Severe Neurodevelopmental Delay Research Articles

3,3',5-tri-iodothyroacetic acid (TRIAC) transporters.

Introduction Thyroid hormone transporters are essential for thyroid hormones to enter target cells. Monocarboxylate transporter MCT8 is a key transporter and expressed at the blood-brain barrier, in neural cells and many other tissues. Patients with MCT8 deficiency have severe neurodevelopmental delays due to cerebral hypothyroidism and chronic sequelae of peripheral thyrotoxicosis. The T3 analog 3,3,5-triiodothyroacetic acid (TRIAC) rescued neurodevelopmental features in animal models mimicking MCT8 deficiency and improved key metabolic features in patients with MCT8 deficiency. However, the identity of the transporter(s) that facilitate TRIAC transport are unknown. Here, we screened candidate transporters that are expressed at the human blood-brain barrier and/or brain-cerebrospinal fluid barrier and known thyroid hormone transporters for TRIAC transport. Materials and methods Plasma membrane expression was determined by cell surface biotinylation assays. Intracellular accumulation of 1 nM TRIAC was assessed in COS-1 cells expressing candidate transporters in Dulbecco's phosphate buffered saline (DPBS)/0.1% glucose or Dulbecco's modified Eagle's medium (DMEM) with or without 0.1% bovine serum albumin (BSA). Expression of Slc22a8 was determined by fluorescent in situ hybridization (FISH) in brain sections from wild-type and Mct8/Oatp1c1 knock-out mice at postnatal day 12, 21 and 120. Results Fifty-nine plasma membrane transporters were selected for screening of TRIAC accumulation (n=40 based on expression at the human blood-brain barrier and/or brain-cerebrospinal fluid barrier and having small organic molecules as substrates; n=19 known thyroid hormone transporters). Screening of the selected transporter panel showed that 18 transporters facilitated significant intracellular accumulation of TRIAC in DPBS/0.1% glucose or DMEM in the absence of BSA. In the presence of BSA, substantial transport was noted for SLCO1B1 and SLC22A8 (in DPBS/0.1% glucose and DMEM) and SLC10A1, SLC22A6 and SLC22A24 (in DMEM). The zebrafish and mouse orthologues of these transporters similarly facilitated intracellular accumulation of TRIAC. Highest Slc22a8 mRNA expression was detected in mouse brain capillary endothelial cells and choroid plexus epithelial cells at early postnatal time points, but wasreduced at P120. Conclusions Human SLC10A1, SLCO1B1, SLC22A6, SLC22A8 and SLC22A24 as well as their mouse and zebrafish orthologues are efficient TRIAC transporters. These findings contribute to the understanding of TRIAC treatment in patients with MCT8 deficiency and animal models thereof.

POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment

POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment

Severe manifestation of Rauch-Azzarello syndrome associated with biallelic deletion of CTNND2.

CTNND2 encodes δ-catenin, a component of an adherens junction complex, and plays an important role in neuronal structure and function. To date, only heterozygous loss-of-function CTNND2 variants have been associated with mild neurodevelopmental delay and behavioral anomalies, a condition, which we named Rauch-Azzarello syndrome. Here, we report three siblings of a consanguineous family of Syrian descent with a homozygous deletion encompassing the last 19 exons of CTNND2 predicted to disrupt the transcript. All presented with severe neurodevelopmental delay with absent speech, profound motor delay, stereotypic behavior, microcephaly, short stature, muscular hypotonia with lower limb hypertonia, and variable eye anomalies. The parents and the fourth sibling were heterozygous carriers of the deletion and exhibited mild neurodevelopmental impairment resembling that of the previously described heterozygous individuals. The present study unveils a severe manifestation of CTNND2-associated Rauch-Azzarello syndrome attributed to biallelic loss-of-function aberrations, clinically distinct from the already described mild presentation of heterozygous individuals. Furthermore, we demonstrate novel clinical features in homozygous individuals that have not been reported in heterozygous cases to date.

