A systematic review on the role of mitochondrial dysfunction/disorders in neurodevelopmental disorders and psychiatric/behavioral disorders.

Introduction: Mitochondrial diseases are known inborn errors affecting energy metabolism and are as common as chronic diseases such as diabetes, affecting approximately 1 in 5,000 people. The role of mitochondrial diseases/dysfunction has been highlighted in neurodevelopmental disorders like ASD, ADHD, intellectual disability, and speech delay, as well as various psychiatric conditions. Neurodevelopmental disorders are increasingly recognized as having behavioral and psychiatric symptoms. Our study aimed to investigate reports of mitochondrial disorders, noting neurodevelopmental disorders and psychiatric/behavioral conditions. Methods: This was done through a systematic review of literature from PubMed/MEDLINE, Scopus, and Cochrane Library up to November 2022. Results: We found 277 publications, of which 139 met the inclusion criteria. We mostly found review articles with mention of mitochondrial dysfunction/disorder in relation to ASD with brief mentions of psychiatric/behavioral comorbidities. Discussion: This suggests a need for broader research efforts beyond ASD to understand the relationship between mitochondrial disorder or dysfunction and various neurodevelopmental and psychiatric/behavioral comorbidities.

Impact of "Black Race" Coefficient in Estimation of Glomerular Filtration Rate on Our Community and Medical Education.

INTRODUCTION: The use of race in estimation of glomerular filtration rate (eGFR) started a critical national conversation on numerous areas of medicine touched by racism; with a call for removal of race from calculation of eGFR. We scrutinized use of "Black race" coefficient in Modification of Diet in Renal Disease (MDRD) eGFR calculation and consequence of its use on our local community in SW Michigan. METHODS: A cross-sectional analysis of de-identified electronic health record data from routine outpatient primary care visits, from January 1, 2019, to December 31, 2019, included variables such as age, race, gender, serum creatinine levels, and calculated eGFRs (if any), using χ2 tests for association and Wald-approximation 95% confidence interval. During the data collection period in 2019, both hospital systems and the outpatient clinic site were all using MDRD. RESULTS: eGFR and associated CKD stage were calculated for 131,863 patients. χ2 tests found significant differences in rates of CKD stages 3, 4, and 5 between "Black" and "not Black." And, the 95% confidence interval for the proportion of Black patients who would advance to the next stage of CKD upon ignoring "Black race" (using Wald-approximated confidence interval for binomial proportion) is between 41.1% and 43.0%. DISCUSSION: The eGFR calculations which place Black patients in lower CKD stages initially may deprive them of important treatment and referral early in their disease course. Removal of the Black race coefficient allows for referral to a nephrologist, Medicare coverage, and the potential need for transplant and/or dialysis. CONCLUSION: Our analysis demonstrates the impact removal of "black race" coefficient from MDRD eGFR calculation could have on our community.

Incidence of Neonatal Seizures in China Based on Electroencephalogram Monitoring in Neonatal Neurocritical Care Units.

Importance: Neonatal seizures pose a significant challenge in critical care, and continuous video electroencephalography (cEEG) monitoring holds promise for early detection of seizures. However, large-scale data on the incidence of neonatal seizures and monitoring systems in China are lacking. Objectives: To determine the incidence of neonatal seizures in infants with high risk in China. Design, Setting, and Participants: A large, cross-sectional multicenter study was conducted from January 2017 to December 2018 in the neonatal intensive care units (NICUs) of 7 tertiary medical centers in China. Neonates with high risk were included, and cEEG monitoring was conducted. Data were collected between January 1, 2017, and January 31, 2020. The data were analyzed between January 2021 and January 2022. Main Outcomes and Measures: The incidence of neonatal seizures, categorized by etiology, and seizure burden. Results: A total of 20 310 neonates with high risk were included (10 495 [51.7%] male; mean [SD] postmenstrual age, 37.7 [3.7] weeks), and seizures were observed in 3423 infants (16.9%). The highest proportion of seizures was attributed to acute neonatal encephalopathy (1448 [42.3%]). The incidence of seizures decreased with postmenstrual age and birth weight, with the highest occurrence observed in neonates with postmenstrual age of less than 28 weeks (237 of 879 [27.0%]) or birth weight of less than 1.0 kg (269 of 914 [29.4%]). Preterm infants had a higher proportion of moderate and severe seizure burdens compared with full-term infants (moderate severity: 248 of 1199 [20.7%] vs 454 of 2224 [20.4%]), but no significant differences were observed in etiology. Seizure burden was highest with genetic syndromes (49 of 188 [26.1%]), central nervous system malformations (33 of 127 [26.0%]), and inborn errors of metabolism (27 of 113 [23.9%]). During hospitalization, 7.8% of neonates with seizures died (267 neonates), with 81.3% of these cases having a moderate or severe seizure burden (217 neonates). Mortality was generally higher in preterm vs full-term infants (98 of 1199 [8.2%] vs 169 of 2224 [7.6%]) and increased with the severity of seizure burden (217 of 267 neonates with moderate or severe burden [81.3%]). Conclusions and Relevance: This cross-sectional study of neonatal seizures underscores the substantial burden seizures pose to high-risk infants with brain injury in China, particularly those who are born prematurely or who have congenital conditions.

