Maria Cotrina-Vidal

Children with familial dysautonomia (FD) are smaller and grow more slowly than the general population. It is unknown whether this abnormal growth is due to comorbidities that patients with FD live with, or if it is a direct effect of the disease-causing homozygous ELP-1 mutations. Here, we created growth curves for weight, height, and body mass index (BMI) in male and female children with FD to monitor the nutritional status of patients with FD. We used the New York University (NYU) FD Registry which includes data from 680 individuals with FD who were followed longitudinally since birth. We generated sex-specific FD growth charts for three age ranges (birth to 36 months, 2 to 20 years, and 2 to 40 years) and compared them to the general population. We generated Kaplan-Meier curves to test the hypothesis that FD patients with low BMI had shorter survival than the rest of the cohort. Growth charts generated from 591 individuals with FD show that these patients grow more slowly, reach less height, and gain less weight than the general population. The impact of FD on height was more pronounced in girls than in boys. However, both groups showed markedly low weights, which resulted in low BMI. Low weight, but not height, is already evident at birth. In a subpopulation of FD patients, we found that treatment with growth hormone or spinal fusion surgery helped patients achieve the expected growth characteristic of FD patients, but these treatments did not lead FD patients to achieve the growth pattern of the general population. Contrary to our hypothesis, low BMI had no impact on patient survival. Pediatric patients with FD have lower height, weight, and BMI compared to the general pediatric population, but this does not appear to affect survival. Growth curves specific to the FD population are an important tool to monitor growth and nutritional status in pediatric patients with FD when the general population growth curves are of limited use.

Central metabolism has a profound impact on the clinical phenotypes and penetrance of neurological diseases such as Alzheimer’s (AD) and Parkinson’s (PD) diseases, Amyotrophic Lateral Sclerosis (ALS) and Autism Spectrum Disorder (ASD). In contrast to the multifactorial origin of these neurological diseases, neurodevelopmental impairment and neurodegeneration in Familial Dysautonomia (FD) results from a single point mutation in the ELP1 gene. FD patients represent a well-defined population who can help us better understand the cellular networks underlying neurodegeneration, and how disease traits are affected by metabolic dysfunction, which in turn may contribute to dysregulation of the gut–brain axis of FD. Here, ¹H NMR spectroscopy was employed to characterize the serum and fecal metabolomes of FD patients, and to assess similarities and differences in the polar metabolite profiles between FD patients and healthy relative controls. Findings from this work revealed noteworthy metabolic alterations reflected in energy (ATP) production, mitochondrial function, amino acid and nucleotide catabolism, neurosignaling molecules, and gut-microbial metabolism. These results provide further evidence for a close interconnection between metabolism, neurodegeneration, and gut microbiome dysbiosis in FD, and create an opportunity to explore whether metabolic interventions targeting the gut–brain–metabolism axis of FD could be used to redress or slow down the progressive neurodegeneration observed in FD patients.

The destruction of the World Trade Center (WTC) on September 11, 2001 (9/11) released large amounts of toxic dusts and fumes into the air that exposed many community members who lived and/or worked in the local area. Many community members, defined as WTC survivors by the federal government, developed lower respiratory symptoms (LRS). We previously reported the persistence of these symptoms in patients with normal spirometry despite treatment with inhaled corticosteroids and/or long-acting bronchodilators. This report expands upon our study of this group with the goal to identify molecular markers associated with exposure and heterogeneity in WTC survivors with LRS using a selected plasma biomarker approach. Samples from WTC survivors with LRS (n = 73, WTCS) and samples from healthy control participants of the NYU Bellevue Asthma Registry (NYUBAR, n = 55) were compared. WTCS provided information regarding WTC dust exposure intensity. Hierarchical clustering of the linear biomarker data identified two clusters within WTCS and two clusters within NYUBAR controls. Comparison of the WTCS clusters showed that one cluster had significantly increased levels of circulating matrix metalloproteinases (MMP1, 2, 3, 8, 12, 13), soluble inflammatory receptors (receptor for advanced glycation end-products-RAGE, Interleukin-1 receptor antagonist (IL-1RA), suppression of tumorigenicity (ST)2, triggering receptor expressed on myeloid cells (TREM)1, IL-6Ra, tumor necrosis factor (TNF)RI, TNFRII), and chemokines (IL-8, CC chemokine ligand- CCL17). Furthermore, this WTCS cluster was associated with WTC exposure variables, ash at work, and the participant category workers; but not with the exposure variable WTC dust cloud at 9/11. A comparison of WTC exposure categorial variables identified that chemokines (CCL17, CCL11), circulating receptors (RAGE, TREM1), MMPs (MMP3, MMP12), and vascular markers (Angiogenin, vascular cell adhesion molecule-VCAM1) significantly increased in the more exposed groups. Circulating biomarkers of remodeling and inflammation identified clusters within WTCS and were associated with WTC exposure.

