Health-related quality of life in paediatric patients with intoxication-type inborn errors of metabolism: Analysis of an international data set.

Acute intoxication-type inborn errors of metabolism (IT-IEM) such as urea cycle disorders and non-acute IT-IEM such as phenylketonuria have a major impact on paediatric patients' life. Patients have to adhere to a strict diet but may face neurocognitive impairment and - in acute diseases - metabolic decompensations nevertheless. Research on the subjective burden of IT-IEM remains sparse. Studies with appropriate sample sizes are needed to make valid statements about health-related quality of life (HrQoL) in children and adolescents with IT-IEM. Six international metabolic centres contributed self-reports and proxy reports of HrQoL (assessed with the Paediatric Quality of Life Inventory) to the final data set (n = 251 patients; age range 2.3-18.8 years). To compare HrQoL of the patient sample with norm data and between acute and non-acute IT-IEM, t tests were conducted. To examine the influence of child age, sex, diagnosis and current dietary treatment on HrQoL, multiple linear regression analyses were conducted. Self-reports and proxy reporst showed significantly lower HrQoL total scores for children with IT-IEM compared to healthy children. Current dietary treatment significantly predicted lower proxy reported total HrQoL. Children with non-acute IT-IEM reported significantly lower psychosocial health and emotional functioning than children with acute IT-IEM. The patient sample showed significantly impaired HrQoL and a diet regimen remains a risk factor for lower HrQoL. Differences in HrQoL between acute and non-acute IT-IEM subgroups indicate that factors beyond symptom severity determine the perception of disease burden. Identifying these factors is of crucial importance to develop and implement appropriate interventions for those in need.

Development and feasibility of the use of an assessment tool measuring treatment efficacy in patients with trimethylaminuria: A mixed methods study.

Trimethylaminuria (TMAU) is a rare metabolic condition characterised by an unpleasant smell resembling rotting fish. Currently, the only measure of treatment efficacy is urine trimethylamine levels which do not always reflect the patient's experience of symptoms. A literature review did not find a specific tool to assess treatment efficacy from the patient's perspective. The aim of this study was to develop an assessment tool to provide a quantitative measure of treatment efficacy in patients diagnosed with TMAU before and after treatment and assess its acceptability (feasibility of use and face and content validity) to people living with TMAU. Mixed methods; a modified, four-round Delphi by email and semi-structured interviews conducted after clinical appointments. Delphi; Eight individuals living with TMAU from the TMAU forum, six medical consultants, and four dieticians in Metabolic Medicine in four National Health Service hospitals in England. Semi-structured interviews; three patients with TMAU in two National Health Service hospitals, United Kingdom. The assessment tool contains 27 items distributed across four domains; Odour characteristics with 6 items, mental well-being with 13 items, social well-being with 5 items, and healthcare professionals support with 3 items. Semi-structured interviews; views on the content and design of the tool. The co-produced tool was successfully developed and considered acceptable to people living with TMAU. While further testing is needed to evaluate the validity and reliability of the assessment tool, the tool may serve as a prompt for questioning for clinicians diagnosing and treating TMAU.

Development of glucocorticoid resistance over one year among mothers of children newly diagnosed with cancer.

Chronic distress associates with peripheral release of cortisol and a parallel upregulation of innate inflammation. Typically, cortisol functions to down-regulate inflammatory processes. However, in the context of chronic stress, it is hypothesized that glucocorticoid receptors within immune cells become less sensitive to the anti-inflammatory effects of cortisol, resulting in increased systemic inflammation. Caring for a child newly diagnosed with cancer is a particularly provocative chronic stressor. Here, we examine evidence for the development of cellular resistance to glucocorticoids among 120 mothers (Aged 18-56 years; 86% Caucasian) across the 12 months following their child's new diagnosis with cancer. Measures of psychological distress, interleukin (IL)-6, and glucocorticoid resistance (GCR) were assessed 1, 6, and 12 months after the diagnosis. A latent factor for distress was derived from the covariation among symptoms of anxiety, depression, and post-traumatic stress. Latent change score models revealed a significant positive association between change in distress and change in GCR from 0 to 6 months, and 6 months-1 year. This finding provides initial evidence for a longitudinal association between change in maternal distress and change in GCR from the onset of a chronic stressor through one year. Although levels of IL-6 increased during the first six months after the child's diagnosis, the magnitude of this change was not related to change in distress or change in GCR. Given the possible health consequences of reduced immune sensitivity to glucocorticoids, future work should further explore this stress response and its clinical significance.

