GM1 gangliosidosis type II: Results of a 10-year prospective study.

PURPOSE: GM1 gangliosidosis (GM1) a lysosomal disorder caused by pathogenic variants in GLB1, is characterized by relentless neurodegeneration. There are no approved treatments. METHODS: Forty-one individuals with type II (late-infantile and juvenile) GM1 participated in a single-site prospective observational study. RESULTS: Classification of 37 distinct variants using American College of Medical Genetics and Genomics criteria resulted in the upgrade of 6 and the submission of 4 new variants. In contrast to type I infantile disease, children with type II had normal or near normal hearing and did not have cherry-red maculae or hepatosplenomegaly. Some older children with juvenile onset disease developed thickened aortic and/or mitral valves. Serial magnetic resonance images demonstrated progressive brain atrophy, more pronounced in late infantile patients. Magnetic resonance spectroscopy showed worsening elevation of myo-inositol and deficit of N-acetyl aspartate that were strongly correlated with scores on the Vineland Adaptive Behavior Scale, progressing more rapidly in late infantile compared with juvenile onset disease. CONCLUSION: Serial phenotyping of type II GM1 patients expands the understanding of disease progression and clarifies common misconceptions about type II patients; these are pivotal steps toward more timely diagnosis and better supportive care. The data amassed through this 10-year effort will serve as a robust comparator for ongoing and future therapeutic trials.

A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants.

BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established. METHODS: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events. CONCLUSIONS: High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.).

KCTD7 deficiency defines a distinct neurodegenerative disorder with a conserved autophagy-lysosome defect.

OBJECTIVE: Several small case series identified KCTD7 mutations in patients with a rare autosomal recessive disorder designated progressive myoclonic epilepsy (EPM3) and neuronal ceroid lipofuscinosis (CLN14). Despite the name KCTD (potassium channel tetramerization domain), KCTD protein family members lack predicted channel domains. We sought to translate insight gained from yeast studies to uncover disease mechanisms associated with deficiencies in KCTD7 of unknown function. METHODS: Novel KCTD7 variants in new and published patients were assessed for disease causality using genetic analyses, cell-based functional assays of patient fibroblasts and knockout yeast, and electron microscopy of patient samples. RESULTS: Patients with KCTD7 mutations can exhibit movement disorders or developmental regression before seizure onset, and are distinguished from similar disorders by an earlier age of onset. Although most published KCTD7 patient variants were excluded from a genome sequence database of normal human variations, most newly identified patient variants are present in this database, potentially challenging disease causality. However, genetic analysis and impaired biochemical interactions with cullin 3 support a causal role for patient KCTD7 variants, suggesting deleterious alleles of KCTD7 and other rare disease variants may be underestimated. Both patient-derived fibroblasts and yeast lacking Whi2 with sequence similarity to KCTD7 have impaired autophagy consistent with brain pathology. INTERPRETATION: Biallelic KCTD7 mutations define a neurodegenerative disorder with lipofuscin and lipid droplet accumulation but without defining features of neuronal ceroid lipofuscinosis or lysosomal storage disorders. KCTD7 deficiency appears to cause an underlying autophagy-lysosome defect conserved in yeast, thereby assigning a biological role for KCTD7. Ann Neurol 2018;84:774-788.

d-Leucine: Evaluation in an epilepsy model.