Propionic acidemia (PA) is an inborn error of metabolism (IEM) caused by mutations in the enzyme propionyl CoA carboxylase (PCC). It is characterized by the inability to break down branched chain amino acids and odd chain fatty acids, causing a buildup of toxic organic acids in blood. PA affects every organ in the body with particularly severe manifestations in the brain, like hyperammonemia, hypomyelination, seizures, cognitive impairments, optic nerve atrophy and autism spectrum disorders. Dietary management and liver transplantation have helped to ameliorate the acute expression of the disorder, but do not prevent the chronic toxicity that builds up in brain. Despite the severe brain manifestation of the disease, little is known about the mechanisms by which PA affects the nervous system. PCCA and PCCB, the two subunits required for a functional PCC enzyme, are both expressed not only in neurons but also in astrocytes. Using the two rodent genetic models of PA currently available, with mutations in PCCA, we have evaluated the involvement of astrocytes in the neuropathology of propionic acidemia. These mice exhibit cardiac pathology and hyperammonemia, similar to what is observed in patients with PA. We found that wild type (wt) astrocytes positively respond to treatment with L-Carnitine, a therapeutic approach commonly used in patients with PA, by improved survival and more efficient mitochondrial morphology. Transcriptome analysis from astrocytes derived from the wt or the mutant mice confirm that these astrocytes lack exons 3 and 4 like in the human mutations of PA. However, no other genes/exons were statistically significant with regards to differential expression between astrocytes derived from KO or from WT animals, suggesting that astrocytes in culture may be able to compensate the PCC deficiency. Histological analysis of neuronal and glial markers during brain development (TUJ1, MAP2 for neurons; nestin and Iba1 for glia) do not show significant alterations neither in distribution nor numbers of cells in the developing brain of the PCCA-/- mice. Analysis in the adult brain of mutant mice shows some variable degree of microgliosis but no indication of reactive astrocytes. No gross abnormalities were observed in cortex, hippocampus, striatum or cerebellum of adult brains of PCCA-/- mice, either. In summary, astrocytes from PCCA deficient mice show surprisingly little alterations both in vitro and in vivo . Our results evidence the need to further understand the effects of PA in brain cells to help develop potential new therapies that can preserve brain function in children affected by this devastating disease. HIGHLIGHTS: Astrocytes detoxify ammonia in brain and may be affected by propionic acidemia, a disorder that causes hyperammonemia in brain. RNA seq of astrocytes in culture derived from PCCA mutant mice does not show effect in these cells. In vivo analysis of glial and neuronal cells also shows no difference in development or adult mutant mice Astrocytes may not be an adequate target of clinical therapies in this disorder

The destruction of the World Trade Center (WTC) towers on the 11th of September, 2001 released a vast amount of aerosolized dust and smoke resulting in acute and chronic exposures to community members as well as responders. The WTC Environmental Health Center (WTC EHC) is a surveillance and treatment program for a diverse population of community members, including local residents and local workers with WTC dust exposure. Many of these patients have reported persistent lower respiratory symptoms (LRS) despite treatment for presumed asthma. Our goal was to identify conditions associated with persistent uncontrolled LRS despite standard asthma management. We recruited 60 patients who were uncontrolled at enrollment and, after a three-month run-in period on high-dose inhaled corticosteroid and long acting bronchodilator, reassessed their status as Uncontrolled or Controlled based on a score from the Asthma Control Test (ACT). Despite this treatment, only 11 participants (18%) gained Controlled status as defined by the ACT. We compared conditions associated with Uncontrolled and Controlled status. Those with Uncontrolled symptoms had higher rates of upper airway symptoms. Many patients had persistent bronchial hyper-reactivity (BHR) and upper airway hyper-reactivity as measured by paradoxical vocal fold movement (PVFM). We found a significant increasing trend in the percentage of Controlled with respect to the presence of BHR and PVFM. We were unable to identify significant differences in lung function or inflammatory markers in this small group. Our findings suggest persistent upper and lower airway hyper-reactivity that may respond to standard asthma treatment, whereas others with persistent LRS necessitate additional diagnostic evaluation, including a focus on the upper airway.

Propionic Acidemia (PA) is characterized by the accumulation of propionic acid (PPA), its toxic derivatives, and ammonia. The disease causes multiorgan damage, especially in heart, pancreas, and brain; seizures and intellectual disability are often described. Some PA children also show autism spectrum disorders (ASD). In this study, we have compiled data from 62 individuals from the Propionic Acidemia International Patient Registry and compared it to the published literature on the prevalence of autism in PA. The PA registry shows a significant proportion of ASD diagnoses that is consistent with the combined prevalence reported in the literature. It also shows that ASD in PA is gender balanced and it is diagnosed at older ages (median age 8 years) than in the national registry for autism (median age 4.3 years), which raises the possibility, among others, of PA specific risk factors affecting the natural history of ASD. Data from patient registries provide valuable information on studying the mechanisms involved in a rare disease, although more outreach effort must be done to increase participation and consistency in data entry.