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Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10-3, 95% confidence interval: 1.5-15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/).
Subject(s)
GABA Plasma Membrane Transport Proteins , Genetic Association Studies , Mutation, Missense , Humans , GABA Plasma Membrane Transport Proteins/genetics , GABA Plasma Membrane Transport Proteins/metabolism , PhenotypeABSTRACT
STUDY OBJECTIVES: CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy, developing in the first months of life, caused by a mutation in the cyclin-dependent kinase-like 5 (CDKL5) gene. Children with CDD often have sleep (90%) and breathing disorders in wake (50%). Sleep disorders may have a significant impact emotional wellbeing and quality of life of caregivers of children with CDD and are challenging to treat. The outcomes of these features are unknown in children with CDD. METHODS: We retrospectively evaluated sleep and respiratory function changes over 5-10 years in a small cohort of Dutch children with CDD, using video-EEG and/or polysomnography (3 × 24 h) and a parental questionnaire, the Sleep Disturbance Scale for Children (SDSC). The present study is a follow-up sleep and PSG study to evaluate if sleep and breathing disturbances persist in children with CDD previously studied. RESULTS: Sleep disturbances persisted during the study period (5.5-10 years). All five individuals had long sleep latency (SL, range 32-174.5 min) and frequent arousals and awakenings (14-50/night), unrelated to apneas/seizures, corresponding to the SDSC findings. Low sleep efficiency (SE, 41-80%) was present and did not improve. In our participants, total sleep time (TST, 3h52min-7h52min) was short and remained so. Time in bed (TIB) was typical for children aged 2-8 years, but did not adjust with ageing. Low duration (4.8-17.4%) or even absent REM sleep persisted over time. No sleep apneas were noted. Central apneas due to episodic hyperventilation were reported during wakefulness in two of the five. CONCLUSION: Sleep disturbances were present and persisted in all. The decreased REM sleep and sporadic breathing disturbances in wake may indicate failure of brainstem nuclei. Sleep disturbances can severely affect the emotional wellbeing and quality of life of the caregivers and the individuals with CDD and are challenging to treat. Hopefully our polysomnographic sleep data contribute to find the optimal treatment of the sleep problems in CDD patients.
Subject(s)
Sleep Apnea Syndromes , Sleep Wake Disorders , Humans , Child , Retrospective Studies , Quality of Life , Sleep , Sleep Apnea Syndromes/complications , Sleep Wake Disorders/etiology , Protein Serine-Threonine Kinases/geneticsABSTRACT
INTRODUCTION: Caring for a child with epilepsy has a significant impact on parental quality of life. Seizure unpredictability and complications, including sudden unexpected death in epilepsy (SUDEP), may cause high parental stress and increased anxiety. Nocturnal supervision with seizure detection devices may lower SUDEP risk and decrease parental burden of seizure monitoring, but little is known about their added value in family homes. METHODS: We conducted semi-structured in-depth interviews with parents of children with refractory epilepsy participating in the PROMISE trial (NCT03909984) to explore the value of seizure detection in the daily care of their child. Children were aged 4-16â¯years, treated at a tertiary epilepsy center, had at least one nocturnal major motor seizure per week, and used a wearable seizure detection device (NightWatch) for two months at home. Data were analyzed using inductive thematic analysis. RESULTS: Twenty three parents of nineteen children with refractory epilepsy were interviewed. All parents expressed their fear of missing a large seizure and the possible consequences of not intervening in time. Some parents felt the threat of child loss during every seizure, while others thought about it from time to time. The fear could fluctuate over time, mainly associated with fluctuations of seizure frequency. Most parents described how they developed a protective behavior, driven by this fear. The way parents handled the care of their child and experienced the burden of care influenced their perceptions on the added value of NightWatch. The experienced value of NightWatch depended on the amount of assurance it could offer to reduce their fear and the associated protective behavior as well as their resilience to handle the potential extra burden of care, due to false alarms or technical problems. CONCLUSION: Healthcare professionals and device companies should be aware of parental protective behavior and the high parental burden of care and develop tailored strategies to optimize seizure detection device care.
