Glutaric Acidemia, Pathogenesis and Nutritional Therapy

Glutaric acidemia (GA) are heterogeneous, genetic diseases that present with specific catabolic deficiencies of amino acid or fatty acid metabolism. The disorders can be divided into type I and type II by the occurrence of different types of recessive mutations of autosomal, metabolically important genes. Patients of glutaric acidemia type I (GA-I) if not diagnosed very early in infanthood, experience irreversible neurological injury during an encephalopathic crisis in childhood. If diagnosed early the disorder can be treated successfully with a combined metabolic treatment course that includes early catabolic emergency treatment and long-term maintenance nutrition therapy. Glutaric acidemia type II (GA- II) patients can present clinically with hepatomegaly, non-ketotic hypoglycemia, metabolic acidosis, hypotonia, and in neonatal onset cardiomyopathy. Furthermore, it features adult-onset muscle-related symptoms, including weakness, fatigue, and myalgia. An early diagnosis is crucial, as both types can be managed by simple nutraceutical supplementation. This review discusses the pathogenesis of GA and its nutritional management practices, and aims to promote understanding and management of GA. We will provide a detailed summary of current clinical management strategies of the glutaric academia disorders and highlight issues of nutrition therapy principles in emergency settings and outline some specific cases.

A Case of Combined Oxidative Phosphorylation Deficiency 35 Associated with a Novel Missense Variant of the TRIT1 Gene

Combined oxidative phosphorylation deficiency 35 (COXPD35) is a rare autosomal recessive disorder associated with homozygous or compound heterozygous mutations in the tRNA isopentenyltransferase (<i>TRIT1</i>) gene in chromosome 1p34.2. To date, only 10 types of allelic variants in the <i>TRIT1</i> gene have been previously reported in 9 patients with COXPD35. Herein, we describe a case with a novel homozygous missense variant in <i>TRIT1</i>. A 6-year, 6-month-old boy presented with global developmental delay, microcephaly, intractable seizures, and failure to thrive. The other main clinical manifestations were intellectual disability, spastic tetraparesis, truncal hypotonia, malnutrition, polyuria and polydipsia, ketotic hypoglycemia, dysmorphic facial features, strabismus, bicuspid aortic valve, and nephrolithiasis. The detailed biochemical, radiological, and metabolic evaluations were unremarkable. Chromosomal analysis confirmed a normal male 46,XY karyotype and the array comparative genomic hybridization analysis revealed no abnormalities. We identified a novel homozygous missense variant of c.246G&#x3e;C (p.Met82Ile) in the <i>TRIT1</i> gene, and the variant was confirmed by Sanger sequencing. The present case is the first report describing strabismus, ketotic hypoglycemia, nephrolithiasis, and bicuspid aortic valve in <i>TRIT1</i>-related COXPD35. This study expands the genotype-phenotype spectrum of <i>TRIT1</i>-related COXPD35.

Neonatal Hypo-Ketotic Hypoglycemia Secondary to Transient Hyperinsulinism: Diazoxide Responsiveness and Experience With Fasting Test After Treatment Withdrawal

Introduction:: Transient neonatal hyperinsulinism (TNH) is frequently reported in neonates with stress factors (intrauterine growth restriction (IUGR), large for gestational age (LGA), perinatal asphyxia, infants of diabetic mother, etc.). Early recognition and treatment are prioritary to avoid neurological morbidity. Objective: Clinical, molecular characterization and treatment response in neonates with hypoglycemia due to transient hyperinsulinism admitted to a tertiary hospital Neonatal Unit from January 2015 to August 2020. Materials and Methods: Prospective cohort study. Newborns older than 7 days of age, with diagnostic criteria of hyperinsulinism: non ketotic hypoglycemia with detectable insulin, low free fatty acids, glucose infusion rate &gt; 10mg/kg/min, and positive response to glucagon test, were recruited. Results: Out of 5374 patients admitted, 46 (0.85%) presented hypoglycemia secondary to TNH (57% males and 43% females). 78% were delivered by Cesarean section, 59% were European, 17% Latino-Americans, 11% Asians, 9% Africans, and 4% Arabs. 78% were preterm newborns (median 33 weeks gestational age), 70% had birth weights or heights &lt;-1.6 SDS (medians: -1.8 SDS and -2 SDS, respectively). Median age at diagnosis was 22 days (IQE 10–29 days), and feeding was exclusively enteral. Median blood glucose at diagnosis was 37mg/dl (IQE 31-44mg/dl), median insulin: 3mu/ml, median ketonemia: 0.2mmol/L, GH: 15 ng/ml, Cortisol: 16 ug/dl and AAL: 75mg/dl. 90% received diazoxide (dose ranged between 5-10mg/kg/day), presenting as most prevalent side effects hypertrichosis (80%) and edema (13%). Diazoxide median treatment duration was 83 days (IQE 41–110). Response was positive in 100%, with fasting tests response yielding a glycemia &gt; 60mg / dl after 10 hours of fasting post treatment withdrawal. Molecular analysis was carried out with help of a custom NGS panel (MonDIAB.V3; 385 genes) in 80% of the patients. No mutations were identified in known genes implicated in the etiology of congenital hyperinsulinism (ABCC8, KCNJ11, HNF4A, GLUD1, HADH, SLC16A1, GCK, UCP2, HNF1A, AKT2, INSR, CACNA1D), however, predicted deleterious variants were found in other candidate genes such as G6PC2, TH, PMM2, and APPL1, implicated in insulin secretion or glycemic homeostasis. Conclusions: TNH is a prevalent entity to be considered in neonates with risk factors. In our series, TNH is also present in term newborns (22% of patients) and in newborns with weight and/or height appropriate for gestational age (30%). Treatment with diazoxide at low doses is effective in the resolution of these hypoglycemias. The fasting test could be useful for a safe treatment withdrawal when resolution is suspected. No monogenic cause explaining the TNH was identified. Most of the cases molecularly examined presented with 2 or more predicted deleterious variants, suggesting a multifactorial genetic component.