BACKGROUND: Current medicines do not provide sufficient seizure control for nearly one-third of patients with epilepsy. New options are needed to address this treatment gap. We recently found that the atypical amino acid d-leucine protected against acutely-induced seizures in mice, but its effect in chronic seizures has not been explored. We hypothesized that d-leucine would protect against spontaneous recurrent seizures. We also investigated whether mice lacking a previously-described d-leucine receptor (Tas1R2/R3) would be protected against acutely-induced seizures. METHODS: Male FVB/NJ mice were subjected to kainic acid-induced status epilepticus and monitored by video-electroencephalography (EEG) (surgically implanted electrodes) for 4weeks before, during, and after treatment with d-leucine. Tas1R2/R3 knockout mice and controls underwent the maximal electroshock threshold (MES-T) and 6-Hz tests. RESULTS: There was no difference in number of calendar days with seizures or seizure frequency with d-leucine treatment. In an exploratory analysis, mice treated with d-leucine had a lower number of dark cycles with seizures. Tas1R2/R3 knockout mice had elevated seizure thresholds in the MES-T test but not the 6-Hz test. CONCLUSIONS: d-Leucine treatment was ineffective against chronic seizures after kainic acid-induced status epilepticus, but there was some efficacy during the dark cycle. Because d-leucine is highly concentrated in the pineal gland, these data suggest that d-leucine may be useful as a tool for studying circadian patterns in epilepsy. Deletion of the Tas1R2/R3 receptor protected against seizures in the MES-T test and, therefore, may be a novel target for treating seizures.

Age and Mortality in Pediatric Severe Traumatic Brain Injury: Results from an International Study.

BACKGROUND: Although small series have suggested that younger age is associated with less favorable outcome after severe traumatic brain injury (TBI), confounders and biases have limited our understanding of this relationship. We hypothesized that there would be an association between age and mortality in children within an ongoing observational, cohort study. METHODS: The first 200 subjects from the Approaches and Decisions for Acute Pediatric TBI trial were eligible for this analysis (inclusion criteria: severe TBI (Glasgow Coma Scale [GCS] score ≤ 8], age 18 years, and intracranial pressure (ICP) monitor placed; exclusion: pregnancy). Children with suspected abusive head trauma (AHT) were excluded to avoid bias related to the association between AHT and mortality. Demographics, and prehospital and resuscitation events were collected/analyzed, and children were stratified based on age at time of injury (< 5, 5-< 11, 11-18 years) and presented as mean ± standard error of the mean (SEM). Analyses of variance were used to test the equality of the means across the group for continuous variable, and Chi-square tests were used to compare percentages for discrete variables (post hoc comparisons were made using t test and Bonferroni corrections, as needed). Kaplan-Meier curves were generated for each age subgroup describing the time of death, and log-rank was used to compare the curves. Cox proportional hazards regression models were used to assess the effect of age on time to death while controlling for covariates. RESULTS: In the final cohort (n = 155, 45 excluded for AHT), overall age was 9.2 years ± 0.4 and GCS was 5.3 ± 0.1. Mortality was similar between strata (14.0, 20.0, 20.9%, respectively, p = 0.58). Motor vehicle accidents were the most common mechanism across all strata, while falls tended to be more common in the youngest stratum (p = 0.08). The youngest stratum demonstrated increased incidence of spontaneous hypothermia at presentation and decreased hemoglobin concentrations and coagulopathies, while the oldest demonstrated lower platelet counts. CONCLUSIONS: In contrast to previous reports, we failed to detect mortality differences across age strata in children with severe TBI. We have discerned novel associations between age and various markers of injury-unrelated to AHT-that may lead to testable hypotheses in the future.

Abusive Head Trauma and Mortality-An Analysis From an International Comparative Effectiveness Study of Children With Severe Traumatic Brain Injury.