Can psychiatric childhood disorders be due to inborn errors of metabolism?

Many patients who visit a centre for hereditary metabolic diseases remarkably also suffer from a child psychiatric disorder. Those child psychiatric disorders may be the first sign or manifestation of an underlying metabolic disorder. Lack of knowledge of metabolic disorders in child psychiatry may lead to diagnoses being missed. Patients therefore are also at risk for not accessing efficacious treatment and proper counselling. To search the literature for the co-occurrence of child psychiatric disorders, such as ADHD, autism, psychosis, learning disorders and eating disorders and metabolic disorders. A search of the literature was conducted by performing a broad search on PubMed, using the terms "ADHD and metabolic disorders", "autism and metabolic disorders", "psychosis and metabolic disorders", "learning disorders and metabolic disorders", and "eating disorders and metabolic disorders". Based on inclusion criteria (concerning a clear psychiatric disorder and concerning a metabolic disorder) 4441 titles and 249 abstracts were screened and resulted in 71 relevant articles. This thorough literature search provides child and adolescent psychiatrists with an overview of metabolic disorders associated with child psychiatric symptoms, their main characteristics and recommendations for further investigations.

Child and family experiences with inborn errors of metabolism: a qualitative interview study with representatives of patient groups.

BACKGROUND: Patient-centered health care for children with inborn errors of metabolism (IEM) and their families is important and requires an understanding of patient experiences, needs, and priorities. IEM-specific patient groups have emerged as important voices within these rare disease communities and are uniquely positioned to contribute to this understanding. We conducted qualitative interviews with IEM patient group representatives to increase understanding of patient and family experiences, needs, and priorities and inform patient-centered research and care. METHODS: We developed a sampling frame of patient groups representing IEM disease communities from Canada, the United States, and United Kingdom. With consent, we interviewed participants to explore their views on experiences, needs, and outcomes that are most important to children with IEM and their families. We analyzed the data using a qualitative descriptive approach to identify key themes and sub-themes. RESULTS: We interviewed 18 organizational representatives between February 28 and September 17, 2014, representing 16 IEMs and/or disease categories. Twelve participants voluntarily self-identified as parents and/or were themselves patients. Three key themes emerged from the coded data: managing the uncertainty associated with raising and caring for a child with a rare disease; challenges associated with the affected child's life transitions, and; the collective struggle for improved outcomes and interventions that rare disease communities navigate. CONCLUSION: Health care providers can support children with IEM and their families by acknowledging and reducing uncertainty, supporting families through children's life transitions, and contributing to rare disease communities' progress toward improved interventions, experiences, and outcomes.

Neurodevelopmental Outcome after Hematopoietic Cell Transplantation in Inborn Errors of Metabolism: Current Considerations and Future Perspectives.

Inborn errors of metabolism (IEM) comprise an assorted group of inherited diseases, some of which are due to disordered lysosomal or peroxisomal function and some of which might be improved following hematopoietic cell transplantation (HCT). In these disorders the onset in infancy or early childhood is typically accompanied by rapid deterioration, resulting in early death in the more severe phenotypes. Timely diagnosis and immediate referral to an IEM specialist are essential steps in optimal management. Treatment recommendations are based on the diagnosis, its phenotype, rate of progression, prior extent of disease, family values, and expectations, and the risks and benefits associated with available therapies, including HCT. International collaborative efforts are of utmost importance in determining outcomes of therapy for these rare diseases, and have improved those outcomes significantly over the last decades. In this review, we will focus on the neurodevelopmental outcomes after HCT in IEM, providing an international perspective on progress, limitations, and future directions.

Inborn error metabolic screening in individuals with nonsyndromic autism spectrum disorders.

