Lower Motor Neuron Disorder Research Articles

Small Ubiquitin-like Modifier (SUMO) Modification of the Androgen Receptor Attenuates Polyglutamine-mediated Aggregation

The neurodegenerative disorder spinal and bulbar muscular atrophy or Kennedy disease is caused by a CAG trinucleotide repeat expansion within the androgen receptor (AR) gene. The resulting expanded polyglutamine tract in the N-terminal region of the receptor renders AR prone to ligand-dependent misfolding and formation of oligomers and aggregates that are linked to neuronal toxicity. How AR misfolding is influenced by post-translational modifications, however, is poorly understood. AR is a target of SUMOylation, and this modification inhibits AR activity in a promoter context-dependent manner. SUMOylation is up-regulated in response to multiple forms of cellular stress and may therefore play an important cytoprotective role. Consistent with this view, we find that gratuitous enhancement of overall SUMOylation significantly reduced the formation of polyglutamine-expanded AR aggregates without affecting the levels of the receptor. Remarkably, this effect requires SUMOylation of AR itself because it depends on intact AR SUMOylation sites. Functional analyses, however, indicate that the protective effects of enhanced AR SUMOylation are not due to alterations in AR transcriptional activity because a branched protein structure in the appropriate context of the N-terminal region of AR is necessary to antagonize aggregation but not for inhibiting AR transactivation. Remarkably, small ubiquitin-like modifier (SUMO) attenuates AR aggregation through a unique mechanism that does not depend on critical features essential for its interaction with canonical SUMO binding motifs. Our findings therefore reveal a novel function of SUMOylation and suggest that approaches that enhance AR SUMOylation may be of clinical use in polyglutamine expansion diseases.

Adductor T reflex abnormalities in patients with decreased patellar reflexes

The adductor reflex (AR) is a tendon reflex that has various features that differ from other tendon reflexes. This reflex was tested in different disorders presenting with diminished patellar reflexes such as diabetic lumbosacral radiculoplexus neuropathy (DLRPN), L2-L4 radiculopathy, and distal symmetric diabetic neuropathy (diabetic PNP). The AR and crossed-AR (elicited by tapping the contralateral patellar tendon) were recorded using concentric needle electrodes. Additionally, the patellar T reflex (vm-TR) and vastus medialis H reflex (vm-HR) were recorded using surface electrodes. AR was recorded in only one out of eight patients with DLRPN, but it was recorded in 21 out of 22 patients with L2-L4 radiculopathy (95.5%). Of these reflexes, only AR showed prolonged latency in the L2-L4 radiculopathy group. The latencies of AR, vm-TR, and vm-HR were prolonged in patients with diabetic PNP. We conclude that AR can be useful in the differential diagnosis of some lower motor neuron disorders that present with patellar reflex disturbance. Muscle Nerve 40: 264-270, 2009.

Seipin/BSCL2 mutation screening in sporadic adult-onset upper motor neuron syndromes

