Search

ObjectiveTo compare characteristics between Black and White patients with amyotrophic lateral sclerosis (ALS) in order to identify disparities and phenotypic variability.MethodsWe performed database review for patients seen between 1997 and 2020 at the Emory ALS Center in Atlanta, Georgia. Patients with ALS were included for analyses if race was self-reported as Black or White and symptom onset was prior to January 1, 2017. Variables examined include race, age at onset, diagnostic delay, site of onset, median income, C9orf72 mutation status, feeding tube and tracheostomy status, vital capacity, Amyotrophic Lateral Sclerosis Functional Rating Scale–revised(ALSFRS-R) score, and survival time.ResultsA total of 2,363 patient records were queried, and 1,298 were included in analysis; 203 self-identified as Black and 1,095 as White. Black patients had younger age at symptom onset, lower frequency of C9orf72 mutations, lower median income, longer diagnostic delay, and lower baseline ALSFRS-R and vital capacity compared to White patients. Black patients had a longer median survival than White patients; however, race was not an independent predictor of survival time when controlling for age at symptom onset, bulbar onset, and C9orf72 positivity.ConclusionsBlack patients with ALS had longer median survival compared to White patients, but race was not independently associated with survival after controlling for age, site of onset, and C9orf72 status, factors known to predict prognosis. Black patients with ALS had longer diagnostic delay and lower baseline ventilatory and functional status at first clinic visit compared to White patients, which could be suggestive of barriers to tertiary care. Further studies are needed to identify the underlying causes of ALS racial differences.

Objective: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is incurable and ultimately fatal. Few therapeutic options are available to patients. In this study, w...

Hannu Laaksovirta konsortion jäsenenä. The Genomics England Research Consortium, The International ALS/FTD Genomics Consortium (iAFGC), The International FTD Genetics Consortium (IFGC), The International LBD Genomics Consortium (iLBDGC), The NYGC ALS Consortium, The PROSPECT Consortium,17 James B. Rowe,17 Luisa Benussi,18 Giuliano Binetti,18,19 Roberta Ghidoni,18 Edwin Jabbari,20,21 Coralie Viollet,22 Jonathan D. Glass,23 Andrew B. Singleton,24 Vincenzo Silani,25,26 Owen A. Ross,27 Mina Ryten,8,28,29 Ali Torkamani,30 Toshiko Tanaka,31 Luigi Ferrucci,31 Susan M. Resnick,32 We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40?64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington?s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

Objective It is essential to develop predictive algorithms for Amyotrophic Lateral Sclerosis (ALS) disease progression to allow for efficient clinical trials and patient care. The best existing predictive models rely on several months of baseline data and have only been validated in clinical trial research datasets. We asked whether a model developed using clinical research patient data could be applied to the broader ALS population typically seen at a tertiary care ALS clinic. Methods Based on the PRO-ACT ALS database, we developed random forest (RF), pre-slope, and generalized linear (GLM) models to test whether accurate, unbiased models could be created using only baseline data. Secondly, we tested whether a model could be validated with a clinical patient dataset to demonstrate broader applicability. Results We found that a random forest model using only baseline data could accurately predict disease progression for a clinical trial research dataset as well as a population of patients being treated at a tertiary care clinic. The RF Model outperformed a pre-slope model and was similar to a GLM model in terms of root mean square deviation at early time points. At later time points, the RF Model was far superior to either model. Finally, we found that only the RF Model was unbiased and was less subject to overfitting than either of the other two models when applied to a clinic population. Interpretation We conclude that the RF Model delivers superior predictions of ALS disease progression.