AIM: To perform metabolic testing on 406 patients (age range 3-22y [mean 6.71, SD 4.15], 343 males and 63 females) with nonsyndromic autism spectrum disorders (ASD) to assess the diagnostic yield. In addition, we reviewed our hospital's clinical database of 8500 patients who had undergone metabolic testing to be identified for inborn errors of metabolism (IEM), and described the characteristics of those with IEM and nonsyndromic ASD. METHOD: Neuropsychological evaluation included the Social Communication Questionnaire and Child Behavior Checklist. For metabolic testing/screening, urine samples were analyzed for the diagnosis of cerebral creatine deficiency syndromes, purine and pyrimidine disorders, amino acid metabolism defects, mucopolysaccharidoses, and organic acidurias. RESULTS: The 406 recruited participants fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) criteria of ASD. No biochemical evidence of a metabolic disorder was detected in any of the 406 patients studied. Concerning the retrospective evaluation from the 8500 who had metabolic testing, 464 individuals had a diagnosis of an IEM (394 without the diagnosis of ASD and 70 with ASD diagnosis). Only one individual with IEM had a diagnosis of nonsyndromic ASD at the time of the metabolic study; the metabolic testing had revealed diagnosis of urea-cycle disorder. INTERPRETATION: Metabolic testing should be considered in the work-up of individuals with syndromic ASD, but metabolic testing is not cost-effective for individuals with nonsyndromic ASD.

Important Considerations in the Initial Clinical Evaluation of the Dysmorphic Neonate.

BACKGROUND: The approach to clinical evaluation of the dysmorphic neonate can be challenging and multifaceted. It requires specialized knowledge of rare diagnoses and awareness of immediate versus long-term needs for the newborn and the family. PURPOSE: This review summarizes important considerations in the initial evaluation of genetic syndromes, which can present in the neonatal period with variable aspects of dysmorphism. METHODS: An overview of the literature in this area is provided. FINDINGS/RESULTS: Several overlapping areas of concern for working with this population are addressed, including communication with the family, fundamentals of the physical examination, common genetic disorders, syndromes, as well as palliative care and end of life decision making for the newborn in the context of family needs. IMPLICATIONS FOR PRACTICE: The initial approach for the neonatal practitioner needs to focus on various aspects of the newborn's care, including medical stabilization, determining whether immediate laboratory or imaging studies are needed, careful physical examination with particular attention to detail, appropriate and timely communication with the family, and knowledge of various specific aspects of rare diseases. IMPLICATIONS FOR RESEARCH: More research is needed to better understand how to best support the newborn born with dysmorphia or a rare disease. Particular attention needs to be focused on strategies to best support the family who is often in crisis during the neonatal period.

The neuropsychological profile of patients with 3-methylglutaconic aciduria type III, Costeff syndrome.

Costeff syndrome is a rare genetic neuro-ophthalmological syndrome consisting of early-onset bilateral optic atrophy along with a progressive complex motor disorder with elevated levels of urinary 3-methylglutaconic acid and 3-methylglutaric acid. While borderline to mild cognitive deficits have been considered to be common in patients with this syndrome, a comprehensive cognitive assessment has never been performed. The aim of the current study was to explore the cognitive profile associated with Costeff syndrome. Sixteen adult patients diagnosed with Costeff syndrome were administered a neuropsychological test battery that was composed of standardized verbal tests adapted for the blind. General intelligence ranged from average to borderline, with a group mean consistent with intact general cognitive functioning (VIQmean = 85, z = -1) in the low-average range of the general population. The auditory immediate and delayed memory indexes were in the average range and were significantly higher than the general cognitive functioning, whereas the working memory index was significantly lower than the general cognitive functioning. Adult patients with Costeff syndrome have intact global cognition and learning abilities and strong auditory memory performance. © 2015 Wiley Periodicals, Inc.

The neuropsychiatry of inborn errors of metabolism.

