Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder.

BACKGROUND: Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy. METHODS: SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy. RESULTS: The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4-14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder's clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation. CONCLUSIONS: Findings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy.

Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits. Current treatment options for SSADHD remain supportive, but there are ongoing attempts to develop targeted genetic therapies. This study aimed to create consensus guidelines for the diagnosis and management of SSADHD. Thirty relevant statements were initially addressed by a systematic literature review, resulting in different evidence levels of strength according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. The highest level of evidence (level A), based on randomized controlled trials, was unavailable for any of the statements. Based on cohort studies, Level B evidence was available for 12 (40%) of the statements. Thereupon, through a process following the Delphi Method and directed by the Appraisal of Guidelines for Research and Evaluation (AGREE II) criteria, expert opinion was sought, and members of an SSADHD Consensus Group evaluated all the statements. The group consisted of neurologists, epileptologists, neuropsychologists, neurophysiologists, metabolic disease specialists, clinical and biochemical geneticists, and laboratory scientists affiliated with 19 institutions from 11 countries who have clinical experience with SSADHD patients and have studied the disorder. Representatives from parent groups were also included in the Consensus Group. An analysis of the survey's results yielded 25 (83%) strong and 5 (17%) weak agreement strengths. These first-of-their-kind consensus guidelines intend to consolidate and unify the optimal care that can be provided to individuals with SSADHD.

ALDH5A1-deficient iPSC-derived excitatory and inhibitory neurons display cell type specific alterations.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a neurometabolic disorder caused by ALDH5A1 mutations presenting with autism and epilepsy. SSADHD leads to impaired GABA metabolism and results in accumulation of GABA and γ-hydroxybutyrate (GHB), which alter neurotransmission and are thought to lead to neurobehavioral symptoms. However, why increased inhibitory neurotransmitters lead to seizures remains unclear. We used induced pluripotent stem cells from SSADHD patients (one female and two male) and differentiated them into GABAergic and glutamatergic neurons. SSADHD iGABA neurons show altered GABA metabolism and concomitant changes in expression of genes associated with inhibitory neurotransmission. In contrast, glutamatergic neurons display increased spontaneous activity and upregulation of mitochondrial genes. CRISPR correction of the pathogenic variants or SSADHD mRNA expression rescue various metabolic and functional abnormalities in human neurons. Our findings uncover a previously unknown role for SSADHD in excitatory human neurons and provide unique insights into the cellular and molecular basis of SSADHD and potential therapeutic interventions.

Glymphatic dysfunction coincides with lower GABA levels and sleep disturbances in succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder of γ-aminobutyrate (GABA) catabolism. Cerebral waste clearance along glymphatic perivascular spaces depends on aquaporin 4 (AQP4) water channels, the function of which was shown to be influenced by GABA. Sleep disturbances are associated independently with SSADHD and glymphatic dysfunction. This study aimed to determine whether indices of the hyperGABAergic state characteristic of SSADHD coincide with glymphatic dysfunction and sleep disturbances and to explicate the modulatory effect that GABA may have on the glymphatic system. The study included 42 individuals (21 with SSADHD; 21 healthy controls) who underwent brain MRIs and magnetic resonance spectroscopy (MRS) for assessment of glymphatic dysfunction and cortical GABA, plasma GABA measurements, and circadian clock gene expression. The SSADHD subjects responded to an additional Children's Sleep Habits Questionnaire (CSHQ). Compared with the control group, SSADHD subjects did not differ in sex and age but had a higher severity of enlarged perivascular spaces in the centrum semiovale (p < 0.001), basal ganglia (p = 0.01), and midbrain (p = 0.001), as well as a higher MRS-derived GABA/NAA peak (p < 0.001). Within the SSADHD group, the severity of glymphatic dysfunction was specific for a lower MRS-derived GABA/NAA (p = 0.04) and lower plasma GABA (p = 0.004). Additionally, the degree of their glymphatic dysfunction correlated with the CSHQ-estimated sleep disturbances scores (R = 5.18, p = 0.03). In the control group, EPVS burden did not correlate with age or cerebral and plasma GABA values. The modulatory effect that GABA may exert on the glymphatic system has therapeutic implications for sleep-related disorders and neurodegenerative conditions associated with glymphatic dysfunction.

Reduced evoked cortical beta and gamma activity and neuronal synchronization in succinic semialdehyde dehydrogenase deficiency, a disorder of γ-aminobutyric acid metabolism.