We investigated whether the C9orf72 expansion mutation in patients with amyotrophic lateral sclerosis (ALS) is associated with unique demographic and clinical features.Between 2001 and 2015, approximately half of all patients attending the Emory ALS Clinic agreed to donate DNA for research. This research cohort of 781 patients was screened for the C9orf72 expansion, and demographic and clinical data were compared between those with and without the C9orf72 mutation. For mutation carriers without a family history of ALS, we sought further family history of dementia and other non-ALS neurodegenerative diseases in first-degree relatives.The C9orf72 expansion was identified in 61 patients (7.8%). Compared to those without the expansion mutation, these patients did not differ in race, age, or site of onset. As expected, C9orf72 patients were more likely to have a family history of ALS (59% vs 7.9%) and to present with comorbid frontotemporal dementia (FTD) (14.8% vs 1.7%). Survival was shorter in patients with the expansion (log-rank χ(2)[1] = 45.323, p0.001). Further investigation in 28 patients initially categorized as having no known family history of ALS identified a family history of dementia in 16 cases; 6 of these had characteristics suggestive of FTD.Comparing the C9orf72 ALS population to the general ALS population, there were no differences in race, age at onset, or proportion of patients with bulbar onset disease. Differences identified in patients with the C9orf72 mutation included shortened survival and an equal proportion of men and women. In addition, we found that assessing family history for dementia may identify other family members likely to be carrying the C9orf72 expansion, reduce the number of sporadic cases, and thus increase our understanding of disease penetrance.

Objective: To test the safety of spinal cord transplantation of human stem cells in patients with amyotrophic lateral sclerosis (ALS) with escalating doses and expansion of the trial to multiple clinical centers. Methods: This open-label trial included 15 participants at 3 academic centers divided into 5 treatment groups receiving increasing doses of stem cells by increasing numbers of cells/injection and increasing numbers of injections. All participants received bilateral injections into the cervical spinal cord (C3-C5). The final group received injections into both the lumbar (L2-L4) and cervical cord through 2 separate surgical procedures. Participants were assessed for adverse events and progression of disease, as measured by the ALS Functional Rating Scale–Revised, forced vital capacity, and quantitative measures of strength. Statistical analysis focused on the slopes of decline of these phase 2 trial participants alone or in combination with the phase 1 participants (previously reported), comparing these groups to 3 separate historical control groups. Results: Adverse events were mostly related to transient pain associated with surgery and to side effects of immunosuppressant medications. There was one incident of acute postoperative deterioration in neurologic function and another incident of a central pain syndrome. We could not discern differences in surgical outcomes between surgeons. Comparisons of the slopes of decline with the 3 separate historical control groups showed no differences in mean rates of progression. Conclusions: Intraspinal transplantation of human spinal cord–derived neural stem cells can be safely accomplished at high doses, including successive lumbar and cervical procedures. The procedure can be expanded safely to multiple surgical centers. Classification of evidence: This study provides Class IV evidence that for patients with ALS, spinal cord transplantation of human stem cells can be safely accomplished and does not accelerate the progression of the disease. This study lacks the precision to exclude important benefit or safety issues.

Importance A new outcome measure for overall disability level with improved responsiveness is needed for amyotrophic lateral sclerosis (ALS) clinical trials. Objective To describe the creation and development of a new self-reported ALS disability scale with improved item targeting and psychometric properties that used a mathematically rigorous Rasch methodology. Design, Setting, and Participants A preliminary ALS disability questionnaire with 119 questions was created based on literature review, clinical judgement of an expert panel, and patient input. Patients with ALS were recruited from January 2017 to June 2019 from the Emory University and Atlanta VA Medical Center ALS clinics, both in Atlanta, Georgia, during regularly scheduled clinic appointments to complete the draft questionnaire and standard ALS outcome measures. All consecutive patients seen at the Emory University and Atlanta VA Medical Center ALS clinics during the recruitment period with a diagnosis of ALS who were able to provide informed consent were invited to participate in the study. Rasch analyses were performed, and items were systematically removed based on missing data, model fit, disordered thresholds, item bias, and clinical judgment. A total of 509 patients with ALS were seen at the 2 sites during the recruitment period, and 264 patients provided informed consent. Interventions Participants completed the draft Rasch questionnaire and the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R). Main Outcomes and Measures Rasch analyses and standard scale metrics were performed to create the new scale, and Rasch analyses were performed on the ALSFRS-R for comparison. Results Overall, 243 participants with ALS completed the draft questionnaire, and 230 participants were included for Rasch analyses. The mean (SD) age for study participants was 61.9 (11.1) years, 146 (60.1%) were men, and site of onset was 23.0% bulbar (n = 56), 36.2% upper extremity (n = 88), and 39.5% lower extremity (n = 96). A 28-question Rasch-Built Overall ALS Disability Scale (ROADS) was constructed with each item scored 0, 1, or 2. The ROADS fulfilled Rasch model requirements, demonstrated improved item targeting compared with the ALSFRS-R, and had test-retest reliability of 0.97. Individual question fit statistics demonstrated infit values from 0.68 to 1.37 and outfit values from 0.66 to 1.43. The difference between the empirical variance explained by the measures and the modeled variance was 0.1%. The ALSFRS-R violated Rasch model expectations and demonstrated disordered thresholds for 9 of 12 questions; 13 of 48 answer choices on the ALSFRS-R were never the most probable answer choice for any overall disability level. Conclusions and Relevance In this study, the 28-question, self-reported ROADS, which is linearly weighted, had improved item targeting compared with the ALSFRS-R, had high test-retest reliability, and was validated. ROADS may serve as a valuable and easily accessible outcome measure for use in ALS trials and in the clinic with improved responsiveness compared with the ALSFRS-R.