Evaluation of three-year neurodevelopmental outcomes in infants prenatally exposed to substance use

IntroductionPrenatal exposure to substance use is associated with long-term deficits in the neurodevelopment of children. The objective was to investigate the association between cognitive, motor, and language neurodevelopment at three years of age in infants prenatally exposed to substance use. Material and methodsA prospective matched case-control study was conducted. Biomarkers of fetal exposure were measured in meconium samples. The Bayley Scales of Infant and Toddler Development (BSID-III) were used to calculate neurodevelopment scores. Results32 non-exposed and 32 exposed infants were evaluated, of which 16 were exposed to cannabis, 8 to ethanol, 2 to cocaine and 6 to more than one substance. Normal BSID-III scores ≥85 in all domains, were detected in 23 exposed infants to any substance and 29 infants non-exposed. Neurodevelopmental delay was detected in the language domain, specifically in male infants exposed to cannabis. Two infants exposed to cannabis had a severe developmental delay (score<70). Infants exposed to any substance obtained significantly lower total scores than control infants in all domains. Infants exposed to cannabis obtained significantly lower composite scores in the cognitive and motor domains. Infants exposed to more than one substance had lower scores in motor skills. By gender, only males exposed obtained significantly lower composite scores than non-exposed males in the cognitive domain. ConclusionsThe most common and severe neurodevelopmental delay at 36 months was detected in the domain of language in male infants prenatally exposed to cannabis. Neurodevelopmental disorders detected can enable an early intervention and plan therapeutic strategies.

Providing quality care for people with CDKL5 deficiency disorder: A European expert panel opinion on the patient journey.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental and epileptic encephalopathy caused by variants in the CDKL5 gene. The disorder is characterized by intractable early-onset seizures, severe neurodevelopmental delay, hypotonia, motor disabilities, cerebral (cortical) visual impairment and microcephaly. With no disease-modifying therapies available for CDD, treatment is symptomatic with an initial focus on seizure control. Another unmet need in the management of people with CDD is the lack of evidence to aid standardized care and guideline development. To address this gap, experts in CDD and representatives from patient advocacy groups from Denmark, Finland, France, Germany, Italy, Poland, Spain, and the United Kingdom convened to form an Expert Working Group. The aim was to provide an expert opinion consensus on how to ensure quality care in routine clinical practice within the European setting, including in settings with limited experience or resources for multidisciplinary care of CDD and other developmental and epileptic encephalopathies. By means of one-to-one interviews around the current treatment landscape in CDD, insights from the Expert Working Group were collated and developed into a Europe-specific patient journey for individuals with CDD, which was later validated by the group. Further discussions followed to gain consensus of opinions on challenges and potential solutions for achieving quality care in this setting. The panel recognized the benefit of early genetic testing, a holistic personalized approach to seizure control (taking into consideration various factors such as concomitant medications and comorbidities), and age- and comorbidity-dependent multidisciplinary care for optimizing patient outcomes and quality of life. However, their insights and experiences also highlighted much disparity in management approaches and resources across different European countries. Development of standardized European recommendations is required to align realistic diagnostic criteria, treatment goals, and management approaches that can be adapted for different settings. PLAIN LANGUAGE SUMMARY: Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare condition caused by a genetic mutation with a broad range of symptoms apparent from early childhood, including epileptic seizures that do not respond to medication and severe delays in development. Due to the lack of guidance on managing CDD, international experts and patient advocates discussed best practices in the care of people with CDD in Europe. The panel agreed that early testing, a personalized approach to managing seizures,and access to care from different disciplines are beneficial. Development of guidelines to ensure that care is standardized would also be valuable.

Nacc1 Mutation in Mice Models Rare Neurodevelopmental Disorder with Underlying Synaptic Dysfunction.

