RFC1 repeat expansions and cerebellar ataxia, neuropathy and vestibular areflexia syndrome: Experience and perspectives from a neuromuscular disorders unit.

INTRODUCTION: Pathogenic expansions in RFC1 have been described as a cause of a spectrum of disorders including late-onset ataxia, chronic cough, and cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Sensory neuronopathy/neuropathy appears to be a major symptom of RFC1-disorder, and RFC1 expansions are common in patients with sensory chronic idiopathic axonal neuropathy or sensory ganglionopathy. We aimed to investigate RFC1 expansions in patients with suspected RFC1-related disease followed-up in a Neuromuscular Diseases Unit, with a particular interest in the involvement of the peripheral nervous system. METHODS: We recruited twenty consecutive patients based on the presence of at least two of the following features: progressive ataxia, sensory neuropathy/neuronopathy, vestibulopathy and chronic cough. Medical records were retrospectively reviewed for a detailed clinical description. More extensive phenotyping of the RFC1-positive patients and clinical comparison between RFC1 positive and negative patients were performed. RESULTS: Biallelic AAGGG repeat expansions were identified in 13 patients (65%). The most frequent symptoms were chronic cough and sensory disturbances in the lower extremities (12/13). Only 4 patients (31%) had complete CANVAS. The phenotypes were sensory ataxia and sensory symptoms in extremities in 4/13; sensory ataxia, sensory symptoms, and vestibulopathy in 3/13; sensory symptoms plus chronic cough in 2/13. Chronic cough and isolated sensory neuronopathy were significantly more prevalent in RFC1-positive patients. CONCLUSION: Pathogenic RFC1 expansions are a common cause of sensory neuropathy/neuronopathy and should be considered in the approach to these patients. Identification of key symptoms or detailed interpretation of nerve conduction studies may improve patient selection for genetic testing.

An Atypical Presentation of Upper Motor Neuron Predominant Juvenile Amyotrophic Lateral Sclerosis Associated with TARDBP Gene: A Case Report and Review of the Literature.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that can rarely affect young individuals. Juvenile ALS (JALS) is defined for individuals with an onset of the disease before the age of 25. The contribution of genetics to ALS pathology is a field of growing interest. One of the differences between adult-onset ALS and JALS is their genetic background, with a higher contribution of genetic causes in JALS. We report a patient with JALS and a pathogenic variant in the TARDBP gene (c.1035C > G; p.Asn345Lys), previously reported only in adult-onset ALS, and with an atypical phenotype of marked upper motor neuron predominance. In addition, the proband presented an additional variant in the NEK1 gene, c.2961C > G (p.Phe987Leu), which is classified as a variant of unknown significance. Segregation studies showed a paternal origin of the TARDBP variant, while the variant in NEK1 was inherited from the mother. We hypothesize that the NEK1 variant acts as a disease modifier and suggests the possibility of a functional interaction between both genes in our case. This hypothesis could explain the peculiarities of the phenotype, penetrance, and the age of onset. This report highlights the heterogeneity of the phenotypic presentation of ALS associated with diverse pathogenic genetic variants.

Long-term safety and effectiveness of levodopa-carbidopa intestinal gel infusion.

INTRODUCTION: Levodopa-carbidopa intestinal gel (LCIG) infusion has demonstrated to improve motor fluctuations. The aim of this study is to assess the long-term safety and effectiveness of LCIG infusion in advanced Parkinson's disease (PD) patients with motor fluctuations and its effect in nonmotor symptoms. METHODS: Adverse events (AE) and their management, clinical motor, and nonmotor aspects were assessed up to 10 years. Thirty-seven patients were treated with LGIC; in three subsets of patients, specific batteries of tests were used to assess cognitive and behavior assessment for 6 months, quality of sleep for 6 months, and quality of life and caregiver burden for 1 year. RESULTS: There was a high number of AE, but manageable, most of mild and moderate severity. All patients experienced significant improvement in motor fluctuations with a reduction in mean daily off time of 4.87 hr after 3 months (n = 37) to 6.25 hr after 9 years (n = 2). Diskynesias remained stables in 28 patients (75.7%) and improved in 5 patients (13.5%). There was no neuropsychological deterioration, but an improvement in attentional functions, voluntary motor control, and semantic fluency. Quality of sleep did not worsen, and there was an improvement in the subjective parameters, although overnight polysomnography did not change. There was a significant sustained improvement of 37% in PD-Q39 after 3 months and to 1 year, and a significant reduction in caregiver burden of 10% after 3 months. CONCLUSION: LCIG infusion is a safe and efficacious treatment for the control of motor fluctuations, and for improvement or nonworsening of nonmotor aspects, long-term sustained, and feasible for use in routine care.

