Get Help in New MexicoGlutaric Acidemia Type 2
Guidance for primary care clinicians receiving a positive newborn screen result
Description
Glutaric acidemia type 2 is a type of electron transport defect caused by a deficient ability to transfer electrons from multiple different FAD-linked dehydrogenases to the mitochondrial respiratory chain. This can either be due to a primary defect in 1 of 3 electron transfer flavoprotein enzymes (ETFA, ETFB, or ETFDH), which are required for fat and protein metabolism, or less commonly due to a secondary defect in riboflavin metabolism. The clinical consequence of this includes a very wide range of symptoms depending on the residual enzyme activity.
Traditionally, 3 subtypes that span the clinical spectrum. The neonatal onset with congenital anomalies (MADD 1) type may present with cystic kidneys, neuronal migration defects, and dysmorphic facies. In addition to the findings of the neonatal onset without congenital anomalies, (MADD 2) type may include hypotonia, hepatomegaly, hypoglycemia, hyperammonemia, and acidosis. The late-onset or mild form (MADD 3) can present symptomatically at any age, typically with episodic vomiting, hypoglycemia, liver dysfunction, muscle weakness, and rhabdomyolysis. MADD3 generally has a good response to treatment. More than 400 mutations in 8 genes have been associated with the glutaric acidemia type 2 phenotypes. [Mereis: 2021]
Clinical Characteristics
Without treatment, patients with the neonatal variety will generally not survive the first few days of life. Patients with the late-onset form may experience progressive proximal muscle myopathy leading to scoliosis or hypoventilation as well as episodic vomiting, hypoglycemia, and less commonly, liver or cardiac disease.
Episodes are usually triggered by metabolic stress due to fasting or illness (fever, vomiting, dehydration). Sometimes, the natural immune response to a vaccine with a low-grade fever may be the initial trigger in a previously well-appearing child.
- Facial dysmorphism (high forehead, midface hypoplasia, low-set ears)
- Neuronal migration defects
- Rocker bottom feet
- Polycystic kidneys
- Anomalies of the external genitalia
- Plus, all that is seen in MADD 2 below
- Hypotonia
- Tachypnea
- Hepatomegaly
- Cardiomyopathy
- Sweaty feet odor
- Laboratory findings:
- Metabolic acidosis
- Hypoketotic hypoglycemia
- Hyperammonemia
- Progressive proximal muscle myopathy
- Episodic muscle weakness with or without rhabdomyolysis
- Recurrent vomiting with or without hypoglycemia
- Liver dysfunction
Primary Care Management
Next Steps After a Positive Screen
- Contact the family and evaluate the infant for facial dysmorphism, poor feeding, vomiting, lethargy, and odor of sweaty feet.
- Provide emergency treatment/referral for signs or symptoms of hypoketotic
hypoglycemia, metabolic acidosis, hyperammonemia, and cardiomyopathy.
See ACT Sheet for Glutaric Aciduria Type 2 (C4 & C5) (ACMG) (
347 KB)
Confirming the Diagnosis
- To confirm the diagnosis, work with Newborn Screening Services (see NM providers [3]).
- Follow-up testing includes quantitative plasma acylcarnitine profile, urine organic acid, and acylglycine analysis, confirmation with ETF/ETF-QO enzyme assay and/or gene sequencing. If negative, consider riboflavin transporter deficiency if biochemical abnormalities (plasma acylcarnitine profile) are persistent.
If the Diagnosis is Confirmed
- For evaluation and ongoing collaborative management, consult Medical Genetics (see NM providers [2]).
- Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill. See Glutaric Acidemia Type 2 - Information for Parents (STAR-G) for additional information.
- Support implementation and maintenance of a low-fat, low-protein diet.
- Glucose, intralipids, carnitine, and fluids given intravenously may be indicated during episodes of acute, intercurrent illness.
- Oral L-carnitine, riboflavin, or glycine supplements may be indicated.
- For those identified after irreversible consequences, assist in management, particularly with developmental and educational interventions.
Resources
Information & Support
Fatty Acid Oxidation Disorders (FAQ)
Answers to questions frequently asked by families with a child
diagnosed with glutaric acidemia type 2.
For Professionals
Glutaric Acidemia Type 2 (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance
in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
For Parents and Patients
Glutaric Acidemia Type 2 - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received
an initial diagnosis of this newborn disorder; Screening, Technology and Research in Genetics.
Glutaric Acidemia Type 2 (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources;
from the National Library of Medicine.
Tools
ACT Sheet for Glutaric Aciduria Type 2 (C4 & C5) (ACMG) ( 347 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical
Genetics.
NM ACT Sheet for Glutaric Acidemia Type II (ACMG) ( 141 KB)
Provides recommendations for clinical and laboratory follow-up of the newborn with out-of-range screening results, along with
national and local resources for clinicians and families; American College of Medical Genetics.
Confirmatory Algorithms for Glutaric Acidemia Type 2 (ACMG) ( 190 KB)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American
College of Medical Genetics.
Services for Patients & Families in New Mexico (NM)
| Service Categories | # of providers* in: | NM | NW | Other states (3) (show) | | NV | RI | UT |
|---|---|---|---|---|---|---|---|---|
| Medical Genetics | 2 | 1 | 5 | 4 | 7 | |||
| Newborn Screening Services | 3 | 1 | 2 | 2 | 3 | |||
For services not listed above, browse our Services categories or search our database.
* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.
Page Bibliography
Mereis M, Wanders RJA, Schoonen M, Dercksen M, Smuts I, van der Westhuizen FH.
Disorders of flavin adenine dinucleotide metabolism: MADD and related deficiencies.
Int J Biochem Cell Biol.
2021;132:105899.
PubMed abstract
Sahai I, Garganta CL, Bailey J, James P, Levy HL, Martin M, Neilan E, Phornphutkul C, Sweetser DA, Zytkovicz TH, Eaton RB.
Newborn Screening for Glutaric Aciduria-II: The New England Experience.
JIMD Rep.
2014;13:1-14.
PubMed abstract / Full Text