A missense mutation in the transcription repressor Nucleus accumbens-associated 1 (NACC1) gene at c.892C>T (p.Arg298Trp) on chromosome 19 causes severe neurodevelopmental delay ( Schoch et al., 2017). To model this disorder, we engineered the first mouse model with the homologous mutation (Nacc1+/R284W ) and examined mice from E17.5 to 8 months. Both genders had delayed weight gain, epileptiform discharges and altered power spectral distribution in cortical electroencephalogram, behavioral seizures, and marked hindlimb clasping; females displayed thigmotaxis in an open field. In the cortex, NACC1 long isoform, which harbors the mutation, increased from 3 to 6 months, whereas the short isoform, which is not present in humans and lacks aaR284 in mice, rose steadily from postnatal day (P) 7. Nuclear NACC1 immunoreactivity increased in cortical pyramidal neurons and parvalbumin containing interneurons but not in nuclei of astrocytes or oligodendroglia. Glial fibrillary acidic protein staining in astrocytic processes was diminished. RNA-seq of P14 mutant mice cortex revealed over 1,000 differentially expressed genes (DEGs). Glial transcripts were downregulated and synaptic genes upregulated. Top gene ontology terms from upregulated DEGs relate to postsynapse and ion channel function, while downregulated DEGs enriched for terms relating to metabolic function, mitochondria, and ribosomes. Levels of synaptic proteins were changed, but number and length of synaptic contacts were unaltered at 3 months. Homozygosity worsened some phenotypes including postnatal survival, weight gain delay, and increase in nuclear NACC1. This mouse model simulates a rare form of autism and will be indispensable for assessing pathophysiology and targets for therapeutic intervention.

Treating Mild Chronic Hypertension During Pregnancy: A Cost-Effectiveness Analysis.

To assess the cost effectiveness of targeting a blood pressure of less than 140/90 mm Hg compared with 160/105 mm Hg. A decision-analytic model was constructed to compare the treatment of chronic hypertension in pregnancy at mild-range blood pressures (140/90 mm Hg) with the treatment of chronic hypertension before 20 weeks of gestation at severe-range blood pressures (160/105 mm Hg) in a theoretical cohort of 180,000 patients with mild chronic hypertension. Probabilities, costs, and utilities were derived from literature and varied in sensitivity analyses. Primary outcomes included incremental cost per quality-adjusted life-year (QALY), cases of preeclampsia, preeclampsia with severe features, severe maternal morbidity (SMM), preterm birth, maternal death, neonatal death, and neurodevelopmental delay. The cost-effectiveness threshold was $100,000 per QALY. Treating chronic hypertension in a population of 180,000 pregnant persons at mild-range blood pressures, compared with severe-range blood pressures, resulted in 14,177 fewer cases of preeclampsia (43,953 vs 58,130), 11,835 of which were cases of preeclampsia with severe features (40,530 vs 52,365). This led to 817 fewer cases of SMM (4,375 vs 5,192), and 18 fewer cases of maternal death (102 vs 120). Treating at a lower threshold also resulted in 8,078 fewer cases of preterm birth (22,000 vs 30,078), which led to 26 fewer neonatal deaths (276 vs 302) and 157 fewer cases of neurodevelopmental delay (661 vs 818). Overall, treating chronic hypertension at a lower threshold was a dominant strategy that resulted in decreased costs of $600 million and increased effectiveness of 12,852 QALYs. Treating chronic hypertension at a threshold of mild-range blood pressures is a dominant (lower costs, better outcomes) and cost-effective strategy that results in fewer neonatal and maternal deaths compared with the standard treatment of treating at severe range blood pressures.

Rare mosaic variant of GJA1 in a patient with a neurodevelopmental disorder

GJA1 is the causative gene for oculodentodigital dysplasia (ODDD). A novel de novo GJA1 variant, NM 000165:c263C > T [p.P88L], was identified in a mosaic state in a patient with short stature, seizures, delayed myelination, mild hearing loss, and tooth enamel hypoplasia. Although the patient exhibited severe neurodevelopmental delay, other clinical features of ODDD, including limb anomalies, were mild. This may be due to differences in the mosaic ratios in different organs.

Novel ERLIN2 variant expands the phenotype of Spastic Paraplegia 18.

