Glutaric acidaemia type II (GA II), also known as multiple acyl-CoA dehydrogenase deficiency (MADD), is a genetic metabolic condition. In glutaric acidaemia type II, the body is unable to properly break down certain fats and amino acids (the building blocks of proteins) to produce energy.¹ As a result, the body often struggles to generate enough energy and maintain blood glucose levels. There may also be build-up of fats affecting different organs.² 

Symptoms of glutaric acidaemia type II can vary widely between individuals, ranging from severe and  life-threatening to milder forms.^3,4 The symptoms are often described as three different forms:^2-6

• Type I (neonatal onset with congenital anomalies) – symptoms develop during the newborn period and often include severe metabolic crisis, which can be life-threatening. Babies are also born with physical differences, such as unusual facial features, large cysts in the kidneys, abnormalities of the penis in males, and differences in brain development.
• Type II (neonatal onset without congenital anomalies) –  symptoms during the newborn period and often include severe metabolic crisis, which can be life-threatening. Babies are not born with physical differences seen in the type I form.
• Type III (late onset) – symptoms develop after the newborn period, which could be sometime in childhood or adulthood. This form is often milder than the neonatal forms.

In Australia, glutaric acidaemia type II is often detected shortly after birth via newborn bloodspot screening (NBS) programs. Additional testing is required to confirm the diagnosis. For individuals who are not screened at birth, glutaric acidaemia type II is often diagnosed after symptoms develop.

Synonyms:^3,4 GAII; GA2; Multiple acyl-CoA dehydrogenase deficiency; MADD; MAD deficiency; Glutaric Aciduria II; Electron transfer flavoprotein dehydrogenase deficiency

Universal rare disease classifications provide a common language for recording, reporting and monitoring diseases. Please visit the Rare Disease Classifications page for more information about these internationally recognised classifications.

ORPHA:26791 Multiple acyl-CoA dehydrogenase deficiency

ICD-11: 5C52.01 Disorders of mitochondrial fatty acid oxidation

Symptoms of glutaric acidaemia type II varies between individuals. The symptoms of glutaric acidaemia type II are often described as three different forms:^1-6 

Type I (Neonatal onset with congenital anomalies)

Symptoms are severe and often present within a first few hours after birth as severe metabolic crisis with low blood glucose (hypoglycaemia), metabolic acidosis (high levels of acid in blood) and hyperammonaemia (toxic build up of ammonia in blood). Babies may have weakness, difficulty feeding, extreme tiredness and lack of energy (lethargy), nausea and vomiting, an enlarged liver (hepatomegaly) as well as having a smell (odor) like sweaty feet. This form usually leads to early death within days or weeks, even with treatment.

Individuals with Type I are also born with physical differences, such as unusual facial features, large cysts in the kidneys, abnormalities of the penis in males, and differences in brain development.

Type II (Neonatal onset without congenital anomalies)

Symptoms often present within the first few days after birth as severe metabolic crisis with similar symptoms to Type I. This form also often leads to early death. For individuals that live past the newborn period, they tend to have further episodes of metabolic crises and hypertrophic cardiomyopathy (heart condition where there is thickening of heart muscle leading to complications), both of which are also life-threatening.

Individuals with Type II are not born with physical differences that are seen in Type I.

Type III (Late onset)

Symptoms of this form present after the newborn period (this may range from sometime in childhood to adulthood) and varies widely between individuals. Individuals may have episodes of metabolic crisis, usually during childhood, and often during times of illness or fasting. If left untreated, this can be life-threatening. Common symptoms that tend to present during adulthood include muscle weakness, intolerance to exercise and muscle pain. Less common symptoms may include heart complications and sensory neuropathy (where there is damage to sensory nerves).

Please speak to your medical team to learn more about the symptoms of this condition.

Rare diseases are often serious and progressive, exhibiting a high degree of symptom complexity, leading to significant disability. Majority of the estimated two million Australians living with a rare disease meet the Australian Government’s definition for disability (in accordance to the Australian Public Service Commission and Australian Bureau of Statistics), and many experience severe and permanent disability impacts. If you or someone you care for is experiencing disability-related impacts from a rare condition, please speak with a health or disability professional for advice. Information about relevant disability support can be found at the RARE Portal’s Disability Support Information page.