Sirs,The ability to distinguish between sporadic presentationsof hereditary spastic paraparesis (HSP) and primary lateralsclerosis (PLS) is important in terms of prognostication andgenetic counseling, but clinical differentiation is problem-atic [6]. Primary lateral scherosis is a sporadic disorder ofprogressive spino-bulbar spasticity and may be part of theclinical spectrum of amyotrophic lateral sclerosis (ALS)[10]. Hereditary spastic paraparesis is a clinically andgenetically heterogeneous group of disorders characterizedby a slowly progressive spastic paraparesis [8, 12].To date, 15 genes and more than 20 additional loci havebeen identified for autosomal dominant (AD), autosomalrecessive and X-linked forms of HSP [5, 7]. The spastingene (SPG4) mutation is the most frequent cause of ADHSP (around 40% of families) and is also frequent insporadic HSP (13%), but not in PLS [3]. We recently foundpathogenic paraplegin gene (SPG7) mutations 11% ofpatients with sporadic HSP [4]. The role of other HSP genesin sporadic upper motor neuron (UMN) syndromes islargely unknown. Two known mutations (c.263G [A/p.N88Sand c.269C[T/p.S90L) in exon 3 of the seipin/BSCL2 gene(SPG17) can cause a range of AD (mixed) upper and lowermotor neuron disorders, including Silver syndrome (HSPwith amyotrophy of the hands), variants of Charcot–Marie-tooth disease type 2, distal hereditary motor neuropathy typeV(dHMNV),butalsopureandcomplicatedformsofHSP[1,13, 14]. Because of incomplete penetrance, the seipin/BSCL2 mutation can manifest as a sporadic disease [14].To investigate whether these two seipin/BSCL2 muta-tions are present in patients with sporadic HSP and PLS,we screened exon 3 of the seipin/BSCL2 gene in 86 Dutchpatients with a sporadic adult-onset UMN syndrome.Inclusion criteria were a gradually progressive UMN syn-drome, adult-onset, disease duration [6 months and anegative family history. Exclusion criteria were lowermotor neuron loss meeting the revised El Escorial criteriafor clinically definite, clinically probable or probable lab-oratory-supported ALS [2] and evidence of other causes ofa UMN syndrome based on a battery of laboratory inves-tigations, including serum biochemistry (including thyroid-stimulating hormone, angiotensin converting enzyme,vitamin B12, folate and vitamin E), analysis of very longchain fatty acids in plasma, serology (syphilis, borreliosis,human T cell lymphotrophic virus type 1 and humanimmunodeficiency virus) and bile alcohol analysis in urine,and cerebral and spinal magnetic resonance imaging(MRI). The presence of the SPG4 and SPG7 mutations wasexcluded in all patients. The study was approved by themedical ethics review board of the University MedicalCenter in Utrecht, and written informed consent wasobtained from all patients.Mutation screening of the seipin/BSCL2 gene was per-formed using automated forward and reverse directsequencing of exon 3. The BSCL2 exon 3 was amplified byPCR using intronic primers (primer sequences available onrequest), and the PCR products were loaded on an Applied

Case series: anesthetic management of patients with spinal and bulbar muscular atrophy (Kennedy’s disease)

Kennedy's disease (KD) is a rare, X-linked recessive, neurodegenerative disorder of lower motor neurons characterized by progressive proximal limb and bulbar muscular atrophy with spontaneous laryngospasm, which may present an anesthetic risk. We undertook a computerized search of the Mayo Clinic medical records database between January 1996 and May 2008 for patients with KD undergoing general anesthesia. Medical records were reviewed for anesthetic techniques and perioperative complications. We identified six patients with KD, confirmed by DNA testing, who underwent 13 general anesthetics. Succinylcholine was used in two patients, and non-depolarizing neuromuscular blockers in seven cases, all without adverse effects. Although laryngospasm was not identified in any patient, one patient with advanced disease experienced postoperative glottic edema, worsening respiratory distress, bulbar dysfunction, requiring tracheostomy and prolonged ventilatory support. One patient experienced a pneumothorax. The potential for bulbar dysfunction and muscle weakness in patients with KD places them at risk for perioperative complications from anesthesia. Anesthesia providers should be cognizant of the different potential anesthetic risk factors in these patients.

Hereditary infantile motor axonal neuropathy mimicking SMA: a case report.

Spinal muscular atrophy (SMA) is a group of allelic autosomal recessive genetic disorders characterized by progressive motor neuron loss, symmetrical weakness, and skeletal muscle atrophy. It is traditionally classified as a pure lower motor neuron disorder, for which currently definitive diagnosis is possible by molecular genetic testing. The problem arises when an infant presents clinically like SMA but is negative for survival motor neuron gene. A 3-month-old infant presented with paucity of limb movement and weak cry. Clinical presentation was suggestive of spinal muscular atrophy type I but genetic test for exon 7 deletion on survival motor neuron gene on chromosome 5 was negative. Detailed investigation revealed this a case of infantile motor axonal neuropathy. Two years follow-up has revealed partial recovery in limb movements and of bulbar function. There is paucity in neurology literature of such cases and the importance of genetic studies is hence emphasized.

