Computer-aided diagnostic screen for Congenital Central Hypoventilation Syndrome with facial phenotype.

BACKGROUND: Congenital Central Hypoventilation Syndrome (CCHS) has devastating consequences if not diagnosed promptly. Despite identification of the disease-defining gene PHOX2B and a facial phenotype, CCHS remains underdiagnosed. This study aimed to incorporate automated techniques on facial photos to screen for CCHS in a diverse pediatric cohort to improve early case identification and assess a facial phenotype-PHOX2B genotype relationship. METHODS: Facial photos of children and young adults with CCHS were control-matched by age, sex, race/ethnicity. After validating landmarks, principal component analysis (PCA) was applied with logistic regression (LR) for feature attribution and machine learning models for subject classification and assessment by PHOX2B pathovariant. RESULTS: Gradient-based feature attribution confirmed a subtle facial phenotype and models were successful in classifying CCHS: neural network performed best (median sensitivity 90% (IQR 84%, 95%)) on 179 clinical photos (versus LR and XGBoost, both 85% (IQR 75-76%, 90%)). Outcomes were comparable stratified by PHOX2B genotype and with the addition of publicly available CCHS photos (n = 104) using PCA and LR (sensitivity 83-89% (IQR 67-76%, 92-100%). CONCLUSIONS: Utilizing facial features, findings suggest an automated, accessible classifier may be used to screen for CCHS in children with the phenotype and support providers to seek PHOX2B testing to improve the diagnostics. IMPACT: Facial landmarking and principal component analysis on a diverse pediatric and young adult cohort with PHOX2B pathovariants delineated a distinct, subtle CCHS facial phenotype. Automated, low-cost machine learning models can detect a CCHS facial phenotype with a high sensitivity in screening to ultimately refer for disease-defining PHOX2B testing, potentially addressing gaps in disease underdiagnosis and allow for critical, timely intervention.

Treatment-naive and post-treatment glucosylsphingosine (lyso-GL1) levels in a cohort of pediatric patients with Gaucher disease.

Glucosylsphingosine (lyso-GL1) is a biomarker used to monitor disease and treatment response in Gaucher disease. Data from adults show that higher values of lyso-GL1 are associated with increased disease progression, however similar data in the pediatric population is lacking. In a cohort of pediatric patients, we present a relationship between lyso-GL1 value and Gaucher type, age, and treatment response. Data from this study may serve as a reference for providers monitoring children with Gaucher disease.

Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants.

PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.

Pegvaliase dose escalation to 80 mg daily may lead to efficacy in patients who do not exhibit an optimal response at lower doses.

In 2018, pegvaliase was approved as the first enzyme substitution treatment for phenylketonuria (PKU) and is now the second medication available for PKU patients since the approval of sapropterin dihydrochloride in 2007. Historically, dietary management has been the mainstay of treatment for PKU. While sapropterin response rate is limited to approximately 50% of PKU patients, pegvaliase has the potential to reduce phenylalanine levels in all PKU patients (Vockley et al., 2014; Longo et al., 2019 [1,3]). Current FDA labeling for pegvaliase includes a dose maximum of 60 mg daily (Longo et al., 2019; BioMarin Pharmaceutical Inc., 2020 [3,4]). We report a case series of four phenylalanine hydroxylase (PAH) deficient patients, previously treated with dietary management only, who initiated treatment with pegvaliase and were titrated to 80 mg daily dosing. The safety profile in these four cases did not differ from lower maintenance dosing (Longo et al., 2019 [3]). Subsequent decreases in Phe levels were observed on 80 mg maintenance dosing, allowing for individualized dietary liberalization in three out of four patients. We conclude that pegvaliase dosing must be personalized to achieve therapeutic goals and that some patients may require higher doses than those included on the product label.

Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome.

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.

Diagnosis and Clinical Management of Long-chain Fatty-acid Oxidation Disorders: A Review.

Long-chain fatty-acid oxidation disorders (LC-FAODs) are autosomal recessive inherited metabolic conditions that occur due to a disruption in the body's ability to perform mitochondrial beta oxidation. Expanded newborn screening is widening phenotypic understanding of these disorders, as well improving our knowledge of disease incidence. Management of these disorders is focused on avoidance of fasting, dietary changes and supplementation with energy sources that bypass the metabolic block. Recent US Food and Drug Administration approval of triheptanoin has improved the outcome for affected individuals. New research into dietary modifications and novel pharmacologic therapies continues for these disorders. In this article, we review the major LC-FAODs and their clinical presentation.

A retrospective study of adult patients with noncirrhotic hyperammonemia.

Adult-onset noncirrhotic hyperammonemia (NCH) is poorly understood and has a high morbidity and mortality. To elucidate the etiology and management of NCH, we performed a retrospective analysis of 23 adults (median age 51) with NCH treated between 2014 and 2020 at two academic medical centers. Hyperammonemia was diagnosed in all cases during the evaluation of altered mental status, with 22% presenting with seizures. Peak ammonia levels were >200 µmol/L in 70% of cases. Defects in ammonia metabolism were assessed using urea cycle biochemical testing, germline genetic testing, and testing for urease-producing infectious agents. Ammonia metabolism defects in these cases appear attributable to four major sources: (a) infection with urease-producing organism (n = 5); (b) previously undiagnosed inborn errors of metabolism (IEMs) (n = 4); (c) clinical exposures causing acquired urea cycle dysfunction (n = 6); and (d) unexplained acquired urea cycle dysfunction (uaUCD) (n = 8), as evidenced by biochemical signatures of urea cycle dysfunction without a genetic or clinical exposure. Severe protein malnutrition appeared to be a reversible risk factor for uaUCD. Overall, 13% of our cohort died prior to resolution of hyperammonemia, 26% died after hyperammonemia resolution, 57% survived after having reversible neurological changes, and 4% survived with irreversible neurological changes. Renal replacement therapy for ammonia clearance was often utilized for patients with an ammonia level above 250 µmol/L and patients were frequently empirically treated with antibiotics targeting urea-splitting organisms. Our study demonstrates that acquired urea cycle dysfunction, IEMs and urease-producing infections are major sources of adult-onset NCH and highlights successful management strategies for adult-onset NCH.

Recent developments in fetal alcohol spectrum disorder.

PURPOSE OF REVIEW: To highlight research, publications, and medical advancements in fetal alcohol spectrum disorder (FASD) over the past 18 months. RECENT FINDINGS: Prevalence numbers have been updated, allowing for a more accurate account of the societal impact. Further work on diagnostic techniques and the underlying mechanisms will allow us to better understand the pathophysiology of FASD and could translate into treatments for the condition. Continued research on new treatments and interventions is needed to improve the affected individual's health care and quality of life. Measurable outcomes allow us to tangibly measure improvements for individuals and families affected by FASD. SUMMARY: The current review highlights recent publications from January 2018 to August 2019 showing continued medical advancement in improving the care for children and families affected by FASD.