Background/Aims: Recent studies suggest that antecedent disease could impact the pathophysiology of the motoneuron disease Amyotrophic Lateral Sclerosis (ALS). We performed a case-control study to examine the prevalence of 11 antecedent diseases in ALS. Methods: Prevalence of antecedent disease in a 1,288 patient ALS population (Emory University ALS Clinic, Atlanta, Ga., USA) is compared to an age, gender, and geography-matched 7,561 subject control population using a statistical odds ratio (OR) with 95% confidence interval. Results: Association of ALS with odds of arthritis (OR = 0.14); non-ALS neurological disease (OR = 0.14); liver disease (OR = 0.19); chronic obstructive pulmonary disorder or COPD (OR = 0.23); kidney disease (OR = 0.32); adult asthma (OR = 0.39); diabetes (OR = 0.47); hypertension (OR = 0.56); obesity (OR = 0.6); hyperlipidemia or hypercholesterolemia (OR = 0.62); and thyroid disease (OR = 0.78). Conclusions: The prevalence of antecedent disease was overall less in the ALS population. We present two potential lines of inquiry to explain these results: (1) ‘Other disease as ALS protection' - antecedent diseases infer biochemical neuroprotection to ALS; (2) ‘ALS as other disease protection' - the underpinnings of ALS could infer protection to other diseases, possibly via the mechanism hypervigilant regulation or ‘too-high' regulatory feedback gains.

We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique individuals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6; P=1 × 10−4) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS (P=8.4 × 10−7). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies., Relatives of patients with amyotrophic lateral sclerosis have an unexpectedly high incidence of schizophrenia. Here, the authors show a genetic link between the two conditions, suggesting shared neurobiological mechanisms.

