Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

ICD-10 Coding

Disorder Category

Abnormal Finding

Tested By

3-methylglutaconic aciduria (3-MGA) is a general term used to describe a group of metabolic disorders that results in increased 3-MGA levels excreted in the urine.

• In 3-MGA type I, the enzyme 3-methylglutaconyl-CoA hydratase involved in leucine metabolism is deficient. The phenotype of 3-MGA1 is variable, ranging from early-onset developmental delays and dystonia to adult-onset neurodegenerative disease.
• In 3-MGA type II (aka Barth syndrome), the chromosome X encoded enzyme tafazzin involved in mitochondrial energy production is deficient. Patients with 3-MGA2 typically present with severe early-onset dilated cardiomyopathy, neutropenia, skeletal myopathy, and prepubertal growth delay.
• In 3-MGA type III (aka Costeff syndrome), the OPA3 protein involved in mitochondrial fission and apoptosis is deficient. Clinically this results in early-onset optic atrophy and/or a choreoathetoid movement disorder.
• In 3-MGA type IV, the remaining unclassified causes of secondary elevated 3-MGA are grouped together and include disorders caused by mutations in POLG1, SUCLA2, TMEM70, and mtDNA.
• In 3-MGA type V (aka dilated cardiomyopathy with ataxia), the DNAJC19 protein involved in the transport of other proteins across the mitochondrial membrane is deficient. Clinically this results in early-onset dilated cardiomyopathy, ataxia, microcytic anemia, growth failure, and genital anomalies in males.

Clinical Characteristics

Incidence

• 3-MGA type I is particularly rare with less than 50 cases reported in the medical literature.
• 3-MGA type II is also rare, with an incidence of 1 out of every 1 million males.
• 3-MGA type III is very rare in most populations but may be as high as 1:10,000 in individuals of Iraqi-Jewish descent.
• Exact numbers of affected individuals with MGA types IV and V are not known. MGA type V has only been reported in the Hutterite population of North America and Canada.

Inheritance

• 3-MGA types I, III, and V are autosomal recessive conditions and therefore impart a 25% risk recurrence for most families.
• 3-MGA type II is X-linked recessive and, therefore, a risk for male offspring of carrier mothers.
• 3-MGA type IV has multiple genetic causes and, therefore, inheritance depends on the specific causative gene.

Next Steps After a Positive Screen

• Contact the family and evaluate the infant for any symptoms.

Confirming the Diagnosis

• To confirm the diagnosis of 3-MGA, work with Newborn Screening Services (see OH providers [1]).
• Follow-up testing may include: 3-MGA type I can be identified by Newborn Screening with an elevated C5-OH, among several other metabolic disorders, which can also be seen on an acylcarnitine profile. Urine organic acids are needed to measure 3-MGA levels, but with some types of 3-MGA may be only mildly elevated. Genetic testing may still be necessary to confirm a diagnosis.

If the Diagnosis is Confirmed

• For evaluation and ongoing collaborative management, consult Biochemical Genetics (Metabolics) (see OH providers [0]).
• For several types of 3-MGA, referral should be made to Pediatric Cardiology (see OH providers [0]) as well.
• Educate the family regarding potential cardiac signs and symptoms, as well as developmental delay, poor growth, abnormal movements, and the need for close follow-up. Also, discuss risk recurrence depending on the inheritance pattern.