Influence of early neurological complications on clinical outcome following lung transplant.

BACKGROUND: Neurological complications after lung transplantation are common. The full spectrum of neurological complications and their impact on clinical outcomes has not been extensively studied. METHODS: We investigated the neurological incidence of complications, categorized according to whether they affected the central, peripheral or autonomic nervous systems, in a series of 109 patients undergoing lung transplantation at our center between January 1 2013 and December 31 2014. RESULTS: Fifty-one patients (46.8%) presented at least one neurological complication. Critical illness polyneuropathy-myopathy (31 cases) and phrenic nerve injury (26 cases) were the two most prevalent complications. These two neuromuscular complications lengthened hospital stays by a median period of 35.5 and 32.5 days respectively. However, neurological complications did not affect patients' survival. CONCLUSIONS: The real incidence of neurological complications among lung transplant recipients is probably underestimated. They usually appear in the first two months after surgery. Despite not affecting mortality, they do affect the mean length of hospital stay, and especially the time spent in the Intensive Care Unit. We found no risk factor for neurological complications except for long operating times, ischemic time and need for transfusion. It is necessary to develop programs for the prevention and early recognition of these complications, and the prevention of their precipitant and risk factors.

Bedside Ultrasound for the Diagnosis of Abnormal Diaphragmatic Motion in Children After Heart Surgery.

OBJECTIVE: To assess the utility of bedside ultrasound combining B- and M-mode in the diagnosis of abnormal diaphragmatic motion in children after heart surgery. DESIGN: Prospective post hoc blinded comparison of ultrasound performed by two different intensivists and fluoroscopy results with electromyography. SETTING: Tertiary university hospital. SUBJECTS: Children with suspected abnormal diaphragmatic motion after heart surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Abnormal diaphragmatic motion was suspected in 26 children. Electromyography confirmed the diagnosis in 20 of 24 children (83.3%). The overall occurrence rate of abnormal diaphragmatic motion during the study period was 7.5%. Median patient age was 5 months (range, 16 d to 14 yr). Sensitivity and specificity of chest ultrasound performed at the bedside by the two intensivists (91% and 92% and 92% and 95%, respectively) were higher than those obtained by fluoroscopy (87% and 83%). Interobserver agreement (k) between both intensivists was 0.957 (95% CI, 0.87-100). CONCLUSIONS: Chest ultrasound performed by intensivists is a valid tool for the diagnosis of diaphragmatic paralysis, presenting greater sensitivity and specificity than fluoroscopy. Chest ultrasound should be routinely used after pediatric heart surgery given its reliability, reproducibility, availability, and safety.

SBF1 mutations associated with autosomal recessive axonal neuropathy with cranial nerve involvement.

Biallelic mutations in the SBF1 gene have been identified in one family with demyelinating Charcot-Marie-Tooth disease (CMT4B3) and two families with axonal neuropathy and additional neurological and skeletal features. Here we describe novel sequence variants in SBF1 (c.1168C>G and c.2209_2210del) as the potential causative mutations in two siblings with severe axonal neuropathy, hearing loss, facial weakness and bulbar features. Pathogenicity of these variants is supported by co-segregation and in silico analyses and evolutionary conservation. Our findings suggest that SBF1 mutations may cause a syndromic form of autosomal recessive axonal neuropathy (AR-CMT2) in addition to CMT4B3.

