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

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

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

Medical management of spinal epidural empyema in five dogs

CASE DESCRIPTION 5 dogs were examined because of clinical signs of myelopathy, including signs of pain associated with the spinal region and rapidly progressive neurologic deficits. CLINICAL FINDINGS In all dogs, results of MRI were consistent with spinal epidural empyema. Concurrent infectious processes were identified at adjacent or distant sites in all dogs, including diskospondylitis, prostatitis, dermatitis, paraspinal infection following a penetrating injury, urinary tract infection, and pyothorax. Bacteria were isolated from 3 dogs; Escherichia coli was isolated from blood, urine, and prostatic wash samples from 1 dog; a Pasteurella sp was isolated from a percutaneous aspirate from an adjacent infected wound in a second dog; and a Corynebacterium sp was isolated from a thoracic fluid sample from a third dog. For the remaining 2 dogs, results of bacterial culture were negative. TREATMENT AND OUTCOME All dogs showed clinical improvement within 2 weeks after initiation of antimicrobial treatment, and all had an excellent long-term outcome. CLINICAL RELEVANCE In dogs, spinal epidural empyema has previously been regarded as a surgical emergency. Findings for dogs in the present report suggested that, as is the case for humans, selected dogs with spinal epidural empyema may be successfully managed with medical treatment alone

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs.

SeSAME/EAST syndrome is a multisystemic disorder in humans, characterised by seizures, sensorineural deafness, ataxia, developmental delay and electrolyte imbalance. It is exclusively caused by homozygous or compound heterozygous variations in the KCNJ10 gene. Here we describe a similar syndrome in two families belonging to the Malinois dog breed, based on clinical, neurological, electrodiagnostic and histopathological examination. Genetic analysis detected a novel pathogenic KCNJ10 c.986T>C (p.(Leu329Pro)) variant that is inherited in an autosomal recessive way. This variant has an allele frequency of 2.9% in the Belgian Malinois population, but is not found in closely related dog breeds or in dog breeds where similar symptoms have been already described. The canine phenotype is remarkably similar to humans, including ataxia and seizures. In addition, in half of the dogs clinical and electrophysiological signs of neuromyotonia were observed. Because there is currently no cure and treatment is nonspecific and unsatisfactory, this canine translational model could be used for further elucidating the genotype/phenotype correlation of this monogenic multisystem disorder and as an excellent intermediate step for drug safety testing and efficacy evaluations before initiating human studies