The Brazilian Northeast region is notable for its high prevalence of consanguineous marriages and isolated populations, which has led to a significant prevalence of rare genetic disorders. This study describes the clinical presentation of four affected individuals from the same family, comprising two siblings and their cousins, with ages ranging from 11 to 20years. In a small and isolated community in Northeastern Brazil, affected individuals initially underwent a clinical assessment. Subsequently, written consent was obtained from their legal guardians, and an extensive clinical evaluation was conducted at a medical genetics center. Family data provided the basis for constructing the pedigree, and biological samples (blood or oral swabs) were collected from both affected and unaffected family members. Following informed consent from one patient, Whole Exome Sequencing (WES) was carried out, encompassing exome sequencing, assembly, genotyping, and annotation. A potentially deleterious variant was then singled out for further segregation analysis through Sanger Sequencing, involving both the proband and select family members. These individuals exhibit severe neurodevelopmental delays, encompassing symptoms such as spastic paraplegia, neuropathy, intellectual impairments, and language challenges. Through next-generation sequencing (NGS) techniques, a previously unreported homozygous variant within the ERLIN2 gene linked to spastic paraplegia 18 (SPG18) was identified across all four patients. Also, all patients displayed childhood cataract, expanding the known clinical spectrum of SPG18.

Establishing Patient-Centered Outcomes for MCT8 Deficiency: Stakeholder Engagement and Systematic Literature Review.

The SCL16A2 gene encodes the thyroid hormone (TH) transporter MCT8. Pathogenic variants result in a reduced TH uptake into the CNS despite high serum T3 concentrations. Patients suffer from severe neurodevelopmental delay and require multidisciplinary care. Since a first compassionate use study in 2008, the development of therapies has recently gained momentum. Treatment strategies range from symptom-based approaches, supplementation with TH or TH-analogs, to gene therapy. All these studies have mainly used surrogate endpoints and clinical outcomes. However, the EMA and FDA strongly encourage researchers to involve patients and their advocacy groups in the design of clinical trials. This should strengthen the patients' perspective and identify clinical endpoints that are clinically relevant to their daily life. We involved patient families to define patient-relevant outcomes for MCT8 deficiency. In close collaboration with patient families, we designed a questionnaire asking for their five most preferred therapeutic goals, which, if achieved at least, make a difference in their lives. In addition, we performed a systematic review according to Cochrane recommendations of the published treatment trials. We obtained results from 15 families with completed questionnaires from 14 mothers and 8 fathers. Improvement in development, especially in gross motor skills, was most important to the parents. 59% wished for head control and 50% for sitting ability. Another 36% wished for weight gain, 32% for improvement of expressive language skills, and 18% for a reduction of dystonia/spasticity, less dysphagia, and reflux. Paraclinical aspects were least important (5-9%). In a treatment trial (n=46) and compassionate use cases (n=83), the results were mainly inconclusive, partly due to a lack of predefined patient-centered clinical endpoints. We recommend that future trials should define a relevant improvement in "development" and/or other patient-relevant outcomes compared to natural history as treatment goals.

Risk factors for catheter-related bloodstream infections associated with home parental nutrition in children with intestinal failure: A prospective cohort study

Catheter-related bloodstream infection (CRBSI) is the most common, potentially life-threatening complication of long-term parenteral nutrition (PN). We prospectively assessed the incidence and risk factors for CRBSI in children receiving long-term home PN (HPN) for intestinal failure (IF) in a single IF rehabilitation center. Data regarding episodes and potential risk factors for CRBSI in children on HPN were prospectively recorded. Forty-one of 75 children were diagnosed with CRBSI. The overall CRBSI rate was 1.61 per 1000 catheter days. The indications for HPN were gastrointestinal motility disorders in 35%, short bowel syndrome (SBS) in 28% graft versus host disease (GvHD) post bone marrow transplant in 17%, congenital enteropathy in 15%, and severe neurodevelopmental impairment in 5%. Gastrointestinal motility disorders had significantly higher CRBSI rate compared to other groups (p<0.0005; 2.74 in motility group vs 1.54 in GvHD group vs 0.52 in congenital enteropathies vs 0.36 in SBS group vs 0.67 in severe neurodevelopmental delay). Multivariate analysis revealed that enterocutaneous distal stoma (ileostomy or colostomy) (HR 3.35 [95% CI, 1.63-6.86]; p<0.001), age <2 years (HR 0.28 [95% CI, 0.15-0.53]; p<0.0001), male sex (HR 2.28 [95% CI, 1.51-3.43]; p<0.0001), non-use of taurolidine citrate lock (HR 2.70 [95% CI, 1.72-4.11]; p<0.0001) and gastrointestinal motility disorder (HR 3.02 [95% CI, 1.81-4.91]; p<0.001) were independent risk factors for developing CRBSI. Extra care in managing PN connections and disconnections should be taken in children with an underlying gastrointestinal motility disorder, distal enterocutaneous stoma, male sex and those aged <2 years since they are at a significantly higher risk of CRBSI. Early introduction of taurolidine lock should be considered.