ABSTRACT
Thirty-two children with frontal lobe epilepsy (FLE) were assessed using different working memory measures. In addition, parents and teachers completed the working memory scale of the Behavioral Rating Inventory of Executive Functioning (BRIEF) to assess the children's "daily life behavior." Results suggested minimal working memory deficits as assessed with performance-based measures. However, the BRIEF showed more working memory deficits suggesting that, on a daily life level, working memory problems seem to be associated with FLE. We discuss why the results of the performance-based measures are not consistent with results of the BRIEF.HighlightsParents as well as teachers report working memory dysfunction in daily life to the same extent.Performance based measures show minimal deficits of working memory.Correlation between working memory tasks and proxy measures are low.
Subject(s)
Epilepsy, Frontal Lobe , Child , Epilepsy, Frontal Lobe/complications , Executive Function , Frontal Lobe , Humans , Memory Disorders , Memory, Short-Term , Neuropsychological TestsABSTRACT
BACKGROUND: Seizures are an under-reported feature of the SATB2-associated syndrome phenotype. We describe the electroencephalographic findings and seizure semiology and treatment in a population of individuals with SATB2-associated syndrome. METHODS: We performed a retrospective review of 101 individuals with SATB2-associated syndrome who were reported to have had a previous electroencephalographic study to identify those who had at least one reported abnormal result. For completeness, a supplemental survey was distributed to the caregivers and input from the treating neurologist was obtained whenever possible. RESULTS: Forty-one subjects were identified as having at least one prior abnormal electroencephalography. Thirty-eight individuals (93%) had epileptiform discharges, 28 (74%) with central localization. Sleep stages were included as part of the electroencephalographies performed in 31 individuals (76%), and epileptiform activity was recorded during sleep in all instances (100%). Definite clinical seizures were diagnosed in 17 individuals (42%) with a mean age of onset of 3.2 years (four months to six years), and focal seizures were the most common type of seizure observed (42%). Six subjects with definite clinical seizures needed polytherapy (35%). Delayed myelination and/or abnormal white matter hyperintensities were seen on neuroimaging in 19 individuals (61%). CONCLUSIONS: Epileptiform abnormalities are commonly seen in individuals with SATB2-associated syndrome. A baseline electroencephalography that preferably includes sleep stages is recommended during the initial evaluation of all individuals with SATB2-associated syndrome, regardless of clinical suspicion of epilepsy.
Subject(s)
Epilepsy , Genetic Diseases, Inborn , Matrix Attachment Region Binding Proteins/genetics , Nervous System Malformations , Sleep Wake Disorders , Transcription Factors/genetics , Adolescent , Adult , Age of Onset , Child , Child, Preschool , Electroencephalography , Epilepsy/diagnosis , Epilepsy/etiology , Epilepsy/genetics , Epilepsy/physiopathology , Female , Genetic Diseases, Inborn/complications , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/physiopathology , Humans , Infant , Male , Nervous System Malformations/diagnosis , Nervous System Malformations/etiology , Nervous System Malformations/genetics , Nervous System Malformations/physiopathology , Retrospective Studies , Sleep Stages/physiology , Sleep Wake Disorders/diagnosis , Sleep Wake Disorders/etiology , Sleep Wake Disorders/genetics , Sleep Wake Disorders/physiopathology , Syndrome , Young AdultABSTRACT
PURPOSE: Variants in IQSEC2, escaping X inactivation, cause X-linked intellectual disability with frequent epilepsy in males and females. We aimed to investigate sex-specific differences. METHODS: We collected the data of 37 unpublished patients (18 males and 19 females) with IQSEC2 pathogenic variants and 5 individuals with variants of unknown significance and reviewed published variants. We compared variant types and phenotypes in males and females and performed an analysis of IQSEC2 isoforms. RESULTS: IQSEC2 pathogenic variants mainly led to premature truncation and were scattered throughout the longest brain-specific isoform, encoding the synaptic IQSEC2/BRAG1 protein. Variants occurred de novo in females but were either de novo (2/3) or inherited (1/3) in males, with missense variants being predominantly inherited. Developmental delay and intellectual disability were overall more severe in males than in females. Likewise, seizures were more frequently observed and intractable, and started earlier in males than in females. No correlation was observed between the age at seizure onset and severity of intellectual disability or resistance to antiepileptic treatments. CONCLUSION: This study provides a comprehensive overview of IQSEC2-related encephalopathy in males and females, and suggests that an accurate dosage of IQSEC2 at the synapse is crucial during normal brain development.