Study of the prevalence of familial autoimmune myasthenia gravis in a Spanish cohort.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease caused by a failure of neuromuscular transmission. Familial clustering has been reported despiteMG usually manifesting as a sporadic condition presumed not to be inherited. Our study investigated the prevalence of FAMG in a Spanish cohort, characterizing their phenotype,antibody titres and thymus findings. MATERIAL/METHODS: We investigated the presence of familial cases in 462 MG patients, characterizing by age and MGFA class at debut, quantitative MG score, antibody titres, MGFA post-intervention status and thymus pathology. RESULTS: Sixteen cases from8 unrelated pedigrees were identified. The prevalence of FAMG caseswas 3.46%.Mean age at onset was 57.8 ± 17.4 years (range=23­82). Distribution at debut was: 6 ocular, 4 IIa, 4IIb, 1 IIIa and 1 IIIb. Thymoma was identified in two of the 7 thymectomized individuals. CONCLUSIONS: The prevalence of FAMG in Spain is similar to other populations. Post-intervention status did not differ from sporadic autoimmune MG. As in other neuromuscular disorders, phenotype and inheritance heterogeneity are present in FAMG. In addition to the interfamilial heterogeneity observed, members of the same family affected with FAMG may even present different ages of onset, severity and thymus involvement. Further studies are necessary to clarify the role of genetic risk factors in this form of autoimmune MG.

Ornithine phenylacetate prevents disturbances of motor-evoked potentials induced by intestinal blood in rats with portacaval anastomosis.

BACKGROUND & AIMS: Ornithine phenylacetate (OP) is a new drug that has been proposed for the treatment of hepatic encephalopathy (HE) because it decreases plasma ammonia. We performed a study to assess if OP would impact on neuronal function. METHODS: Motor-evoked potentials (MEP), a surrogate of hepatic encephalopathy, were assessed (without anesthesia) in rats with portacaval anastomosis (PCA) that received gastrointestinal blood (GIB). Rats were pre-treated with OP prior to GIB. Ammonia and related metabolites (plasma, urine, and brain microdialysis) were assessed by HPLC and mass spectroscopy. RESULTS: OP (one dose or 3 days) prevented disturbances in MEP induced by GIB in PCA rats. In rats treated with OP for 3 days, the amplitude and latency of MEP remained stable (-1% and +1%), while in the control group the amplitude decreased -21% and the latency increased +12% (p<0.01). OP attenuated the rise of ammonia in plasma by 45%, ammonia in brain microdialysate by 48%, induced a faster glutamine rise and the appearance of phenylacetylglutamine in plasma and urine. In addition, OP was associated with a lower concentration of ammonia and glutamate in brain microdialysate (approx. 50%). CONCLUSIONS: OP prevents abnormalities in MEP precipitated by GIB in a model of HE. This is probably due to the enhancement of glutamine synthesis and metabolism, which results in a lower rise of plasma ammonia and the prevention of changes in glutamate in microdialysate. Thus, OP may be a good drug to prevent HE precipitated by gastrointestinal bleeding.

Motor-evoked potentials in awake rats are a valid method of assessing hepatic encephalopathy and of studying its pathogenesis.

