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Congenital myasthenic syndrome-22 (CMS22, OMIM 616224) is a rare genetic disorder caused by deleterious genetic variation in the prolyl endopeptidase-like (PREPL) gene. Previous reports have described patients with deletions and nonsense variants in PREPL, but nothing is known about the effect of missense variants in the pathology of CMS22. In this study, we have functionally characterized missense variants in PREPL from three CMS22 patients, all with hallmark phenotypes. Biochemical evaluation revealed that these missense variants do not impair hydrolase activity, thereby challenging the conventional diagnostic criteria and disease mechanism. Structural analysis showed that the variants affect regions most likely involved in intra-protein or protein-protein interactions. Indeed, binding to a selected group of known interactors was differentially reduced for the three mutants. The importance of non-hydrolytic functions of PREPL was investigated in catalytically inactive PREPL p.Ser559Ala cell lines which showed that hydrolytic activity of PREPL is needed for normal mitochondrial function but not for regulating AP1-mediated transport in the trans-Golgi network. In conclusion, these studies showed that CMS22 can be caused not only by deletion and truncation of PREPL but also by missense variants that do not necessarily result in a loss of hydrolytic activity of PREPL.
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OBJECTIVES: To determine the impact of the COVID-19 pandemic on the incidence rates of infection and islet autoimmunity in children at risk for type 1 diabetes. METHODS: 1050 children aged 4 to 7 months with an elevated genetic risk for type 1 diabetes were recruited from Germany, Poland, Sweden, Belgium and the UK. Reported infection episodes and islet autoantibody development were monitored until age 40 months from February 2018 to February 2023. RESULTS: The overall infection rate was 311 (95% Confidence Interval [CI], 304-318) per 100 person years. Infection rates differed by age, country, family history of type 1 diabetes, and period relative to the pandemic. Total infection rates were 321 per 100 person-years (95% CI 304-338) in the pre-pandemic period (until February 2020), 160 (95% CI 148-173) per 100 person-years in the first pandemic year (March 2020-February 2021; P < 0.001) and 337 (95% CI 315-363) per 100 person-years in subsequent years. Similar trends were observed for respiratory and gastrointestinal infections. Islet autoantibody incidence rates were 1.6 (95% CI 1.0-2.4) per 100 person-years in the pre-pandemic period, 1.2 (95% CI 0.8-1.9) per 100 person-years in the first pandemic year (P = 0.46), and 3.4 (95% CI 2.3-4.8) per 100 person-years in subsequent years (P = 0.005 vs. pre-pandemic year; P < 0.001 vs. first pandemic year). CONCLUSIONS: The COVID-19 pandemic was associated with significantly altered infection patterns. Islet autoantibody incidence rates increased two-fold when infection rates returned to pre-pandemic levels.
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BACKGROUND: Weight retention between pregnancies is associated with increased risk of perinatal complications, but it is unclear whether there is an association with offspring weight status. This study aimed to determine whether maternal interpregnancy weight change is associated with offspring overweight/obesity, controlling for confounding variables. SUBJECTS/METHODS: Routinely collected linked data from perinatal and child datasets, in Flanders, Belgium were used. Women having their first and second live births between 2009-2018 were included. The association between maternal interpregnancy weight change and overweight/obesity in the second child at 2 years was examined by logistical regression models. RESULTS: A total of 33,172 women were included. 52.7% (n = 17478) had a stable interpregnancy BMI, 24.1% (n = 8024) and 8.5% (n = 2821) had moderate and substantial BMI increases respectively. At 2 years, 91.6% (n = 30383) of the second offspring had a healthy weight, 0.6% (n = 210), 7.0% (n = 2312) and 0.8% (n = 267) were in the underweight, overweight and obesity BMI categories respectively. Multivariate analysis showed no statistical evidence that maternal interpregnancy BMI change is independently associated with overweight/obesity in the second child. The strongest independent factors were the first child (sibling) being in the obesity category at 2 years (odds ratio [OR] 7.2, [95% CI, 5.49-9.45] and being born Large for Gestational Age (LGA) (2.13 [1.92-2.37]). The following variables were also independently associated with the outcome measure: maternal African origin (1.90 [1.59-2.26]), maternal obesity at start of first pregnancy (1.33 [1.16-1.53]), excessive gestational weight gain in the second pregnancy (1.15 [1.04-1.28]), being born after a < 1-year interpregnancy time interval (1.17 [1.05-1.30]) and not being exclusively breastfed at 12 weeks old (1.29 [1.10-1.52]). CONCLUSION: Sibling obesity and being born LGA were most strongly independently associated with overweight/obesity at 2 years. This supports the need for family interventions and to address risk factors for development of LGA infants. There was no independent association with interpregnancy weight gain, contrary to what was hypothesised.
