ACAD Deficiency

Introduction

Acyl-CoA dehydrogenase 9 (ACAD9) is a protein that helps in breaking down fats in the mitochondria, the “powerhouses of the cell.” It is found in high amounts in the liver and heart, as well as in specific cell types in the lung and kidney. Like other fatty acid oxidation disorders, an ACAD9 deficiency prevents the body from making enough energy during stress, illness and fasting. It can also have a serious impact on an infant’s heart and liver function. Because ACAD9 deficiency is difficult to diagnose, its incidence in the U.S. population is not known.

Signs and symptoms

ACAD9 deficiency patients most often have a poorly functioning, enlarged heart (hypertrophic cardiomyopathy) as their first symptom. This can occur early as in a newborn. Other common features include liver disease, large head (macrocephaly), and Leigh syndrome, a slowly developing neurological condition of energy production. The symptoms in a baby include difficulty in suckling; loss of head control and motor skills; poor feeding; vomiting; and seizures. As the condition worsens, infants may have muscle weakness and lack of muscle tone; extreme muscle tightness (spasticity); movement disorders; inability to coordinate joints and eye movements (cerebellar ataxia); and loss of nerve function in feet and legs and fingers (peripheral neuropathy).  Some patients can have more severe disease, while others may readily respond to vitamin B2 treatment. One mildly-affected 36-year-old patient reported a lifetime history of not being able to tolerate exercise, to have a higher than normal level of acid in her blood, and to episodes of vomiting.

Diagnosis

ACAD9 deficiency cannot be identified by prenatal diagnosis or by newborn screening. Also, there is no test for ACAD 9 protein activity, unlike many other ACAD defects. Instead, diagnosis may involve a search for biochemical markers in blood or urine. The liver may also be tested for abnormal levels of various products of fat metabolism called acylcarnitines.  Most ACAD9 deficiency cases today are identified through whole exome sequencing, a method that looks for errors in all of the genes that make proteins that work in the body . Milder cases of ACAD9 deficiency may not be identified until adolescence or adulthood.

Genetics

ACAD9 deficiency occurs when an individual inherits one genetic change or mutation in the ACAD9 gene from each parent. With each pregnancy, the parents have a 25% chance of having another child with ACAD9 deficiency. Many different mutations in the ACAD9 gene have been identified.

Treatment

Management and treatment of ACAD9 deficiency focuses on preventing low blood sugar (hypoglycemia). However, care must be taken to avoid causing a secondary problem called lactic acidosis. It may also be helpful to provide Vitamin B2 (riboflavin) at 100 mg/kg/day because it may help improve the function of some ACAD9 changes. Cardiomyopathy or other serious heart or liver problems should receive appropriate medical treatment.

 Investigational Therapies

Information on current clinical trials is posted at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

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