Miglustat in late-onset Tay-Sachs disease: a 12-month, randomized, controlled clinical study with 24 months of extended treatment.

PURPOSE: To evaluate the safety and efficacy of miglustat in patients with GM2 gangliosidosis. METHODS: A randomized, multicenter, open-label, 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.

Entrapment and compressive neuropathies.

Entrapment and compressive neuropathies of the upper and lower extremities are frequently encountered disorders in the office. Certain clinical clues in the history and examination, along with electrodiagnostic testing and imaging studies, often suggest the correct diagnosis. Some of the more common neuropathies are discussed, along with suggestions regarding testing and treatment.

Needle electromyography. Fundamentals, normal and abnormal patterns.

The needle electromyographic (EMG) examination is a challenging component of the electrophysiologic study. Knowledge of anatomy and physiology, sound EMG technique, and good patient rapport are required. Every muscle sampled by needle EMG is assessed for insertional activity, spontaneous activity, and voluntary motor-unit action potentials. Key pieces of information obtained from the needle EMG examination include the localization of the disorder, its chronicity, severity, and whether or not the underlying pathophysiology is neuropathic, myopathic, or associated with a neuromuscular junction disorder.

Repetitive nerve stimulation and exercise testing.

Repetitive nerve stimulation and exercise testing are useful in the evaluation of patients with suspected disorders of the NMJ and muscle membrane excitability when performed with close attention to technical factors. They can be very helpful in the diagnosis of myasthenia gravis. Lambert-Eaton myasthenic syndrome, and botulism, as well as rare disorders of skeletal muscle membrane excitability, including paramyotonia congenita, myotonia congenita, myotonic dystrophy, and the periodic paralyses.

Do brainstem omnipause neurons terminate saccades?

Saccade-generating burst neurons (BN) are inhibited by omnipause neurons (OPN), except during saccades. OPN activity pauses before saccade onset and resumes at the saccade end. Microstimulation of OPN stops saccades in mid-flight, which shows that OPN can end saccades. However, OPN pause duration does not correlate well with saccade duration, and saccades are normometric after OPN lesions. We tested whether OPN were responsible for stopping saccades both in late-onset Tay-Sachs, which causes premature saccadic termination, and in individuals with cerebellar hypermetria. We studied gaze shifts between two targets at different distances aligned on one eye, which consist of a disjunctive saccade followed by vergence. High-frequency conjugate oscillations during the vergence movements that followed saccades were present in all subjects studied, indicating OPN silence. Thus, mechanisms other than OPN discharge (e.g., cerebellar caudal fastigial nucleus-promoting inhibitory BN discharge) must contribute to saccade termination.

Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions.

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 fused in sarcoma/translocated in liposarcoma (FUS/TLS) 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.

Entrapment and compressive neuropathies.

Entrapment and compressive neuropathies of the upper and lower extremities are frequently encountered disorders in the office. Certain clinical clues in the history and examination, along with electrodiagnostic testing and imaging studies, often suggest the correct diagnosis. Some of the more common neuropathies are discussed, along with suggestions regarding testing and treatment.

Late-onset Tay-Sachs disease: the spectrum of peripheral neuropathy in 30 affected patients.

Late-onset Tay-Sachs (LOTS) disease is a chronic, progressive, lysosomal storage disorder caused by a partial deficiency of beta-hexosaminidase A (HEXA) activity. Deficient levels of HEXA result in the intracellular accumulation of GM2-ganglioside, resulting in toxicity to nerve cells. Clinical manifestations primarily involve the central nervous system (CNS) and lower motor neurons, and include ataxia, weakness, spasticity, dysarthria, dysphagia, dystonia, seizures, psychosis, mania, depression, and cognitive decline. The prevalence of peripheral nervous system (PNS) involvement in LOTS has not been well documented, but it has traditionally been thought to be very low. We examined a cohort of 30 patients with LOTS who underwent clinical and electrophysiologic examination, and found evidence of a predominantly axon loss polyneuropathy affecting distal nerve segments in the lower and upper extremities in eight patients (27%).

Adult polyglucosan body disease: a case report of a manifesting heterozygote.

A 62-year-old man developed progressive gait instability, bladder dysfunction, proximal weakness, distal sensory loss, and mild cognitive impairment over 6 years. Neurologic examination revealed upper and lower motor neuron dysfunction in the lower extremities, with distal sensory loss. Electrodiagnostic studies, magnetic resonance imaging of the brain, and sural nerve biopsy were consistent with adult polyglucosan body disease. Biochemical and genetic analyses demonstrated reduced glycogen brancher enzyme levels associated with a heterozygous point mutation (Tyr329Ser or Y329S) in the glycogen brancher enzyme gene on chromosome 3. Mutational heterozygosity in the glycogen brancher enzyme gene has not been previously reported as a cause for this rare disease. A review of the clinical presentation, pathogenesis, etiology, and diagnosis of this disease is presented.

Iatrogenic complications and risks of nerve conduction studies and needle electromyography.

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.

Lumbrical and interossei recording in severe carpal tunnel syndrome.

Patients with severe carpal tunnel syndrome (CTS) may occasionally have absent median motor and sensory responses; in these cases, it is not possible to accurately localize the median mononeuropathy to the wrist using standard electrodiagnostic tests. We prospectively investigated the use of comparing the median motor latency to the second lumbrical and the ulnar motor latency to the interossei muscles in 28 patient hands with severe CTS and absent median motor and sensory responses. We found a prolonged latency difference in 92.8%. Along with its use in mild CTS, study of the lumbrical-interossei latency difference is helpful in patients with severe CTS with absent median motor and sensory responses.