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Loss of prolyl endopeptidase-like (PREPL) encoding a serine hydrolase with (thio)esterase activity leads to the recessive metabolic disorder Congenital Myasthenic Syndrome-22 (CMS22). It is characterized by severe neonatal hypotonia, feeding problems, growth retardation, and hyperphagia leading to rapid weight gain later in childhood. The phenotypic similarities with Prader-Willi syndrome (PWS) are striking, suggesting that similar pathways are affected. The aim of this study was to identify changes in the hypothalamic-pituitary axis in mouse models for both disorders and to examine mitochondrial function in skin fibroblasts of patients and knockout cell lines. We have demonstrated that Prepl is downregulated in the brains of neonatal PWS-IC-p/+m mice. In addition, the hypothalamic-pituitary axis is similarly affected in both Prepl-/- and PWS-IC-p/+m mice resulting in defective orexigenic signaling and growth retardation. Furthermore, we demonstrated that mitochondrial function is altered in PREPL knockout HEK293T cells and can be rescued with the supplementation of coenzyme Q10. Finally, PREPL-deficient and PWS patient skin fibroblasts display defective mitochondrial bioenergetics. The mitochondrial dysfunction in PWS fibroblasts can be rescued by overexpression of PREPL. In conclusion, we provide the first molecular parallels between CMS22 and PWS, raising the possibility that PREPL substrates might become therapeutic targets for treating both disorders.
Subject(s)
Mice, Knockout , Myasthenic Syndromes, Congenital , Prader-Willi Syndrome , Prolyl Oligopeptidases , Animals , Humans , Prader-Willi Syndrome/metabolism , Prader-Willi Syndrome/genetics , Prader-Willi Syndrome/pathology , Mice , Myasthenic Syndromes, Congenital/genetics , Myasthenic Syndromes, Congenital/metabolism , Myasthenic Syndromes, Congenital/pathology , HEK293 Cells , Prolyl Oligopeptidases/metabolism , Fibroblasts/metabolism , Fibroblasts/pathology , Mitochondria/metabolism , Mitochondria/pathology , Mitochondria/genetics , Metabolic Networks and Pathways/genetics , Disease Models, Animal , Ubiquinone/analogs & derivatives , Ubiquinone/metabolism , Serine Endopeptidases/metabolism , Serine Endopeptidases/genetics , Male , FemaleABSTRACT
Introduction A variable near adult height (NAH) outcome after growth hormone (GH) therapy in Noonan syndrome (NS) patients with short stature has been reported. The main objective of this study was to evaluate NAH and body mass index (BMI) evolution in a large Belgian cohort of NS patients treated for short stature. The secondary objectives were to investigate whether sex, genotype, the presence of a thoracic deformity and/or a heart anomaly might affect NAH and to validate the recently developed NAH prediction model by Ranke et al. Methods Clinical and auxological data of GH treated short NS patients born before 2001 were extracted from the national Belgrow registry. NAH was available in 54 (35 male) genotyped NS using a gene panel of 9 genes, showing pathogenic variants in PTPN11 in 32 and in SOS1 in 5 patients, while in 17 patients gene panel analysis was inconclusive (no mutation group). Results After a median (P10; P90) duration of 5.4 (2.2-10.3) years of GH therapy with a median dose of 0.05 mg/kg/day NS patients reached a median NAH of -1.7 (-3.4; -0.8) SDS. Median total height gain was 1.1 (0.1; 2.3) SDS. Sex, genotype and the presence of a thoracic or cardiac malformation did not correlate with NAH or total height gain. Linear regression modelling revealed that height SDS at start (beta=0.90, p<0.001), mid-parental height SDS (beta =0.27; p=0.005), birth weight SDS (beta=0.15; p=0.051), age at start (beta=0.07; p=0032) were independently associated with NAH SDS. Median BMI SDS increased significantly (p<0.001) from -1.0 (-2.5; 0.0) at start to -0.2 (-1.5; 0.9) at NAH. The observed NAH in a subgroup of 44 patients with more than 3 years of GH treatment was not statistically different from the predicted NAH by the Noonan NAH prediction model of Ranke. Conclusion Long-term GH therapy at a dose of 0.05 mg/kg/day in short NS patients is effective in improving adult height and BMI, irrespective of the genotype and presence or absence of cardiac and or thoracic anomalies.