PRIMARY LATERAL SCLEROSIS WITH HIV-1 INFECTION

Amyotrophic lateral sclerosis (ALS) (also referred to as motor neuron disease [MND]) is characterized clinically by progressive weakness of limb, bulbar, and respiratory muscles. Clinically definite ALS is characterized by the presence of mixed upper and lower motor neuron deficits in three or more anatomic areas. Patients with isolated upper motor neuron disorder (primary lateral sclerosis [PLS]) or lower motor neuron disorder (progressive muscular atrophy [PMA]) exhibit a relatively benign clinical course compared to that in classic ALS. A viral etiology of ALS has been hypothesized for over four decades. Retroviral hypothesis of MND is particularly attractive because retroviruses replicate by synthesizing and integrating a DNA copy that persists into the host genome. HIV type 1 (henceforth called HIV)–associated ALS or PMA have been previously reported.1–5 We describe HIV-associated PLS in two patients. ### Case reports. #### Case 1. A 57-year-old man was first hospitalized for Pneumocystis carinii pneumonia in December 2001. Laboratory testing revealed that he was HIV seropositive by enzyme-linked immunosorbent assay and Western blot analysis. In early 2004, he …

Increased nodal persistent Na + currents in human neuropathy and motor neuron disease estimated by latent addition

Objective To investigate the changes in nodal persistent Na + currents in human neuropathy and motor neuron disease. In human motor axons, approximately 1.0% of total Na + channels are active at rest, termed “persistent” Na + channels, and the conductance can be non-invasively estimated by the technique of latent addition in vivo. Methods Latent addition was performed in median motor axons of 93 patients with axonal neuropathy ( n = 38), lower motor neuron disorder (LMND; n = 19) or amyotrophic lateral sclerosis (ALS; n = 36) and in 27 age-matched normal subjects. Brief hyperpolarizing conditioning current pulses were delivered, and threshold change at the conditioning-test interval of 0.2 ms was measured as an estimator of the magnitude of persistent Na + currents. Threshold electrotonus and supernormality were also measured as indicators of resting membrane potential. Results Threshold changes at 0.2 ms were significantly greater in patients with neuropathy or LMND ( p < 0.05), and tended to be greater in ALS patients ( p = 0.075) than in normal controls. Threshold electrotonus and supernormality did not differ in each patient group and normal controls, suggesting that membrane potential is not altered in patients. In the recovery phase of axonal neuropathy, the threshold changes increased in parallel with an increase in amplitudes of compound muscle action potential. Conclusions Persistent Na + currents appear to increase commonly in disorders involving lower motor neurons, possibly associated with axonal regeneration or collateral sprouting or changes in Na + channel gating. Significance The increased axonal excitability could partly be responsible for positive motor symptoms such as muscle cramping frequently seen in lower motor neuron disorders.

Prediction of response to IVIg treatment in patients with lower motor neurone disorders

The distinction between multifocal motor neuropathy, treatable by intravenous immunoglobulins (IVIg), and degenerative motor neurone disorders is often difficult. To find predictive factors for the response to IVIg treatment, 40 consecutive patients with pure lower motor neurone disorders (LMND) were prospectively examined. They all received at least two times IVIg (2 g/kg bodyweight). Prior to the first and before all the following treatments a standardized evaluation was performed including clinical examination, neurophysiological and laboratory evaluation. According to changes in the neurological examination and the Neuromuscular Symptom Score, the patients were divided into responders and non-responders after the second course of treatment. In our study, no single clinical, neurophysiological, or laboratory parameter was sensitive enough to predict response. The only single parameter that highly correlated with a positive response to treatment was an elevated GM1 antibody titre. Lack of response to IVIg treatment is likely in patients with generalization of electromyographic signs of denervation beyond the clinically involved site, proximal localization of the weakness, and an elevated level of the creatinekinase. Conduction blocks do not distinguish between both groups. We propose a scoring system combining clinical, serological and neurophysiological data in order to decide which patients with LMND may receive IVIg.