OBJECTIVES: Small series have suggested that outcomes after abusive head trauma are less favorable than after other injury mechanisms. We sought to determine the impact of abusive head trauma on mortality and identify factors that differentiate children with abusive head trauma from those with traumatic brain injury from other mechanisms. DESIGN: First 200 subjects from the Approaches and Decisions in Acute Pediatric Traumatic Brain Injury Trial-a comparative effectiveness study using an observational, cohort study design. SETTING: PICUs in tertiary children's hospitals in United States and abroad. PATIENTS: Consecutive children (age < 18 yr) with severe traumatic brain injury (Glasgow Coma Scale ≤ 8; intracranial pressure monitoring). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics, injury-related scores, prehospital, and resuscitation events were analyzed. Children were dichotomized based on likelihood of abusive head trauma. A total of 190 children were included (n = 35 with abusive head trauma). Abusive head trauma subjects were younger (1.87 ± 0.32 vs 9.23 ± 0.39 yr; p < 0.001) and a greater proportion were female (54.3% vs 34.8%; p = 0.032). Abusive head trauma were more likely to 1) be transported from home (60.0% vs 33.5%; p < 0.001), 2) have apnea (34.3% vs 12.3%; p = 0.002), and 3) have seizures (28.6% vs 7.7%; p < 0.001) during prehospital care. Abusive head trauma had a higher prevalence of seizures during resuscitation (31.4 vs 9.7%; p = 0.002). After adjusting for covariates, there was no difference in mortality (abusive head trauma, 25.7% vs nonabusive head trauma, 18.7%; hazard ratio, 1.758; p = 0.60). A similar proportion died due to refractory intracranial hypertension in each group (abusive head trauma, 66.7% vs nonabusive head trauma, 69.0%). CONCLUSIONS: In this large, multicenter series, children with abusive head trauma had differences in prehospital and in-hospital secondary injuries which could have therapeutic implications. Unlike other traumatic brain injury populations in children, female predominance was seen in abusive head trauma in our cohort. Similar mortality rates and refractory intracranial pressure deaths suggest that children with severe abusive head trauma may benefit from therapies including invasive monitoring and adherence to evidence-based guidelines.

Response to treatment in a prospective national infantile spasms cohort.

OBJECTIVE: Infantile spasms are seizures associated with a severe epileptic encephalopathy presenting in the first 2 years of life, and optimal treatment continues to be debated. This study evaluates early and sustained response to initial treatments and addresses both clinical remission and electrographic resolution of hypsarrhythmia. Secondarily, it assesses whether response to treatment differs by etiology or developmental status. METHODS: The National Infantile Spasms Consortium established a multicenter, prospective database enrolling infants with new diagnosis of infantile spasms. Children were considered responders if there was clinical remission and resolution of hypsarrhythmia that was sustained at 3 months after first treatment initiation. Standard treatments of adrenocorticotropic hormone (ACTH), oral corticosteroids, and vigabatrin were considered individually, and all other nonstandard therapies were analyzed collectively. Developmental status and etiology were assessed. We compared response rates by treatment group using chi-square tests and multivariate logistic regression models. RESULTS: Two hundred thirty infants were enrolled from 22 centers. Overall, 46% of children receiving standard therapy responded, compared to only 9% who responded to nonstandard therapy (p < 0.001). Fifty-five percent of infants receiving ACTH as initial treatment responded, compared to 39% for oral corticosteroids, 36% for vigabatrin, and 9% for other (p < 0.001). Neither etiology nor development significantly modified the response pattern by treatment group. INTERPRETATION: Response rate varies by treatment choice. Standard therapies should be considered as initial treatment for infantile spasms, including those with impaired development or known structural or genetic/metabolic etiology. ACTH appeared to be more effective than other standard therapies.

Response to second treatment after initial failed treatment in a multicenter prospective infantile spasms cohort.

OBJECTIVE: Infantile spasms (IS) represent a severe epileptic encephalopathy presenting in the first 2 years of life. Recommended first-line therapies (hormonal therapy or vigabatrin) often fail. We evaluated response to second treatment for IS in children in whom the initial therapy failed to produce both clinical remission and electrographic resolution of hypsarhythmia and whether time to treatment was related to outcome. METHODS: The National Infantile Spasms Consortium established a multicenter, prospective database enrolling infants with new diagnosis of IS. Children were considered nonresponders to first treatment if there was no clinical remission or persistence of hypsarhythmia. Treatment was evaluated as hormonal therapy (adrenocorticotropic hormone [ACTH] or oral corticosteroids), vigabatrin, or "other." Standard treatments (hormonal and vigabatrin) were compared to all other nonstandard treatments. We compared response rates using chi-square tests and multivariable logistic regression models. RESULTS: One hundred eighteen infants were included from 19 centers. Overall response rate to a second treatment was 37% (n = 44). Children who received standard medications with differing mechanisms for first and second treatment had higher response rates than other sequences (27/49 [55%] vs. 17/69 [25%], p < 0.001). Children receiving first treatment within 4 weeks of IS onset had a higher response rate to second treatment than those initially treated later (36/82 [44%] vs. 8/34 [24%], p = 0.040). SIGNIFICANCE: Greater than one third of children with IS will respond to a second medication. Choosing a standard medication (ACTH, oral corticosteroids, or vigabatrin) that has a different mechanism of action appears to be more effective. Rapid initial treatment increases the likelihood of response to the second treatment.