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AIMS/HYPOTHESIS: The aim of this study was to determine whether BMI in early childhood was affected by the COVID-19 pandemic and containment measures, and whether it was associated with the risk for islet autoimmunity. METHODS: Between February 2018 and May 2023, data on BMI and islet autoimmunity were collected from 1050 children enrolled in the Primary Oral Insulin Trial, aged from 4.0 months to 5.5 years of age. The start of the COVID-19 pandemic was defined as 18 March 2020, and a stringency index was used to assess the stringency of containment measures. Islet autoimmunity was defined as either the development of persistent confirmed multiple islet autoantibodies, or the development of one or more islet autoantibodies and type 1 diabetes. Multivariate linear mixed-effect, linear and logistic regression methods were applied to assess the effect of the COVID-19 pandemic and the stringency index on early-childhood BMI measurements (BMI as a time-varying variable, BMI at 9 months of age and overweight risk at 9 months of age), and Cox proportional hazard models were used to assess the effect of BMI measurements on islet autoimmunity risk. RESULTS: The COVID-19 pandemic was associated with increased time-varying BMI (ß = 0.39; 95% CI 0.30, 0.47) and overweight risk at 9 months (ß = 0.44; 95% CI 0.03, 0.84). During the COVID-19 pandemic, a higher stringency index was positively associated with time-varying BMI (ß = 0.02; 95% CI 0.00, 0.04 per 10 units increase), BMI at 9 months (ß = 0.13; 95% CI 0.01, 0.25) and overweight risk at 9 months (ß = 0.23; 95% CI 0.03, 0.43). A higher age-corrected BMI and overweight risk at 9 months were associated with increased risk for developing islet autoimmunity up to 5.5 years of age (HR 1.16; 95% CI 1.01, 1.32 and HR 1.68, 95% CI 1.00, 2.82, respectively). CONCLUSIONS/INTERPRETATION: Early-childhood BMI increased during the COVID-19 pandemic, and was influenced by the level of restrictions during the pandemic. Controlling for the COVID-19 pandemic, elevated BMI during early childhood was associated with increased risk for childhood islet autoimmunity in children with genetic susceptibility to type 1 diabetes.
Subject(s)
COVID-19 , Diabetes Mellitus, Type 1 , Islets of Langerhans , Humans , Child, Preschool , Autoimmunity/genetics , Body Mass Index , Pandemics , Overweight/complications , COVID-19/epidemiology , COVID-19/complications , AutoantibodiesABSTRACT
INTRODUCTION: Suprasellar tuberculoma are extremely rare in children and most of those patients present with headache, vomiting, visual disturbances, and hypofunction of the pituitary gland. In this case report, we present a girl with tuberculosis, who developed significant weight gain in combination with pituitary dysfunction, which recovered after antituberculosis treatment. CASE PRESENTATION: An 11-year old girl presented with headache, fever and anorexia that progressively evolved into an encephalopathic status with cranial nerves III and VI paresis. Brain MRI showed meningeal contrast capture along cranial nerves II (including optic chiasm), III, V and VI bilaterally and multiple contrast enhancing brain parenchyma lesions. Tuberculin skin test was negative but interferon-gamma release assay was positive. The clinical and radiological working diagnosis was consistent with tuberculous meningoencephalitis. Pulse corticosteroids for 3 days and quadruple antituberculosis therapy were started and the girl demonstrated obvious improvement of her neurological symptoms. However, after a few months of therapy she developed remarkable weight gain (+20 kg in 1 year) and growth arrest. Her hormone profile revealed insulin resistance (homeostasis model assessment-estimated insulin resistance [HOMA-IR] 6.8) despite putative growth hormone deficiency (circulating insulin-like growth factor-I [IGF-I] 104 µg/L [-2.4 SD]). Follow-up brain MRI showed a decrease in basal meningitis, but increased parenchymal lesions in the suprasellar region extending medially into the nucleus lentiformis, with now a voluminous tuberculoma at this site. Antituberculosis treatment was continued for a total of 18 months. The patient improved clinically, she regained her pre-illness Body Mass Index (BMI) SDS and her growth rate increased slightly. On the hormonal side, disappearance of insulin resistance (HOMA-IR 2.5) and an increase in IGF-I (175 µg/L, -1.4 SD) was noted, and her last brain MRI showed a remarkable volume reduction of the suprasellar tuberculoma. CONCLUSION: Suprasellar tuberculoma can have a very dynamic presentation during the active stage of the disease, which can be reversed by prolonged antituberculosis treatment. Previous studies showed that the tuberculous process can also cause long term and irreversible changes in the hypothalamic-pituitary axis. Prospective studies are however needed in the pediatric population to know the exact incidence and type of pituitary dysfunction.