UNLABELLED: Experimental models of hepatic encephalopathy (HE) are limited by difficulties in objectively monitoring neuronal function. There are few models that examine a well-defined neuronal pathway and lack the confounding effects of anesthetics. Motor-evoked potentials (MEPs) assess the function of the motor tract, which has been shown to be impaired in patients with cirrhosis. MEPs were elicited by cranial stimulation (central) and compound motor action potential by sciatic nerve stimulation (peripheral) in several models of HE in the rat. The experiments were performed using subcutaneous electrodes without anesthetics. Brain water content was assessed by gravimetry, brain metabolites were measured by magnetic resonance spectroscopy, and amino acids in microdialysates from the frontal cortex were analyzed by high-performance liquid chromatography. Abnormalities of MEP were observed in acute liver failure (ALF) induced by hepatic devascularization in relation to the progression of neurological manifestations. Similar disturbances were seen in rats with portocaval anastomosis after the administration of blood or lipopolysaccharide, but were absent in rats with biliary duct ligation. Hypothermia (≤35°C) and mannitol prevented the development of brain edema in acute liver failure, but only hypothermia avoided the decrease in the amplitude of MEP. Disturbances of MEP caused by the administration of blood into the gastrointestinal tract in rats with portocaval anastomosis were associated with an increase in ammonia, glutamine, and glutamate in brain microdialysate. CONCLUSION: Assessment of MEP in awake rats is a valid method to monitor HE in models of ALF and precipitated HE. This method shows the lack of efficacy of mannitol, a therapy that decreases brain edema, and relates disturbances of the function of the motor tract to ammonia and its metabolites.

Cellular transplants in amyotrophic lateral sclerosis patients: an observational study.

BACKGROUND AIMS: Cytotherapy is a promising option for neurodegenerative disease treatment. Because of the fatal prognosis and imperative need for effective treatment, amyotrophic lateral sclerosis (ALS) patients request this therapy before its effectiveness has been verified. The increase in clinics offering cytotherapies but providing little scientific information has prompted considerable medical tourism. We present an observational study of Spanish ALS patients receiving cytotherapy, analyzing the experiences arising from the treatment (TX) and considering two progression markers, FVC and ALSFRS-R. METHODS: Twelve ALS patients with a mean age of 48.6 years (SD 12.8) received cytotherapy 26.9 months (SD 15.8) after clinical onset. ALSFRS-R and FVC at TX were 32.3 (SD 6.8) and 63.4% (SD 15.3), respectively. TX involved transplants of olfactory ensheathing cells in three patients, and autologous mesenchymal stromal cells in the remainder. RESULTS: One patient died 33 months post-TX after surviving for 49 months. Five required mechanical non-invasive home ventilation 7.4 months post-TX. Two required invasive ventilation 13 months post-TX. Five patients needed gastrostomy feeding 23.3 months post-TX. Survival between clinical onset and the study end date was 50 months (SD 17.2). No significant adverse events or changes in the decline of FVC and ALSFRS-R compared with the disease's natural history were observed. CONCLUSIONS: Our observations suggest that these therapies do not halt the course of the disease. Cytotherapy cannot yet be considered a curative treatment for ALS.

A new method for measuring motor evoked potentials in the awake rat: effects of anesthetics.

The goal of this investigation was to develop a method to study the neurophysiological integrity of the central motor tract using motor evoked potentials in the awake rat and assess the effects of different anesthetics in this model. Rats were implanted with six subcutaneous electrodes (pediatric myocardial pacing leads) and one cranial screw. Motor evoked potentials of the hind limb were elicited after cranial and sciatic nerve stimulation. Experiments were repeated on different days during three weeks studying the effect of three different anesthetics (propofol, ketamine/xylazine, pentobarbital) at three different doses. Stimulation of motor evoked potentials in the awake rat was well tolerated with no effects on behavior. The electrodes could be kept chronically in place without signs of infection. The repeated recordings on different days showed high reproducibility after the fourth day following implantation of the electrodes. All three anesthetics induced an increase in the latency and a decrease in the amplitude of the motor evoked potentials which were dose dependent. Propofol (up to 1 mg/kg x min(1)) affected motor evoked potentials to a lesser extent than the other anesthetics. Based upon these findings, we believe that our approach provides a new method of chronically implanting electrodes in the rat to assess the neurophysiological function of the motor tract without the need of anesthetics. This model may prove useful in the investigation of various diseases that affect the motor pathways without the confounding effects of anesthesia.

Investigation of the role of SMN1 and SMN2 haploinsufficiency as a risk factor for Hirayama's disease: clinical, neurophysiological and genetic characteristics in a Spanish series of 13 patients.

