Última actualización:
September 17, 2019
Años publicados: 1987, 1988, 1990, 1992, 1997, 2004, 2019
NORD gratefully acknowledges Bryan Min and Lauren Milac, NORD Editorial Interns from the University of Notre Dame and Dr. S. Olpin, MSc, PhD, CSci, EuSpLM, RCPath, Head of Department & Director of Regional Newborn Screening, Consultant Clinical Scientist in Inherited Metabolic Disease, Sheffield Children’s Hospital, for assistance in the preparation of this report.
Glutaric aciduria type II (GAII) is one of the conditions termed organic acidemias. Individuals with these conditions have a deficiency or absence of an enzyme that prevents the breakdown of certain chemicals (proteins and fats) in the body, resulting in the accumulation of several organic acids in the blood and urine. Two enzymes that may be deficient in GAII are electron transfer flavoprotein (ETF) and ETF-dehydrogenase (ETFDH). The severity of GAll varies widely among affected individuals. A complete enzyme deficiency causes a severe form of the disorder termed neonatal GAll that is associated with a short life span and, sometimes, with specific physical birth defects. Individuals with this form may be born with physical abnormalities including brain malformations, enlarged liver, kidney malformations, unusual facial features, and genital abnormalities. They may also emit an odor resembling sweaty feet. The less severe form of the disorder is termed late onset GAll, which may appear in infancy, childhood, or even adulthood. Most often, GAll first appears in infancy or early childhood as a sudden episode of a metabolic crisis, that can cause weakness, behavior changes (such as poor feeding and decreased activity) nausea, vomiting and low blood sugar (hypoglycemia). GAII is an autosomal recessive genetic disorder caused by mutations in the ETFA, ETFB, or ETFDH genes. Treatment varies depending on the severity and symptoms but often includes a low fat, low protein, and high carbohydrate diet.
Signs and symptoms of GAII vary greatly depending on the age of onset and severity of the condition in each affected individual.
There are three main subtypes of GAII: the neonatal form with congenital anomalies, the neonatal form without congenital anomalies, and the late onset form. Newborns with the neonatal (first 4 weeks of life) form without congenital anomalies may have severe hypoglycemia, respiratory distress, low muscle tone, an odor of sweaty feet, liver (hepatomegaly), heart (cardiomyopathy) and kidney abnormalities.
In addition to these symptoms, neonates having GAII with congenital anomalies may also present with an abnormally large head (macrocephaly), high forehead, flat nasal bridge, malformed ears, genital abnormalities, brain malformations, enlarged weak heart (cardiomyopathy), fluid-filled renal cysts, and unusual facial features. Complete enzyme deficiency found in severely affected patients with the neonatal form is not compatible with life beyond the first few days/weeks of life.
Symptoms present in patients with the late onset form of GAII generally appear in childhood to adulthood, are less severe and highly variable. Muscle weakness is the most common symptom of this late onset form and individuals may have intermittent vomiting and hypoglycemia. Some of these patients may respond very well to high dose oral riboflavin treatment.
Glutaric aciduria type II is an autosomal recessive disease caused by changes (mutations) in the ETF-A (subunit alpha), ETF-B (subunit beta) or ETFDH genes. The mutations result in deficient or complete absence of activity of multiple acyl-CoA dehydrogenase (MADD) enzymes needed to break down fats and proteins that the body uses for energy. This results in the accumulation of several organic acids in the blood and urine. Mutations in ETFA and ETFB generally cause the neonatal forms of this disorder and the ETFDH gene mutation is found in many late onset forms of GAII. Dysfunction of either ETF or ETFDH flavoproteins leads to compromised fatty acid oxidation and amino acid degradation that alters energy production as well as production of other molecules needed for fuel storage and use.
Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Prevalence is estimated to be 1/200,000 and GAll affects both males and females. Prevalence in ethnicities is not known.
The diagnosis of GAll begins with examining urine organic acids. The characteristic pattern for glutaric aciduria is an elevation of a range of organic acids which may include glutaric, lactic, ethylmalonic, isovaleric, adipic,butyric, isobutyric, suberic & sebacic acids with a number of characteristic acylglycines. Blood acylcarnitine analysis by tandem mass spectrometry will show increases in a wide range of acylcarnitines from C4-C18. Some mildly affected individuals may not have an abnormal pattern of urine organic acids except when they are ill. Diagnosis of GAll can also be made by demonstrating reduced fatty acid oxidation in cultured fibroblasts obtained from a skin biopsy or by molecular genetic testing.
Treatment
The goal of treatment is to support development by regular monitoring & avoidance of acute life-threatening events through careful medical management & dietary control. However, children who have repeated metabolic crises may develop life-long learning & other health problems. Where necessary, treatment should be continued throughout life & this will apply to most patients. Glutaric aciduria type II is treated with a high carbohydrate, low protein and low fat diet. It is recommended that affected individuals eat often to avoid low blood sugar. Dietary supplementation with riboflavin, carnitine & other supplements may be helpful. It is important to have an emergency regimen ready & to alert the patient’s doctor if they should become ill, as illness can trigger a metabolic crisis.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Saral NY, Aksungar FB, Aktuglu-Zeybek C, Coskun J, Demirelce O, Serteser M. Glutaric acidemia type II patient with thalassemia minor and novel electron transfer flavoprotein-A gene mutations: A case report and review of literature. World Journal of Clinical Cases. 2018;6(14):786-790.
Ersoy EO, Rama D, Ünal Ö, Sivri S, Topeli A. Glutaric aciduria type 2 presenting with acute respiratory failure in an adult. Respir Med Case Rep. 2015; 15: 92–94. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501457/
Mareska MC, Adams KK, Muenzer J, Frerman F, Braun TG, Howard JF. Adult-onset presentation of glutaric acidemia type II with myopathy. Journal of Clinical Neuromuscular Disease. 2003;4(3):124-128.
Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF. Expanded newborn screening foriInborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications. Pediatrics. 2003;111(6):1399-1406.
INTERNET
Glutaric acidemia type II. Genetic and Rare Diseases Information Center. Last updated: 8/16/2013. https://rarediseases.info.nih.gov/diseases/6523/glutaric-acidemia-type-ii. Accessed August 22, 2019.
Glutaric acidemia type II – Genetics Home Reference – NIH. U.S. National Library of Medicine. Reviewed: February 2014. https://ghr.nlm.nih.gov/condition/glutaric-acidemia-type-ii Published February 14, 2014. Accessed August 22, 2019.
Olpin S. Multiple acyl-CoA dehydrogenase deficiency. Orphanet. Last update: February 2014. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=26791 Accessed August 22, 2019.
Glutaric aciduria, type 2. Genetic Testing Registry. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/gtr/conditions/C0268596/
Accessed August 22, 2019.
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Aprende más https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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