Subject(s)
Insulin Resistance , Tuberculoma , Female , Humans , Child , Insulin-Like Growth Factor I/therapeutic use , Prospective Studies , Tuberculoma/diagnosis , Tuberculoma/drug therapy , Tuberculoma/pathology , Magnetic Resonance Imaging/adverse effects , Headache/drug therapy , Headache/etiology , Antitubercular Agents/therapeutic use , Weight Gain , Obesity/complicationsABSTRACT
In adults with type 1 diabetes (T1D), time in range (TIR) [70-180 mg/dL] has been proposed as an additional metric besides glycated hemoglobin (HbA1c). This retrospective monocentric cohort study determined the correlation between HbA1c and TIR during the 2, 4, and 12 weeks (TIR2w, TIR4w, and TIR12w) before consultation in a pediatric T1D population. A total of 168 children with T1D were included. Continuous glucose monitoring data, HbA1c, and demographic variables were collected. We found strong linear correlations between HbA1c and TIR2w (R = -0.571), HbA1c and TIR4w (R = -0.603), and between HbA1c and TIR12w (R = -0.624). A strong correlation exists between TIR2w and TIR12w, HbA1c and time above range (TAR), and between TIR and TAR at different time points. In conclusion, a strong correlation was found between HbA1c and TIR, making TIR a potentially complementary metric to HbA1c. TIR2w seems a viable alternative to TIR12w. TAR also seems promising in assessing glycemic control.
Subject(s)
Blood Glucose Self-Monitoring , Blood Glucose , Diabetes Mellitus, Type 1 , Glycated Hemoglobin , Humans , Glycated Hemoglobin/analysis , Retrospective Studies , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/complications , Female , Male , Child , Blood Glucose/analysis , Adolescent , Glycemic Control/statistics & numerical data , Child, Preschool , Time Factors , Hypoglycemic Agents/therapeutic useABSTRACT
PURPOSE: Oral-facial-digital (OFD) syndromes are genetically heterogeneous developmental disorders, caused by pathogenic variants in genes involved in primary cilia formation and function. We identified a previously undescribed type of OFD with brain anomalies, ranging from alobar holoprosencephaly to pituitary anomalies, in 6 unrelated families. METHODS: Exome sequencing of affected probands was supplemented with alternative splicing analysis in patient and control lymphoblastoid and fibroblast cell lines, and primary cilia structure analysis in patient fibroblasts. RESULTS: In 1 family with 2 affected males, we identified a germline variant in the last exon of ZRSR2, NM_005089.4:c.1211_1212del NP_005080.1:p.(Gly404GlufsTer23), whereas 7 affected males from 5 unrelated families were hemizygous for the ZRSR2 variant NM_005089.4:c.1207_1208del NP_005080.1:p.(Arg403GlyfsTer24), either occurring de novo or inherited in an X-linked recessive pattern. ZRSR2, located on chromosome Xp22.2, encodes a splicing factor of the minor spliceosome complex, which recognizes minor introns, representing 0.35% of human introns. Patient samples showed significant enrichment of minor intron retention. Among differentially spliced targets are ciliopathy-related genes, such as TMEM107 and CIBAR1. Primary fibroblasts containing the NM_005089.4:c.1207_1208del ZRSR2 variant had abnormally elongated cilia, confirming an association between defective U12-type intron splicing, OFD and abnormal primary cilia formation. CONCLUSION: We introduce a novel type of OFD associated with elongated cilia and differential splicing of minor intron-containing genes due to germline variation in ZRSR2.