A number of metabolic disorders that affect the central nervous system can present in childhood, adolescence or adulthood as a phenocopy of a major psychiatric syndrome such as psychosis, depression, anxiety or mania. An understanding and awareness of secondary syndromes in metabolic disorders is of great importance as it can lead to the early diagnosis of such disorders. Many of these metabolic disorders are progressive and may have illness-modifying treatments available. Earlier diagnosis may prevent or delay damage to the central nervous system and allow for the institution of appropriate treatment and family and genetic counselling. Metabolic disorders appear to result in neuropsychiatric illness either through disruption of late neurodevelopmental processes (metachromatic leukodystrophy, adrenoleukodystrophy, GM2 gangliosidosis, Niemann-Pick type C, cerebrotendinous xanthomatosis, neuronal ceroid lipofuscinosis, and alpha mannosidosis) or via chronic or acute disruption of excitatory/inhibitory or monoaminergic neurotransmitter systems (acute intermittent porphyria, maple syrup urine disease, urea cycle disorders, phenylketonuria and disorders of homocysteine metabolism). In this manuscript we review the evidence for neuropsychiatric illness in major metabolic disorders and discuss the possible models for how these disorders result in psychiatric symptoms. Treatment considerations are discussed, including treatment resistance, the increased propensity for side-effects and the possibility of some treatments worsening the underlying disorder.

Assessment of quality of life of the children and parents affected by inborn errors of metabolism with restricted diet: preliminary results of a cross-sectional study.

INTRODUCTION: The development in therapeutic strategies has increased survival of children affected by inborn errors of metabolism with restricted diet (IEMRD). These diseases have mild- and long-term consequences on the health. Little is known about the impact on the quality of life (QoL) of children and their families. The aims of this study were: to compare the QoL of the children and parents affected by IEMRD with the QoL of the general population and one pathology associated with long-term consequences. PATIENTS AND METHODS: This cross-sectional study was performed at the French Reference Center for inborn metabolic disorders (Marseille, France). Inclusion criteria were: a child with a diagnosis of organic aciduria, urea cycle defect, or maple syrups urine disease (MSUD). Socio-demographics, clinical data, and QoL were recorded. RESULTS: Twenty-one of 32 eligible families were included during a planned routine visit. Ten (47%, 95% CI 27-69%) children were affected by organic aciduria, six (29%, 95% CI 10-48%) by urea cycle defects, and five (24%, 95% CI 6-42%) by MSUD. Among the younger children, the general well-being was significantly lower in the children with IEMRD than in the leukemia children (58 ± 16 versus 76 ± 15, p = 0.012), and among the older children, the leisure activities were significantly lower in the children with IEMRD than in the leukemia children (29 ± 18 versus 62 ± 22, p < 10-3), while the relationships with teachers were better (76 ± 23 versus 60 ± 23, p = 0.01). The physical QoL score was lower in the parents than in the French norms (66 ± 21 versus 75 ± 1, p = 0.05). Factors modulating QoL were: eating and neurologic disorders, enteral nutrition, and feeding modalities. CONCLUSION: The children and the parents of children affected presented altered 'physical' and 'social' QoL scores compared with the norms and patients with leukemia and their families. Future studies based on larger cohort studies should determine the different weights of potential predictive factors of QoL.

Delusional disorder, somatic type: olfactory reference syndrome in a patient with delusional trimethylaminuria.

Delusions of foul body odors (often referred to as olfactory reference syndrome [ORS]) currently fall under the category of delusional disorder, somatic type (DDST), in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). We present the case of a 51-year-old man with no previous psychiatric history who presented with perceived foul odors that he delusionally attributed to trimethylaminuria (TMAU). TMAU is a rare metabolic disorder associated with foul body odors. The patient also experienced severe concurrent mood symptoms because of social isolation resulting from his delusion about his body odors. After considerable discussion of differential diagnoses, a diagnosis of DDST was ultimately made, given the patient's unrelenting nonbizarre delusions and lack of insight pertaining to his body odors. However, this case proved to be very useful in exploring the diagnostic challenges in this type of disorder and recent discussions of ORS and its proposed inclusion in the DSM-5.

Cultural aspects in the management of inborn errors of metabolism.

