Barbara E. Shapiro

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.

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.

Mechanisms of confabulation

Patients who exhibited frank confabulation were examined with four tests designed to elucidate the nature of confabulation in a structured situation, test the ability of confabulators to use cues, and examine the degree to which certain cognitive deficits are associated with confabulation. Two groups of confabulators emerged: mild and severe. Severity of confabulation was associated with perseveration, impaired self-monitoring facility, and failure to inhibit incorrect responses. Attenuation of these cognitive deficits with resolution of confabulation in a single patient suggested that the two levels of confabulation represented different levels of impairment of the same disorder.

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.

Delayed radiation-induced bulbar palsy

We report a man with a slowly progressive bulbar palsy 14 years after radiation therapy for nasopharyngeal carcinoma.Electromyography demonstrated prominent myokymic and neuromyotonic discharges in muscles innervated by the lower cranial nerves. Late effects of radiation therapy can occur in the cranial nerve musculature that are similar to well-recognized syndromes affecting the brachial plexus and spinal cord. NEUROLOGY 1996;46: 1604-1606

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. Muscle Nerve, 2005

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.

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%). Muscle Nerve, 2008

Late-onset Tay-Sachs disease: Adverse effects of medications and implications for treatment

The authors conducted a retrospective and brief prospective study of adverse effects of approximately 350 medications in 44 adults with late-onset Tay–Sachs disease (LOTS). Some medications were relatively safe, whereas others, particularly haloperidol, risperidone, and chlorpromazine, were associated with neurologic worsening.

Pulmonary arteriovenous fistula and brain abscess

A 23-year-old woman presented with 3 days of headache followed by complex partial seizures. Stereotactic aspiration of a large right temporal mass revealed purulent material with Gram-positive cocci …