Subject(s)
Alternative Splicing , Orofaciodigital Syndromes , Male , Humans , Alternative Splicing/genetics , Orofaciodigital Syndromes/genetics , RNA Splicing , Introns , Spliceosomes/genetics , Ribonucleoproteins/geneticsABSTRACT
Behavioral and psychiatric problems are common in patients with Prader-Willi syndrome (PWS), while physical complaints such as pain, fever, and vomiting are rare due to a high pain threshold and dysregulation of temperature control. PWS patients have an increased mortality rate, some due to undiagnosed life-threatening diseases. We describe 2 patients with PWS whose behavioral changes, initially thought to be part of their behavioral phenotype, delayed the final diagnosis of a life-threatening underlying illness. A 13-year-old girl with PWS presented with a sudden change in behavior including aggression, scratching, and self-injury. She was seen by several health care providers, and after 5 months the diagnosis of pyosalpinx was made, for which laparoscopic resection of an infected tailgut cyst was performed, resolving the behavioral symptoms. A 38-year-old man with PWS presented with recurrent vague inguinal pain and nonepileptic seizures. After several years of consulting physicians and psychiatrists, including several hospital admissions, the diagnosis of bilateral inguinal hernia was made. After surgical correction, the pain and seizures ceased. In PWS patients presenting with unexplained behavioral changes and unusual somatic complaints, clinicians should perform an extensive clinical examination and consider underlying physical illness rather than attribute the problem to the behavioral phenotype.
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Importance: The incidence of diabetes in childhood has increased during the COVID-19 pandemic. Elucidating whether SARS-CoV-2 infection is associated with islet autoimmunity, which precedes type 1 diabetes onset, is relevant to disease etiology and future childhood diabetes trends. Objective: To determine whether there is a temporal relationship between SARS-CoV-2 infection and the development of islet autoimmunity in early childhood. Design, Setting, and Participants: Between February 2018 and March 2021, the Primary Oral Insulin Trial, a European multicenter study, enrolled 1050 infants (517 girls) aged 4 to 7 months with a more than 10% genetically defined risk of type 1 diabetes. Children were followed up through September 2022. Exposure: SARS-CoV-2 infection identified by SARS-CoV-2 antibody development in follow-up visits conducted at 2- to 6-month intervals until age 2 years from April 2018 through June 2022. Main Outcomes and Measures: The development of multiple (≥2) islet autoantibodies in follow-up in consecutive samples or single islet antibodies and type 1 diabetes. Antibody incidence rates and risk of developing islet autoantibodies were analyzed. Results: Consent was obtained for 885 (441 girls) children who were included in follow-up antibody measurements from age 6 months. SARS-CoV-2 antibodies developed in 170 children at a median age of 18 months (range, 6-25 months). Islet autoantibodies developed in 60 children. Six of these children tested positive for islet autoantibodies at the same time as they tested positive for SARS-CoV-2 antibodies and 6 at the visit after having tested positive for SARS-CoV-2 antibodies. The sex-, age-, and country-adjusted hazard ratio for developing islet autoantibodies when the children tested positive for SARS-CoV-2 antibodies was 3.5 (95% CI, 1.6-7.7; P = .002). The incidence rate of islet autoantibodies was 3.5 (95% CI, 2.2-5.1) per 100 person-years in children without SARS-CoV-2 antibodies and 7.8 (95% CI, 5.3-19.0) per 100 person-years in children with SARS-CoV-2 antibodies (P = .02). Islet autoantibody risk in children with SARS-CoV-2 antibodies was associated with younger age (<18 months) of SARS-CoV-2 antibody development (HR, 5.3; 95% CI, 1.5-18.3; P = .009). Conclusion and relevance: In young children with high genetic risk of type 1 diabetes, SARS-CoV-2 infection was temporally associated with the development of islet autoantibodies.