Subject(s)
Brain Diseases/genetics , Guanine Nucleotide Exchange Factors/genetics , Intellectual Disability/genetics , Seizures/genetics , Brain/growth & development , Brain/metabolism , Brain Diseases/epidemiology , Brain Diseases/physiopathology , Female , Humans , Infant , Infant, Newborn , Intellectual Disability/epidemiology , Intellectual Disability/physiopathology , Male , Mutation , Pedigree , Phenotype , Protein Isoforms/genetics , Seizures/epidemiology , Seizures/physiopathology , Sex CharacteristicsABSTRACT
This Article was originally published under Nature Research's License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.
ABSTRACT
The original version of this article contained an error in the spelling of the author Erik H. Niks, which was incorrectly given as Erik Niks. This has now been corrected in both the PDF and HTML versions of the article.
ABSTRACT
PURPOSE: To define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway METHODS: We analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. RESULTS: The GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign. CONCLUSION: Our data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.
Subject(s)
Epilepsy/genetics , GTPase-Activating Proteins/genetics , Repressor Proteins/genetics , Tumor Suppressor Proteins/genetics , Adolescent , Brugada Syndrome/genetics , Brugada Syndrome/mortality , Brugada Syndrome/physiopathology , Child , Child, Preschool , DNA Copy Number Variations/genetics , Epilepsy/complications , Epilepsy/epidemiology , Epilepsy/physiopathology , Female , Genetic Predisposition to Disease , Humans , INDEL Mutation/genetics , Infant , Infant, Newborn , Loss of Function Mutation/genetics , Male , Mechanistic Target of Rapamycin Complex 1/genetics , Multiprotein Complexes/genetics , Pedigree , Seizures/complications , Seizures/epidemiology , Seizures/genetics , Seizures/physiopathology , Signal Transduction/geneticsABSTRACT
The original version of this Article contained an error in the author list where the corresponding author Stéphanie Baulac was repeated twice. This has now been corrected in the HTML, the PDF was correct at the time of publication.
ABSTRACT
OBJECTIVE: Epilepsy, as a chronic and neurological disease, is generally associated with an increased risk for social and emotional behavior problems in children. These findings are mostly derived from studies on children with different epilepsy types. However, there is limited information about the associations between frontal lobe epilepsy (FLE) and cognitive and behavioral problems. The aim of this study was to examine relationships between FLE and executive and behavioral functioning reported by parents and teachers. MATERIAL AND METHODS: Teachers and parents of 32 children (18 boys, 14 girls, mean age 9; 2â¯years ±1;6) with a confirmed diagnosis of FLE completed the Behavioral Rating Inventory of Executive Function (BRIEF), the Child Behavior Checklist (CBCL), and Teacher Report Form (TRF). RESULTS: About 25 to 35% of the parents and teachers rated children in the abnormal range of the main scales of the BRIEF, CBCL, and TRF. Teachers tend to report more metacognition problems, whereas parents tend to report more behavior regulation problems. Children with left-sided FLE showed more problems than children with bilateral or right-sided FLE. The whole range of executive dysfunctioning is linked to behavioral dysfunctioning in FLE, but ratings vary across settings and informants. The epilepsy variables age of onset, lateralization, drug load, and duration of epilepsy had only a small and scattered contribution. CONCLUSION: Ratings on the BRIEF, CBCL, and TRF are moderately to highly correlated, suggesting a (strong) link between executive and behavioral functioning. Subtle differences between parents and teachers ratings suggest different executive function demands in various settings.