Potent anti-seizure effects of D-leucine.

There are no effective treatments for millions of patients with intractable epilepsy. High-fat ketogenic diets may provide significant clinical benefit but are challenging to implement. Low carbohydrate levels appear to be essential for the ketogenic diet to work, but the active ingredients in dietary interventions remain elusive, and a role for ketogenesis has been challenged. A potential antiseizure role of dietary protein or of individual amino acids in the ketogenic diet is understudied. We investigated the two exclusively ketogenic amino acids, L-leucine and L-lysine, and found that only L-leucine potently protects mice when administered prior to the onset of seizures induced by kainic acid injection, but not by inducing ketosis. Unexpectedly, the D-enantiomer of leucine, which is found in trace amounts in the brain, worked as well or better than L-leucine against both kainic acid and 6Hz electroshock-induced seizures. However, unlike L-leucine, D-leucine potently terminated seizures even after the onset of seizure activity. Furthermore, D-leucine, but not L-leucine, reduced long-term potentiation but had no effect on basal synaptic transmission in vitro. In a screen of candidate neuronal receptors, D-leucine failed to compete for binding by cognate ligands, potentially suggesting a novel target. Even at low doses, D-leucine suppressed ongoing seizures at least as effectively as diazepam but without sedative effects. These studies raise the possibility that D-leucine may represent a new class of anti-seizure agents, and that D-leucine may have a previously unknown function in eukaryotes.

Christianson syndrome: spectrum of neuroimaging findings.

Christianson syndrome (CS) is caused by mutations in SLC9A6 and is characterized by severe intellectual disability, absent speech, microcephaly, ataxia, seizures, and behavioral abnormalities. The clinical phenotypes of CS and Angelman syndrome (AS) are similar. Differentiation between CS and AS is important in terms of genetic counseling. We report on two children with CS and confirmed mutations in SLC9A6 focusing on neuroimaging findings and review the available literature. Cerebellar atrophy (CA) occurs in approximately 60% of the patients with CS and develops after the age of 12 months. Hyperintense signal of the cerebellar cortex (CbC) is less common, and may be diffuse, patchy, or involve only the inferior part of the cerebellum and is best seen on coronal fluid attenuation inversion recovery images. CA and CbC-hyperintensity are not neuroimaging features of AS. In a child with the phenotype of AS, CA and/or CbC-hyperintensity are rather specific for CS and should prioritize sequencing of SLC9A6.

Global health for rare diseases through primary care.

Rare diseases affect over 300 million people worldwide and are gaining recognition as a global health priority. Their inclusion in the UN Sustainable Development Goals, the UN Resolution on Addressing the Challenges of Persons Living with a Rare Disease, and the anticipated WHO Global Network for Rare Diseases and WHO Resolution on Rare Diseases, which is yet to be announced, emphasise their significance. People with rare diseases often face unmet health needs, including access to screening, diagnosis, therapy, and comprehensive health care. These challenges highlight the need for awareness and targeted interventions, including comprehensive education, especially in primary care. The majority of rare disease research, clinical services, and health systems are addressed with specialist care. WHO Member States have committed to focusing on primary health care in both universal health coverage and health-related Sustainable Development Goals. Recognising this opportunity, the International Rare Diseases Research Consortium (IRDiRC) assembled a global, multistakeholder task force to identify key barriers and opportunities for empowering primary health-care providers in addressing rare disease challenges.

Telehealth for rare disease care, research, and education across the globe: A review of the literature by the IRDiRC telehealth task force.