Subject(s)
COVID-19 , Diabetes Mellitus, Type 1 , Islets of Langerhans , Child, Preschool , Female , Humans , Infant , Antibodies, Viral/immunology , Autoantibodies/immunology , Autoimmunity/immunology , COVID-19/complications , COVID-19/immunology , Diabetes Mellitus, Type 1/etiology , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , Pandemics , SARS-CoV-2 , Islets of Langerhans/immunology , Male , Genetic Predisposition to DiseaseABSTRACT
The implementation of high-throughput and deep sequencing methods in routine genetic diagnostics has significantly improved the diagnostic yield in patient cohorts with growth disturbances and becomes increasingly important as the prerequisite of personalized medicine. They provide considerable chances to identify even rare and unexpected situations; nevertheless, we must be aware of their limitations. A simple genetic test in the beginning of a testing cascade might also help to identify the genetic cause of specific growth disorders. However, the clinical picture of genetically caused growth disturbance phenotypes can vary widely, and there is a broad clinical overlap between different growth disturbance disorders. As a consequence, the clinical diagnosis and therewith connected the decision on the appropriate genetic test is often a challenge. In fact, the clinician asking for genetic testing has to weigh different aspects in this decision process, including appropriateness (single gene test, stepwise procedure, comprehensive testing), turnaround time as the basis for rapid intervention, and economic considerations. Therefore, a frequent question in that context is 'what to test when'. In this review, we aim to review genetic testing strategies and their strengths and limitations and to raise awareness for the future implementation of interdisciplinary genome medicine in diagnoses, treatment, and counselling of growth disturbances.
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BACKGROUND: Cytochrome P450 4F3 (CYP4F3) is an ω-hydroxylase that oxidizes leukotriene B4 (LTB4), prostaglandins, and fatty acid epoxides. LTB4 is synthesized by leukocytes and acts as a chemoattractant for neutrophils, making it an essential component of the innate immune system. Recently, involvement of the LTB4 pathway was reported in various immunological disorders such as asthma, arthritis, and inflammatory bowel disease. We report a 26-year-old female with a complex immune phenotype, mainly marked by exhaustion, muscle weakness, and inflammation-related conditions. The molecular cause is unknown, and symptoms have been aggravating over the years. METHODS: Whole exome sequencing was performed and validated; flow cytometry and enzyme-linked immunosorbent assay were used to describe patient's phenotype. Function and impact of the mutation were investigated using molecular analysis: co-immunoprecipitation, western blot, and enzyme-linked immunosorbent assay. Capillary electrophoresis with ultraviolet detection was used to detect LTB4 and its metabolite and in silico modelling provided structural information. RESULTS: We present the first report of a patient with a heterozygous de novo missense mutation c.C1123 > G;p.L375V in CYP4F3 that severely impairs its activity by 50% (P < 0.0001), leading to reduced metabolization of the pro-inflammatory LTB4. Systemic LTB4 levels (1034.0 ± 75.9 pg/mL) are significantly increased compared with healthy subjects (305.6 ± 57.0 pg/mL, P < 0.001), and immune phenotyping shows increased total CD19+ CD27- naive B cells (25%) and decreased total CD19+ CD27+ IgD- switched memory B cells (19%). The mutant CYP4F3 protein is stable and binding with its electron donors POR and Cytb5 is unaffected (P > 0.9 for both co-immunoprecipitation with POR and Cytb5). In silico modelling of CYP4F3 in complex with POR and Cytb5 suggests that the loss of catalytic activity of the mutant CYP4F3 is explained by a disruption of an α-helix that is crucial for the electron shuffling between the electron carriers and CYP4F3. Interestingly, zileuton still inhibits ex vivo LTB4 production in patient's whole blood to 2% of control (P < 0.0001), while montelukast and fluticasone do not (99% and 114% of control, respectively). CONCLUSIONS: A point mutation in the catalytic domain of CYP4F3 is associated with high leukotriene B4 plasma levels and features of a more naive adaptive immune response. Our data provide evidence for the pathogenicity of the CYP4F3 variant as a cause for the observed clinical features in the patient. Inhibitors of the LTB4 pathway such as zileuton show promising effects in blocking LTB4 production and might be used as a future treatment strategy.