There is growing interest in the use of stem cells1–10 as a therapy in amyotrophic lateral sclerosis (ALS), a lethal neurological disorder characterized by the degeneration of motor neurons. Stem cells offer a means to replace lost cells, provide neurotrophic support, and improve the diseased microenvironment.1,7–10 Preclinical in vitro and in vivo evidence supports the therapeutic translation of stem cells,9 and studies by our group and others demonstrate that human spinal stem cells (HSSCs) produce protective growth factor profiles, differentiate into neurons, form synapses with host motor neurons, and have beneficial effects after intraspinal transplantation in G93A-SOD1 rats, an established model of ALS.2–6 In 2009, the US Food and Drug Administration (FDA) approved a phase 1 clinical trial examining the safety and feasibility of HSSC injections into the spinal cords of 18 ALS subjects. HSSCs were delivered using a novel intraspinal stabilization and injection device developed by our group.11–14 The first 12 trial subjects, representing Cohorts A to C, received HSSC transplants into the L2–L4 lumbar segments of the spinal cord. Group A subjects were nonambulatory and received 5 unilateral (A1, n = 3) or 10 total bilateral (A2, n = 3) lumbar injections. Subjects in Groups B and C were ambulatory and received 5 unilateral (n = 3) or 10 total bilateral (n = 3) lumbar injections, respectively. As previously described, interim results from these first 12 subjects demonstrated no serious adverse events associated with HSSC transplantation.15,16 Those encouraging results along with the critical need to maintain respiratory function in ALS subjects enabled FDA approval to complete HSSC injections into C3–C5 cervical segments of the spinal cord, the region where motor neurons involved in diaphragmatic function reside. To support these injections, the lumbar stabilization and injection device was adapted and optimized for cervical intraspinal HSSC delivery.12–14 Ambulatory subjects in Groups D (n = 3) and E (n = 3) received 5 unilateral cervical injections. Based on previous preclinical data demonstrating enhanced therapeutic efficacy of HSSC transplantation when injections were targeted to multiple spinal cord segments,2,4 subjects in Group E were the same subjects who previously received bilateral lumbar injections as part of Group C. This cohort represents the first examination of the feasibility of targeting both lumbar and cervical spinal cord segments in ALS subjects in separate surgeries. The phase 1 trial consisting of 18 intraspinal transplantation surgeries in 15 ALS subjects was completed in May 2013. Here, we present the functional outcome data from the 6 subjects undergoing cervical stem cell transplantation surgery, including 3 subjects receiving both bilateral lumbar and unilateral cervical HSSC transplants. Data are also presented from the continued follow-up of the first 12 subjects receiving lumbar intraspinal HSSC transplants. Overall, results demonstrate that HSSCs can be safely transplanted into both lumbar and/or cervical human spinal cord segments, warranting future trial phases focused on cellular dosing and therapeutic efficacy.

BACKGROUND: No United States-based clinical trials have attempted delivery of biological therapies directly to the spinal cord for treatment of amyotrophic lateral sclerosis (ALS) because of the lack of a meaningful US Food and Drug Administration-authorized cell candidate and a validated delivery approach. OBJECTIVE: To assess safety of delivery of a neural stem cell-based treatment into the upper lumbar segments of the ALS spinal cord in the first US Food and Drug Administration-authorized phase I trial. METHODS: Each microinjection series comprised 5 injections (10 μL/injection) separated by 4 mm. Each injection deposited 100,000 neural stem cells derived from a fetal spinal cord. Twelve patients were treated with either unilateral or bilateral injections. Group A, nonambulatory patients, underwent unilateral (n = 3) or bilateral (n = 3) lumbar microinjections. Groups B and C were ambulatory (n = 3 each) and, respectively, received unilateral or bilateral injections. Patients are followed clinically and radiologically to assess potential toxicity of the procedure. RESULTS: Twelve patients have received a transplant. There was one instance of transient intraoperative somatosensory-evoked potentials depression. In the immediate postoperative period, there was 1 episode of urinary retention requiring Foley catheter reinsertion. By discharge, none had a documented motor function decrement. Two patients required readmission and reoperation for cerebrospinal fluid leak or suprafascial wound dehiscence (n = 1 each). Two deaths occurred at 8 and 13 months postsurgery; neither was related to the surgical transplant. CONCLUSION: Our experience in 12 patients supports the procedural safety of unilateral and bilateral intraspinal lumbar microinjection. Completion of this phase I safety trial is planned by proceeding to cervical and combined cervical + lumbar microinjections in ALS patients.

Objective The first US Food and Drug Administration–approved clinical trial to treat amyotrophic lateral sclerosis (ALS) with neural stem cell–based therapy is in progress. The goal of the current study was to identify and assess the survival of human spinal cord–derived neural stem cells (HSSCs) transplanted into the spinal cord in patients with ALS. Methods Spinal cords transplanted with HSSCs were examined from six autopsy cases. Homogenized tissues were interrogated for the presence of donor versus recipient DNA using real-time PCR methods (qPCR). Fluorescence in situ hybridization (FISH) was performed using DNA probes for XY chromosomes to identify male donor HSSCs in one female case, and immunohistochemistry (IHC) was used to characterize the identified donor cells. Results Genomic DNA from donor HSSCs was identified in all cases, comprising 0.67–5.4% of total tissue DNA in patients surviving 196 to 921 days after transplantation. In the one female patient a “nest” of cells identified on H&E staining were XY-positive by FISH, confirming donor origin. A subset of XY-positive cells labeled for the neuronal marker NeuN and stem cell marker SOX2. Interpretation This is the first study to identify human neural stem cells transplanted into a human spinal cord. Transplanted HSSCs survived up to 2.5 years posttransplant. Some cells differentiated into neurons, while others maintained their stem cell phenotype. This work is a proof of concept of the survival and differentiation of human stems cell transplanted into the spinal cord of ALS patients.

