CACT Deficiency

Other Names

Carnitine acylcarnitine carrier (CAC) deficiency

Carnitine acylcarnitine translocase (CACT or CAT) deficiency

Solute carrier family 25 member 20 (SLC25A20) deficiency

Diagnosis Coding

E71.318, Other disorders of fatty-acid oxidation

Disorder Category

A fatty acid oxidation disorder

Screening

Finding

Elevated C16 and/or C18:1 (acylcarnitines)

Tested By

Tandem mass spectrometry (MS/MS); sensitivity=100%; specificity=99.98% [Schulze: 2003]

Overview

Mutations in the SLC25A20 gene cause carnitine-acylcarnitine translocase (CACT) deficiency. CACT is a mitochondrial membrane carrier protein responsible for transport of long-chain fatty acids conjugated with carnitine into mitochondria for oxidation. During prolonged fasting and/or periods of increased energy demands (fever, stress), energy production relies increasingly on fatty acid oxidation. Without CACT, long-chain acylcarnitines cannot enter mitochondrion to undergo subsequent beta-oxidation, with resultant insufficient energy production. This process is particularly important in fatty acid-dependent tissues like the heart, liver, and skeletal muscles. Build-up of long-chain acylcarnitines can also have toxic effects and alter the electrical properties of cardiac cells resulting in cardiac arrhythmias. Patients with the most severe forms (and most frequent) present shortly after birth with hypoketotic hypoglycemia, hyperammonemia, liver dysfunction, and cardiac arrest, independently from fasting or any other stressor beyond the normal birth process. Therapy comprises avoidance of fasting, a modified diet low in long-chain fatty acids, and supplementation with medium-chain fatty acids or triheptanoin, though prognosis may still remain poor despite timely treatment.

Incidence

Approximately1:250,000 live births [Schulze: 2003] and 1:60,000 in some Asian populations [Yan: 2017]

Inheritance

Autosomal recessive

Maternal & Family History

There may be a family history of sudden infant death syndrome (SIDS). Maternal preeclampsia has been reported.

Prenatal Testing

DNA testing by amniocentesis or chorionic villus sampling (CVS) if both disease-causing mutations of an affected family member have been previously identified.

Other Testing

Most cases will be identified soon after birth by Newborn Screening programs. Genetic testing is possible for at-risk family members if both disease-causing mutations of an affected family member have been previously identified.

Clinical Characteristics

Mild and severe forms of the disease may respond to treatment with medium-chain triglycerides that do not require carnitine to enter the mitochondria, although the initial phase of the disease may be fatal or leave irreversible brain damage. [Iacobazzi: 2004] In most cases, affected newborns will become symptomatic before newborn screening results can return. Triheptanoin received FDA approval in 2020 with evidence for improved outcomes, including the potential for reversal of severe heart failure in CACT deficiency. [Mahapatra: 2018]

Without treatment, hypoglycemic crises lead to coma and death; cardiomyopathy and cardiac arrhythmia may also be fatal. The neonatal type, with essentially no CACT activity, is the most common type and comes with high morbidity and mortality. The childhood type, with some residual CACT activity, is milder and usually does not have cardiac involvement.

Initial symptoms/signs may include:
  • Poor feeding
  • Lethargy
  • Weakness
  • Hepatomegaly
  • Cardiac insufficiency and/or arrhythmia
  • Lab findings:
    • Hyperammonemia
    • Metabolic acidosis
    • Hypoketotic hypoglycemia
    • Elevated CK and liver enzymes
    • Elevated C16 and/or C18:1 on acylcarnitines (most specific finding)

Follow-up Testing after Positive Screen

Quantitative plasma acylcarnitine profile, urine organic acid analysis. Diagnosis is confirmed by enzyme activity assay in cultured fibroblasts or DNA sequencing of the SLC25A20 gene. Carnitine palmitoyl transferase 2 (CPT2) deficiency can have a similar clinical and biochemical presentation, making DNA testing necessary to differentiate the 2 conditions.

Primary Care Management

Upon Notification of the + Screen

If the Diagnosis is Confirmed

  • Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill (see CACT Deficiency - Information for Parents (STAR-G) for additional information).
  • Support maintenance of regularly scheduled nutritional intake and strict dietary limitation of long-chain fatty acids as guided by metabolic dietitian.
  • Treatment with medium-chain triglyceride (MCT) oil or triheptanoin as an additional energy source, as outlined by metabolic team.
  • Supplementation of carnitine and essential fatty acids may be indicated.
  • For those identified after irreversible neurological sequelae, assist in management, particularly with developmental and educational services.

Specialty Care Collaboration

  • Initial consultation and ongoing collaboration with a Metabolic Geneticist. See Pediatric Metabolic Clinics (see UT providers [3]).
  • A dietician may work with the family to devise an optimal approach to dietary management.
  • Genetic counseling for the family.

Resources

Information & Support

For Professionals

CACT Deficiency (GARD)
Compilation of information, articles, research, case studies, and genetics; Genetic and Rare Diseases from the National Institute of Health.

CACT Deficiency (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

CACT Deficiency - 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.

CACT Deficiency (MedlinePlus)
Excellent, detailed review of condition for patients and families; U.S. National Library of Medicine.

Fatty Oxidation Disorders (FOD) Family Support Group
Information for families about fatty acid oxidation disorders, support groups, coping, finances, and links to other sites.

Tools

ACT Sheet for Elevated C16 and/or C18:1 Acylcarnitine (ACMG) (PDF Document 345 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical Genetics.

Newborn Screening ACT Sheets & Confirmatory Algorithms (ACMG)
ACTion (ACT) Sheets and algorithms for responding to positive newborn screening test results, membership required; American College of Medical Genetics.

Services for Patients & Families in Utah (UT)

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.

Helpful Articles

PubMed search for articles about CACT deficiency in infants

Longo N, Amat di San Filippo C, Pasquali M.
Disorders of carnitine transport and the carnitine cycle.
Am J Med Genet C Semin Med Genet. 2006;142C(2):77-85. PubMed abstract / Full Text

Authors & Reviewers

Initial publication: March 2007; last update/revision: April 2021
Current Authors and Reviewers:
Author: Brian J. Shayota, MD, MPH
Authoring history
2012: revision: Kimberly Hart, MS, LCGCR
2007: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Iacobazzi V, Pasquali M, Singh R, Matern D, Rinaldo P, Amat di San Filippo C, Palmieri F, Longo N.
Response to therapy in carnitine/acylcarnitine translocase (CACT) deficiency due to a novel missense mutation.
Am J Med Genet A. 2004;126(2):150-5. PubMed abstract

Mahapatra S, Ananth A, Baugh N, Damian M, Enns GM.
Triheptanoin: A Rescue Therapy for Cardiogenic Shock in Carnitine-acylcarnitine Translocase Deficiency.
JIMD Rep. 2018;39:19-23. PubMed abstract / Full Text

Schulze A, Lindner M, Kohlmuller D, Olgemoller K, Mayatepek E, Hoffmann GF.
Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications.
Pediatrics. 2003;111(6 Pt 1):1399-406. PubMed abstract

Yan HM, Hu H, Ahmed A, Feng BB, Liu J, Jia ZJ, Wang H.
Carnitine-acylcarnitine translocase deficiency with c.199-10 T>G and novel c.1A>G mutation: Two case reports and brief literature review.
Medicine (Baltimore). 2017;96(45):e8549. PubMed abstract / Full Text