A novel DOCK7 variant as a rare reason for epileptic encephalopathy, cortical blindness, dysmorphic features: A case report and brief review of the literature

Early infantile epileptic encephalopathy 23 (EIEE23; OMIM #615859) is a rare autosomal recessive disorder. It is characterized by refractory seizures, multifocal epileptic activity on electroencephalography, psychomotor development delay, dysmorphic facial features and cortical blindness/visual impairment. DOCK7 is involved in intracellular signaling networks and plays a role in axon formation and neuronal polarization. Function loss of this gene has previously been described in the molecular etiology of EIEE23. Here, we report a boy with a pathogenic novel variant in the DOCK7 gene presenting with, infantile-onset epileptic encephalopathy, severe neurodevelopmental delay, dysmorphic facial features, cortical blindness as well as previously unreported minor dental and extremity anomalies. Few cases with DOCK7 mutations have been reported in the literature. Due to its high genetic heterogeneity and scarcity, it is extremely important to report a novel and specific mutations and their associated clinical phenotypes. Whole exome sequencing revealed a novel pathogenic homozygous frameshift variant which has not been reported (c.5669dup (p.Cys1891ValfsTer2) mutation in the exon 44 of DOCK7).

Diagnostic accuracy of ASQ for screening of neurodevelopmental delays in low resource countries

ObjectiveThe Bayley Scales of Infant Development (BSID) is the most used diagnostic tool to identify neurodevelopmental disorders in children under age 3 but is challenging to use in low-resource countries....

Developmental and epileptic encephalopathy 89: A novel bi-allelic variant, molecular dynamics simulation, and a comprehensive clinical and molecular profile.

Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the adult central nervous system, plays an important role during embryonic neural network formation. GAD67 is the rate-limiting enzyme in GABA synthesis, and its deficiency leads to developmental and epileptic encephalopathy 89 (DEE 89). Patients who suffered from this syndrome generally manifested severe to profound neurodevelopmental delay, seizures, and often congenital anomalies such as the cleft palate or/and omphalocele. Up to now, only three papers on this syndrome have been published, and our knowledge about the disease's clinical course and pathophysiology is in its infancy. We used whole-exome sequencing (WES) and multiple in-silico tools to detect a potential causative variant in a patient with severe neurodevelopmental delay and refractory epilepsy. Moreover, by molecular docking and molecular dynamics simulation, we investigate the effect of the candidate variant on the GAD67 function and structure. WES data analysis revealed a novel deleterious variant (NM_000817.3: c.850C>T; p.Leu284Phe) in the GAD1 gene, which encodes the GAD67 enzyme. Molecular docking and molecular dynamics simulation showed that this variant has deleterious effects on the structure and function of the GAD67. This study's patient, in addition to typical symptoms of the DEE89, showed microcephaly and clonus in the toe, which were novel clinical findings. Our findings expand the mutational and clinical spectrum of DEE 89. Also, by gathering clinical symptoms and genetic findings of previously reported cases, moreover providing a comprehensive clinical picture of the disease, we found that there was no common drug therapy among patients whose epilepsy was controlled. Furthermore, the comparison of clinical symptoms between patients with missense and truncating mutations did not show any significant clinical difference, except that patients with missense mutations did not show cleft palates or omphaloceles.

