We describe 5 patients with a relapsing encephalopathy in association with Hashimoto's disease and high titers of anti-thyroid antibodies. The presentation is usually with a subacute onset of confusion, alteration in conscious level, and focal or generalized seizures. The relapsing course, association with myoclonus or tremulousness, and episodes of stroke-like deterioration are characteristic features. The long-term prognosis is favorable with steroid therapy, though additional immunosuppressive therapy may be required. Neurologic investigation typically shows a diffusely abnormal EEG, high CSF protein level without pleocytosis, and normal brain CT and cerebral angiogram. Isotope brain scan may show patchy abnormal uptake. Hashimoto's encephalopathy should be recognized as a definite neurologic entity and added to the list of CNS complications of thyroid disease.

Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed whole-exome sequencing to determine the underlying defect in a group of individuals with an inherited limb-girdle pattern of myasthenic weakness. We identify DPAGT1 as a gene in which mutations cause a congenital myasthenic syndrome. We describe seven different mutations found in five individuals with DPAGT1 mutations. The affected individuals share a number of common clinical features, including involvement of proximal limb muscles, response to treatment with cholinesterase inhibitors and 3,4-diaminopyridine, and the presence of tubular aggregates in muscle biopsies. Analyses of motor endplates from two of the individuals demonstrate a severe reduction of endplate acetylcholine receptors. DPAGT1 is an essential enzyme catalyzing the first committed step of N-linked protein glycosylation. Our findings underscore the importance of N-linked protein glycosylation for proper functioning of the neuromuscular junction. Using the DPAGT1-specific inhibitor tunicamycin, we show that DPAGT1 is required for efficient glycosylation of acetylcholine-receptor subunits and for efficient export of acetylcholine receptors to the cell surface. We suggest that the primary pathogenic mechanism of DPAGT1 mutations is reduced levels of acetylcholine receptors at the endplate region. These individuals share clinical features similar to those of congenital myasthenic syndrome due to GFPT1 mutations, and their disorder might be part of a larger subgroup comprising the congenital myasthenic syndromes that result from defects in the N-linked glycosylation pathway and that manifest through impaired neuromuscular transmission.

Congenital myasthenic syndromes are associated with impairments in neuromuscular transmission. Belaya et al. show that mutations of the glycosylation pathway enzyme GMPPB, which has previously been implicated in muscular dystrophy dystroglycanopathy, also cause a congenital myasthenic syndrome. This differential diagnosis is important to ensure that affected individuals receive appropriate medication.

The properties of neuromuscular junctions (NMJs) were studied in motor-point biopsy samples from eight patients with congenital myasthenic syndromes affecting primarily proximal limb muscles ['limb-girdle myasthenia' (LGM)]. All had moderate to severe weakness of the proximal muscles, without short-term clinical fatigability but with marked variation in strength over periods of weeks or months, with little or no facial weakness or ptosis and no ophthalmoplegia. Most had a characteristic gait and stance. All patients showed decrement of the compound muscle action potential (CMAP) on repetitive stimulation at 3 Hz, and increased jitter and blocking was detected by SFEMG, confirming the presence of impaired neuromuscular transmission. None of the patients had serum antibodies against acetylcholine receptors (AChRs). Two of the patients had similarly affected siblings. Intracellular recording from isolated nerve-muscle preparations revealed that the quantal content (the number of ACh quanta released per nerve impulse) was only approximately 50% of that in controls. However, the quantal size (amplitude of miniature end-plate currents) and the kinetic properties of synaptic potentials and currents were similar to control values. The area of synaptic contact and extent of post-synaptic folding were approximately 50% of control values. Thus, the quantal content per unit area of synaptic contact was normal. The number of AChRs per NMJ was also reduced to approximately 50% of normal, so the local AChR density was normal. Immunolabelling studies revealed qualitatively normal distributions and abundance of each of 14 proteins normally concentrated at the NMJ, including components of the basal lamina, post-synaptic membrane and post-synaptic cytoskeleton. DNA analysis failed to detect mutations in the genes encoding any of the following proteins: AChR subunits, rapsyn, ColQ, ChAT or muscle-specific kinase. Response of these patients to treatment was varied: few showed long-term improvement with pyridostigmine and some even deteriorated with treatments, while others had intolerable side-effects. Several patients showed improvement with 3,4-diaminopyridine, but this was generally only transient. Ephedrine was helpful in half of the patients. We conclude that impaired neuromuscular transmission in these LGM patients results from structural abnormalities of the NMJ, including reduced size and post-synaptic folding, rather from any abnormality in the immediate events of neuromuscular transmission.

Endplate acetylcholinesterase (AChE) consists of globular catalytic subunits attached to the basal lamina by a collagen-like tail. Different genes encode the catalytic subunit and the tail portion of the enzyme. Endplate AChE deficiency was reported previously in a single case (Engel et al., 1977, patient 1). We describe here our observations in four additional patients (patients 2-5). Three cases were sporadic; patients 2 and 3 were sisters. All had generalized weakness increased by exertion but ophthalmoparesis was not a constant feature. All had mild slowing of the pupillary light reflex; other dysautonomic features were absent. None benefited from anticholinesterase therapy. All patients had a decremental electromyogram response; in four of the five patients, single nerve stimuli evoked a repetitive response. Miniature endplate potential amplitude was reduced in patient 5 only. Endplate amplitudes and currents were prolonged but the open-time of the acetylcholine receptor ion channel was normal. In patients 1-4 the quantal content of the endplate potential was reduced due to a reduced number of readily releasable quanta. Quantitative electron microscopy revealed abnormally small nerve terminals, abnormal encasement of the presynaptic membrane by Schwann cells and degeneration of junctional folds and of organelles in the junctional sarcoplasm. Acetylcholinesterase was absent from all endplates of all patients by cytochemical and immunocytochemical criteria. Density gradient ultracentrifugation of muscle extracts from patients 1, 3, 4 and 5 revealed an absence of the collagen-tailed form of the enzyme in patients 1, 3 and 4 but not in patient 5. The kinetic properties of the residual AChE in muscle were normal. Erythrocyte AChE activity and Km values, determined in three patients, were also normal. Studies of the catalytic subunit gene of AChE in patients 2 and 3 revealed no abnormality in those exons that encode the domain to which the tail subunit binds. In patients 1-4 the molecular defect is likely to reside in the gene encoding the tail subunit of AChE, or in a protein necessary to assemble the catalytic and tail subunits. In patient 5, the absence of AChE from the endplate may be due to a faulty tail subunit, a defect in the basal lamina site that binds the tail subunit or failure of transport of the assembled asymmetric enzyme from the cell interior to the basal lamina. The cause of the weakness in these patients is not fully understood but possible mechanisms are discussed.