OBJECTIVE: The effect of the number of copies in the SMN1 and SMN2 genes - the most extensively studied susceptibility and modifying genetic factors in adult onset motor neuron diseases - as a genetic risk factor for Hirayama's disease (HirD) has never been studied. The purpose of this study was to investigate the influence of the number of copies of the SMN1/SMN2 genes on the resulting phenotype in 13 HirD Spanish patients. PATIENTS AND METHODS: We performed a qualitative and quantitative SMN1/SMN2 gene analysis in 13 unrelated HirD patients. The phenotype-genotype correlation was investigated, paying particular attention to the effect of the SMN1/SMN2 copy number on the disease's phenotype. RESULTS: No patient had a homozygous deletion of the SMN1 or SMN2. No differences were found when comparing the SMN1 and SMN2 copy number distributions of the healthy population and HirD patients, and they do not therefore appear to be a susceptibility factor. There was also no correlation found between the number of copies of the SMN1 and SMN2 and the severity of the resulting phenotype. CONCLUSION: Our results suggest that SMN1 and SMN2 are not predisposing factors for HirD and therefore support a lack of association between these genes and the resulting phenotype.

Functional abnormalities of the motor tract in the rat after portocaval anastomosis and after carbon tetrachloride induction of cirrhosis.

INTRODUCTION: Hepatic encephalopathy is a neurologic syndrome secondary to liver failure that causes cognitive and motor abnormalities. Impairment in the function of the first neuron of the motor tract (corticospinal tract) has been demonstrated in patients with cirrhosis and minimal hepatic encephalopathy. AIM: Investigate the function of the first neuron of the motor tract in experimental models of minimal hepatic encephalopathy. MATERIAL AND METHODS: Rats with portocaval anastomosis (n = 8) and rats with carbon tetrachloride induced cirrhosis (n = 11) underwent neurophysiological recording under light anesthesia with propofol. Motor evoked potentials were elicited applying a transcranial electric pulse and were recorded in the tibialis anterior muscle. The effect of the dose of anesthesia was assessed in a group of normal rats (n = 10). RESULTS: Rats with portocaval anastomosis exhibited a decrease in motor evoked potentials amplitude following surgery (67 +/- 11 to 41 +/- 16%, P < 0.001). Cirrhotic rats exhibited an increase in motor evoked potentials latency after the appearance of ascites (4.65 +/- 0.43 to 5.15 +/- 0.67 ms., P = 0.04). Increasing doses of propofol produced a decrease in the amplitude and an increase in the latency of motor evoked potentials. CONCLUSION: It is possible to reproduce functional abnormalities of the central motor tract in rats with portocaval anastomosis and carbon tetrachloride induced cirrhosis. The development of motor abnormalities in experimental models of minimal hepatic encephalopathy offers the possibility to investigate the mechanisms involved in the pathogenesis of hepatic encephalopathy and test therapeutic strategies.

Mutational analysis of the Cu/Zn superoxide dismutase gene in a Catalan ALS population: should all sporadic ALS cases also be screened for SOD1?

BACKGROUND: SOD1 gene mutations are the most common identified cause of ALS, accounting for approximately 20% of familial ALS cases and around 4% of sporadic ALS cases. However, the prevalence of SOD1 varies in different ethnic groups. No previous epidemiological studies have been carried out in Catalonia. OBJECTIVE: To determine the prevalence of SOD1 gene mutations in a Catalan ALS population, and to analyze the genotype-phenotype relationship. MATERIALS AND METHODS: 30 different FALS pedigrees and 94 sporadic ALS patients were screened for SOD1 mutations using direct sequence analysis. RESULTS: Five of the 30 FALS pedigrees (16.6%) carried a SOD1 mutant. The mutations identified in this group were G37R, D76V, S105L, I112M and N139H. Four SOD1 mutants (4.25%) were found in the sporadic ALS group (SALS). The overall frequency (FALS plus SALS) of SOD1 mutations in our series was 6.45%. In the SALS group, D90A was identified in a patient presenting the typical Scandinavian phenotype. A 53-year-old woman with no family history of ALS carried the N139H mutation. Two unrelated sporadic ALS cases carried the A140A SOD1 mutant. CONCLUSIONS: The prevalence of the SOD1 mutation in FALS in Catalonia is similar to levels in other Mediterranean countries, but lower than those in reports studying the Belgian, Japanese, and Scottish populations. The prevalence of the SOD1 mutation was 4.25% in patients with no family history of ALS. These results may have significant repercussions on genetic counseling, and screening for the SOD1 mutation in sporadic ALS cases must therefore be considered.