The International Rare Diseases Research Consortium (IRDiRC) Telehealth (TH) Task Force explored the use of TH for improving diagnosis, care, research, and education for rare diseases (RDs). The Task Force reviewed related literature published from January 2017 to August 2023, and identified various models and implementation strategies of TH for RD. The Task Force highlighted the reported value and benefits of using TH for RDs, along with the limitations and opportunities. The number of publications sharply increased since 2021, coinciding with the onset of the COVID-19 pandemic, which forced the rapid adoption of TH in many healthcare settings. One of the major benefits of TH for RDs lies in its capacity to surmount geographical barriers, which helps in overcoming the constraints posed by limited numbers and geographical dispersion of specialists. This was evident during the pandemic when TH was used to maintain a level of continued medical care and research when face-to-face visits were severely restricted. TH, through which clinical research can be decentralized, can also facilitate and enhance RD research by decreasing burden, expanding access, and enhancing efficiency. This will be especially beneficial when coupled with the adoption of digital health technologies, such as mobile health (mHealth) and wearable devices for remote monitoring (i.e., surveillance of outpatient data transmitted through devices), along with big data solutions. TH has also been shown to be an effective means for RD education and peer mentoring, enabling local health care providers (HCPs) to care for RD patients, which indirectly ensures that RD patients get the expertise and multidisciplinary care they need. However, limitations and weaknesses associated with using TH for RD care and research were also identified, including the inability to perform physical examinations and build relationships with HCPs. Therefore, TH has been recommended as a complement to, rather than substitute for, face-to-face consultations. There is also a concern that TH may lead to an amplification of health disparities and inequities related to social determinants of health for those with RDs due to lack of access to TH technologies, inadequate digital literacy, and geographical, socio-cultural, and linguistic barriers. Finally, the Task Force also discussed evidence and knowledge gaps that will benefit from future research efforts to help advance and expand the use of TH for RD care, research, and education.

GM1 Gangliosidosis Type II: Results of a 10-Year Prospective Study.

Purpose: GM1 gangliosidosis (GM1) is an ultra-rare lysosomal storage disease caused by pathogenic variants in galactosidase beta 1 (GLB1; NM_000404), primarily characterized by neurodegeneration, often in children. There are no approved treatments for GM1, but clinical trials using gene therapy (NCT03952637, NCT04713475) and small molecule substrate inhibitors (NCT04221451) are ongoing. Understanding the natural history of GM1 is essential for timely diagnosis, facilitating better supportive care, and contextualizing the results of therapeutic trials. Methods: Forty-one individuals with type II GM1 (n=17 late infantile and n=24 juvenile onset) participated in a single-site prospective observational study. Here, we describe the results of extensive multisystem assessment batteries, including clinical labs, neuroimaging, physiological exams, and behavioral assessments. Results: Classification of 37 distinct variants in this cohort was performed according to ACMG criteria and resulted in the upgrade of six and the submission of four new variants to pathogenic or likely pathogenic. In contrast to type I infantile, children with type II disease exhibited normal or near normal hearing and did not have cherry red maculae or significant hepatosplenomegaly. Some older children with juvenile onset developed thickened aortic and/or mitral valves with regurgitation. Serial MRIs demonstrated progressive brain atrophy that were more pronounced in those with late infantile onset. MR spectroscopy showed worsening elevation of myo-inositol and deficit of N-acetyl aspartate that were strongly correlated with scores on the Vineland Adaptive Behavior Scale and progress more rapidly in late infantile than juvenile onset disease. Conclusion: The comprehensive serial phenotyping of type II GM1 patients expands the understanding of disease progression and clarifies some common misconceptions about type II patients. Findings from this 10-year endeavor are a pivotal step toward more timely diagnosis and better supportive care for patients. The wealth of data amassed through this effort will serve as a robust comparator for ongoing and future therapeutic trials.

Posthemispherectomy hydrocephalus: results of a comprehensive, multiinstitutional review.