Abnormalities of Germ Cell Maturation and Sertoli Cell Cytoskeleton in Androgen Receptor 113 CAG Knock-In Mice Reveal Toxic Effects of the Mutant Protein

An unresolved question in the study of the polyglutamine neurodegenerative disorders is the extent to which partial loss of normal function of the mutant protein contributes to the disease phenotype. To address this, we studied Kennedy disease, a degenerative disorder of lower motor neurons caused by a CAG/glutamine expansion in the androgen receptor (Ar) gene. Signs of partial androgen insensitivity, including testicular atrophy and decreased fertility, are common in affected males, although the underlying mechanisms are not well understood. Here, we describe a knock-in mouse model that reproduces the testicular atrophy, diminished fertility, and systemic signs of partial androgen insensitivity that occur in Kennedy disease patients. Using this model, we demonstrate that the testicular pathology in this disorder is distinct from that mediated by loss of AR function. Testes pathology in 113 CAG knock-in mice was characterized by morphological abnormalities of germ cell maturation, decreased solubility of the mutant AR protein, and alterations of the Sertoli cell cytoskeleton, changes that are distinct from those produced by AR loss-of-function mutation in testicular feminization mutant mice. Our data demonstrate that toxic effects of the mutant protein mediate aspects of the Kennedy disease phenotype previously attributed to a loss of AR function.

Spectrum of motor neuron diseases with HIV-1 infection

Background: The cause of sporadic motor neuron disease (MND) or amyotrophic lateral sclerosis (ALS) is unknown. During the last 20 years, at least 23 cases of MND have been reported in HIV-1 (HIV) seropositive individuals. Objective: To describe two patients with HIV infection and MND and to review the literature regarding HIV-associated MND. Setting: A multidisciplinary ALS center and Neuro-AIDS clinic at tertiary care university hospitals. Patients/Design: We prospectively studied two HIV-infected patients with motor neuron disease. A detailed review of the literature employing the PubMed search strategy revealed 23 additional cases of MND in HIV-infected persons. These were reviewed for comparison and contrast with the characteristics of sporadic classical MND. Results: The clinical features of MND in our two cases, mirrored that of the sporadic MND (upper and lower motor neuron disorder) and primary lateral sclerosis (PLS, isolated upper motor neuron disorder). The review of 23 previously reported patients with MND and HIV infection revealed that they could be categorized into clinically definite MND (6 cases) or clinically probable or possible MND (17 cases). MND commenced at different stages of the HIV; in 9 patients HIV infection was discovered contemporaneously with the diagnosis of MND. As in our one patient, 14 of 18 patients with HIV-associated MND syndrome receiving highly active antiretroviral therapy (HAART), demonstrated at least partial recovery of their motor deficit. Conclusions: A clinical picture similar to MND or PLS may occur in association with HIV infection. An aggressive HAART regimen to reduce viral load should be pursued in all such cases.

A polymorphism in the poliovirus receptor gene differs in motor neuron disease.

Poliovirus has been implicated in the etiology of sporadic motor neuron disease. DNA polymorphisms in the poliovirus receptor gene (PVR) are associated with persistent poliovirus infection in cell culture. PVR DNA polymorphisms were therefore studied in 110 cases of amyotrophic lateral sclerosis, 30 cases of progressive muscular atrophy (a disorder of lower motor neurons) and 280 normal controls. In exon 2 of PVR the heterozygous Ala67Thr change was detected in 20.0% of progressive muscular atrophy, 11.8% of amyotrophic lateral sclerosis and 6.8% of control subjects. The frequency of the polymorphism was significantly higher in patients with progressive muscular atrophy than in controls. Differences in the poliovirus receptor gene may result in slowly progressive viral cytopathic effects that lead to lower motor neuron forms of motor neuron disease.

Electrodiagnostic studies in the management and prognosis of neuromuscular disorders.

Prognosis remains a neglected aspect of modern medical care and research, behind diagnosis and treatment. The very term "electrodiagnosis" implies as much. Despite this, much has been published regarding the use and benefit of electrodiagnostic techniques in assessing prognosis and assisting in management of patients after the diagnosis has been established. This information is often hidden or otherwise not emphasized. This review summarizes the literature regarding the use of such techniques for prognosis and management of disorders of lower motor neurons, peripheral nerves, neuromuscular transmission, and muscle.