Role of Psychologists in Pediatric Metabolic Disorders.

Metabolic disorders or inborn errors of metabolism (IEMs) can have a wide range of neurodevelopmental and behavioral presentations. These can vary with age and/or management or stressors from common childhood/intercurrent illnesses/procedures/interventions. Collaborative care models such as multidisciplinary metabolic clinics or colocated models with behavioral health clinics and metabolic clinics in the same location can be valuable resources in improving long-term outcomes in patients with IEM. Psychologists' expertise using behavioral interventions, screening, or adaptive/cognitive measures can help with diagnosis, treatment adherence, school performance, family support, community resources, transition to adolescence and young adulthood using health belief concepts to improve outcomes.

Ethical Considerations on Pediatric Genetic Testing Results in Electronic Health Records.

BACKGROUND: Advances in technology and access to expanded genetic testing have resulted in more children and adolescents receiving genetic testing for diagnostic and prognostic purposes. With increased adoption of the electronic health record (EHR), genetic testing is increasingly resulted in the EHR. However, this leads to challenges in both storage and disclosure of genetic results, particularly when parental results are combined with child genetic results. PRIVACY AND ETHICAL CONSIDERATIONS: Accidental disclosure and erroneous documentation of genetic results can occur due to the nature of their presentation in the EHR and documentation processes by clinicians. Genetic information is both sensitive and identifying, and requires a considered approach to both timing and extent of disclosure to families and access to clinicians. METHODS: This article uses an interdisciplinary approach to explore ethical issues surrounding privacy, confidentiality of genetic data, and access to genetic results by health care providers and family members, and provides suggestions in a stakeholder format for best practices on this topic for clinicians and informaticians. Suggestions are made for clinicians on documenting and accessing genetic information in the EHR, and on collaborating with genetics specialists and disclosure of genetic results to families. Additional considerations for families including ethics around results of adolescents and special scenarios for blended families and foster minors are also provided. Finally, administrators and informaticians are provided best practices on both institutional processes and EHR architecture, including security and access control, with emphasis on the minimum necessary paradigm and parent/patient engagement and control of the use and disclosure of data. CONCLUSION: The authors hope that these best practices energize specialty societies to craft practice guidelines on genetic information management in the EHR with interdisciplinary input that addresses all stakeholder needs.

Newborn screening and changing face of inborn errors of metabolism in the United States.

Newborn screening (NBS) in the United States helps each year diagnose, 1 in every 320 newborns (12,500 of the 4 million births), with a potentially severe or lethal condition prior to clinical symptoms manifestation. 10% of these are inborn errors of metabolism (IEM). Coordinated efforts of NBS program, primary care physicians, and metabolic centers can help with pre-symptomatic identification and interventions for such conditions to ameliorate or resolve associated morbidity and mortality. NBS in the United States is a successful public health program to improve short and long term health outcomes for newborns. Federal and State agencies provide the regulatory and funding framework to implement NBS programs, while professional societies provide medical guidelines to help identify and manage such conditions. However, each State independently organizes and administers its own NBS program. This article reviews the common NBS program workflow, federal regulatory framework, uniform screening panel recommendations, the testing processes and ethical considerations involved.

