Mitochondrial ETF insufficiency drives neoplastic growth by selectively optimizing cancer bioenergetics

Mitochondrial electron transport flavoprotein (ETF) insufficiency causes metabolic diseases known as a multiple acyl-CoA dehydrogenase deficiency (MADD). In contrast to muscle, ETFDH is a non-essential gene in acute lymphoblastic leukemia NALM6 cells, and its expression is reduced across human cancers. In various human cancer cell lines and mouse models, ETF insufficiency caused by decreased ETFDH expression limits flexibility of OXPHOS fuel utilisation but paradoxically increases bioenergetics and accelerates neoplastic growth via activation of the mTORC1/BCL-6/4E-BP1 axis. Collectively, these findings reveal that while ETF insufficiency is rare and has detrimental effects in non-malignant tissues, it is common in neoplasia, where ETFDH downregulation leads to bioenergetic and signaling reprogramming that accelerates neoplastic growth.

Glutaric aciduria type 1 is a rare metabolic disease and an inborn error of lysine hydroxylysine and tryptophan metabolism caused by deficiency of glutaryl coenzyme A dehydrogenase The clinical picture typically shows varying degrees of muscular hypotonia motor delay dystonia and dyskinesia beginning acutely or gradually in the first few years of life in often macrocephalic children Patients with glutaric aciduria type 1 appear to have a bitemporal arachnoid cysts Here we present glutaric aciduria type 1 in a 6 month old boy with bilateral temporal cysts and macrocephaly Turk Arch Ped 2008; 43: 102 4 Key words: Glutaric aciduria type 1 temporal arachnoid cyst macrocephaly

Incorporating second-tier genetic screening for multiple acyl-CoA dehydrogenase deficiency

Glutaric aciduria type 1(GA-1) is an inherited cerebral organic aciduria. Untreated patients with GA-1 have a risk of acute encephalopathic crises during the first 6 years of life. In so far as GA-1 desperately does not exist in Turkish newborn screening (NBS) program, most patients in our study were late-diagnosed. This study included 41 patients diagnosed with acylcarnitine profile, urinary organic acids, mutation analyses in the symptomatic period. We presented with clinical, neuroradiological, and molecular data of our 41 patients. The mean age at diagnosis was 14.8 ± 13.9 (15 days to 72 months) and, high blood glutaconic acid, glutarylcarnitine and urinary glutaric acid (GA) levels in 41 patients were revealed. Seventeen different mutations in the glutaryl-CoA dehydrogenase gene were identified, five of which were novel. The patients, most of whom were late-diagnosed, had a poor neurological outcome. Treatment strategies made a little improvement in dystonia and the frequency of encephalopathic attacks. All GA-1 patients in our study were severely affected since they were late-diagnosed, while others show that GA-1 is a treatable metabolic disorder if it is diagnosed with NBS. This study provides an essential perspective of the severe impact on GA-1 patients unless it is diagnosed with NBS. We immediately advocate GA-1 to be included in the Turkish NBS.

Patient with multiple acyl-CoA dehydrogenation deficiency disease and FLAD1 mutations benefits from riboflavin therapy

Since 2001, tandem mass spectrometry was introduced for newborn screening by two Taiwan national newborn screening centers: Taipei Institute of Pathology and Chinese Foundation of Health, in Taiwan, respectively. A total of 24 metabolic disorders, including 6 amino acidopathies, 8 organic acid disorders and 9 fatty acid disorders, etc., were screened and the newborns with positive screening result were referred to Taipei Veterans General Hospital for confirmatory diagnosis. Until Dec 2014, a total of 1,391,583 newborns have been screened by these two newborn screening centers. The overall incidence of inborn errors of metabolism identified by tandem mass was approximately 1/6,000. The most common inborn errors were defects of phenylalanine metabolism (phenylketonuria: 1/60,000; 6-pyruvoyltertrahydropterin synthase (PTPS): 1/110,000). Maple syrup urine disease was the second most common amino acidopathy (1/100,000) and, significantly, most MSUD patients (75%) belonged to the Austronesian aboriginal tribes of southern Taiwan. The most frequently detected organic acid disorder was 3-methylcrotonyl-CoA carboxylase deficiency (1/35,000). Glutaric aciduria type 1 and methylmalonic academia were the second most common organic acid disorders (1/100,000 for each disease). The incidence of fatty acid disorder is relatively less than most western countries. Out of them, carnitine transport defect was the most common fatty acid disease (1/100,000). In this report we will present this large population study of tandem mass newborn screening in Chinese population.