POLD3 deficiency is associated with severe combined immunodeficiency, neurodevelopmental delay, and hearing impairment

Combined immunodeficiency diseases (CID) represent the most severe forms of inborn errors of immunity. Defective T cell development and/or function, leading to an impairment in adaptive immunity are responsible for these diseases. The DNA polymerase δ complex is important for genome duplication and maintenance and consists of the catalytic subunit POLD1, and the accessory subunits POLD2 and POLD3 which stabilizes the complex. Mutations in POLD1 and POLD2 have been recently shown to be associated with a syndromic CID characterized by T cell lymphopenia with or without intellectual deficiency and sensorineural hearing loss. Here we report a homozygous POLD3 variant (NM_006591.3; p.Ile10Thr) in a Lebanese patient, the product of a consanguineous family, presenting with a syndromic severe combined immunodeficiency (SCID) with neurodevelopmental delay and hearing loss. The homozygous POLD3Ile10Thr variant abolishes POLD3 as well as POLD1 and POLD2 expression. Our findings implicate POLD3 deficiency as a novel cause of syndromic SCID.

A prospective study of prenatal ventriculomegaly: natural course, survival, and neurodevelopmental status.

Prenatal ventriculomegaly (VM) is classified as mild, moderate, or severe on the basis of the diameter of the atrium. Neurodevelopmental status in prenatal VM is associated with various factors such as the course of VM, VM type, progression, and associated anomalies. In this study, the authors aimed to evaluate neurodevelopmental outcome in patients with prenatal VM and to detect possible associated risk factors. In this study, 73 pregnancies with VM who were referred to Children's Medical Center, Tehran, Iran, between 2019 and 2021 were prospectively followed. They were followed up every 2-4 weeks with ultrasonography (US) before delivery and were then observed for an average time of 14.6 months. The authors collected demographic and ultrasound information, associated abnormalities, pregnancy outcomes, and developmental status according to Centers for Disease Control criteria. The mean gestational age at the time of diagnosis was 28.1 weeks, and 46.6% of fetuses were female. According to the first US, 46.6% had mild, 21.9% had moderate, and 31.5% had severe VM. Serial US scans showed that VM had regressed in 20.5% of patients, remained stable in 35.6%, and progressed in 43.8%. Other cranial abnormalities were detected in 38.4% of fetuses. During follow-up, 62.5% of cases had normal developmental status, 26.6% had mild delay, and 10.9% had severe neurodevelopmental delay. Pregnancy was terminated in 9 (12.3%) cases. Normal neurodevelopment was reported in 75.8% of patients with mild VM versus 50% of those with severe VM (p = 0.19). Neurodevelopmental status was normal in 72.5% of cases without other cranial abnormalities (p = 0.018) and in 86.7% of cases with regression of VM (p = 0.028). Despite analysis of different factors in prenatal VM, only progression of VM and associated cranial abnormalities had significant relationships with neurodevelopmental prognosis.

Infancy-onset diabetes caused by de-regulated AMPylation of the human endoplasmic reticulum chaperone BiP.

Dysfunction of the endoplasmic reticulum (ER) in insulin-producing beta cells results in cell loss and diabetes mellitus. Here we report on five individuals from three different consanguineous families with infancy-onset diabetes mellitus and severe neurodevelopmental delay caused by a homozygous p.(Arg371Ser) mutation in FICD. The FICD gene encodes a bifunctional Fic domain-containing enzyme that regulates the ER Hsp70 chaperone, BiP, via catalysis of two antagonistic reactions: inhibitory AMPylation and stimulatory deAMPylation of BiP. Arg371 is a conserved residue in the Fic domain active site. The FICDR371S mutation partially compromises BiP AMPylation in vitro but eliminates all detectable deAMPylation activity. Overexpression of FICDR371S or knock-in of the mutation at the FICD locus of stressed CHO cells results in inappropriately elevated levels of AMPylated BiP and compromised secretion. These findings, guided by human genetics, highlight the destructive consequences of de-regulated BiP AMPylation and raise the prospect of tuning FICD's antagonistic activities towards therapeutic ends.

Equity factors in pediatric transplant listing: Initial findings from a single center review.