Glutaric acidaemia type II is a genetic condition. It is caused by disease-causing genetic changes (variants) in either the ETFA (on chromosome 15), ETFB (on chromosome 19) or ETFDH (on chromosome 4) genes.^3-5 These genes encode the alpha and beta subunits of electron transfer flavoprotein (ETF) and ETF-coenzyme Q oxidoreductase, which are mitochondrial enzymes involved in fatty acid oxidation. Defects in the ETFA and ETFB genes often cause symptoms early on in life, usually at birth or just after birth, whilst individuals with have an affected ETFDH enzyme tend to have later onset, with symptoms appearing later on in life.²

All individuals have two copies (alleles) of those genes – one copy inherited from each parent. Glutaric acidaemia type II is an autosomal recessive condition, which means both copies of the affected gene must have the disease-causing genetic variants. More information on autosomal recessive inheritance pattern can be found at Centre for Genetics Education: Autosomal recessive inheritance.

If you would like to learn more about the inheritance and impact of this condition, please ask your doctor for a referral to a genetic counsellor. Genetic counsellors are qualified allied health professionals who can provide information and support regarding genetic conditions and testing. More information about genetic counselling can be found at:

• Information on Genetic Services
• The National and State Services pages underneath the ‘Genetic Counselling’ sections listed

Newborn screening

In Australia, glutaric acidaemia type II is usually detected via the newborn bloodspot screening (NBS) programs.  Shortly after birth and with parental consent, a nurse or midwife will collect the baby’s blood via a heel prick blood test. The healthcare provider will then send it to a specific laboratory to test for a range of rare conditions, including glutaric acidaemia type II. If the test results suggest that there is a risk of the baby having one of the screened conditions, laboratory staff will promptly get in touch with healthcare providers. The healthcare providers will then arrange for the baby to have further testing to confirm if the baby actually has the condition. The healthcare providers will also organise for the baby to receive urgent care if required. Depending on your state or territory, parents may or may not receive a notification if the test results are clear. You can find out more about NBS in your state or territory at Australian Government Department of Health, Disability and Ageing: Delivering newborn bloodspot screening programs.

Newborn bloodspot screening is a reliable way to check for certain rare conditions early in life. Although it’s extremely rare, cases can sometimes be missed. If you are concerned your baby may have a condition that they have already been screened for, you should contact a medical professional.

Diagnosis

A diagnosis of glutaric acidaemia type II may be suspected based on an abnormal result from NBS but additional tests or a clinical examination will be required to confirm a diagnosis. For individuals who are not screened at birth, glutaric acidaemia type II is often diagnosed after symptoms develop.

Diagnosis of glutaric acidaemia type II may be made based on clinical evaluation of symptoms, laboratory tests on blood and urine samples to detect for increased levels of specific acylcarnitines (in blood) and certain organic acids (in urine), and confirmed by genetic testing.^3,4

As part of the diagnostic process, doctors may do a differential diagnosis, which is to rule out other conditions that have similar symptoms, such as other causes of autosomal resessive polycystic kidney disease, the neonatal form of carnitine palmitoyl transferase II deficiency, Zellweger syndrome, sterol biosynthesis disorders, riboflavin metabolism disorders, glutaric acidaemia type 1, glutaric acidaemia type III and medium chain acyl-CoA dehydrogenase deficiency (MCAD).^3-5

Please speak to your medical team to learn more about the available pathways for diagnosis of this condition.

There is currently no curative treatment for glutaric acidaemia type II. Early diagnosis and appropriate management can help reduce the risk of serious life-threatening complications for the Type III form.^2-5 For Type I and Type II, early death often still occurs even with treatment. 

Metabolic crisis, such as hypoglycaemia, metabolic acidosis and hyperammonaemia, are medical emergencies and should be treated promptly and accordingly.

