CACT Deficiency
Other Names
Carnitine acylcarnitine carrier (CAC) deficiency
Carnitine acylcarnitine translocase (CACT or CAT) deficiency
Solute carrier family 25 member 20 (SLC25A20) deficiency
Screening
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]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
- Contact the family and evaluate the infant for poor feeding, vomiting, lethargy, hepatomegaly, and cardiac insufficiency/arrhythmia (bradycardia, cardiac arrest)
- To confirm the diagnosis, work with the following service(s): Newborn Screening Services (see NW providers [1]).
- For evaluation and ongoing collaborative management, consult the following service(s): Pediatric Genetics (see NW providers [1]).
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 NW providers [1]).
- 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) (
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 Nationwide (NW)
| Service Categories | # of providers* in: | NW | Partner states (5) (show) | | MT | NM | NV | RI | UT | |
|---|---|---|---|---|---|---|---|---|---|---|
| Newborn Screening Services | 1 | 4 | 1 | 2 | 1 | 3 | ||||
| Pediatric Genetics | 1 | 7 | 4 | 4 | 4 | 6 | ||||
| Pediatric Metabolic Clinics | 1 | 2 | 1 | 2 | 1 | 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.
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
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