Succinic semialdehyde dehydrogenase deficiency is a rare autosomal recessively inherited metabolic disorder of γ-aminobutyric acid catabolism manifested by intellectual disability, expressive aphasia, movement disorders, psychiatric ailments and epilepsy. Subjects with succinic semialdehyde dehydrogenase deficiency are characterized by elevated γ-aminobutyric acid and related metabolites, such as γ-guanidinobutyric acid, and an age-dependent downregulation of cerebral γ-aminobutyric acid receptors. These findings indicate impaired γ-aminobutyric acid and γ-aminobutyric acid sub-type A (GABAA) receptor signalling as major factors underlying the pathophysiology of this neurometabolic disorder. We studied the cortical oscillation patterns and their relationship with γ-aminobutyric acid metabolism in 18 children affected by this condition and 10 healthy controls. Using high-density EEG, we recorded somatosensory cortical responses and resting-state activity. Using electrical source imaging, we estimated the relative power changes (compared with baseline) in both stimulus-evoked and stimulus-induced responses for physiologically relevant frequency bands and resting-state power. Stimulus-evoked oscillations are phase locked to the stimulus, whereas induced oscillations are not. Power changes for both evoked and induced responses as well as resting-state power were correlated with plasma γ-aminobutyric acid and γ-guanidinobutyric acid concentrations and with cortical γ-aminobutyric acid measured by proton magnetic resonance spectroscopy. Plasma γ-aminobutyric acid, γ-guanidinobutyric acid and cortical γ-aminobutyric acid were higher in patients than in controls (P < 0.001 for both). Beta and gamma relative power were suppressed for evoked responses in patients versus controls (P < 0.01). No group differences were observed for induced activity (P > 0.05). The mean gamma frequency of evoked responses was lower in patients versus controls (P = 0.002). Resting-state activity was suppressed in patients for theta (P = 0.011) and gamma (P < 0.001) bands. Evoked power changes were inversely correlated with plasma γ-aminobutyric acid and with γ-guanidinobutyric acid for beta (P < 0.001) and gamma (P < 0.001) bands. Similar relationships were observed between the evoked power changes and cortical γ-aminobutyric acid for all tested areas in the beta band (P < 0.001) and for the posterior cingulate gyrus in the gamma band (P < 0.001). We also observed a negative correlation between resting-state activity and plasma γ-aminobutyric acid and γ-guanidinobutyric acid for theta (P < 0.001; P = 0.003), alpha (P = 0.003; P = 0.02) and gamma (P = 0.02; P = 0.01) bands. Our findings indicate that increased γ-aminobutyric acid concentration is associated with reduced sensory-evoked beta and gamma activity and impaired neuronal synchronization in patients with succinic semialdehyde dehydrogenase deficiency. This further elucidates the pathophysiology of this neurometabolic disorder and serves as a potential biomarker for therapeutic trials.

Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants.

To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders.

Eating disorders occur at high rates in adolescents with epilepsy and are associated with psychiatric comorbidities and suicidality.

OBJECTIVES: To assess the occurrence rate, characteristics, and impact of eating disorders (EDs) in adolescents with epilepsy. METHODS: In this observational study, adolescents with epilepsy seen in a single center between 2013 and 2022 who had comorbid EDs were compared to two control groups of adolescents with only epilepsy and only EDs. Patients with intellectual disability or autism spectrum disorder were excluded. Data retrieved included demographic and anthropometric details and clinical variables relating to seizure types, EDs, and psychiatric disorders and behaviors. RESULTS: A total of 376 subjects were included in the study: 84 adolescents with both epilepsy and eating disorders, 135 with only epilepsy, and 157 with only EDs. The rate of EDs in adolescents with epilepsy was 7.0% (95% confidence interval [CI] 5.6%-8.5%) overall, 11.3% (95% CI 8.8%-14.3%) in females, and 3.1% (95% CI 1.9%-4.8%) in males. The median (interquartile range [IQR]) time difference between the onset of epilepsy to an ED was 1.6 (.5-3.6) years. Among adolescents with epilepsy, those with an ED were more likely to be female (p = .001) and have a lower body mass index z-score (zBMI) percentile (p < .001). Epilepsy type, seizure frequency, or seizure duration were not specific for having or not having EDs. Among adolescents with EDs, those with epilepsy had a younger onset of their EDs (p < .001), included relatively more males (p = .007), and consisted of more cases of anorexia-nervosa-restrictive type (p < .001), and fewer cases of bulimia nervosa (p = .04) and binge eating disorder (p = .003). Adolescents with epilepsy and a comorbid ED were more likely to have psychiatric comorbidities such as depression, anxiety, and suicidality than adolescents with only epilepsy or EDs. SIGNIFICANCE: EDs should be suspected and screened for in intellectually intact female and male adolescents with epilepsy, irrespective of their epilepsy type. If disturbed eating behaviors or EDs are identified, further evaluation should be directed at detecting other psychopathologies, including suicidality.