UNLABELLED: In patients with cystic fibrosis (CF), glucose intolerance preceding diabetes (prediabetes) may have adverse effects on nutritional status and respiratory function, which are reversible after the start of insulin therapy. Respiratory function (forced vital capacity and forced expiratory volume in one second) and body mass index (BMI) were compared retrospectively in a French cohort of 14 patients during the 5 y preceding insulin therapy for diabetes and in 14 age- and sex-matched controls with normal oral glucose tolerance tests. In the diabetic group, all three parameters deviated increasingly from the values in the controls; the differences became statistically different during the 6 mo before insulin therapy. The effect was more important in patients for whom diabetes mellitus was diagnosed on the basis of symptoms of hyperglycaemia than in patients for whom it was diagnosed by systematic screening, but still present in the latter. After insulin was started, respiratory function improved and the BMI returned to normal within 1 y. The annual insulin requirement increased from 0.62 during the first year to 1.25 during the fifth year. Glycosylated haemoglobin (HbAIc) values ranged from 6.6 to 7.8%. Only 2 episodes of severe hypoglycaemia were recorded over 42 patient-years of follow-up. The insulin regimen most often used was two daily injections of a mixture of short- and intermediate-acting insulin (n = 10) given with an insulin pen. CONCLUSION: The clinical status of CF patients who will need insulin therapy deteriorates before the start of insulin. In patients with CF-related diabetes, with or without fasting hyperglycaemia, insulin therapy improves anabolism and provides good glycaemic control with few severe hypoglycaemic episodes.

Background The first US Food and Drug Administration approved clinical trial for a stem cell-based treatment of amyotrophic lateral sclerosis has now been completed. Objective Primary aims assessed the safety of a direct microinjection-based technique and the toxicity of neural stem cell transplantation to the ventral horn of the cervical and thoracolumbar spinal cord. Results from thoracolumbar-only microinjection groups have been previously published. Cervical and cervical plus thoracolumbar microinjection group perioperative morbidity results are presented. Methods Eighteen microinjection procedures (n = 12 thoracolumbar [T10/11], n = 6 cervical [C3-5]) delivered NSI-566RSC (Neuralstem, Inc), a human neural stem cell, to 15 patients in 5 cohorts. Each injection series comprised 5 injections of 10 μL at 4-mm intervals. The patients in group A (n = 6) were nonambulatory and received unilateral (n = 3) or bilateral (n = 3) thoracolumbar microinjections. The patients in groups B to E were ambulatory and received either unilateral (group B, n = 3) or bilateral (group C, n = 3) thoracolumbar microinjection. Group D and E patients received unilateral cervical (group D, n = 3) or cervical plus bilateral thoracolumbar microinjection (group E, n = 3). Results Unilateral cervical (group D, n = 3) and cervical plus thoracolumbar (group E, n = 3) microinjections to the ventral horn have been completed in ambulatory patients. One patient developed a postoperative kyphotic deformity prompting completion of a laminoplasty in subsequent patients. Another required reoperation for wound dehiscence and infection. The solitary patient with bulbar amyotrophic lateral sclerosis required perioperative reintubation. Conclusion Delivery of a cellular payload to the cervical or thoracolumbar spinal cord was well tolerated by the spinal cord in this vulnerable population. This encouraging finding supports consideration of this delivery approach for neurodegenerative, oncologic, and traumatic spinal cord afflictions.