European Health Care Systems have not yet accommodated both previous and current migration waves. Children from immigrant families, especially children with chronic conditions, are particularly affected from the shortcomings in medical care. One condition, phenylketonuria (PKU), is an inborn error of metabolism (IEM) which results in intellectual disability unless treated with a lifelong phenylalanine (Phe) restricted diet. In our PKU clinic, patients from families who previously had emmigrated from the geographic area of Turkey to Austria, exhibited worse blood Phe control and cognitive development than comparable patients from native Austrian families. Using structured and semi-structured interviews, questionnaires, and illness narratives, we identified language, psychosocial, economic, educational and cultural barriers as factors influencing adherence to treatment. Our findings led us to conclude that access to interpreter services, exploration of the socio-cultural background and of family ecology, as well as bi-directional communication and medical decision making according to the "best interest of the child" principle, may improve outcomes in patients requiring complex treatment and care.

Trimethylaminuria: an under-recognised and socially debilitating metabolic disorder.

Primary flavin mono-oxygenase 3 deficiency, an inborn error of choline metabolism, leads to an accumulation of trimethylamine, which because of its associated pungent odour of rotting fish, is a socially crippling disorder. Although it often has its onset in early childhood, it may take years or even decades before the diagnosis is established. In this review the clinical biochemical and genetic features of the disorder are reported. The principles of therapy will also be covered, including dietary, pharmacological approaches, as well as techniques used to manipulate the gastrointestinal environment as a strategy to reduce the gastrointestinal load of trimethylamine.

Three cases of a rare disease, congenital chloride diarrhea, summons up the variation in the clinical course and significance of early diagnosis and adequate treatment in the prevention of intellectual disability.

Congenital chloride diarrhea (CLD) (OMIM #214700) is a rare, autosomal recessive disease that is characterized by increased chloride loss in stool. As a result of electrolyte loss, surviving patients might have some complications, one of them being mental retardation. Here, we present three new Turkish patients with new mutations in the SLC26A3 gene. Although the clinical picture of the patients might be similar, consequences of the disease and complications might differ greatly among patients. Pediatricians should be aware of CLD as a potentially fatal or disabling disease if untreated. History of polyhydramnios, watery diarrhea, failure to thrive, poor growth, soiling, metabolic alkalosis and hypokalemia/hypochloremia should be an alarming set of findings for the diagnosis. Salt substitution therapy started early in life prevents early complications, allows normal growth and development, and favors good long-term prognosis.

[Psychiatric and cognitive signs associated with inborn errors of metabolism]. / Troubles psychiatriques et cognitifs associées aux maladies neurométaboliques.

BACKGROUND: Inborn errors of metabolism are rare disease and forms with presenting psychiatric signs are even rarer. However, some of them are treatable and early treatment (which may start when psychiatric signs are the only manifestation) may lead to more efficacy and better improvement for either psychiatric and organic signs. Recognition by psychiatrist, and non-specialized practionners, is therefore a major issue for patients and health care. OBSERVATION: After an illustrating case report, we propose a short description of psychiatric signs, focusing on presenting signs, associated with neurometabolic disease. We also propose a pragmatic and simple clinical diagnostic strategy for practionners when facing to atypical psychiatric signs leading to a minimum reasonable exploratory assessment. CONCLUSION: Atypical psychiatric signs must be known by psychiatrists in order to seek neurometabolic disease. Multidisciplinary approach, especially between psychiatrists and neurologists, is crucial in this topic.

Brief Report: Delayed Diagnosis of Treatable Inborn Errors of Metabolism in Children with Autism and Other Neurodevelopmental Disorders.

The objective of our study was to evaluate the frequency of treatable inborn errors of metabolism (IEM) in a clinical sample of Mexican children and adolescents with neurodevelopmental disorders (NDD). Amino acids and acylcarnitines in blood samples of 51 unrelated children and adolescents were analyzed by tandem mass spectrometry to detect treatable IEM of small molecules. One patient with isovaleric acidemia and autism spectrum disorder (ASD) and another with beta-ketothiolase deficiency and ASD/intellectual disability/attention-deficit/hyperactivity disorder (ADHD) were diagnosed, indicating an IEM frequency of 3.9% (1:26 subjects). The high frequency of treatable IEM indicates the need to perform a minimum metabolic screening as part of the diagnostic approach for patient with NDD, particularly when newborn screening programs are limited to a few disorders.

Frequency and status of depression and anxiety in mothers of children with inborn errors of metabolism with restricted diet, with and without risk of metabolic crises.