In order to improve transparency within the patient selection process, a transplant listing advisory committee was formed within the Boston Children's Hospital Pediatric Transplant Center. Its mission is to promote equity in access to organ transplantation by ensuring that the institutional transplant selection criteria are fair, unbiased, and nondiscriminatory. The committee conducts comprehensive case and data review of individual characteristics and reviews in aggregate to identify potential systems bias. Charts for 256 patients evaluated for transplant from 3/2016 to 3/2019 were reviewed. Among these, 64 (25%) patients were declined for transplant. Univariate logistic regression analysis was used to identify demographic variables and vulnerable status factors associated with being declined. Odds ratios (OR) are reported. Among all patients, median age was 8.5 years and 58% were male. Asian patients were more likely to be declined than White patients (OR=5.3, Wald p=.007). Socioeconomic factors that affected likelihood of listing decline included concerns for caregivers' ability to manage and understand care requirements (OR=3.8, p=.011), caregiver employment status (OR=1.9, p=.042), and use of public assistance programs (OR=2.2, p=.05). Patients with severe neurodevelopmental delay were more likely to be declined for listing (OR=3.7, p=.019). This analysis identified areas of potential bias related to race, socioeconomic status, and neurodevelopmental delay where initiatives can be targeted. Advisory committees are an important aspect of evaluating equity in transplant center selection policy and practice.

Treating mild chronic hypertension during pregnancy: a cost-effectiveness analysis of the CHAP trial

The CHAP trial, a recently published large randomized controlled trial, found improved outcomes with treating chronic hypertension (cHTN) during pregnancy at a lower threshold than the current standard. However, the cost-effectiveness of this strategy has not been examined. A decision-analytic model was constructed to compare treatment of cHTN once above a systolic blood pressure (SBP) of 140 mmHg and/or diastolic blood pressure (DBP) of 90 mmHg, to treatment of cHTN once above a SBP of 160 mmHg and/or DBP of 110 mmHg in a theoretical cohort of 200,000 patients with mild cHTN. Probabilities, costs, and utilities were derived from literature and varied in sensitivity analysis. Primary outcomes included incremental cost per quality-adjusted life year (QALY), cases of preeclampsia, preeclampsia with severe features, severe maternal morbidity (SMM), preterm birth (PTB), maternal death, neonatal death (NND), and neurodevelopmental delay (NDD). The cost-effectiveness threshold was $100,000/QALY. Treating cHTN at a lower threshold resulted in 15,752 fewer cases of preeclampsia, 13,149 of which were cases of preeclampsia with severe features. This led to 910 fewer cases of SMM, and 19 fewer cases of maternal death. Treating at a lower threshold also resulted in 8,976 fewer cases of preterm birth, which led to 228 fewer neonatal deaths and 175 fewer cases of neurodevelopmental delay. Overall, treating cHTN at a lower threshold was a dominant strategy resulting in lower costs ($704 million) and increased effectiveness (16,073 QALYs). Treating cHTN at a reduced threshold is a dominant, cost-effective strategy resulting in fewer neonatal and maternal deaths compared to the standard treatment of treating at higher BP.

A Missense Variant in PDK1 Associated with Severe Neurodevelopmental Delay and Epilepsy.

The pyruvate dehydrogenase complex (PDC) is responsible for the conversion of pyruvate into acetyl-CoA, which is used for energy conversion in cells. PDC activity is regulated by phosphorylation via kinases and phosphatases (PDK/PDP). Variants in all subunits of the PDC and in PDK3 have been reported, with varying phenotypes including lactic acidosis, neurodevelopmental delay, peripheral neuropathy, or seizures. Here, we report a de novo heterozygous missense variant in PDK1 (c.1139G &gt; A; p.G380D) in a girl with developmental delay and early onset severe epilepsy. To investigate the role of PDK1G380D in energy metabolism and neuronal development, we used a zebrafish model. In zebrafish embryos we show a reduced number of cells with mitochondria with membrane potential, reduced movements, and a delay in neuronal development. Furthermore, we observe a reduction in the phosphorylation of PDH-E1α by PDKG380D, which suggests a disruption in the regulation of PDC activity. Finally, in patient fibroblasts, a mild reduction in the ratio of phosphorylated PDH over total PDH-E1α was detected. In summary, our findings support the notion that this aberrant PDK1 activity is the cause of clinical symptoms in the patient.