Background The phosphorylated neurofilament heavy subunit (pNF-H), a major structural component of motor axons, is a promising putative biomarker in amyotrophic lateral sclerosis (ALS) but has been studied mainly in CSF. We examined pNF-H concentrations in plasma, serum and CSF as a potential biomarker for disease progression and survival in ALS. Methodology We measured pNF-H concentration by monoclonal sandwich ELISA in plasma (n=43), serum and CSF (n=20) in ALS patients collected at the Mayo Clinic Florida and Emory University. We included plasma from an ALS cohort (n=20) from an earlier pilot study in order to evaluate baseline pNF-H levels in relation to disease progression using the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), survival and anatomical region of ALS onset. Results Higher pNF-H levels in plasma, serum and CSF showed evidence of association with faster decline in ALSFRS-R. There was evidence for a relationship of higher serum and plasma pNF-H levels with shorter survival, although evidence was weaker for CSF. pNF-H concentration in plasma (n=62) may be higher in patients with bulbar onset than in patients with spinal onset. Conclusions In ALS, increased pNF-H concentration in plasma, serum and CSF appears to be associated with faster disease progression. Factors affecting pNF-H levels or their detection in serum and plasma in relation to disease course may differ from those in CSF. Data raising the possibility that site of ALS onset (bulbar vs spinal) may influence pNF-H levels in peripheral blood seems noteworthy but requires confirmation. These data support further study of pNF-H in CSF, serum and plasma as a potential ALS biomarker.

Advances in stem cell biology have generated intense interest in the prospect of transplanting stem cells into the nervous system for the treatment of neurodegenerative diseases. Here, we report the results of an ongoing phase I trial of intraspinal injections of fetal-derived neural stems cells in patients with amyotrophic lateral sclerosis (ALS). This is a first-in-human clinical trial with the goal of assessing the safety and tolerability of the surgical procedure, the introduction of stem cells into the spinal cord, and the use of immunosuppressant drugs in this patient population. Twelve patients received either five unilateral or five bilateral (10 total) injections into the lumbar spinal cord at a dose of 100,000 cells per injection. All patients tolerated the treatment without any long-term complications related to either the surgical procedure or the implantation of stem cells. Clinical assessments ranging from 6 to 18 months after transplantation demonstrated no evidence of acceleration of disease progression due to the intervention. One patient has shown improvement in his clinical status, although these data must be interpreted with caution since this trial was neither designed nor powered to measure treatment efficacy. These results allow us to report success in achieving the phase I goal of demonstrating safety of this therapeutic approach. Based on these positive results, we can now advance this trial by testing intraspinal injections into the cervical spinal cord, with the goal of protecting motor neuron pools affecting respiratory function, which may prolong life for patients with ALS. STEM CELLS 2012;30:1144–1151

Objective To evaluate the feasibility of a clinical trial designed to delay or prevent the onset of disease amongst subjects at risk for familial amyotrophic lateral sclerosis (fALS). Background The success of many agents in prolonging survival in the SOD1 model of ALS has not been translated into effective therapies for patients with ALS. It is our hypothesis that a trial in fALS may reproduce the positive effects seen in fALS animals. Methods Pedigrees with at least two affected family members were constructed. Unaffected family members were assigned a risk status based on their relationship to affected subjects. Attitudes towards genetic testing were ascertained amongst the at-risk family members. Results We obtained data about 5544 people (116 families) including 516 subjects with ALS (169 from SOD1 positive families) as well as 1056 subjects “definitely” or “probably” at risk for fALS (335 from SOD1 positive families). In excess of 80% of subjects indicated an interest in participating in a future clinical trial directed at delaying the onset of the disease. Assuming the use of a therapeutic agent that will prolong the time to the onset of fALS by 50%, we estimate that a sample size of between 261 and 610 subjects ‘definitely at risk’ will be required (power 0.8) depending on whether patients are followed for 10 or 5 years respectively. Conclusions A clinical trial in fALS may be feasible although such a trial would likely require prolonged follow-up and would require a therapeutic agent with a large clinical effect in order to be adequately powered.

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.