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Patients with galactosemia who carry the S135L (c.404C>T) variant of GALT, documented to encode low-level residual GALT activity, have been under-represented in most prior studies of outcomes in Type 1 galactosemia. What is known about the acute and long-term outcomes of these patients, therefore, is based on very limited data. Here, we present a study comparing acute and long-term outcomes of 12 patients homozygous for S135L, 25 patients compound heterozygous for S135L, and 105 patients homozygous for two GALT-null (G) alleles. This is the largest cohort of S135L patients characterized to date. Acute disease following milk exposure in the newborn period was common among patients in all 3 comparison groups in our study, as were long-term complications in the domains of speech, cognition, and motor outcomes. In contrast, while at least 80% of both GALT-null and S135L compound heterozygous girls and women showed evidence of an adverse ovarian outcome, prevalence was only 25% among S135L homozygotes. Further, all young women in this study with even one copy of S135L achieved spontaneous menarche; this is true for only about 33% of women with classic galactosemia. Overall, we observed that while most long-term outcomes trended milder among groups of patients with even one copy of S135L, many individual patients, either homozygous or compound heterozygous for S135L, nonetheless experienced long-term outcomes that were not mild. This was true despite detection by newborn screening and both early and life-long dietary restriction of galactose. This information should empower more evidence-based counseling for galactosemia patients with S135L. This article is protected by copyright. All rights reserved.

CD4 T cell-intrinsic engagement of the complement receptor CD46 controls nutrient influx and the metabolic reprogramming events that are essential for both the initiation and contraction of human Th1 responses, characterized by IFN-g and IL-10 production respectively. Here, we demonstrate that CD46 also orchestrates T cell arginine metabolism by upregulating the arginine transporter CAT-1 and, unexpectedly, Arginase 1 (Arg1). Arg1 has been well characterized in macrophages where it is associated with the IL-10 secreting M2 type, but its expression or function in T cells has not been described. Surprisingly, in CD4 T cell, Arg1 seems to restrain IL-10 production and contraction: T cells isolated from four patients with rare Arg1 deficiency mount strong Th1 responses but display significantly increased IL-10 switching and early contraction when compared to healthy control cells. Similarly, Arg1fl/fl CD4-cre+ mice infected with influenza virus are characterized by an enhanced Th1 response that contracts more rapidly, resulting in viral control and significantly reduced lung pathology. Unexpectedly, both Arg1-deficient mouse and human T cells produce normal levels of nitric oxide (NO) and polyamines. Metabolic profiling rather revealed that T cells lacking Arg1 have enhanced glycolysis, reduced TCA-cycle intermediates, and engage an “alternative” glutamine pathway often utilized by cancer cells. Normalization of these metabolic perturbations, through the targeting of specific metabolic enzymes, restored typical Th1 induction/contraction. Overall, these data unveil an unexpected intrinsic role for Arginase 1 as a pacemaker of the Th1 lifecycle, which could be harnessed for the amelioration Th1-driven pathologies.

GI symptoms such as diarrhoea, nausea and vomiting are frequent coronavirus disease (COVID-19) symptoms and affect up to 28% of patients.1–5 The pathophysiology of COVID-19-associated GI symptoms is currently unclear. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-RNA was detected in the faeces in ~50% of patients with COVID-193 5 6; SARS-CoV-2 viral particles were observed by electron microscopy in stool samples from two patients without diarrhoea2; and one study reported SARS-CoV-2 infection of the oesophagus, stomach, duodenum and rectum.5 Faecal calprotectin (FC) has evolved as a reliable faecal biomarker allowing detection of intestinal inflammation in IBD and infectious colitis.7 In this pilot study, we explored a relation between GI symptoms, intestinal inflammation (determined by FC) and faecal SARS-CoV-2-RNA in hospitalised patients with COVID-19 who did not require intensive care measures. We analysed 40 patients with COVID-19 hospitalised at the University Hospital of Innsbruck, Austria. Confirmation of SARS-CoV-2 infection was performed by nasopharyngeal swab, and faecal SARS-CoV-2-RNA detection was performed using previously described real-time PCR6 as recommended by the Centers for Disease Control and Prevention (DeKalb, Georgia). Diarrhoea was defined as loose stools >3 times/day. We excluded other causes of acute GI infection by stool analysis for common viral, …

Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP for almost all eukaryotic cells, depends on the translation of 13 mtDNA-encoded polypeptides by mitochondria-specific ribosomes in the mitochondrial matrix. These mitoribosomes are dual-origin ribonucleoprotein complexes, which contain mtDNA-encoded rRNAs and tRNAs and ∼80 nucleus-encoded proteins. An increasing number of gene mutations that impair mitoribosomal function and result in multiple OXPHOS deficiencies are being linked to human mitochondrial diseases. Using exome sequencing in two unrelated subjects presenting with sensorineural hearing impairment, mild developmental delay, hypoglycemia, and a combined OXPHOS deficiency, we identified mutations in the gene encoding the mitochondrial ribosomal protein S2, which has not previously been implicated in disease. Characterization of subjects' fibroblasts revealed a decrease in the steady-state amounts of mutant MRPS2, and this decrease was shown by complexome profiling to prevent the assembly of the small mitoribosomal subunit. In turn, mitochondrial translation was inhibited, resulting in a combined OXPHOS deficiency detectable in subjects' muscle and liver biopsies as well as in cultured skin fibroblasts. Reintroduction of wild-type MRPS2 restored mitochondrial translation and OXPHOS assembly. The combination of lactic acidemia, hypoglycemia, and sensorineural hearing loss, especially in the presence of a combined OXPHOS deficiency, should raise suspicion for a ribosomal-subunit-related mitochondrial defect, and clinical recognition could allow for a targeted diagnostic approach. The identification of MRPS2 as an additional gene related to mitochondrial disease further expands the genetic and phenotypic spectra of OXPHOS deficiencies caused by impaired mitochondrial translation.

Children diagnosed with Long-Chain-3-Hydroxy-Acyl-CoA-Dehydrogenase-Deficiency (LCHADD) or Very-Long-Chain-3-Hydroxy-Acyl-CoA-Dehydrogenase-Deficiency (VLCADD) frequently present with hypertrophic cardiomyopathy or muscle weakness which is caused by the accumulation of fatty acid metabolites due to inactivating mutations in the mitochondrial trifunctional protein. By analyzing mitochondrial morphology we uncovered that mutations within the HADHA or the ACADVL gene not only affect fatty acid oxidation, but also cause significant changes in the DNM1L/MFN2 ratio leading to the significant accumulation of truncated and punctate mitochondria in contrast to network-like mitochondrial morphology in controls. These striking morphological abnormalities correlate with changes in OXPHOS, an imbalance in ROS levels, reduced mitochondrial respiration, reduced growth rates and significantly increased glucose uptake per cell, suggesting that HADHA and ACADVL mutations shift cellular energy household into glycolysis. Experiments using the NOX2-specific inhibitor Phox-I2 suggest that NOX2 is activated by accumulating long-chain fatty acids and generates ROS, which in turn changes mitochondrial morphology and activity. We thereby provide novel insights into the cellular energy household of cells from LCHADD/VLCADD patients and demonstrate for the first time a connection between fatty acid metabolism, mitochondrial morphology and ROS in patients with these rare genetic disorders.

Background:Published data on breast milk feeding in infants suffering from inherited metabolic disorders (IMDs) other than phenylketonuria (PKU) are limited and described outcome is variable.Objective:We aimed to evaluate retrospectively whether breastfeeding and/or breast milk feeding are feasible in infants with IMDs including organic acidemias, fatty acid oxidation disorders, urea cycle disorders, aminoacidopathies or disorders of galactose metabolism.Methods:Data on breastfeeding and breast milk feeding as well as monitoring and neurological outcome were collected retrospectively from our database of patients with the mentioned IMD, who were followed in our metabolic center within the last 10 years.Results:Twenty patients were included in the study, who were either breast fed on demand or received expressed breast milk. All the infants were evaluated clinically and biochemically at 2–4-week intervals, with weight gain as the leading parameter to determine metabolic control. Good metabolic control and adequate neurological development were achieved in all patients but one, who experienced the only metabolic crisis observed within the study period.Conclusion:Breast milk feeding with close clinical and biochemical monitoring is feasible in most IMD and should be considered as it offers nutritional and immunological benefits.