Subject(s)
Child Behavior Disorders/epidemiology , Child Behavior Disorders/psychology , Epilepsy, Frontal Lobe/epidemiology , Epilepsy, Frontal Lobe/psychology , Executive Function/physiology , Child , Child Behavior Disorders/diagnosis , Epilepsy, Frontal Lobe/diagnosis , Female , Humans , Male , Mental Disorders/diagnosis , Mental Disorders/epidemiology , Mental Disorders/psychologyABSTRACT
Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation.
Subject(s)
Anticonvulsants/therapeutic use , Epilepsy/genetics , NAV1.6 Voltage-Gated Sodium Channel/genetics , Phenytoin/therapeutic use , Child , Child, Preschool , Epilepsy/drug therapy , Female , Humans , Male , Mutation, Missense/genetics , NAV1.6 Voltage-Gated Sodium Channel/drug effects , Treatment OutcomeABSTRACT
OBJECTIVE: To study the effect of vaccination-associated seizure onset on disease course and estimate the risk of subsequent seizures after infant pertussis combination and measles, mumps, and rubella (MMR) vaccinations in Dravet syndrome (DS). METHODS: We retrospectively analyzed data from hospital medical files, child health clinics, and the vaccination register for children with DS and pathogenic SCN1A mutations. Seizures within 24 hours after infant whole-cell, acellular, or nonpertussis combination vaccination or within 5 to 12 days after MMR vaccination were defined as "vaccination-associated." Risks of vaccination-associated seizures for the different vaccines were analyzed in univariable and in multivariable logistic regression for pertussis combination vaccines and by a self-controlled case series analysis using parental seizure registries for MMR vaccines. Disease courses of children with and without vaccination-associated seizure onset were compared. RESULTS: Children who had DS (n = 77) with and without vaccination-associated seizure onset (21% and 79%, respectively) differed in age at first seizure (median 3.7 vs 6.1 months, p < 0.001) but not in age at first nonvaccination-associated seizure, age at first report of developmental delay, or cognitive outcome. The risk of subsequent vaccination-associated seizures was significantly lower for acellular pertussis (9%; odds ratio 0.18, 95% confidence interval [CI] 0.05-0.71) and nonpertussis (8%; odds ratio 0.11, 95% CI 0.02-0.59) than whole-cell pertussis (37%; reference) vaccines. Self-controlled case series analysis showed an increased incidence rate ratio of seizures of 2.3 (95% CI 1.5-3.4) within the risk period of 5 to 12 days following MMR vaccination. CONCLUSIONS: Our results suggest that vaccination-associated earlier seizure onset does not alter disease course in DS, while the risk of subsequent vaccination-associated seizures is probably vaccine-specific.
Subject(s)
Diphtheria-Tetanus-Pertussis Vaccine/adverse effects , Diphtheria-Tetanus-acellular Pertussis Vaccines/adverse effects , Disease Progression , Epilepsies, Myoclonic/physiopathology , Measles-Mumps-Rubella Vaccine/adverse effects , Seizures/etiology , Vaccination/adverse effects , Adolescent , Adult , Age of Onset , Child , Child, Preschool , Epilepsies, Myoclonic/complications , Epilepsies, Myoclonic/genetics , Female , Humans , Incidence , Infant , Male , NAV1.1 Voltage-Gated Sodium Channel/genetics , Retrospective Studies , Risk , Young AdultABSTRACT
This is the second report of a family with a recurrence of a CDKL5 mutation (c. 283-3_290del) in 2 sisters. Both parents tested negative for the mutation in all tissues, but germline mosaicism is likely. Clinically CDKL5 patients resemble those with Rett syndrome, caused by a MECP2 mutation, who experience a regression, after an initial normal development. Even though both siblings showed a typical CDKL5 phenotype, their presentation is different. From birth, the oldest daughter had a severe developmental delay, feeding problems, and hypotonia and experienced daily refractory seizures. The youngest daughter appeared to be normal until age 3 months. At that age seizures started, deterioration and regression became evident, and an epileptic encephalopathy developed. This report of familial recurrence, with suspected germline mosaicism in a healthy parent, has important consequences for genetic counseling. Although it is not possible to predict an exact recurrence risk, it is likely to be increased.