Introduction:Glutaric aciduria type I is an autosomal recessive disorder of lysine metabolism due to the defect of the enzyme glutaryl-CoA dehydrogenase. The regression of milestones following an intercurrent infection with disabling dystonia is the common presentation. We report the clinical features, diagnosis, and management of 14 south Indian children with glutaric aciduria type I.Results:Males predominated the study (57.1%). The mean age of onset of the symptoms was 8.57 ± 3.57 months. The mean age at the time of diagnosis was 35.21 ± 48.31 months. The history of consanguinity was noted in 57.1%. Development was normal prior to the onset of acute crises in nearly three fourths. Acute crises triggered by infection followed by the regression of milestones was the major presenting feature in 10 children (71.4%). Macrocephaly was another prominent feature in an equal number. Bat's wing appearance (fronto temporal atrophy) was present in all children. Nearly 80% had moderate to severe disability in the form of dystonic movement disorder and spastic quadriparesis.Conclusion:Glutaric aciduria type Ihas to be identified and managed early to have a better outcome.

Glutaric aciduria type 2 is a rare inborn disease of fatty acid metabolism. The clinical manifestation of this disease is heterogeneous and ranges from severe neonatal forms to mild late-onset forms. We present a case of a previously healthy 22-year-old woman with unexplainable hypoglycemia and encephalopathic hyperammonemia. Acylcarnitine profile and organic acids analysis were compatible with glutaric aciduria type 2. On suspicion of this disease, the patient started supplements with carnitine and riboflavin, along with hemodialysis with a complete recovery. The genetic test confirmed the diagnosis. Glutaric aciduria type 2 has no cure and the metabolic decompensation can be a severe event, but treatable and preventable, if this pathology gets recognized.

Comparative frequency and severity of hypoglycemia in selected organic acidemias, branched chain amino acidemia, and disorders of fructose metabolism

215 Background: Programmed death 1 (PD-1) protein and its ligands (PD-L1 & L2) play a key role in the evasion of the host immune system by tumor cells via inhibition of T-cells. It is of therapeutic interest that a number of tumor types selectively over-express PD-L1, since antibodies directed against PD-L1 have recently been shown to induce durable tumor regression. Methods: In this study we evaluated the expression of PD-L1 in pancreatic tissue obtained from 145 patients with localized pancreatic adenocarcinoma who underwent curative resection at our institution (stage IA – IIB). Of the 145 patients, 44 had paired pancreatic tissue samples of the tumor and adjacent non-malignant pancreatic tissue. These paired samples were used to compare expression of PD-L1 in malignant and nonmalignant tissue. Immunohistochemical staining was performed using rabbit primary antibody against PD-L1 (CD274/B7-H1) on formalin-fixed, paraffin-embedded core sections in tissue microarrays. Immunostain intensity and percentage cells stained were each scored on a scale of 0 to 3, with 3 being maximal. The product of intensity and percentage was used as a semi-quantitative measure of PD-L1 expression. Only patients with a product score greater than 0 on either the malignant or non-malignant tissue were included in this study. Results: PD-L1 expression (product score) was higher in 81% (36/44) of the malignant tissue samples than in paired non-malignant samples, equal in 7% (3/44) and lower in 11% (5/44). PD-L1 expression in malignant tissue (mean product score = 4.23) was significantly higher than the non-malignant pancreatic tissue (mean product score = 1.73) (p < 0.0001). The median product score was also statistically significantly higher for malignant versus non-malignant (4 vs. 2) tissue. Conclusions: Pancreatic adenocarcinoma tumor cells express PD-L1 at a higher level than their non-malignant counterparts. Future trials should evaluate drugs targeting the PD-1/PD-L pathway in the treatment of pancreatic cancer.

Glutaric acidemia type 1 (GA1) is a neurotoxic metabolic disorder due to glutaryl-CoA dehydrogenase (GCDH) deficiency. The high number of missense variants associated with the disease and their impact on GCDH activity suggest that disturbed protein conformation can affect the biochemical phenotype. We aimed to elucidate the molecular basis of protein loss of function in GA1 by performing a parallel analysis in a large panel of GCDH missense variants using different biochemical and biophysical methodologies. Thirteen GCDH variants were investigated in regard to protein stability, hydrophobicity, oligomerization, aggregation, and activity. An altered oligomerization, loss of protein stability and solubility, as well as an augmented susceptibility to aggregation were observed. GA1 variants led to a loss of enzymatic activity, particularly when present at the N-terminal domain. The reduced cellular activity was associated with loss of tetramerization. Our results also suggest a correlation between variant sequence location and cellular protein stability (p < 0.05), with a more pronounced loss of protein observed with variant proximity to the N-terminus. The broad panel of variant-mediated conformational changes of the GCDH protein supports the classification of GA1 as a protein-misfolding disorder. This work supports research toward new therapeutic strategies that target this molecular disease phenotype.