A novel thymidine phosphorylase mutation in a Spanish MNGIE patient.

A 29-year-old Spanish man presented with chronic intestinal pseudo-obstruction, progressive external ophthalmoplegia, peripheral neuropathy, and diffuse leukoencephalopathy. This combination of clinical features is characteristic of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Genetic analysis revealed a novel 18-base pair (bp) duplication (5044-5061 dup) in exon 8 of the thymidine phosphorylase (TP) gene. The mutation is predicted to produce a 6 amino acid insertion in the alpha-beta-domain of the protein. This 18-bp insertion in the thymidine phosphorylase gene is the first duplication mutation identified in MNGIE.

T2 hyperintensity along the cortico-spinal tract in cirrhosis relates to functional abnormalities.

Magnetic resonance has shown T2 hyperintensity along the cortico-spinal tract in the brain of cirrhotic patients. This abnormality, which is reversible after liver transplantation, appears to correspond to mild edema. Because astrocytic edema present in hepatic encephalopathy may be responsible for neuronal dysfunction, we studied whether T2 hyperintensity along the cortico-spinal tract may relate to functional abnormalities. Twenty patients with cirrhosis underwent neuropsychologic tests, neurophysiologic study of the cortico-spinal tract with transcranial magnetic stimulation, and (1)H-magnetic resonance. The study was repeated 6 months after liver transplantation (n = 15) and was compared with a control group of healthy subjects (n = 11). Cirrhotic patients exhibited increased T2 signal and several functional abnormalities along the cortico-spinal tract (increased central motor conduction time, increased motor cortical threshold, and decreased motor-evoked potential amplitude). Functional abnormalities reversed after liver transplantation and were associated with normalization of T2 cortico-spinal hyperintensity and with improvement of minimal hepatic encephalopathy. In conclusion, T2 hyperintensity along the cortico-spinal tract in cirrhosis relates to functional abnormalities that are reversible after liver transplantation. These findings suggest that mild cerebral edema along the cortico-spinal pathway may cause neuronal dysfunction. These results support the participation of astrocytic edema in the pathogenesis of hepatic encephalopathy.

Magnetic resonance imaging measurement of brain edema in patients with liver disease: resolution after transplantation.

PURPOSE OF REVIEW: Results from experimental studies indicate that widespread osmotic disturbance induced by astrocytic accumulation of glutamine as a result of ammonia detoxification may lead to brain edema, not only in cases of fulminant hepatic failure, but in the entire spectrum of liver disease. This review summarizes recent magnetic resonance imaging data obtained in patients with chronic liver failure before and after liver transplantation that support the hypothesis that mild brain edema exists in these patients in the absence of clinical hepatic encephalopathy. RECENT FINDINGS: Diffuse white matter abnormalities have been detected with several magnetic resonance imaging techniques such as magnetization transfer ratio measurements, which show significantly low values in otherwise normal appearing brain white matter, and fast-Flair sequences, which show abnormal high-signal intensity of the hemispheric white matter tracts. Both these abnormalities return to normal with restoration of liver function, indicating their reversibility and supporting the hypothesis that they reflect mild diffuse brain edema. SUMMARY: It is likely that magnetic resonance imaging will be increasingly used to evaluate the mechanisms involved in the pathogenesis of hepatic encephalopathy and to assess the effects of therapeutic measures focused on correcting astrocyte swelling in these patients.