Ludwig Gutmann

DCTN1 mutations in Perry syndrome

Perry syndrome consists of early-onset parkinsonism, depression, severe weight loss and hypoventilation, with brain pathology characterized by TDP-43 immunostaining. We carried out genome-wide linkage analysis and identified five disease-segregating mutations affecting the CAP-Gly domain of dynactin (encoded by DCTN1) in eight families with Perry syndrome; these mutations diminish microtubule binding and lead to intracytoplasmic inclusions. Our findings show that DCTN1 mutations, previously associated with motor neuron disease, can underlie the selective vulnerability of other neuronal populations in distinct neurodegenerative disorders.

Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research

Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.

Current management of ALS: Comparison of the ALS CARE Database and the AAN Practice Parameter

Background: The American Academy of Neurology (AAN) ALS Practice Parameter was published in April 1999. The ALS CARE Database has been collecting data on the management of patients with ALS in North America since 1996. Objective: To compare the management of patients with ALS in North America as recorded in the ALS CARE Database with the recommendations of the AAN ALS Practice Parameter. Methods: Data were analyzed from 2018 patients at enrollment and from 373 of these patients who died between enrollment and May 1999. Results: Eighty-two percent of the enrolled patients reported that they had been given enough information about ALS. Only 54% of patients with drooling were receiving medication for this problem. Only 41% of those who reported being depressed most of the time were receiving antidepressant medications. Only 28% of those with dyspnea and only 9.2% of those with a forced vital capacity <40% predicted were receiving noninvasive positive pressure ventilator support. Only 30% of those with moderate to severe dysphagia had a gastrostomy tube. Half of the patients who died did so at home, but only 47% of them received residential hospice services. Although 89% of patients who died were recorded as having done so peacefully, 17% were reported to have had breathing difficulties (i.e., respiratory distress), 8% anxiety, 3.3% pain, and 2.5% choking. Advance directives were in place for 90% of the patients who died, and in 97% of cases these directives were followed. Conclusions: These findings indicate that in the 3-year period prior to the publication of the AAN Practice Parameter, many but not all patients received the care that is recommended in that parameter; there were deficiencies, particularly in the key areas of gastrostomy and noninvasive positive pressure ventilation.

Diabetic 3rd nerve palsy Evidence for a mesencephalic lesion

Eleven consecutive adult chronic diabetic patients presented with an isolated 3rd nerve palsy (8 with pupillary sparing) of which 10 had abnormal ipsilateral or bilateral masseter reflexes (MassR). Three patients had an MRI lesion in the ipsilateral oculomotor fasciculus and 3 had subsequent mild brainstem signs. An additional 13 patients with Webers syndrome had similar ipsilateral or bilateral MassR abnormalities, while 7 patients with 3rd nerve palsies on a known extra-axial basis had none. The findings suggest that an isolated diabetic 3rd nerve palsy, with or without pupillary sparing, is much more likely on the basis of a focal mesencephalic infarct than a peripheral nerve lesion.

Picornavirus‐like crystals in subacute polymyositis

RECENT STUDIES suggest that viruses may play a role in the etiology of poIymyositis-dermatomyositis. Myxovirus-like structures have been demonstrated in both sarcolemmal nuclei and sarcoplasm of muscle biopsy specimens obtained from a patient with chronic polymyositis.lV2 These structures were observed in 3 specimens taken during an eighteen-month period, suggesting that a chronic virus infection was involved in the pathogenesis of chronic polymyositis. Two other patients with clinicopathological diagnosis of chronic polymyositis demonstrated similar findings.3,4 The complexity and variability of the clinical pictures described in cases of polymyositis does not, however, permit the generalization that the disease might be related to a single etiologic agent. Because many different neurotropic viruses are known to cause muscle infections in mice,6 it seems reasonable to assume that different viral agents may play a pathogenic role in different types of human polymyositis. The present report describes the electron-microscopic findings of numerous intracytoplasmic crystalline arrays resembling those of the picornavirus group in muscle of 2 patients who died after a subacute clinical course of dermatomvositis. CASE REPORTS

The Eaton-Lambert syndrome and autoimmune disorders

Abstract The Eaton-Lambert syndrome is a myasthenic disorder often associated with small cell carcinoma of the lung. We describe a patient with hypothyroidism and pernicious anemia in addition to this syndrome to document its association with diseases having autoimmune concomitants.

End‐plate dysfunction in acute organophosphate intoxication

Acute organophosphate intoxication resulting from suicide attempts in 14 patients produced a series of electrophysiologic abnormalities that correlated with the clinical course. Spontaneous repetitive firing of single evoked compound muscle action potentials (CMAP) was the earliest and most sensitive indicator of the acetylcholinesterase inhibition. A decrement of evoked CMAP following repetitive nerve stimulation was the most severe abnormality. At the height of the intoxication no CMAP was evoked after the first few stimuli. The decrement-increment phenomenon occurred only at milder stages of intoxication and its features are characteristic of acetylcholinesterase inhibition. These electrophysiologic features proved to be the most useful for determining initial severity and clinical course of the acute organophosphate intoxication and differentiated this syndrome from those of myasthenia gravis, Eaton-Lambert syndrome, and botulism.

Acute trimethyltin limbic‐cerebellar syndrome

An acute limbic-cerebellar syndrome was seen in six industrial workers who inhaled trimethyltin (TMT). Clinical features included hearing loss, disorientation, confabulation, amnesia, aggressiveness, hyperphagia, disturbed sexual behavior, complex partial and tonic-clonic seizures, nystagmus, ataxia, and mild sensory neuropathy. Severity paralleled maximal urinary organotin levels. One patient died and two remained seriously disabled.

Mitochondria1 encephalomyopathy with decreased succinate‐cytochrome c reductase activity

We report two siblings with a mitochondrial encephalomyopathy. The syndrome was characterized by ataxia, intellectual impairment, myoclonic jerks, rare seizures, and small stature. Muscle biopsy specimens showed abnormal accumulations of mitochondria and lipid droplets. Biochemical studies on muscle demonstrated decreased succinate-cytochrome c reductase activity in the mitochondrial respiratory chain.

Myokymia and neuromyotonia 2004.

Myokymia and neuromyotonia are related clinical phenomena that result from hyperexcitability of peripheral nerve motor axons.Whether they are really separate and distinct clinical entities or just reflect a difference in the severity of the same underlying electrophysiological abnormality remains undetermined. Both may occur in a generalized or focal fashion and reflect a generalized or focal alteration in the microenvironment or membrane of the peripheral nerve. Other related terms include facial myokymia, generalized myokymia, myokymia with impaired muscular relaxation, syndrome of continuous muscle-fiber activity, Isaacs’ syndrome, neurotonia, Morvan’s syndrome, and Morvan’s fibrillary chorea [1, 5.6, 9.12, 13, 14, 15]. Alterations of peripheral nerve voltage gated K+channels (VGKC) have recently been associated with several examples of both phenomena, e. g. VGKC antibodies in generalized neuromyotonia (Isaacs’ syndrome) [21] and persistent facial myokymia [11]. Adding to the confusion surrounding the two clinical phenomena are the terms myokymic and neuromyotonic discharges – the spontaneous repetitive discharges arising from the hyperexcitable axon membrane – that reflect the underlying pathophysiology of myokymia and neuromyotonia [6]. Myokymic and neuromyotonic discharges