Real-Life Outcome After Gene Replacement Therapy for Spinal Muscular Atrophy: A Multicenter Experience.

BACKGROUND: Onasemnogene abeparvovec-xioi (OA) has been available since 2019 as a gene replacement therapy for individuals with spinal muscular atrophy (SMA) under age two years. We aim to expand upon the sparse knowledge about its safety and clinical efficacy. METHODS: The clinical outcome data of all the individuals with SMA who were treated with gene therapy in four tertiary hospitals in Israel were retrieved and analyzed. RESULTS: The study participants included 25 individuals who received the gene therapy between age 11 days and 23 months and whose median follow-up duration was 18.0 (interquartile range [IQR], 12.4 to 18.3) months. Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores increased by a median (IQR) of 13 (8 to 20) points at the last follow-up compared with baseline. None of the patients experienced regression in motor abilities after gene therapy, which was generally well tolerated. There was gradual improvement in motor function, especially among presymptomatic patients (P ≤ 0.001) whose disease duration was shorter (≤8 months) before receiving gene therapy (P ≤ 0.001) and who did not experience recurrent infections and illnesses in the months following treatment (P ≤ 0.001). CONCLUSIONS: OA was well tolerated and led to favorable functional motor outcomes at six to 24 months after treatment initiation. Better progress in motor function was observed in individuals who received OA earlier and who were presymptomatic, irrespective of the SMN2 copy number or type. Our results further strengthen the clinical efficacy of OA and reinforce the importance of early recognition of SMA via newborn screening programs.

Autism spectrum disorder and GABA levels in children with succinic semialdehyde dehydrogenase deficiency.

AIM: To elucidate the etiological aspects of autism spectrum disorder (ASD) in succinic semialdehyde dehydrogenase deficiency (SSADHD), related to dysregulation of γ-aminobutyric acid (GABA) and the imbalance of excitatory and inhibitory neurotransmission. METHOD: In this prospective, international study, individuals with SSADHD underwent neuropsychological assessments, as well as biochemical, neurophysiological, and neuroimaging evaluations. RESULTS: Of the 29 individuals (17 females) enrolled (median age [IQR] 10 years 5 months [5 years 11 months-18 years 1 month]), 16 were diagnosed with ASD. ASD severity significantly increased with age (r = 0.67, p < 0.001) but was inversely correlated with plasma GABA (r = -0.67, p < 0.001) and γ-hydroxybutyrate levels (r = -0.538, p = 0.004), and resting motor threshold as measured by transcranial magnetic stimulation (r = -0.44, p = 0.03). A discriminative analysis indicated that an age older than 7 years 2 months (p = 0.004) and plasma GABA levels less than 2.47 µM (p = 0.01) are the threshold values beyond which the likelihood of ASD presenting in individuals with SSADHD is increased. INTERPRETATION: ASD is prevalent but not universal in SSADHD, and it can be predicted by lower levels of plasma GABA and GABA-related metabolites. ASD severity in SSADHD increases with age and the loss of cortical inhibition. These findings add insight into the pathophysiology of ASD and may facilitate its early diagnosis and intervention in individuals with SSADHD.

Establishment and validation of a clinical severity scoring system for succinic semialdehyde dehydrogenase deficiency.

Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder with a variable phenotype and rate of progression. We aimed to develop and validate a clinical severity scoring (CSS) system applicable to the clinical setting and composed of five domains reflecting the principal manifestations of this disorder: cognitive, communication, motor, epilepsy, and psychiatry. A prospectively characterized cohort of 27 SSADHD subjects (55% females, median [IQR] age 9.2 [4.6-16.2] years) who enrolled in the SSADHD Natural History Study were included. The CSS was validated by comparison to an objective severity scoring (OSS) system based on comprehensive neuropsychologic and neurophysiologic assessments, which mirror and complement the domains of the CSS. The total CSS was sex and age-independent, and 80% of its domains lacked interdependence. With increasing age, there was a significant improvement in communication abilities (p = 0.05) and a worsening of epilepsy and psychiatric manifestations (p = 0.004 and p = 0.02, respectively). There was a significant correlation between all the CSS and OSS domain scores, as well as between the total CSS and OSS (R = 0.855, p < 0.001). Additionally, there were no significant demographic or clinical differences in the ratio of individuals in the upper quartile to the lower three quartiles of the CSS and OSS. The SSADHD CSS is validated using objective measures and offers a reliable condition-specific instrument universally applicable in clinical settings. This severity score may be utilized for family and patient counseling, genotype-phenotype correlations, biomarker development, clinical trials, and objective descriptions of the natural history of SSADHD.