Engagement of the complement receptor CD46 on T cells drives Th1 responses and upregulates nutrient and amino acid channels, such as GLUT1 and LAT1. We found that CD46 stimulation upregulates both the arginine transporter SLC7A1 (CAT-1) on human CD4 T cells and, unexpectedly, Arginase 1 expression in these cells, indicating that CD46 may regulate arginine metabolism in T cells. While Arginase 1 has been well characterized in macrophages where it is associated with the IL-10 secreting M2 type, its function in T cells has not been described. During contraction human Th1 cells switch from IFN-γ to IL-10 production and to a self-regulatory phenotype, thus we assessed the role of Arginase 1 in Th1 induction and/or contraction. Surprisingly, CD4 T cells isolated from four patients with rare Arginase 1 deficiency initially mount Th1 responses but display significantly increased IL-10 switching with earlier cellular collapse when compared to healthy control cells. Importantly, although T cells from patients with Arginase 1 deficiency have increased arginine levels, as expected, they produce normal levels of polyamines and NO. Metabolic profiling of the patients’ cells demonstrates that they shunt into a compensatory ‘glutamine usage pathway’ for their critical ornithine and polyamine generation. Analysis of changes in glutamine metabolites and their corresponding downstream pathways, along with in vivo influenza infections of Arg1fl/fl CD4-cre+ mice validate and further define the in vivo role of this novel T cell modulating pathway. Overall, these data demonstrate an unexpected intrinsic role for Arginase 1 and unveil an important compensatory mechanism used to maintain protective Th1 function in the absence of normal arginine catabolism.

Introduction: Lipin 1 gene (LPIN1) mutations lead to cellular energy deficiency and cause up to 50% of the rhabdomyolysis episodes seen in pediatric patients. These episodes are associated with poor prognosis, as treatment options have been limited. We propose a novel therapeutic strategy based on prevention and early treatment of catabolism. Methods: Five patients were diagnosed with LPIN1 mutations. They were instructed to maintain high caloric intake in situations possibly leading to catabolism such as viral infections or excessive physical activity. When an episode of rhabdomyolysis occurred, patients were treated with intravenous high-concentration glucose at first symptoms. Results: The therapeutic strategies described limited the number of rhabdomyolyis episodes, and the duration of episodes was reduced from 7–10 days, as reported in the literature, to 5 days. Conclusion: In this small series, patients with LPIN1 mutations appear to have benefited from prevention and early treatment of catabolism. Muscle Nerve 52:437–439, 2015

Levetiracetam (LEV) is approved as second line treatment for partial onset seizures in adults and children older than four years of age. Recently, an intravenous formulation was developed as an alternative to standard oral medication. We report the successful treatment of two children suffering from myoclonic status epilepticus with intravenous LEV. Intravenous application of LEV was safe and not associated with significant side effects. In conclusion, intravenous application of LEV appears to be a further option in treatment of children with myoclonic status epilepticus.

Lipin 1 gene (LPIN1) mutations lead to cellular energy deficiency and cause up to 50% of the rhabdomyolysis episodes seen in pediatric patients. These episodes are associated with poor prognosis, as treatment options have been limited. We propose a novel therapeutic strategy based on prevention and early treatment of catabolism.Five patients were diagnosed with LPIN1 mutations. They were instructed to maintain high caloric intake in situations possibly leading to catabolism such as viral infections or excessive physical activity. When an episode of rhabdomyolysis occurred, patients were treated with intravenous high-concentration glucose at first symptoms.The therapeutic strategies described limited the number of rhabdomyolyis episodes, and the duration of episodes was reduced from 7-10 days, as reported in the literature, to 5 days.In this small series, patients with LPIN1 mutations appear to have benefited from prevention and early treatment of catabolism.

This is a report on the successful treatment of a 6-year-old girl with genetically proven glucose transporter type 1 deficiency syndrome (GLUT1-DS) with modified Atkins diet (MAD). GLUT1-DS is an inborn disorder of glucose transport across the blood-brain barrier, which leads to energy deficiency of the brain with a broad spectrum of neurological symptoms including therapy-resistant epilepsy. Usually classical ketogenic diet (KD) is the standard treatment for patients with GLUT1-DS. Treatment with MAD, a variant of KD, for an observation period of 17 months resulted in improvement of seizures, alertness, cognitive abilities, and electroencephalography in this patient.

