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ACAD9 deficiency
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Condition

ACAD9 deficiency

ACAD9 deficiency is a rare genetic disorder that disrupts mitochondrial energy production, causing muscle weakness, heart problems, and lactic acidosis.

Overview

ACAD9 deficiency is a condition that varies in severity and can cause muscle weakness (myopathy), heart problems, and intellectual disability. Nearly all affected individuals have a buildup of a chemical called lactic acid in the body (lactic acidosis). Additional signs and symptoms that affect other body systems occur in rare cases.

Mildly affected individuals with ACAD9 deficiency usually experience nausea and extreme fatigue in response to physical activity (exercise intolerance). People with ACAD9 deficiency who are moderately affected have low muscle tone (hypotonia) and weakness in the muscles used for movement. Severely affected individuals have brain dysfunction combined with myopathy (encephalomyopathy); these individuals usually also have an enlarged and weakened heart muscle, which is typically fatal in infancy or childhood.

Individuals with ACAD9 deficiency who survive past early childhood often have intellectual disability and may develop seizures. Rare signs and symptoms of ACAD9 deficiency include movement disorders and problems with liver and kidney function.

Some individuals with ACAD9 deficiency have had improvement in muscle strength and a reduction in lactic acid levels with treatment.

Frequency

The prevalence of ACAD9 deficiency is unknown. At least 25 people with this condition have been described in the scientific literature.

Causes

ACAD9 deficiency is caused by mutations in the ACAD9 gene. This gene provides instructions for making an enzyme that is critical in helping assemble a group of proteins known as complex I. Complex I is found in mitochondria, which are the energy‑producing structures inside cells. Complex I is one of several complexes that carry out a multistep process called oxidative phosphorylation, through which cells derive much of their energy.

The ACAD9 enzyme also plays a role in fatty acid oxidation, a multistep process that occurs within mitochondria to break down (metabolize) fats and convert them into energy. The ACAD9 enzyme helps metabolize a certain group of fats called long‑chain fatty acids. Fatty acids are a major source of energy for the heart and muscles. During periods without food (fasting), fatty acids are also an important energy source for the liver and other tissues.

Some ACAD9 gene mutations disrupt complex I assembly as well as long‑chain fatty acid oxidation, while others affect only complex I assembly. The mutations that affect both of the enzyme's functions tend to be associated with the most severe signs and symptoms of ACAD9 deficiency, such as encephalomyopathy and cardiomyopathy. Although the exact mechanism is unclear, it is likely that cells that are less able to produce energy die off, particularly cells in the brain, skeletal muscle, and other tissues and organs that require a lot of energy. The loss of cells in these tissues is thought to lead to the signs and symptoms of ACAD9 deficiency.

Learn more about the gene associated with ACAD9 deficiency

  • ACAD9

Inheritance

This condition is inherited in an autosomal recessive manner, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Other Names for This Condition

  • Acyl‑CoA dehydrogenase 9 deficiency
  • Deficiency of acyl‑CoA dehydrogenase family member 9
  • Mitochondrial complex I deficiency due to ACAD9 deficiency

Additional Information & Resources

Genetic Testing Information

  • Genetic Testing Registry: Acyl‑CoA dehydrogenase 9 deficiency

Genetic and Rare Diseases Information Center

  • Isolated complex I deficiency

Patient Support and Advocacy Resources

  • National Organization for Rare Disorders (NORD)