Multifocal motor neuropathy: Diagnostic criteria that predict the response to immunoglobulin treatment

As multifocal motor neuropathy (MMN) is a potentially treatable disorder, its differentiation from lower motor neuron disease is important. Evidence of conduction block (CB) is considered one of the relevant criteria for the diagnosis of MMN. Strict criteria for CB may lead to underdiagnosis of MMN, however. Using a standardized examination, we studied the clinical, laboratory, and electrophysiological characteristics of 37 patients presenting with a lower motor neuron disorder and electrophysiological features compatible with segmental demyelination. We propose a set of clinical, laboratory, and electrophysiological criteria for the diagnosis of MMN, which has been verified by follow-up and response to treatment with intravenous immunoglobulins. Based on the clinical, laboratory, and electrodiagnostic features, 21 patients were diagnosed with definite MMN (17 responders), 7 were diagnosed with probable MMN (5 responders), and 9 were diagnosed with possible MMN (1 responder). Age at onset, the number of affected limb regions, and the number of patients with a creatine kinase level greater than 180 U/L were significantly lower in responders than in nonresponders. Elevated anti-GM1 antibodies and definite CB were found significantly more often in responders. The proposed diagnostic criteria may be useful in clinical practice and therapeutic trials.

Use of human intravenous immunoglobulin in lower motor neuron syndromes

OBJECTIVETo determine whether patients with the clinical phenotype of multifocal motor neuropathy but without the electrophysiological criteria for conduction block would respond to intravenous immunoglobulin (IVIg).METHODSTen patients were selected with...

Time dependent selective recurrent discharge of motor units in F-response

The interaction among the recurrent discharge of motor units is studied in surface recorded composite F-response. In the first experiment, 200 serially elicited polyphasic F-responses from foot muscles of patients with different lower motor neurone (LMN) disorders were rearranged to understand the behaviour of individual negative and positive peaks. These peaks were considered on the basis of simultaneous recording with a single fibre EMG needle, to be the partial expression of either a single motor unit potential (MUP) or more than one MUP generated simultaneously. In another experiment, two serially averaged F-responses (50 each) were superimposed over each other to look for their similarities at 15 min intervals 6 times. Result analysis indicated interaction of MUPs by in-phase summation and out-of-phase subtraction. Less affected MUPs recurred as negative or positive peaks in morphologically different F-responses. Certain peaks were observed more frequently than the others. Two serially averaged F-responses were nearly identical on superimposition over each other but their morphologies differed at different time intervals. The study suggests more frequent generation of F-response in a specific group of alpha motoneurones at one point of time, which is replaced by another group at another point of time. The characteristic variation in F parameters is, however, mainly due to the interaction of these frequently generated F-response MUPs with other sporadically generated ones. This interaction can be appreciated on visual screening of F-responses in patients with lower motor neurone disorders, perhaps because of a reduction in the number of participating MUPs.

Sensitivity of motor unit potential and turns-amplltude analysis in early diagnosis of motor neuron disease

The interaction among the recurrent discharge of motor units is studied in surface recorded composite F-response. In the first experiment, 200 serially elicited polyphasic F-responses from foot muscles of patients with different lower motor neurone (LMN) disorders were rearranged to understand the behaviour of individual negative and positive peaks. These peaks were considered on the basis of simultaneous recording with a single fibre EMG needle, to be the partial expression of either a single motor unit potential (MUP) or more than one MUP generated simultaneously. In another experiment, two serially averaged F-responses (50 each) were superimposed over each other to look for their similarities at 15 min intervals 6 times. Result analysis indicated interaction of MUPs by in-phase summation and out-of-phase subtraction. Less affected MUPs recurred as negative or positive peaks in morphologically different F-responses. Certain peaks were observed more frequently than the others. Two serially averaged F-responses were nearly identical on superimposition over each other but their morphologies differed at different time intervals. The study suggests more frequent generation of F-response in a specific group of alpha motoneurones at one point of time, which is replaced by another group at another point of time. The characteristic variation in F parameters is, however, mainly due to the interaction of these frequently generated F-response MUPs with other sporadically generated ones. This interaction can be appreciated on visual screening of F-responses in patients with lower motor neurone disorders, perhaps because of a reduction in the number of participating MUPs.

PS-35-5 F response multiplicity in lower motor neuron disorders

PS-35-5 F response multiplicity in lower motor neuron disorders

Electronic integration of glottic closure and circopharyngeal relaxation for the control of aspiration: a canine study.