Subject(s)
Mental Retardation, X-Linked/genetics , Mental Retardation, X-Linked/physiopathology , Protein Serine-Threonine Kinases/genetics , Brain/physiopathology , Child , Child, Preschool , Electroencephalography , Female , Genotype , Humans , Infant , Phenotype , Seizures/genetics , Seizures/physiopathology , SiblingsABSTRACT
Rett syndrome is a neurodevelopmental disorder characterized by cognitive and locomotor regression and stereotypic hand movements. The disorder is caused by mutations in the X chromosomal MECP2 a gene encoding methyl CpG-binding protein. It has been associated with disturbances of cerebral folate homeostasis, as well as with speculations on a compromised DNA-methylation. Folinic acid is the stable form of folate. Its derived intermediate 5-MTHF supports the conversion of homocysteine to methionine, the precursor of S-adenosylmethionine (SAM). This in turn donates its methyl group to various acceptors, including DNA, thereby being converted to S-adenosylhomocysteine (SAH). The SAM/SAH ratio reflects the methylation potential. The goal of our study was to influence DNA methylation processes and ameliorate the clinical symptoms in Rett syndrome. Therefore we examined the hypothesis that folinic acid supplementation, besides increasing cerebrospinal fluid (CSF) 5-MTHF (p = 0.003), influences SAM and SAH and their ratio. In our randomized, double-blind crossover study on folinic acid supplementation, ten female Rett patients received both folinic acid and placebo for 1 year each. It was shown that both SAM and SAH levels in the CSF remained unchanged following folinic acid administration (p = 0.202 and p = 0.097, respectively) in spite of a rise of plasma SAM and SAH (p = 0.007; p = 0.009). There was no significant change in the SAM/SAH ratio either in plasma or CSF. The apparent inability of Rett patients to upregulate SAM and SAH levels in the CSF may contribute to the biochemical anomalies of the Rett syndrome. Our studies warrant further attempts to promote DNA methylation in the true region of interest, i.e. the brain.
Subject(s)
Folic Acid/therapeutic use , Rett Syndrome/drug therapy , S-Adenosylhomocysteine/blood , S-Adenosylhomocysteine/cerebrospinal fluid , S-Adenosylmethionine/blood , S-Adenosylmethionine/cerebrospinal fluid , Adolescent , Adult , Child , Child, Preschool , Dietary Supplements , Female , Folic Acid/analogs & derivatives , Folic Acid/cerebrospinal fluid , Folic Acid/pharmacology , Humans , Infant , Rett Syndrome/blood , Rett Syndrome/cerebrospinal fluid , Young AdultABSTRACT
AIM: In female children with drug-resistant seizures and developmental delay from birth, atypical Rett syndrome caused by mutations in the CDKL5 gene should be considered. Several clinical features resemble classic Rett syndrome. Respiratory and sleep abnormalities are frequently present in Rett syndrome, whereas little is known in patients with CDKL5 mutations. METHOD: In four genetically confirmed female patients with CDKL5 mutations (age range 2-15 y), the presence of breathing and sleep abnormalities was evaluated using the validated Sleep Disturbance Scale for Children and polysomnography (PSG). RESULTS: The Sleep Disturbance Scale for Children indicated disorders of initiating and maintaining sleep, daytime somnolence, and sleep breathing disorders. In one patient, PSG showed central apnoeas during sleep: her total apnoea-hypopnoea index (AHI) was 4.9, of which the central AHI was 3.4/h. When awake, central apnoeas were present in two of the four female children (central AHI 28/h and 41/h respectively), all preceded by hyperventilation. PSG showed low rapid eye movement (REM) sleep (9.7-18.3%), frequent awakenings, and low sleep efficiency (range 59-78%). INTERPRETATION: Episodic hyperventilation followed by central apnoeas was present while awake in two of four patients. This may indicate failure of brainstem respiratory centres. In addition, low REM sleep, frequent arousals (not caused by apnoeas/seizures), and low sleep efficiency were present. Similar to Rett syndrome, in patients with CDKL5 mutations PSG seems warranted to evaluate breathing and sleep disturbances.