Catalog of Genes and Diseases from OMIM

  • MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 20; MC1DN20

Scientific Articles on PubMed

  • Aintablian HK, Narayanan V, Belnap N, Ramsey K, Grebe TA. An atypical presentation of ACAD9 deficiency: Diagnosis by whole exome sequencing broadens the phenotypic spectrum and alters treatment approach. Mol Genet Metab Rep. 2016 Dec 29;10:38-44. doi: 10.1016/j.ymgmr.2016.12.005.
  • Collet M, Assouline Z, Bonnet D, Rio M, Iserin F, Sidi D, Goldenberg A, Lardennois C, Metodiev MD, Haberberger B, Haack T, Munnich A, Prokisch H, Rotig A. High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood. Eur J Hum Genet. 2016 Aug;24(8):1112-6. doi: 10.1038/ejhg.2015.264.
  • Dewulf JP, Barrea C, Vincent MF, De Laet C, Van Coster R, Seneca S, Marie S, Nassogne MC. Evidence of a wide spectrum of cardiac involvement due to ACAD9 mutations: Report on nine patients. Mol Genet Metab. 2016 Jul;118(3):185-189. doi: 10.1016/j.ymgme.2016.05.005.
  • Gerards M, van den Bosch BJ, Danhauser K, Serre V, van Weeghel M, Wanders RJ, Nicolaes GA, Sluiter W, Schoonderwoerd K, Scholte HR, Prokisch H, Rotig A, de Coo IF, Smeets HJ. Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene. Brain. 2011 Jan;134(Pt 1):210-9. doi: 10.1093/brain/awq273.
  • Haack TB, Danhauser K, Haberberger B, Hoser J, Strecker V, Boehm D, Uziel G, Lamantea E, Invernizzi F, Poulton J, Rolinski B, Iuso A, Biskup S, Schmidt T, Mewes HW, Wittig I, Meitinger T, Zeviani M, Prokisch H. Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nat Genet. 2010 Dec;42(12):1131-4. doi: 10.1038/ng.706.
  • Nouws J, Nijtmans L, Houten SM, van den Brand M, Huynen M, Venselaar H, Hoefs S, Gloerich J, Kronick J, Hutchin T, Willems P, Rodenburg R, Wanders R, van den Heuvel L, Smeitink J, Vogel RO. Acyl‑CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I. Cell Metab. 2010 Sep 8;12(3):283-94. doi: 10.1016/j.cmet.2010.08.002.
  • Nouws J, Te Brinke H, Nijtmans LG, Houten SM. ACAD9, a complex I assembly factor with a moonlighting function in fatty acid oxidation deficiencies. Hum Mol Genet. 2014 Mar 1;23(5):1311-9. doi: 10.1093/hmg/ddt521.
  • Schiff M, Haberberger B, Xia C, Mohsen AW, Goetzman ES, Wang Y, Uppala R, Zhang Y, Karunanidhi A, Prabhu D, Alharbi H, Prochownik EV, Haack T, Haberle J, Munnich A, Rotig A, Taylor RW, Nicholls RD, Kim JJ, Prokisch H, Vockley J. Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency. Hum Mol Genet. 2015 Jun 1;24(11):3238-47. doi: 10.1093/hmg/ddv074.
  • Schrank B, Schoser B, Klopstock T, Schneiderat P, Horvath R, Abicht A, Holinski‑Feder E, Augustis S. Lifetime exercise intolerance with lactic acidosis as key manifestation of novel compound heterozygous ACAD9 mutations causing complex I deficiency. Neuromuscul Disord. 2017 May;27(5):473-476. doi: 10.1016/j.nmd.2017.02.005.

MedlinePlus Links

  • Genetics
  • Hypertrophic cardiomyopathy

Understanding Genetics

  • What is the prognosis of a genetic condition?
  • How can gene variants affect health and development?
  • What does it mean if a disorder seems to run in my family?
  • What are the different ways a genetic condition can be inherited?
  • How are genetic conditions treated or managed?

Frequently Asked Questions

Diagnosis typically involves genetic testing to identify mutations in the ACAD9 gene, often after initial suspicion from clinical symptoms and metabolic tests showing elevated lactic acid. Since ACAD9 deficiency is a genetic condition, a diagnosis means that genetic counseling is highly recommended for affected individuals and their families. This counseling can help understand the inheritance pattern, assess the risk for future children, and discuss options like prenatal diagnosis or preimplantation genetic diagnosis.
Parents or caregivers should be alert for signs such as unusual fatigue or nausea after minimal physical activity, which can indicate mild forms. In infants, look for low muscle tone (hypotonia), general muscle weakness, or difficulty feeding. More severely affected infants may show signs of brain dysfunction, an enlarged heart, or rapid breathing due to lactic acidosis, which are medical emergencies requiring immediate attention.
While specific dietary recommendations can vary, some individuals may benefit from a diet that helps manage lactic acid buildup, often involving careful carbohydrate and fat intake. Avoiding prolonged fasting and ensuring adequate hydration are generally important. For exercise intolerance, physical activity should be carefully monitored and adjusted to prevent overexertion and subsequent fatigue or nausea. A medical team, including a dietitian, can provide personalized guidance.
Treatment for ACAD9 deficiency is primarily supportive and aims to manage symptoms. This can include medications to support heart function, manage seizures, and address lactic acidosis. Some individuals have shown improvement in muscle strength and reduced lactic acid levels with specific treatments, though these are often individualized. The long-term outlook varies significantly depending on the severity of the condition, with severe forms often being fatal in infancy or childhood, while milder forms may allow individuals to live into adulthood with ongoing management of symptoms like muscle weakness and intellectual disability. Regular monitoring by a specialist team is crucial.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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