Epilepsy and attention-deficit/hyperactivity disorder in children and adolescents: An overview of etiology, prevalence, and treatment.

Epilepsy and attention-deficit/hyperactivity disorder (ADHD) are closely connected and commonly seen in both children and adults. Each of the disorders has major psychosocial and quality of life (QOL) effects, and their co-occurrence makes coping even more challenging for both the patients and their families. Moreover, an adverse effect of some anti-seizure medications can potentially induce or exacerbate symptoms of ADHD on the one hand, while some ADHD medications may increase seizure risk on the other. The combination of proper diagnosis and appropriate treatment may improve or even prevent many of the complications associated with these conditions. The objectives of this review are to present the complex relationship between epilepsy and ADHD, looking into the pathophysiological, anatomical, and functional perspectives along with the psychosocial and QOL influences and the recommended treatment approaches in accordance with the latest literature.

Sleep Disturbances in Adolescents With Idiopathic Intracranial Hypertension.

BACKGROUND: We aimed to assess the presence of sleep disturbances in adolescents with idiopathic intracranial hypertension (IIH) and to determine whether demographic, anthropometric, and clinical factors are associated with disrupted sleep. METHODS: Sleep disturbances and patterns were evaluated in a cohort of adolescents (aged 12 to 18 years) with ongoing IIH and compared with a healthy age- and sex-matched control group. All participants responded to three self-rating questionnaires: the School Sleep Habits Survey (SSHS), the Pediatric Sleep Questionnaire (PSQ), and the Depression, Anxiety, and Stress Scale. The study group's demographic, clinical, laboratory, and radiological data were documented, and their association with sleep patterns was examined. RESULTS: Thirty-three adolescents with ongoing IIH and 71 healthy controls were included. There was a significantly higher prevalence of sleep disturbances in the IIH group compared with the controls (SSHS, P < 0.001 and PSQ, P < 0.001), as well as of their independent subscales: sleep-related breathing disorders (P = 0.006), daytime sleepiness (P = 0.04), sleep/wake disruptions (P < 0.001), and sleep-related depressive tendencies (P < 0.001). According to subgroup analyses, these differences were also present between the normal-weight adolescents but not between the overweight IIH and control adolescents. No differences were found in the demographic, anthropometric, and IIH disease-related clinical measures between individuals with IIH with disrupted and normal sleep patterns. CONCLUSIONS: Sleep disturbances are common among adolescents with ongoing IIH, irrespective of their weight and disease-related characteristics. Screening adolescents with IIH for sleep disturbances is recommended as part of their multidisciplinary management.

Treatment of neurometabolic epilepsies: Overview and recent advances.

The rarity and heterogeneity of neurometabolic diseases make it challenging to reach evidence-based principles for their specific treatments. Indeed, current treatments for many of these diseases remain symptomatic and supportive. However, an ongoing scientific and medical revolution has led to dramatic breakthroughs in molecular sciences and genetics, revealing precise pathophysiologic mechanisms. Accordingly, this has led to significant progress in the development of novel therapeutic approaches aimed at treating epilepsy resulting from these conditions, as well as their other manifestations. We overview recent notable treatment advancements, from vitamins, trace minerals, and diets to unique medications targeting the elemental pathophysiology at a molecular or cellular level, including enzyme replacement therapy, enzyme enhancing therapy, antisense oligonucleotide therapy, stem cell transplantation, and gene therapy.

The presence and severity of epilepsy coincide with reduced γ-aminobutyrate and cortical excitatory markers in succinic semialdehyde dehydrogenase deficiency.