Aspiration can result from muscular weakness or paralysis of laryngopharyngeal muscles after lower motor neuron disorders (e.g., stroke) or unchecked gastroesophageal reflux. We submit that rehabilitation of the finely tuned swallowing mechanism should provide at least restoration of the normal dynamic relationships between glottic closure and cricopharyngeal relaxation. In three dogs under general endotracheal anesthesia, the recurrent laryngeal nerves and the pharyngeal musculature were exposed through a midline cervical incision. A tracheotomy was performed to allow unhindered laryngoscopic exposure of the vocal cords. A no. 9 endotracheal tube passed through the upper esophageal sphincter was used as a pressure transducer by saline inflation of its cuff and linked to an oscilloscope. The cricopharyngeus was placed under baseline tension with pulse trains administered by an intramuscular needle with a circuit previously used for agonist/antagonist coupling of reinnervated facial musculature. A second output channel was linked to the contralateral recurrent laryngeal nerve by a bipolar electrode. As the pulse width of the current to the recurrent laryngeal nerve increased, that to the cricopharyngeus was reciprocally decreased, producing snug glottic closure and synchronous cricopharyngeal relaxation. Results were documented on videotape. These findings were highly reproducible. We believe that the novel approach proposed in the current model offers an attractive solution to long-term aspiration problems resulting from an imbalance between vocal cord and cricopharyngeal activities.

Electronic integration of glottic closure and cricopharyngealrelaxation for the control of aspiration: A canine study

Aspiration can result from muscular weakness or paralysis of laryngopharyngeal muscles after lower motor neuron disorders (e.g., stroke) or unchecked gastroesophageal reflux. We submit that rehabilitation of the finely tuned swallowing mechanism should provide at least restoration of the normal dynamic relationships between glottic closure and cricopharyngeal relaxation. In three dogs under general endotracheal anesthesia, the recurrent laryngeal nerves and the pharyngeal musculature were exposed through a midline cervical incision. A tracheotomy was performed to allow unhindered laryngoscopic exposure of the vocal cords. A no. 9 endotracheal tube passed through the upper esophageal sphincter was used as a pressure transducer by saline inflation of its cuff and linked to an oscilloscope. The cricopharyngeus was placed under baseline tension with pulse trains administered by an intramuscular needle electrode with a circuit previously used for agonist/antagonist coupling of reinnervated facial musculature. A second output channel was linked to the contralateral recurrent laryngeal nerve by a bipolar electrode. As the pulse width of the current to the recurrent laryngeal nerve increased, that to the cricopharyngeus was reciprocally decreased, producing snug glottic closure and synchronous cricopharyngeal relaxation. Results were documented on videotape. These findings were highly reproducible. We believe that the novel approach proposed in the current model offers an attractive solution to long-term aspiration problems resulting from an imbalance between vocal cord and cricopharyngeal activities. (OTOLARYNGOL HEAD NECK SURG 1995;112:424-9.)

Axonal ion channel dysfunction in amyotrophic lateral sclerosis

In amyotrophic lateral sclerosis (ALS) it is not known how or why the motor neurons die, but a clue is provided by observations that the dying cells discharge spontaneously, producing muscle fasciculations. The fasciculations can arise either proximally or distally in the motor unit, suggesting a widespread disturbance of membrane excitability. To test for this, we applied the technique of threshold electrotonus to ulnar motor axons at the wrist, comparing the responses to 100 ms polarizing currents in 11 ALS patients with those from 15 normal controls, six patients with benign fasciculations, 19 with lower motor neuron disorders and six with upper motor neuron disorders. We found that the motor axons of ALS patients, unlike those in the neurological control groups, responded abnormally to subthreshold depolarizing currents, becoming either more (seven cases) or much less excitable (four cases) than normal. Both types of abnormality could be reproduced in rat nerves in vitro, and in a computer model of human motor axons, by reducing voltage dependent potassium conductances. When sufficient potassium channels were blocked, the model axon became unstable and depolarized regeneratively, resulting in an abrupt fall in excitability. We conclude that the fasciculations in ALS are caused by an imbalance between functional sodium and potassium channels, and we propose that this ion channel dysfunction could also be responsible for the motor neuron degeneration in this disease.