Common metabolic disorder (inborn errors of metabolism) concerns in primary care practice.

Inborn errors of metabolism (IEMs) are rare genetic or inherited disorders resulting from an enzyme defect in biochemical and metabolic pathways affecting proteins, fats, carbohydrates metabolism or impaired organelle function presenting as complicated medical conditions involving several human organ systems. They involve great complexity of the underlying pathophysiology, biochemical workup, and molecular analysis, and have complicated therapeutic options for management. Age of presentation can vary from infancy to adolescence with the more severe forms appearing in early childhood accompanied by significant morbidity and mortality. The understanding of these complex disorders requires special in-depth training, American Board of Medical Genetics and Genomics (ABMGG) certification and experience. Most primary care physicians (PCPs) are reluctant to deal with IEM due to unfamiliarity and rarity of such conditions compounded by prompt progression to crisis situations along with paucity of time involved in dealing with such complex disorders. While there are biochemical geneticists aka metabolic specialists' expertise available, mostly in larger academic medical centers, with expertise to deal with these rare complex issues, their initial clinical presentation in most newborns, children, adolescents or adults including asymptomatic positive newborn screen (NBS), occur in the out-patient PCP settings. Therefore, it is important that PCPs' comfort to recognize early signs and symptoms is important to initiate appropriate diagnostic and therapeutic interventions, and be able to make appropriate referrals. The following article reviews common IEM clinical presentations for a robust diagnostic differential and discuss evaluation and management approaches of patients with known or suspected IEM.

Organic acid disorders.

Organic acids (OAs) are intermediary products of several amino acid catabolism or degradation via multiple biochemical pathways for energy production. Vitamins or co-factors are often quintessential elements in such degradation pathways and OA metabolism. OAs that result from enzyme defects in these pathways can be identified in body fluids utilizing gas chromatography-mass spectrometry techniques (GC/MS). OAs are silent contributor to acid base imbalance and can affect nitrogen balance and recycling. Since OA production occurs in distal steps of a specific amino acid catabolism, offending amino acid accumulation is not characteristic. OA disorders as inborn errors of metabolism (IEM) are included in differential diagnosis of metabolic acidosis, as the common mnemonic MUDPILES taught in medical schools. High anion gap metabolic acidosis with hyperammonemia is a characteristic OA biochemical finding. VOMIT (valine, odd chain fatty acids, methionine, isoleucine, and threonine) is a smart acronym and a common clinical presentation of OA disorders and can present as early life-threatening illness, prior to Newborn Screening results availability. Easy identification and available medical formula make the field of metabolic nutrition vital for management of OA disorders. Treatment strategies also involve cofactor/vitamin utilization to aid specific pathways and disorder management. Optimal metabolic control and regular monitoring is key to long-term management and prevention of morbidity, disability and mortality. Prompt utilization of acute illness protocol (AIP) or emergency protocol and disorder specific education of family members or caregivers, primary care physicians and local emergency health care facilities; cautiously addressing common childhood illnesses in patients with OA disorders, can help avoid poor short- and long-term morbidity, disability and mortality outcomes.

Amino acid disorders.

Amino acids serve as key building blocks and as an energy source for cell repair, survival, regeneration and growth. Each amino acid has an amino group, a carboxylic acid, and a unique carbon structure. Human utilize 21 different amino acids; most of these can be synthesized endogenously, but 9 are "essential" in that they must be ingested in the diet. In addition to their role as building blocks of protein, amino acids are key energy source (ketogenic, glucogenic or both), are building blocks of Kreb's (aka TCA) cycle intermediates and other metabolites, and recycled as needed. A metabolic defect in the metabolism of tyrosine (homogentisic acid oxidase deficiency) historically defined Archibald Garrod as key architect in linking biochemistry, genetics and medicine and creation of the term 'Inborn Error of Metabolism' (IEM). The key concept of a single gene defect leading to a single enzyme dysfunction, leading to "intoxication" with a precursor in the metabolic pathway was vital to linking genetics and metabolic disorders and developing screening and treatment approaches as described in other chapters in this issue. Amino acid disorders also led to the evolution of the field of metabolic nutrition and offending amino acid restricted formula and foods. This review will discuss the more common disorders caused by inborn errors in amino acid metabolism.

