Presynaptic congenital myasthenic syndrome with altered synaptic vesicle homeostasis linked to compound heterozygous sequence variants in RPH3A.

Background: Monogenic defects of synaptic vesicle (SV) homeostasis have been implicated in many neurologic diseases, including autism, epilepsy, and movement disorders. In addition, abnormal vesicle exocytosis has been associated with several endocrine dysfunctions.

Methods: We report an 11 year old girl with learning disabilities, tremors, ataxia, transient hyperglycemia, and muscle fatigability responsive to albuterol sulfate.

Neuropathological evaluation of an 84-year-old man after 422 ECT treatments.

Concern remains among many that electroconvulsive therapy (ECT) causes "brain damage." This ambiguous term presumably refers to lesions that could, in principle, be observed either grossly or microscopically in postmortem studies, and the assertion that it occurs appears to be based largely on old reports with dubious relevance to modern practice. Fortunately, using modern technique, ECT is so safe that mortality around the time of treatment is extraordinarily rare and as a result there has been little opportunity for postmortem examination of individuals who had recently had ECT.

Acute encephalopathy as the initial manifestation of CADASIL.

A 29-year-old right-handed G1P1 Caucasian woman presented with acute bifrontal headache (which resolved within 1 day), confusion, and difficulty using her right hand on postpartum day 10. She did not report nausea, vomiting, or visual complaints. The patient was previously healthy except for her recent preeclampsia, which required emergent cesarean section.

Advanced neuroimaging studies in a patient with brain metastases from transitional cell carcinoma of the bladder.

Background And Purpose: The differential diagnosis in single or oligo-brain lesions in metastatic cancer patients remains broad. Advanced imaging studies can be employed to help refine the differential and potentially guide treatment.

Methods: Case report of a 52-year-old male patient with known transitional cell carcinoma of the bladder presented with headaches, cognitive symptoms, and episodic presyncope.

Exome sequencing detection of two untranslated GFPT1 mutations in a family with limb-girdle myasthenia.

The term 'limb-girdle myasthenia' (LGM) was first used to describe three siblings with proximal limb weakness without oculobulbar involvement, but with EMG decrement and responsiveness to anticholinesterase medication. We report here that exome sequencing in the proband of this family revealed several sequence variations in genes linked to proximal limb weakness. However, the only mutations that cosegregated with disease were an intronic IVS7-8A>G mutation and the previously reported 3'-UTR c.

Synaptic basal lamina-associated congenital myasthenic syndromes.

Proteins associated with the basal lamina (BL) participate in complex signal transduction processes that are essential for the development and maintenance of the neuromuscular junction (NMJ). Most important junctional BL proteins are collagens, such as collagen IV (α3-6), collagen XIII, and ColQ; laminins; nidogens; and heparan sulfate proteoglycans, such as perlecan and agrin. Mice lacking Colq (Colq(-/-)), laminin β2 (Lamb2(-/-)), or collagen XIII (Col13a1(-/-)) show immature nerve terminals enwrapped by Schwann cell projections that invaginate into the synaptic cleft and decrease contact surface for neurotransmission.

Histopathologic changes in the extraocular muscle in centronuclear myopathy with a Dynamin 2 mutation.

Background: Centronuclear myopathy (CNM) is a rare inherited neuromuscular disorder characterized by centrally placed nuclei in striated muscle. In this report, we describe the histological changes in the extraocular muscle (EOM) from a CNM patient with a mutation in Dynamic 2 (DNM2).

Materials And Methods: A 33-year-old Caucasian female presented with horizontal diplopia and left exotropia for 6 months prior to which she was asymptomatic.

LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin.

We describe a severe form of congenital myasthenic syndrome (CMS) caused by two heteroallelic mutations: a nonsense and a missense mutation in the gene encoding agrin (AGRN). The identified mutations, Q353X and V1727F, are located at the N-terminal and at the second laminin G-like (LG2) domain of agrin, respectively. A motor-point muscle biopsy demonstrated severe disruption of the architecture of the neuromuscular junction (NMJ), including: dispersion and fragmentation of endplate areas with normal expression of acetylcholinesterase; simplification of postsynaptic membranes; pronounced reduction of the axon terminal size; widening of the primary synaptic cleft; and, collection of membranous debris material in the primary synaptic cleft and in the subsynaptic cytoplasm.

Acute severe animal model of anti-muscle-specific kinase myasthenia: combined postsynaptic and presynaptic changes.

Objectives: To determine the pathogenesis of anti-muscle-specific kinase (MuSK) myasthenia, a newly described severe form of myasthenia gravis associated with MuSK antibodies characterized by focal muscle weakness and wasting and absence of acetylcholine receptor antibodies, and to determine whether antibodies to MuSK, a crucial protein in the formation of the neuromuscular junction (NMJ) during development, can induce disease in the mature NMJ. Design, Setting, and

Participants: Lewis rats were immunized with a single injection of a newly discovered splicing variant of MuSK, MuSK 60, which has been demonstrated to be expressed primarily in the mature NMJ. Animals were assessed clinically, serologically, and by repetitive stimulation of the median nerve.

The L-coding region of the DA strain of Theiler's murine encephalomyelitis virus causes dysfunction and death of myelin-synthesizing cells.

The DA strain and other members of the TO subgroup of Theiler's murine encephalomyelitis virus (TMEV) induce an early transient subclinical neuronal disease followed by a chronic progressive inflammatory demyelination, with persistence of the virus in the central nervous system (CNS) for the life of the mouse. Although TMEV-induced demyelinating disease (TMEV-IDD) is thought to be immune mediated, there is also evidence that supports a role for the virus in directly inducing demyelination. In order to clarify the function of DA virus genes, we generated a transgenic mouse that had tamoxifen-inducible expression of the DA L-coding region in oligodendrocytes (and Schwann cells), a cell type in which the virus is known to persist.