PURPOSE: Hemispherectomy surgery for medically intractable epilepsy is known to cause hydrocephalus in a subset of patients. Existing data regarding the incidence of, and risk factors for, developing posthemispherectomy hydrocephalus have been limited by the relatively small number of cases performed by any single center. Our goal was to better understand this phenomenon and to identify risk factors that may predispose patients to developing hydrocephalus after hemispherectomy surgery. METHODS: Fifteen pediatric epilepsy centers participated in this study. A retrospective chart review was performed on all available patients who had hemispherectomy surgery. Data collected included surgical techniques, etiology of seizures, prior brain surgery, symptoms and signs of hydrocephalus, timing of shunt placement, and basic demographics. KEY FINDINGS: Data were collected from 736 patients who underwent hemispherectomy surgery between 1986 and 2011. Forty-six patients had preexisting shunted hydrocephalus and were excluded from analysis, yielding 690 patients for this study. One hundred sixty-two patients (23%) required hydrocephalus treatment. The timing of hydrocephalus ranged from the immediate postoperative period to 8.5 years after surgery, with 43 patients (27%) receiving shunts >90 days after surgery. Multivariate regression analysis revealed anatomic hemispherectomies (odds ratio [OR] 4.1, p < 0.0001) and previous brain surgery (OR 1.7, p = 0.04) as independent significant risk factors for developing hydrocephalus. There was a trend toward significance for the use of hemostatic agents (OR 2.2, p = 0.07) and the involvement of basal ganglia or thalamus in the resection (OR 2.2, p = 0.08) as risk factors. SIGNIFICANCE: Hydrocephalus is a common sequela of hemispherectomy surgery. Surgical technique and prior brain surgery influence the occurrence of posthemispherectomy hydrocephalus. A significant portion of patients develop hydrocephalus on a delayed basis, indicating the need for long-term surveillance.

Harnessing the power of metabolism for seizure prevention: focus on dietary treatments.

The continued occurrence of refractory seizures in at least one-third of children and adults with epilepsy, despite the availability of almost 15 conventional and novel anticonvulsant drugs, speaks to a dire need to develop novel therapeutic approaches. Cellular metabolism, the critical pathway by which cells access and utilize energy, is essential for normal neuronal function. Furthermore, mounting evidence suggests direct links between energy metabolism and cellular excitability. The high-fat, low-carbohydrate ketogenic diet has been used as a treatment for drug-refractory epilepsy for almost a century. Yet, the multitude of alternative therapies to target aspects of cellular metabolism and hyperexcitability is almost untapped. Approaches discussed in this review offer a wide diversity of therapeutic targets that might be exploited by investigators in the search for safer and more effective epilepsy treatments.

The IRDiRC Chrysalis Task Force: making rare disease research attractive to companies.

Background: The International Rare Diseases Research Consortium (IRDiRC) is an international initiative that aims to use research to facilitate rapid diagnosis and treatment of rare diseases. Objective: IRDiRC launched the Chrysalis Task Force to identify key financial and nonfinancial factors that make rare disease research and development attractive to companies. Methods: The Chrysalis Task Force was comprised of thought leaders from companies, patient advocacy groups, regulatory agencies, and research funders. The Task Force created a survey that was distributed to companies of different sizes with varied investment portfolios and interests in rare disease research. Based on the survey results, the Task Force then conducted targeted interviews. Results: The survey and interview respondents identified several factors that make rare disease research and development attractive (e.g. a good understanding of the underlying biology) as well as barriers (e.g. absence of an advocacy organization representing the affected community's needs). The concept of Return On Investment allowed the exploration of factors that were weighed differently by survey and interview respondents, depending on a number of intrinsic and extrinsic issues. Conclusions: The Chrysalis Task Force identified factors attributable to rare disease research and development that may be of interest to and actionable by funders, academic researchers, patients and their families, companies, regulators, and payers in the medium term to short term. By addressing the identified challenges, involved parties may seek solutions to significantly advance the research and development of treatments for rare diseases.