OBJECTIVE: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of γ-aminobutyrate (GABA) catabolism. Despite the resultant hyper-GABAergic environment facilitated by the metabolic defect, individuals with this disorder have a paradoxically high prevalence of epilepsy. We aimed to study the characteristics of epilepsy in SSADHD and its concordance with GABA-related metabolites and neurophysiologic markers of cortical excitation. METHODS: Subjects in an international natural history study of SSADHD underwent clinical assessments, electroencephalography, transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy for GABA/N-acetyl aspartate quantification, and plasma GABA-related metabolite measurements. RESULTS: A total of 61 subjects with SSADHD and 42 healthy controls were included in the study. Epilepsy was present in 49% of the SSADHD cohort. Over time, there was an increase in severity in 33% of the subjects with seizures. The presence of seizures was associated with increasing age (p = .001) and lower levels of GABA (p = .002), γ-hydroxybutyrate (GHB; p = .004), and γ-guanidinobutyrate (GBA; p = .003). Seizure severity was associated with increasing age and lower levels of GABA-related metabolites as well as lower TMS-derived resting motor thresholds (p = .04). The cutoff values with the highest discriminative ability to predict seizures were age > 9.2 years (p = .001), GABA < 2.57 µmol·L-1 (p = .002), GHB < 143.6 µmol·L-1 (p = .004), and GBA < .075 µmol·L-1 (p = .007). A prediction model for seizures in SSADHD was comprised of the additive effect of older age and lower plasma GABA, GHB, and GBA (area under the receiver operating characteristic curve of .798, p = .008). SIGNIFICANCE: Epilepsy is highly prevalent in SSADHD, and its onset and severity correlate with an age-related decline in GABA and GABA-related metabolite levels as well as TMS markers of reduced cortical inhibition. The reduction of GABAergic activity in this otherwise hyper-GABAergic disorder demonstrates a concordance between epileptogenesis and compensatory responses. These findings may furthermore inform the timing of molecular interventions for SSADHD.

New Therapeutic Approaches to Inherited Metabolic Pediatric Epilepsies.

Treatment options for inherited metabolic epilepsies are rapidly expanding with advances in molecular biology and the genomic revolution. Traditional dietary and nutrient modification and inhibitors or enhancers of protein and enzyme function, the mainstays of therapy, are undergoing continuous revisions to increase biological activity and reduce toxicity. Enzyme replacement and gene replacement and editing hold promise for genetically targeted treatment and cures. Molecular, imaging, and neurophysiologic biomarkers are emerging as key indicators of disease pathophysiology, severity, and response to therapy.

Cerebrospinal fluid characteristics of patients treated with intrathecal nusinersen for spinal muscular atrophy.

INTRODUCTION/AIMS: There is limited information on the potential effects of repeated intrathecal antisense oligonucleotide drug delivery on cerebrospinal fluid (CSF) biochemical and blood cell profiles. This study aimed to examine longitudinal changes in the biochemical components (glucose, protein) and blood cell counts in the CSF of spinal muscular atrophy (SMA) patients treated with intrathecal nusinersen. METHODS: We collected and analyzed clinical and CSF parameters (cell count, protein, glucose, culture) of 50 individuals with SMA during nusinersen treatment (22 type 1, 17 type 2, and 11 type 3). RESULTS: The median protein concentration at baseline and during treatment was within the normal range but rose during treatment and was significantly above baseline at the time of the ninth intrathecal injection (p = 0.02, two-tailed Wilcoxon matched-pairs test, and p = 0.0015, Friedman test for repeated measures). Further analysis showed that the increase in CSF protein concentration was evident for SMA types 2 and 3 patients, but not for type 1. This observation was also demonstrated by a significant correlation between the SMN2 gene copy number and the increase in CSF protein concentration (Spearman rank correlation test). DISCUSSION: Our results demonstrate that a delayed increase in CSF protein concentration is expected during nusinersen treatment for SMA types 2 and 3. This might reflect the medication's effect and a possible therapeutic biochemical marker.

Muscle microRNAs in the cerebrospinal fluid predict clinical response to nusinersen therapy in type II and type III spinal muscular atrophy patients.