PurposeGlutaric acidemia type 1 (GA1), a rare hereditary metabolic disease caused by biallelic mutations of GCDH, can result in acute or insidious striatal degeneration within the first few years of life. We reviewed the orthopaedic sequelae and management of 114 neurologically injured patients with a confirmed molecular diagnosis of GA1.MethodsWe performed a retrospective chart review spanning 28 years identifying 114 GA1 patients, most from the Old Order Amish population of Lancaster County, Pennsylvania, who were homozygous for a pathogenic founder variant of GCDH (c.1262C>T). We collected demographics, medical comorbidities, muscle tone patterns, Gross Motor Function Classification System level, gastrostomy tube status, seizure history, inpatient events, orthopaedic diagnoses and operative characteristics.ResultsOver an average follow-up of 4.7 ± 3.4 years, 24 (21%) of 114 patients had musculoskeletal problems requiring orthopaedic consultation. Scoliosis (n = 14), hip dislocation (n = 8/15 hips), hip subluxation (n = 2/three hips), and windswept hip deformity (n = 2) in the spine and hip joint were most common. In total, 35 orthopaedic surgeries were performed in 17 (71%) patients. The most common primary operations were one-stage procedures with proximal femoral varus derotation osteotomy and/or pelvic osteotomy (n = 8/14 hips) for subluxation or dislocation. In all, 11 patients had posterior spinal fusion for severe scoliosis. With the recommended metabolic management, there were no disease-specific complications in this cohort.ConclusionsChildren with GA1 who have static striatal lesions are at risk for musculoskeletal complications, especially scoliosis and hip dislocation, and appropriate operative management requires consultation with a metabolic specialist with specific considerations for fluid management and nutrition.Level of EvidenceIV

Next generation sequencing of RNA reveals novel targets of resveratrol with possible implications for Canavan disease

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a disease of rare autosomal recessive disorder. There are three types of MADD. Type I is a neonatal-onset form with congenital anomalies. Type II is a neonatal-onset form without congenital anomalies. Type III is considered to a milder form and usually responds to riboflavin. However, late-onset form could also be fatal and not responsive to treatments. We report a severe case of a young man with onset type III MADD induced by drugs and strenuous exercise characterized by rhabdomyolysis and liver dysfunction. Urine analysis indicated 12 out of 70 kinds of organic acids like glutaric acid-2 were detected. Serum analysis in genetic metabolic diseases revealed 24 out of 43 tested items were abnormal, revealing the elevation of several acylcarnitines and the reduction of carnitine in the patient. By next generation sequencing technology for gene sequencing related to fatty acid oxidation and carnitine cycle defects, a rare ETFDH gene variant was identified: NM_004453:4:C.1448C>T(p.Pro483 Leu). The patient was diagnosed with late-onset GAII. He was not responsive to riboflavin and progressively worsened into multiple organ failure that finally led to death. Type III MADD can also be fatal and not responsive to treatments.

Three clinical entities of multiple acyl-CoA dehydrogenase deficiency (MADD, OMIM#231680) can be differentiated: two severe neonatal forms and one later-onset form that can manifest in adulthood. The latter typically presents with muscle-related symptoms, such as exercise intolerance and muscle weakness, with an increase in all chain-length acylcarnitine species on the acylcarnitine profile. Here, we report the case of a 33-year-old woman who experienced severe psychiatric issues complicated by an eating disorder resulting in a significant malnutrition a few months before presenting with a profound muscle weakness, fatigue, intermittent ptosis, and a major rhabdomyolysis (creatine kinase (CK) > 15 000 IU/L). Biochemical blood tests, including acylcarnitine profile, urinary organic acid analysis, and invitro beta-oxidation, were not suggestive of a metabolic disease. Given the absence of an etiology and the worsening health condition of the patient, whole exome sequencing (WES) was performed and revealed two pathogenic variants in the electron transfer flavoprotein dehydrogenase (ETFDH) gene, whose association has not been reported before. Unlike other beta oxidation deficiencies, which have a typical biochemical signature, the diagnosis of MADD was made by genetic analyses, which allowed the introduction of vitamin B2 supplementation and the rapid improvement of symptoms.