Subject(s)
Leukotriene B4 , Mutation, Missense , Cytochrome P-450 Enzyme System/genetics , Cytochrome P-450 Enzyme System/metabolism , Cytochrome P450 Family 4/genetics , Electrons , Female , Humans , Leukotriene B4/metabolismABSTRACT
Thyroid hormones play an essential role in central nervous system development, normal physiological brain function, and repair mechanisms. On one hand, thyroid hormone alterations influence cortical excitability, and on the other hand antiseizure medications (ASMs) are associated with alterations in thyroid hormone metabolism. Although this interaction has long been described, and epilepsy is a common and chronic neurological disease, studies describing the interplay are often small and retrospective. We performed a systematic review of the current literature on epilepsy, ASMs, and thyroid hormone metabolism according to PRISMA guidelines. Forty-seven studies were included. Most studies were retrospective cross-sectional studies (n = 25) and investigated thyroid function alterations in patients on older ASMs such as phenobarbital, phenytoin, carbamazepine, and valproate. Overall, almost one third of patients with epilepsy had thyroid hormone alterations, especially patients on valproate (25%) and carbamazepine (10%-25%). Studies with patients receiving polytherapy are scarce, but reported a higher risk for hypothyroidism in patients with older age (p = .004), female sex (p = .014), longer duration of epilepsy (p = .001), intractable epilepsy (p = .009), and polytherapy. Studies on newer ASMs are also limited, and further studies on an interplay with thyroid hormone homeostasis are essential to improve the care for epilepsy patients. ASMs are associated with alterations in thyroid hormone metabolism. Thyroid function monitoring is indicated in patients on ASMs, especially those with refractory epilepsy and those on polytherapy. We provide a practical guidance for thyroid function monitoring for the clinician taking care of patients on ASMs.
Subject(s)
Epilepsy , Valproic Acid , Anticonvulsants/adverse effects , Benzodiazepines/therapeutic use , Carbamazepine/adverse effects , Cross-Sectional Studies , Epilepsy/chemically induced , Epilepsy/drug therapy , Female , Homeostasis , Humans , Retrospective Studies , Thyroid Hormones/therapeutic use , Valproic Acid/therapeutic useABSTRACT
BACKGROUND: Sudden Unexpected Death in Pediatrics (SUDP) is a tragic event, likely caused by the complex interaction of multiple factors. The presence of hippocampal abnormalities in many children with SUDP suggests that epilepsy-related mechanisms may contribute to death, similar to Sudden Unexplained Death in Epilepsy. Because of known associations between the genes SCN1A and SCN5A and sudden death, and shared mechanisms and patterns of expression in genes encoding many voltage-gated sodium channels (VGSCs), we hypothesized that individuals dying from SUDP have pathogenic variants across the entire family of cardiac arrhythmia- and epilepsy-associated VGSC genes. METHODS: To address this hypothesis, we evaluated whole-exome sequencing data from infants and children with SUDP for variants in VGSC genes, reviewed the literature for all SUDP-associated variants in VGSCs, applied a novel paralog analysis to all variants, and evaluated all variants according to American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: In our cohort of 73 cases of SUDP, we assessed 11 variants as pathogenic in SCN1A, SCN1B, and SCN10A, genes with long-standing disease associations, and in SCN3A, SCN4A, and SCN9A, VGSC gene paralogs with more recent disease associations. From the literature, we identified 82 VGSC variants in SUDP cases. Pathogenic variants clustered at conserved amino acid sites intolerant to variation across the VGSC genes, which is unlikely to occur in the general population (p < .0001). For 54% of variants previously reported in literature, we identified conflicting evidence regarding pathogenicity when applying ACMG criteria and modern population data. CONCLUSION: We report variants in several VGSC genes in cases with SUDP, involving both arrhythmia- and epilepsy-associated genes. Accurate variant assessment as well as future studies are essential for an improved understanding of the contribution of sodium channel-related variants to SUDP.
