showed that recovery from desensitization was determined by the M3-M4 cytoplasmic loops of the γ- and ε-subunits. Expression of rapsyn in TE671/CN21 cells induced AChR aggregation and also, surprisingly, shortened recovery time constants in both fetal and adult AChRs. However, this was not dependent on clustering because rapsyn also facilitated recovery from desensitization in HEK293 cells expressing a δ-R375H AChR mutant that did not form clusters in C2C12 myotubes. Thus, rapsyn interactions with AChRs lead not only to clustering, but also to a clustering independent faster recovery from desensitization. Both effects of rapsyn could be a necessary adjustment to the motor neuron firing rates that increase around the time of birth