Juvenile amyotrophic lateral sclerosis (ALS) with basophilic inclusions is a well-recognized entity. However, the molecular underpinnings of this devastating disease are poorly understood. Here, we present genetic and neuropathological characterizations in two young women with fatal rapidly progressive ALS with basophilic inclusions. In one case, a germline mutation (P525L) was detected in the FUS/TLS (fused in sarcoma/translocated in liposarcoma) gene, whereas no mutation was identified in the other case. Postmortem examination in both cases revealed severe loss of spinal motor neurons with remaining neurons showing basophilic inclusions that contain abnormal aggregates of FUS proteins and disorganized intracellular organelles, including mitochondria and endoplasmic reticulum. In both patients, the FUS-positive inclusions were also detected in neurons in layers IV-V of cerebral cortex and several brainstem nuclei. In contrast, spinal motor neurons in patients with late-onset sporadic ALS showed no evidence of abnormal accumulation of FUS protein. These results underscore the importance of FUS mutations and pathology in rapidly progressive juvenile ALS. Furthermore, our study represents the first detailed characterizations of neuropathological findings in rapidly progressive juvenile ALS patients with a mutation in the FUS/TLS gene.
Purpose: To evaluate the safety and efficacy of miglustat in patients with G M2 gangliosidosis. Methods: A randomized, multicenter, openlabel, 12-month study involving patients aged 18 years or older, randomized 2:1 to miglustat (200 mg TID) or "no miglustat treatment." This study was followed by 24 months of extended treatment during which all patients received miglustat. Primary efficacy endpoints were change in eight measures of isometric muscle strength in the limbs and isometric grip strength, evaluated at baseline, and months 12 and 36. Secondary efficacy endpoints included gait, balance, disability, and other neurological assessments. Safety evaluations included adverse event reporting. Results: Thirty patients (67% male, age range 18 -56 years) with late-onset Tay-Sachs disease were enrolled; 20 were randomized to miglustat and 10 to "no miglustat treatment." Muscle and grip strength generally decreased over the study period. No differences were observed between the two groups in any efficacy measure, either during the 12-month randomized phase or the full 36 months. The most common treatment-related adverse events were decrease in weight and diarrhea. Conclusion: Miglustat treatment was not shown to lead to measurable benefits in this cohort of patients with late-onset Tay-Sachs disease. The observed safety profile was consistent with that of the approved dose (100 mg TID) in type 1 Gaucher disease. Genet Med 2009:11(6):425-433.
Electrodiagnostic procedures are routinely performed in patients with a variety of neuromuscular disorders. These studies are generally well tolerated and rarely thought to be associated with any significant side effects. However, needle electromyography is an invasive procedure and under certain situations has the potential to be associated with iatrogenic complications, including bleeding, infection, nerve injury, pneumothorax, and other local trauma. Similar complications are possible if needles are used for either stimulating or recording. In addition, like all other electrical devices and monitoring equipment connected to patients, electrodiagnostic testing carries the risk of stray leakage currents that under certain circumstances can result in electrical injury, especially in patients in the intensive care setting. Similarly, certain precautions are required during nerve conduction studies (NCS) in patients with pacemakers and other similar cardiac devices. In this review, we address the known and theoretical complications of NCS and needle electrode examination, and the possible methods to avoid such hazards.
Patients with late-onset Tay-Sachs disease (LOTS) show characteristic abnormalities of saccades but normal afferent visual systems. Hypometria, transient decelerations, and premature termination of saccades suggest disruption of a "latch circuit" that normally inhibits pontine omnipause neurons, permitting burst neurons to discharge until the eye movement is completed. These measurable abnormalities of saccades provide a means to evaluate the effects of novel treatments for LOTS.
A brief monophasic pulse through an electromagnetic coil preferentially activates motor pathways of each hemisphere, depending on the direction of coil current flow. Using the preferred direction for each hemisphere, the minimum stimulus intensity (threshold) that evoked compound muscle action potentials in the contralateral abductor digiti minimi (ADM) muscle was significantly less for the left hemisphere than the right. Threshold for biceps on each side was significantly higher than ADM, but there was no side-to-side difference. Assessing handedness using a standard handedness index, those who had less tendency to use the right hand for everyday tasks had greater differences between hemispheres for ADM thresholds. The lower threshold of the left-hemisphere projection to hand muscles is probably related to the asymmetry of corticomotoneuronal monosynaptic connections; a greater number project to the motor neuron pool of the right- than left-hand muscles.
Tay-Sachs Disease is an autosomal recessive neurodegenerative disorder that is typically fatal within the first two or three years of life. Its incidence is highest among Ashkenazi Jews (Jews of Eastern European descent), approximately 100 times higher than in the general population. Juvenile and adult onset variants of the disease exist, but are extremely rare and will not be discussed here. The disease was characterized by two doctors working independently, resulting in its hyphenated name; a British physician named Warren Tay, and an American physician named Bernard Sachs. Tay, an ophthalmologist was, in 1881, the first to notice the characteristic red spot on the eye that is now considered a typical finding in the disease. Sachs, researching independently from Tay, began to characterize this syndrome, noting its familial characteristics and propensity to appear in Jewish children. In addition to the ophthalmologic findings made by Tay, Sachs, in 1887, characterized the disease as involving a halt to mental development, a deficiency in normal reflexes, progressive blindness, paresis, and mortality at about two years of age. 1
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