Congenital myasthenic syndrome associated with epidermolysis bullosa caused by homozygous mutations in PLEC1 and CHRNE.

Mutations in the plectin gene (PLEC1) cause epidermolysis bullosa simplex (EBS), which may associate with muscular dystrophy (EBS-MD) or pyloric atresia (EBS-PA). The association of EBS with congenital myasthenic syndrome (CMS) is also suspected to result from PLEC1 mutations. We report here a consanguineous patient with EBS and CMS for whom mutational analysis of PLEC1 revealed a homozygous 36 nucleotide insertion (1506_1507ins36) that results in a reduced expression of PLEC1 mRNA and plectin in the patient muscle.

Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction.

We describe a severe congenital myasthenic syndrome (CMS) caused by two missense mutations in the gene encoding the muscle specific receptor tyrosine kinase (MUSK). The identified MUSK mutations M605I and A727V are both located in the kinase domain of MuSK. Intracellular microelectrode recordings and microscopy studies of the neuromuscular junction conducted in an anconeus muscle biopsy revealed decreased miniature endplate potential amplitudes, reduced endplate size and simplification of secondary synaptic folds, which were consistent with postsynaptic deficit.

Fingolimod and related compounds in a spontaneous autoimmune polyneuropathy.

We investigated potential therapeutic effects of sphingosine-1-phosphate (S1P) receptor modulators FTY720 (fingolimod) and selective S1P1 agonist SEW2871 on a spontaneous autoimmune polyneuropathy (SAP) when given orally at 7 mo (anticipated disease onset) for 4 weeks. Clinical severity, electrophysiologic and histological findings were ameliorated in mice treated with 1 mg/kg of FTY720. Subsequent studies showed that SEW2871 was also effective in halting the progression of SAP, which was accompanied by decreased proliferative and cytokine responses to myelin protein zero (P0), and an increase in regulatory T cells.

Mutations in LAMB2 causing a severe form of synaptic congenital myasthenic syndrome.

Background: We describe a severe form of congenital myasthenic syndrome (CMS) associated with congenital nephrosis and ocular malformations caused by two truncating mutations in the gene encoding the laminin beta2 subunit (LAMB2).

Methods And Results: Mutational analysis in the affected patient, who has a history of a serious untoward reaction to treatment with acetylcholinesterase inhibition, revealed two frame-shifting heteroallelic mutations, a maternally inherited 1478delG and a paternally inherited 4804delC. An anconeus muscle biopsy demonstrated a profound distortion of the architecture and function of the neuromuscular junction, which was strikingly similar to that seen in mice lacking laminin beta2 subunit.

A 59 year-old man with sellar lesion.

A 59 year-old man presented with a large sellar mass. Pathologic examination revealed a tumor with two distinct cell populations. The majority of the tumor showed typical pituitary gonadotroph adenoma morphology and staining.

Nur7 is a nonsense mutation in the mouse aspartoacylase gene that causes spongy degeneration of the CNS.

Aspartoacylase (ASPA) is an oligodendrocyte-restricted enzyme that catalyzes the hydrolysis of neuronally derived N-acetylaspartate (NAA) to acetate and aspartic acid. ASPA deficiency leads to the fatal childhood autosomal recessive leukodystrophy Canavan disease (CD). Here we demonstrate that the previously described ENU-induced nur7 mouse mutant is caused by a nonsense mutation, Q193X, in the Aspa gene (Aspa(nur7)).

Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection.

Background: Worldwide, approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences.

Methods: To better understand long-term effects and pathogenesis of this common, persistent brain infection, mice were infected at a time in human years equivalent to early to mid adulthood and studied 5-12 months later. Appearance, behavior, neurologic function and brain MRIs were studied.

A subgenomic segment of Theiler's murine encephalomyelitis virus RNA causes demyelination.

The DA strain of Theiler's murine encephalomyelitis virus (TMEV) causes a persistent central nervous system (CNS) infection of mice with a restricted virus gene expression and induces an inflammatory demyelinating disease that is thought to be immune mediated and a model of multiple sclerosis (MS). The relative contribution of virus vis-à-vis the immune system in the pathogenesis of DA-induced white matter disease remains unclear, as is also true in MS. To clarify the pathogenesis of DA-induced demyelination, we used Cre/loxP technology to generate a transgenic mouse that has tamoxifen (Tm)-inducible expression of a subgenomic segment of DA RNA in oligodendrocytes and Schwann cells.

Variable phenotypes associated with mutations in DOK7.

Many patients with the limb-girdle variant of congenital myasthenic syndrome (CMS) possess mutations in the human Dok-7 gene (DOK7). We identified six unrelated CMS patients with DOK7 mutations. Two patients, one mildly and the other moderately affected, were homozygous for the previously described 1263insC mutation.

Proprioceptive sensory neuropathy in mice with a mutation in the cytoplasmic Dynein heavy chain 1 gene.

Mice heterozygous for the radiation-induced Sprawling (Swl) mutation display an early-onset sensory neuropathy with muscle spindle deficiency. The lack of an H reflex despite normal motor nerve function in the hindlimbs of these mutants strongly suggests defective proprioception. Immunohistochemical analyses reveal that proprioceptive sensory neurons are severely compromised in the lumbar dorsal root ganglia of newborn Swl/+ mice, whereas motor neuron numbers remain unaltered even in aged animals.