Subject(s)
Death, Sudden, Cardiac/etiology , Mutation , Sodium Channels/genetics , Sudden Infant Death/genetics , Sudden Unexpected Death in Epilepsy/etiology , Child , Child, Preschool , Genetic Testing , Hippocampus/pathology , Humans , Infant , Sudden Infant Death/pathology , Sudden Unexpected Death in Epilepsy/pathology , Exome SequencingABSTRACT
Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH, OMIM 225790), also known as Fowler syndrome, is a rare autosomal recessive disorder of brain angiogenesis. PVHH has long been considered to be prenatally lethal. We evaluated the phenotypes of the first three siblings with survival into adulthood, performed a systematic review of the Fowler syndrome literature and delineated genotype-phenotype correlations using a scoring system to rate the severity of the disease. Thirty articles were included, describing 69 individual patients. To date, including our clinical reports, 72 patients have been described with Fowler syndrome. Only 6/72 (8%) survived beyond birth. Although our three patients carry the same mutations (c.327T>A-p.Asn109Lys and c.887C>T-p.Ser296Leu) in FLVCR2, only two of them presented with the same cerebral features, ventriculomegaly and cerebral calcifications, as affected fetuses. The third sibling has a surprisingly milder clinical and radiological phenotype, suggesting intrafamilial variability. Although no clear phenotype-genotype correlation exists, some variants appear to be associated with a less severe phenotype compatible with life. As such, it is important to consider Fowler syndrome in patients with gross ventriculomegaly, cortical malformations and/or cerebral calcifications on brain imaging.
Subject(s)
Hydranencephaly/genetics , Membrane Transport Proteins/genetics , Neovascularization, Pathologic/genetics , Receptors, Virus/genetics , Brain/metabolism , Brain/pathology , Genetic Association Studies , Humans , Hydranencephaly/pathology , Mutation/genetics , Neovascularization, Pathologic/pathology , PhenotypeABSTRACT
OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated. METHODS: Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data. RESULTS: Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling. ANN NEUROL 2020;87:897-906.
Subject(s)
Abnormalities, Drug-Induced/genetics , Anticonvulsants/adverse effects , Genetic Load , Genetic Variation/genetics , Teratogens , Abnormalities, Drug-Induced/epidemiology , Adult , DNA/genetics , DNA Copy Number Variations/genetics , Exome/genetics , Female , Humans , Infant, Newborn , Male , Paternal Age , Polymorphism, Single Nucleotide/genetics , PregnancyABSTRACT
BACKGROUND: Intracranial lipomas are rare, congenital lesions, most often located at the midline. Most hypothalamic lipomas are asymptomatic, but some cases have been associated with precocious puberty, hypothermia, headache and/or obesity. CASE PRESENTATION: A 7-year-old boy was referred for short stature and proved to be partially growth-hormone deficient. Magnetic resonance imaging (MRI) revealed a lipoma in the paramedian hypothalamus. Growth hormone treatment resulted in swift and uncomplicated catch-up growth. CONCLUSIONS: The present case appears to be the first to link hypothalamic lipoma to GH deficiency. The neuro-endocrine pathophysiology underpinning this link remains to be explored.
ABSTRACT
OBJECTIVE: We evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well-phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology. METHODS: We identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection-related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. We analyzed WES data and compared the yield in participants with and without prior clinical genetic testing. RESULTS: Overall, we identified pathogenic or likely pathogenic variants in 40% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy-related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26% (23/90). Of the 67 participants whose molecular diagnoses were "unsolved" through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25%). SIGNIFICANCE: Our data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well-phenotyped patients with epilepsy leads to a broader understanding of gene-specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease-associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.
Subject(s)
Epilepsy/diagnosis , Epilepsy/genetics , Exome/genetics , Adolescent , Adult , Age of Onset , Brain Diseases/etiology , Brain Diseases/genetics , Child , Child, Preschool , Chromosomes, Human/genetics , Cohort Studies , Epilepsy/complications , Epilepsy, Generalized/genetics , Female , Genetic Testing , Genetic Variation , Humans , Infant , Male , Microarray Analysis , Phenotype , Exome Sequencing , Young AdultABSTRACT
Epilepsy of infancy with migrating focal seizures (EIMFS), one of the most severe developmental and epileptic encephalopathy syndromes, is characterized by seizures that migrate from one hemisphere to the other. EIMFS is genetically heterogeneous with 33 genes. We report five patients with EIMFS caused by recessive BRAT1 variants, identified via next generation sequencing. Recessive pathogenic variants in BRAT1 cause the rigidity and multifocal seizure syndrome, lethal neonatal with hypertonia, microcephaly, and intractable multifocal seizures. The epileptology of BRAT1 encephalopathy has not been well described. All five patients were profoundly impaired with seizure onset in the first week of life and focal seizure migration between hemispheres. We show that BRAT1 is an important recessive cause of EIMFS with onset in the first week of life, profound impairment, and early death. Early recognition of this genetic aetiology will inform management and reproductive counselling.