Subject(s)
Mutation/genetics , Protein Serine-Threonine Kinases/genetics , Rett Syndrome/complications , Rett Syndrome/genetics , Sleep Apnea Syndromes/etiology , Adolescent , Child, Preschool , Female , Humans , Polysomnography , Sleep Apnea Syndromes/diagnosisABSTRACT
Rett syndrome is characterized by loss of motor and social functions, development of stereotypic hand movements, seizures, and breathing disturbances. This study evaluates the presence of overnight respiratory disturbances. Polysomnography in combination with a questionnaire (the Sleep Disturbance Scale for Children) was performed in 12 Dutch patients with Rett. Respiratory disturbances were present in all, clinically relevant in 10 (apnea hypopnea per hour 1.0-14.5). In 8 children, central apneas were present during the day often with obstructive apneas at night. In 6, obstructive sleep apnea syndrome was diagnosed, in 3 severe, with frequent oxygen desaturations. Significant respiratory complaints were present in 3 patients, all had obstructive sleep apnea syndrome. Of the 12 patients with Rett, 8 (67%) snored, and in 5 obstructive sleep apnea syndrome was present. In children, hypertrophied tonsils and adenoids are a common cause of obstructive sleep apnea syndrome, which may benefit from therapeutic intervention. We recommend performing polysomnography in patients with Rett syndrome and respiratory complaints.
Subject(s)
Airway Obstruction/diagnosis , Airway Obstruction/etiology , Rett Syndrome/complications , Sleep Apnea, Obstructive/diagnosis , Sleep Apnea, Obstructive/etiology , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Male , PolysomnographyABSTRACT
Rett syndrome is a neurodevelopmental disorder in girls, related to mutations in MECP2 gene. It has been postulated that low 5-methyltetrahydrofolate (5-MTHF) levels are present in cerebrospinal fluid. Folinic acid demonstrated clinical improvement. However, because studies have produced conflicting results, we performed a randomized, double-blind crossover, long-term, follow-up study on folinic acid. Eight Rett syndrome patients received both folinic acid and placebo, for 1 year each. Measurements included plasma folate, 5-MTHF, and clinical outcome scores like Rett Syndrome Motor Behavioral Assessment, Hand Apraxia Scale, and the parental Overall Well-Being Index. In 2 patients, low 5-MTHF levels were present. Folinic acid supplementation increased cerebrospinal fluid 5-MTHF levels, but with no objective evidence of clinical improvement. The Overall Well-Being Index showed a significant difference in favor of folinic acid, not confirmed objectively. In our double-blind randomized study, folinic acid supplementation resulted in increased 5-MTHF levels, but with no objective signs of clinical improvement.
Subject(s)
Dietary Supplements , Leucovorin/administration & dosage , Rett Syndrome/diet therapy , Adolescent , Adult , Child , Child, Preschool , Cross-Over Studies , Double-Blind Method , Female , Folic Acid/blood , Humans , Linear Models , Longitudinal Studies , Methyl-CpG-Binding Protein 2/genetics , Mutation/genetics , Neurologic Examination , Rett Syndrome/cerebrospinal fluid , Rett Syndrome/genetics , Tetrahydrofolates/blood , Tetrahydrofolates/cerebrospinal fluid , Time Factors , Treatment Outcome , Young AdultABSTRACT
Rett syndrome is characterized by the development of stereotypic hand movements and seizures, which are often difficult to treat. Previous studies have shown conflicting results during add-on folinic acid. Here, the authors reevaluate the response to folinic acid in terms of epilepsy control and electroencephalography features. They performed a randomized, placebo-controlled, double-blind crossover trial, with a follow-up of more than 2 years. Twelve girls with Rett syndrome participated, comparable in clinical stage and disease severity. The Rett syndrome patients were given either folinic acid or placebo, for 1 year each. Only 3 girls benefited to some extent: 2 had a reduction and/or decrease in seizures, and all 3 showed some decreased epileptiform activity on electroencephalography during the addition of folinic acid. Despite this, antiepileptic drugs were adjusted. Because the effect of added folinic acid was limited and did not prevent antiepileptic drug increase, the authors do not recommend adding on folinic acid in Rett syndrome girls with epilepsy.