OBJECTIVES: This study aimed to investigate the frequency and status of depression and anxiety among mothers of children with inborn errors of metabolism (IEM) who were on a restricted diet and previously experienced metabolic crises. METHODS: This cross-sectional multicenter descriptive study included 93 children with IEM who were on restricted diet. The patients were divided into two groups: those who had experienced metabolic crises (n=44, urea cycle defect, organic acidemia, maple syrup urine disease, hereditary fructose intolerance) and those who had not experienced previous metabolic crises (n=49; phenylketonuria, galactosemia, and non-ketotic hyperglycinemia). The control group comprised 37 healthy children. The mothers of the patients and control participants answered a questionnaire about their and their children's demographic and clinical characteristics and completed the Beck Depression Inventory (BDI) and the State-Trait Anxiety Inventory (STAI-S and STAI-T). RESULTS: The maternal BDI, STAI-S, and STAI-T scores were 6.3±5.2, 36.1±11.2, and 39.9±8.8, respectively, in the control group. The maternal BDI, STAI-S, and STAI-T scores of the children who had experienced (19.2±9.7; 44.0±12.4; 47.9±10.6) and those who had not experienced (13.9±9.1; 40.7 ±8.6; 45.3±8.3) a crisis were significantly higher than for the controls. The BDI score was significantly higher for the mothers of children who had experienced a crisis (p=0.011), whereas no significant difference was determined between the two patient groups regarding STAI-S and STAI-T scores. The mothers of four children who had experienced metabolic crises were on antidepressant therapy. CONCLUSION: Although their children were on a similar restricted diet, the mothers of children who previously experienced or who had the risk of experiencing metabolic crises had higher depression scores as compared with the mothers of children who did not experience a previous crisis. Early supportive therapy may be required for the families of these patients to lower the burden of stress.

Considerations of expanded carrier screening: Lessons learned from combined malonic and methylmalonic aciduria.

BACKGROUND: Expanded carrier screening (ECS) utilizes high-throughput next-generation sequencing to evaluate an individual's carrier status for multiple conditions. Combined malonic and methylmalonic aciduria (CMAMMA) due to ACSF3 deficiency is a rare inherited disease included in such screening panels. Some cases have been reported with metabolic symptoms in childhood yet other cases describe a benign clinical course, suggesting the clinical phenotype is not well defined. METHODS/CASE REPORT: Clinical and laboratory findings during the prenatal period were obtained retrospectively from medical records. RESULTS: A 37-year-old nulliparous woman and her partner were each identified as carriers of ACSF3 variants and presented at 9 weeks gestation for prenatal genetic consultation. The couple received extensive genetic counseling and proceeded with chorionic villus sampling at 11 weeks gestation. Subsequent analysis confirmed that the fetus inherited both parental ACSF variants. The couple was devastated by the results and after reviewing options of pregnancy continuation and termination, they decided to terminate the pregnancy. Following this decision, the patient was diagnosed with acute stress disorder. CONCLUSION: This case highlights how expanded carrier screening adds complexity to reproductive decision-making. Stronger guidelines and additional research are needed to direct and evaluate the timing, composition, and implementation of ECS panels.

[Genetics of mental retardation]. / Retards mentaux d'origine génétique.

Mental retardation affects nearly 3 % of the population. The causes of these disorders are various and are often not identified. Recent advances focused on the molecular basis of mental retardation. Nearly half of mental retardation syndromes have a genetic origin and the description of molecular, cytogenetic and metabolic alterations in these disorders led to the development of diagnostic tools. Indeed, identifying the precise origin of the mental retardation allows to improve patient care and to refine the prognosis. Moreover, these molecular tools will help the geneticist to evaluate the recurrence risk in the family in the genetic counseling step. On a fundamental point of view, the knowledge of molecular basis of mental retardation will help to understand the biological pathway which constitutes the first step before therapeutic strategies. Every patient with mental retardation should be investigated for causal origin of the disease. We will detail the diagnostic methods necessary to investigate a patient presenting with mental retardation. Then different examples of syndromes including a mental retardation will be chosen to illustrate different clinical situations.