Fatty acid oxidation disorders.

Fatty acid oxidation disorders (FAODs) are inborn errors of metabolism due to disruption of either mitochondrial ß-oxidation or the fatty acid transport using the carnitine transport pathway. The presentation of a FAOD will depend upon the specific disorder, but common elements may be seen, and ultimately require a similar treatment. Initial presentations of the FAODs in the neonatal period with severe symptoms include cardiomyopathy, while during infancy and childhood liver dysfunction and hypoketotic hypoglycemia are common. Episodic rhabdomyolysis is frequently the initial presentation during or after adolescence; although, these symptoms may develop at any age for most of the FAODs The treatment of all FAOD's include avoidance of fasting, aggressive treatment during illness, and supplementation of carnitine, if necessary. The long-chain FAODs differ by requiring a fat-restricted diet and supplementation of medium chain triglyceride oil and often docosahexaenoic acid (DHA)-an essential fatty acid, crucial for brain, visual, and immune functions and prevention of fat soluble vitamin deficiencies. The FAOD are a group of autosomal recessive disorders associated with significant morbidity and mortality, but early diagnosis on newborn screening (NBS) and early initiation of treatment are improving outcomes. There is a need for clinical studies including randomized, controlled, therapeutic trials to continue to evaluate current understanding and to implement future therapies.

Glycogen metabolism and glycogen storage disorders.

Glucose is the main energy fuel for the human brain. Maintenance of glucose homeostasis is therefore, crucial to meet cellular energy demands in both - normal physiological states and during stress or increased demands. Glucose is stored as glycogen primarily in the liver and skeletal muscle with a small amount stored in the brain. Liver glycogen primarily maintains blood glucose levels, while skeletal muscle glycogen is utilized during high-intensity exertion, and brain glycogen is an emergency cerebral energy source. Glycogen and glucose transform into one another through glycogen synthesis and degradation pathways. Thus, enzymatic defects along these pathways are associated with altered glucose metabolism and breakdown leading to hypoglycemia ± hepatomegaly and or liver disease in hepatic forms of glycogen storage disorder (GSD) and skeletal ± cardiac myopathy, depending on the site of the enzyme defects. Overall, defects in glycogen metabolism mainly present as GSDs and are a heterogenous group of inborn errors of carbohydrate metabolism. In this article we review the genetics, epidemiology, clinical and metabolic findings of various types of GSD, and glycolysis defects emphasizing current treatment and implications for future directions.

Mitochondrial disorders.

Primary mitochondrial disorders are a group of clinically variable and heterogeneous inborn errors of metabolism (IEMs), resulting from defects in cellular energy, and can affect every organ system of the body. Clinical presentations vary and may include symptoms of fatigue, skeletal muscle weakness, exercise intolerance, short stature, failure to thrive, blindness, ptosis and ophthalmoplegia, nystagmus, hearing loss, hypoglycemia, diabetes mellitus, learning difficulties, intellectual disability, seizures, stroke-like episodes, spasticity, dystonia, hypotonia, pain, neuropsychiatric symptoms, gastrointestinal reflux, dysmotility, gastrointestinal pseudo-obstruction, cardiomyopathy, cardiac conduction defects, and other endocrine, renal, cardiac, and liver problems. Most phenotypic manifestations are multi-systemic, with presentations varying at different age of onset and may show great variability within members of the same family; making these truly complex IEMs. Most primary mitochondrial diseases are autosomal recessive (AR); but maternally-inherited [from mitochondrial (mt) DNA], autosomal dominant and X-linked inheritance are also known. Mitochondria are unique energy-generating cellular organelles, geared for survival and contain their own unique genetic coding material, a circular piece of mtDNA about 16,000 base pairs in size. Additional nuclear (n)DNA encoded genes maintain mitochondrial biogenesis by supervising mtDNA replication, repair and synthesis, which is modified during increased energy demands or physiological stress. Despite our growing knowledge of the hundreds of genetic etiologies for this group of disorders, diagnosis can also remain elusive due to unique aspects of mitochondrial genetics. Though cure and FDA-approved therapies currently elude these IEMs, and current suggested therapies which include nutritional supplements and vitamins are of questionable efficacy; multi-center, international clinical trials are in progress for primary mitochondrial disorders.