BACKGROUND AND PURPOSE: The antisense oligonucleotide nusinersen (Spinraza) regulates splicing of the survival motor neuron 2 (SMN2) messenger RNA to increase SMN protein expression. Nusinersen has improved ventilator-free survival and motor function outcomes in infantile onset forms of spinal muscular atrophy (SMA), treated early in the course of the disease. However, the response in later onset forms of SMA is highly variable and dependent on symptom severity and disease duration at treatment initiation. Therefore, we aimed to identify novel noninvasive biomarkers that could predict the response to nusinersen in type II and III SMA patients. METHODS: Thirty-four SMA patients were included. We applied next generation sequencing to identify microRNAs in the cerebrospinal fluid (CSF) as candidate biomarkers predicting response to nusinersen. Hammersmith Functional Motor Scale Expanded (HFMSE) was conducted at baseline and 6 months after initiation of nusinersen therapy to assess motor function. Patients changing by ≥3 or ≤0 points in the HFMSE total score were considered to be responders or nonresponders, respectively. RESULTS: Lower baseline levels of two muscle microRNAs (miR-206 and miR-133a-3p), alone or in combination, predicted the clinical response to nusinersen after 6 months of therapy. Moreover, miR-206 levels were inversely correlated with the HFMSE score. CONCLUSIONS: Lower miR-206 and miR-133a-3p in the CSF predict more robust clinical response to nusinersen treatment in later onset SMA patients. These novel findings have high clinical relevance for identifying early treatment response to nusinersen in later onset SMA patients and call for testing the ability of miRNAs to predict more sustained long-term benefit.

Attention-Deficit/Hyperactivity Disorder and Obesity: A National Study of 1.1 Million Israeli Adolescents.

PURPOSE: The incidences of obesity and attention-deficit/hyperactivity disorder (ADHD) have increased in parallel over recent decades. We assessed the association between obesity and ADHD in a national sample of adolescents. METHOD: In a nationwide population-based study of 1 118 315 adolescents (57% males; mean age 17 years), risks of obesity were compared between individuals with severe and mild ADHD and those without ADHD. Diagnoses of ADHD were confirmed by specialists in either neurology or psychiatry. Adolescents requiring regular and continuous treatment with stimulants with no improvement of symptoms under treatment were classified as having severe ADHD; data were available from 2004 to 2019. During 2015 to 2019, the diagnosis of ADHD was defined, and 65 118 (16.76%) of 388 543 adolescents with mild symptoms who required medications only for learning or who used stimulants irregularly were defined as having mild ADHD. RESULTS: The prevalence of severe and mild ADHD was 0.3% and 20.1%, respectively. Obesity was more prevalent among adolescents with severe ADHD than among those without ADHD (13.5% vs 7.5%). In the mild ADHD group 12.6% of males and 8.4% of females were diagnosed with obesity compared to 9.7% and 6.4%, respectively, in the non-ADHD group. The adjusted odds of severe ADHD for males and females with obesity were 1.77 (1.56-2.02) and 2.09 (1.63-2.66) times the odds for males and females with low-normal body mass index, respectively, and 1.42 (1.37-1.48) and 1.42 (1.34-1.50) for males and females with mild ADHD, respectively. The elevated risk persisted in several sensitivity analyses. CONCLUSIONS: Both adolescents with severe and mild ADHD are at increased risk for obesity.

Sleep Quality and Eating Disorder-Related Psychopathologies in Patients with Night Eating Syndrome and Binge Eating Disorders.

Night eating syndrome (NES) is an eating disorder (ED) characterized by nocturnal ingestion (NI), evening hyperphagia, morning anorexia, as well as mood and sleep disturbances. This study compared subjective and objective sleep quality and ED-related psychopathologies in patients seeking treatment for ED. Method: The sample was composed of 170 women, aged 18-68, who were referred for an ED assessment from 2011 to 2020. The participants were divided into three subgroups: NES-NI only (n = 30), NES+ binge eating (BE) (including binge eating disorders or bulimia nervosa (n = 52), and BE-only (n = 88). The measures consisted of a psychiatric evaluation, objective sleep monitoring measured by an actigraph for 1 week, a subjective sleep self-report, and ED-related psychopathology questionnaires. Results: Objective sleep monitoring revealed significant group differences, with higher sleep efficiency in participants with BE-only and longer sleep durations for the NES-NI only group. Subjectively, the BE-only group described a significantly lower sleep quality than either the NES-NI only or the NES+BE groups. ED-related psychopathology was lower in the NES-NI-only group. A stepwise linear regression revealed that general psychopathology (the brief symptom inventory total score) was a significant predictor of subjective sleep quality. Conclusion: NES-NI-only was correlated with less psychopathology, but with more subjective and objective sleep disturbances. These results lend weight to the supposition that NES lies on a continuum of ED psychopathologies, and that NES-NI-only appears to be a separate entity from NES+BE and BE-only in terms of its psychopathology.