Towards enhanced understanding of idiopathic ketotic hypoglycemia: a literature review and introduction of the patient organization, Ketotic Hypoglycemia International

Background Idiopathic Ketotic hypoglycemia (IKH) is a diagnosis of exclusion. Although considered as the most frequent cause of hypoglycemia in childhood, little progress has been made to advance the understanding of IKH since the medical term was coined in 1964. We aimed to review the literature on ketotic hypoglycemia (KH) and introduce a novel patient organization, Ketotic Hypoglycemia International (KHI). Results IKH may be diagnosed after the exclusion of various metabolic and hormonal diseases with KH. Although often mild and self-limiting, more severe and long-lasting IKH occurs. We therefore divide IKH in physiological KH and pathological KH, the latter defined as recurrent symptomatic, or occasionally symptomatic, episodes with beta-hydroxybutyrate ≥ 1.0 mmol/L and blood glucose < 70 mg/dL (3.9 mol/L), in the absence of prolonged fasting, acute infections and chronic diseases known to cause KH. Pathological KH may represent undiscovered diseases, e.g. glycogen storage disease IXa, Silver–Russel syndrome, and ketone transporter defects, or suggested novel disease entities identified by exome sequencing. The management of KH aims to prevent hypoglycemia, fatty acid oxidation and protein deficiency by supplying adequate amounts of carbohydrates and protein, including nutritional therapy, uncooked cornstarch, and sometimes continuous tube feeding by night. Still, intravenous dextrose may be needed in acute KH episodes. Failure to acknowledge that IKH can be more than normal variation may lead to under-treatment. KHI is a non-profit, patient-centric, global organization established in 2020. The organization was created by adult IKH patients, patient family members, and volunteers. The mission of KHI is to enhance the understanding of IKH while advocating for patients, their families and the continued research into KH. Conclusion IKH is a heterogeneous disorder including physiological KH and pathological KH. IKH may represent missed diagnoses or novel disease entities, but shares common management principles to prevent fatty acid oxygenation. KHI, a novel patient organization, aims to enhance the understanding of IKH by supporting IKH families and research into IKH.

A Sensitive Plasma Insulin Immunoassay to Establish the Diagnosis of Congenital Hyperinsulinism

BackgroundThe diagnosis of congenital hyperinsulinism (CHI) may be hampered by a plasma (p-) insulin detection limit of 12–18 pmol/L (2–3 mU/L).ObjectiveTo evaluate the diagnostic performance of a sensitive insulin immunoassay and to find the optimal p-insulin cut-off for the diagnosis of CHI.MethodsDiagnostic fasting tests, performed without medication or i.v.-glucose, were investigated in children with a clinical diagnosis of CHI, or idiopathic ketotic hypoglycemia (IKH). The CHI diagnosis was either clinical or by the alternative, p-insulin-free criteria; hypoglycemia plus disease-causing genetic mutations and/or CHI-compatible pancreatic histopathology. We included diagnostic p-insulin samples with simultaneous p-glucose &lt;3.2 mmol/L and used a sensitive insulin assay (Cobas e411 immunoassay analyzer; lower detection limit 1.2 pmol/L; normal range 15.1–147.1 pmol/L). Receiver operating characteristics area under the curve (ROC AUC) values and optimal cut-offs were analyzed for the performance of p-insulin to diagnose CHI.ResultsIn 61 CHI patients, the median (range) p-insulin was 76.5 (17–644) pmol/L compared to 1.5 (1.5–7.7) pmol/L in IKH patients (n=15). The ROC AUC was 1.0 for the diagnosis of CHI defined both by the clinical diagnosis (n=61) and by alternative criteria (n=57). The optimal p-insulin cut-offs were 12.3 pmol/L, and 10.6 pmol/L, at p-glucose &lt;3.2 mmol/L (n=61), and &lt;3.0 mmol/L (n=49), respectively.ConclusionsThe sensitive insulin assay performed excellent in diagnosing CHI with optimal p-insulin cut-offs at 12.3 pmol/L (2.0 mU/L), and 10.6 pmol/L (1.8 mU/L), at p-glucose &lt;3.2 mmol/L, and &lt;3.0 mmol/L, respectively. A sensitive insulin assay may serve to simplify the diagnosis of CHI.

Carnitine Palmitoyltranferase Type 1 Deficiency: A Case Report of Fatty Acid Oxidation Disorder Encephalopathy

Background: Carnitine palmitoyltransferase-1 (CPT-1) deficiency is a rare autosomal recessive disorder of mitochondrial long-chain fatty acid oxidation with fewer than 30 case reports. Case report: A 30-month-old child with fever and loss of consciousness was referred to our hospital. She had symptoms of colds for three days that were treated, but she had anorexia.Her abdomen was soft and hepatomegaly 5 cm below the edge of the rib was detected. According to a neurological consultation, with the probability of a seizure, the patient beganto receive levetiracetam. The patient was treated with sodium benzoate due to her decreased level of consciousness and increased blood ammonia (300). In the acylcarnitine profile, mildlyelevated levels of single acylcarnitine were seen to confirm the diagnosis of CPT-1 deficiency. Conclusions: CPT-1 deficiency is a rare autosomal recessive defect of mitochondrial longchain fatty acid oxidation that presents as an acute “Reye-like” hepatic encephalopathy andnon-ketotic hypoglycemia, developmental delay, and hepatomegaly.