Herein, we describe a case of a now 28-month-old boy who presented at the age of 17 months with four episodes of recurrent vomiting and somnolence during a period of four months with increasing severity. A comprehensive clinical and metabolic evaluation revealed normal blood pH and blood glucose, normal cerebral computed tomography and electroencephalogram but an elevated plasma ammonia concentration, which raised the suspicion of a urea cycle disorder. The combination of elevated urinary orotic acid and plasma glutamine with normal citrulline suggested the diagnosis of ornithine transcarbamylase (OTC) deficiency, which was confirmed by molecular genetic testing revealing the novel hemizygous mutation c.535C > T (p.Leu179Phe) of the OTC gene. After restitution of anabolism by administration of parenteral glucose, substitution of citrulline and detoxification of ammonia with sodium benzoate, the patient recovered rapidly and is in a stable metabolic and neurological state since then. This case underlines that the diagnosis of a urea cycle defect should be considered in the differential diagnosis of recurrent idiopathic vomiting in combination with unexplained neurological symptoms also beyond the neonatal period due to the possibility of mild or atypical late-onset presentation (e.g. OTC deficiency in hemizygous males).

Gastric lactobezoar, a pathological conglomeration of milk and mucus in the stomach of milk-fed infants often causing gastric outlet obstruction, is a rarely reported disorder (96 cases since its first description in 1959). While most patients were described 1975-1985 only 26 children have been published since 1986. Clinically, gastric lactobezoars frequently manifest as acute abdomen with abdominal distension (61.0% of 96 patients), vomiting (54.2%), diarrhea (21.9%), and/or a palpable abdominal mass (19.8%). Respiratory (23.0%) and cardiocirculatory (16.7%) symptoms are not uncommon. The pathogenesis of lactobezoar formation is multifactorial: exogenous influences such as high casein content (54.2%), medium chain triglycerides (54.2%) or enhanced caloric density (65.6%) of infant milk as well as endogenous factors including immature gastrointestinal functions (66.0%), dehydration (27.5%) and many other mechanisms have been suggested. Diagnosis is easy if the potential presence of a gastric lactobezoar is thought of, and is based on a history of inappropriate milk feeding, signs of acute abdomen and characteristic features of diagnostic imaging. Previously, plain and/or air-, clear fluid- or opaque contrast medium radiography techniques were used to demonstrate a mass free-floating in the lumen of the stomach. This feature differentiates a gastric lactobezoar from intussusception or an abdominal neoplasm. Currently, abdominal ultrasound, showing highly echogenic intrabezoaric air trapping, is the diagnostic method of choice. However, identifying a gastric lactobezoar requires an investigator experienced in gastrointestinal problems of infancy as can be appreciated from the results of our review which show that in not even a single patient gastric lactobezoar was initially considered as a possible differential diagnosis. Furthermore, in over 30% of plain radiographs reported, diagnosis was initially missed although a lactobezoar was clearly demonstrable on repeat evaluation of the same X-ray films. Enhanced diagnostic sensitivity would be most rewarding since management consisting of cessation of oral feedings combined with administration of intravenous fluids and gastric lavage is easy and resolves over 85% of gastric lactobezoars. In conclusion, gastric lactobezoar is a disorder of unknown prevalence and is nowadays very rarely published, possibly because of inadequate diagnostic sensitivity and/or not yet identified but beneficial modifications of patient management.

Idiopathic osteolysis or disappearing bone disease is a condition characterized by the spontaneous onset of rapid destruction and resorption of a single bone or multiple bones. Disappearing bone disorder is a disease of several diagnostic types. We are presenting three patients with osteolysis who have different underlying pathological features. Detailed phenotypic assessment, radiologic and CT scanning, and histological and genetic testing were the baseline diagnostic tools utilized for diagnosis of each osteolysis syndrome. The first patient was found to have Gorham-Stout syndrome (non-heritable). The complete destruction of pelvic bones associated with aggressive upward extension to adjacent bones (vertebral column and skull base) was notable and skeletal angiomatosis was detected. The second patient showed severe and aggressive non-hereditary multicentric osteolysis with bilateral destruction of the hip bones and the tarsal bones as well as a congenital unilateral solitary kidney and nephropathy. The third patient was phenotypically and genotypically compatible with Winchester syndrome resulting in multicentric osteolysis (autosomal recessive). Proven mutation of the (MMP2-Gen) was detected in this third patient that was associated with 3MCC deficiency (3-Methylcrontonyl CoA Carboxylase deficiency). The correct diagnoses in our 3 patients required the exclusion of malignant osteoclastic tumours, inflammatory disorders of bone, vascular disease, and neurogenic arthropathies using history, physical exam, and appropriate testing and imaging. This review demonstrates how to evaluate and treat these complex and difficult patients. Lastly, we described the various management procedures and treatments utilized for these patients.