Making rare disease research attractive to companies The International Rare Diseases Research Consortium (IRDiRC) is an international initiative that aims to speed the diagnosis and treatment of rare diseases through research. The IRDiRC Chrysalis Task Force, comprised of thought leaders from companies, patient advocacy groups, regulatory agencies, and research funders, identified key factors that make rare disease research and development attractive to companies. The Task Force distributed a survey to companies with varied investment portfolios and interests in rare disease research, followed by in-depth interviews based on the survey results. The survey and interview respondents identified both attractive factors and barriers to rare disease research and development. The concept of Return On Investment was used to frame discussion of factors that companies weighed differently, depending on a number of issues that were a function of both the company itself and outside factors. The identified challenges can be addressed by funders, academic researchers, patients and their families, companies, regulators, and payers, which hopefully will lead to significant advances in the research and development of treatments for rare diseases.

Ketone bodies in epilepsy.

Seizures that are resistant to standard medications remain a major clinical problem. One underutilized option for patients with medication-resistant seizures is the high-fat, low-carbohydrate ketogenic diet. The diet received its name based on the observation that patients consuming this diet produce ketone bodies (e.g., acetoacetate, ß-hydroxybutyrate, and acetone). Although the exact mechanisms of the diet are unknown, ketone bodies have been hypothesized to contribute to the anticonvulsant and antiepileptic effects. In this review, anticonvulsant properties of ketone bodies and the ketogenic diet are discussed (including GABAergic and glutamatergic effects). Because of the importance of ketone body metabolism in the early stages of life, the effects of ketone bodies on developing neurons in vitro also are discussed. Understanding how ketone bodies exert their effects will help optimize their use in treating epilepsy and other neurological disorders.

Ketogenic diets: new advances for metabolism-based therapies.

PURPOSE OF REVIEW: Despite myriad anticonvulsants available and in various stages of development, there are thousands of children and adults with epilepsy worldwide still refractory to treatment and not candidates for epilepsy surgery. Many of these patients will now turn to dietary therapies such as the ketogenic diet, medium-chain triglyceride diet, modified Atkins diet, and low glycemic index treatment. RECENT FINDINGS: In the past several years, neurologists are finding new indications to use these dietary treatments, perhaps even as first-line therapy, including infantile spasms, myoclonic-astatic epilepsy (Doose syndrome), Dravet syndrome, and status epilepticus (including FIRES syndrome). Adults are also one of the most rapidly growing populations being treated nowadays; this group of patients previously was not typically offered these treatments. In 2009, two controlled trials of the ketogenic diet were published, as well as an International Expert Consensus Statement on dietary treatment of epilepsy. Ketogenic diets are also now being increasingly studied for neurological conditions other than epilepsy, including Alzheimer's disease and cancer. Insights from basic science research have helped elucidate the mechanisms by which metabolism-based therapy may be helpful, in terms of both an anticonvulsant and possibly a neuroprotective effect. SUMMARY: Dietary therapy for epilepsy continues to grow in popularity worldwide, with expanding use for adults and conditions other than epilepsy.

Diagnosis delay in West syndrome: misdiagnosis and consequences.

West syndrome or infantile spasms is one of the most frequent epileptic syndromes in the first year of life. The clinical symptoms of infantile spasms are very different than any other type of seizure because of both the absence of paroxysmal motor phenomena (i.e., as in a convulsion) and the lack of significant duration of loss of consciousness (i.e., as in absence epilepsy). Infantile spasms may lead to misdiagnosis by pediatricians and other primary care providers. We assessed the missed diagnoses prior to the diagnosis of infantile spasms. We hypothesized that a delay in treatment may have consequences on neurologic outcome. We conducted a multicenter, retrospective, observational study to evaluate occurrence of misdiagnosis and its possible consequences. We performed a multivariate analysis to evaluate the risk for the outcome 2 years after the diagnosis of infantile spasms. We included 83 infants over a 5-year period. The majority of consulted physicians (301 of 362) did not suggest any specific diagnosis while the others suggested gastroesophageal reflux (7 %), constipation (7 %), or colitis (3 %). Results indicated that a poor outcome was related to a delay in diagnosis, which was observed regardless of the existence of cognitive involvement prior to the start of infantile spasms (Relative Risk: RR 12.08 [1.52-96.3]). These results highlight the importance of making an early diagnosis of infantile spasms.