The role of integrated behavioral health in caring for patients with metabolic disorders.

This review of integrated behavioral health (IBH) provides a background on IBH models, and the benefits of IBH in pediatric practice with an emphasis on how IBH specialists can collaborate with families and clinicians. An overview of intellectual disability (ID) and psychiatric disorders focused on disorders of inborn errors of metabolism (IEM) highlights issues in assessment and monitoring of these patients with implications for clinical practice and the role of IBH in caring for patients with IEM disorders.

Developmental-behavioral pediatric teaching of medical students: a national COMSEP survey.

BACKGROUND: The Council on Medical Student Education in Pediatrics (COMSEP) pediatric clerkship curriculum is widely followed. To date, there are no known studies on clerkship instruction related to developmental-behavioral pediatric (DBP) curricular elements. PURPOSES: The goals of this study are to examine pediatric clerkships' current DBP teaching methods and to identify barriers and solutions to recommended curriculum implementation. METHODS: Electronic survey was conducted with COMSEP-member pediatric clerkship directors. Descriptive statistics and qualitative data analysis was conducted. RESULTS: Response rate was 66%. General Pediatricians (87.1%) were mostly responsible for clerkship DBP teaching. Around 18% of directors reported not assessing DBP competencies. Most clerkship directors report time constraints (61.8%) as a barrier to implementing the curriculum, along with faculty availability and resources. Suggested solutions included DBP faculty collaboration and resources. CONCLUSIONS: General pediatricians should collaborate with DBP faculty for instructional content creation, and community-based observational opportunities and web-based shared resources could help clerkship directors achieve the COMSEP DBP curriculum competencies.

Sterol metabolism disorders and neurodevelopment-an update.

Cholesterol has numerous quintessential functions in normal cell physiology, as well as in embryonic and postnatal development. It is a major component of cell membranes and myelin, and is a precursor of steroid hormones and bile acids. The development of the blood brain barrier likely around 12-18 weeks of human gestation makes the developing embryonic/fetal brain dependent on endogenous cholesterol synthesis. Known enzyme defects along the cholesterol biosynthetic pathway result in a host of neurodevelopmental and behavioral findings along with CNS structural anomalies. In this article, we review sterol synthesis disorders in the pre- and post-squalene pathway highlighting neurodevelopmental aspects that underlie the clinical presentations and course of Smith-Lemli-Opitz Syndrome (SLOS), mevalonic aciduria (MVA) or the milder version hyper-immunoglobulinemia D and periodic fever syndrome (HIDS), Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (ABS1), congenital hemidysplasia with icthyosiform nevus and limb defects (CHILD) syndrome, CK syndrome, sterol C4 methyl oxidase (SC4MOL) deficiency, X-linked dominant chondrodysplasia punctata 2(CDPX2)/ Conradi Hunermann syndrome, lathosterolosis and desmosterolosis, We also discuss current controversies and share thoughts on future directions in the field.

Incidence of galactorrhea in young women using Depot-Medroxyprogesterone Acetate.

Galactorrhea is rarely mentioned as a possible side effect of the use of Depot-Medroxyprogesterone Acetate (DMPA). Over the last few years, we have noticed an increased number of patients complaining of galactorrhea. A review of clinical data showed that between 1999 and 2005, 360 adolescents in our clinic used DMPA for at least 6 months. After medical follow-up, 13 (3.6%) of these patients were found to have developed galactorrhea. The mean age of the patients was 19.4 years with a range from 13-24. Prolactin levels in these patients were normal, and in all subjects, the galactorrhea resolved spontaneously within the next year in both patients who continued use and those who discontinued use of DMPA. It appears that galactorrhea is a benign side effect and as previous reports have suggested, it did not seem to be related to changes in Prolactin levels in our patients. It is thought that this is a progesterone-mediated effect. We believe that reassurance and education of patients is sufficient and there is no evidence of need for further intervention. Since the sample size is small in this study, additional research is recommended as to validate the presence of progesterone-mediated effects secondary to the use of DMPA.