The Type III form can be managed with nutritional treatment, which involves a low protein, low fat and high carbohydrate diet, avoidance of fasting, and riboflavin supplementation to stabilize the ETF/ETFDH complex.^2-4 Some individuals may also benefit from carnitine supplementation and coenzyme Q₁₀ supplements. There needs to be careful management of the nutritional treatment, which may need to be adjusted with age, during times of illness and pregnancy.⁴ There are reported cases of woman with glutaric acidaemia type II who have been pregnant and given birth without any complications, with careful clinical monitoring and nutritional management.^2,4

Symptomatic management (management of symptoms) may include feeding therapy, physiotherapy, occupational therapy, speech therapy, management of heart complications and sensory neuropathy.⁴

Please speak to your medical team to learn more about the possible treatment or management options for your condition. Treatment will depend on an individual’s specific condition and symptoms. It is also important to stay connected to your medical team so that you can be made aware of any upcoming clinical trial opportunities. For many rare diseases, treatment options may be limited. Participation in a clinical trial may provide access to new or emerging therapies.

Healthcare professionals involved in the clinical care of individuals with glutaric acidaemia type II may include general practitioners (GP), paediatricians, metabolic physicians, metabolic dietitians, neurologists, cardiologists,  and other healthcare professionals trained to look after metabolic disorders. The need for different healthcare professionals may change over a person’s lifetime and extend beyond those listed here.  It is recommended that care be managed by a metabolic specialist team.

Clinical care for rare diseases often involves a multidisciplinary team of medical, care and support professionals. Please note that the information provided here is as a guide and that RVA does not necessarily monitor or endorse specific clinics or health experts.

This may not be applicable to all rare diseases but for many, palliative care services may be relevant and useful. Palliative care services are available for people (adults, children and their families) living with a life-limiting illness and is not only for end-of-life care. It can also help at any stage of illness from diagnosis onwards, and will look different for different people. Palliative care services provide assistance, support, resources and tools to help people manage their illness and the symptoms, ease pain, and improve comfort and quality of life. If this is relevant to you and you wish to find out more information about palliative care and how it can help you, please visit:

• Australian Institute of Health and Welfare: Palliative care Overview
• Australian Government Department of Health, Disability and Ageing: Palliative care
• Palliative Care Australia

If you know of any relevant clinical care guidelines, please let us know via the  Contribute page.

Individuals living with rare diseases may have complex medical issues and disabilities, which are not always visible. It is often useful to refer to their medical history as well as personal information such as a medical card, doctor’s letter, or if available, a rare disease passport, for relevant information.

In addition, individuals, their parents, families and carers often develop extensive expertise on their specific rare disease. It is important to recognise that they can contribute valuable knowledge about their rare condition. Rare diseases often impact individuals differently, so it’s important to consider a person’s lived experience.

Below are some considerations for the emergency management of individuals living with glutaric acidaemia type II, including when presenting to emergency departments:²

• individuals are at risk of hypoglycaemia, metabolic acidosis and hyperammonaemia, particularly during fasting, illness, or other metabolic stress. These are medical emergencies that require immediate treatment. Administration of intravenous intralipids during an acute metabolic crisis is contraindicated; it is recommended that supplemental calories be provided in the form of carbohydrates.
• extended fasting, inadequate caloric provision and high-fat, high-protein diet are to be avoided
• individuals should be monitored to ensure they are not dehydrated (as this leads to risk of rhabdomyolysis and acute renal failure)
• volatile anesthetics and those that contain high doses of long-chain fatty acids should be avoided
• metabolic specialist team should be consulted

Metabolic Dietary Disorders Association (MDDA): Latest Research Updates has information about key areas of ongoing research for various inborn errors of metabolism conditions, including organic acidemias.

Australian Organisations:

Mito Foundation
Website: https://www.mito.org.au/

The Mito Foundation is the only organisation dedicated to supporting and empowering people impacted by mitochondrial disease (mito) in Australia. It provides resources and support services for people impacted by mito, and their families, while increasing awareness and understanding of this devastating disease. The foundation aims to transform outcomes for the mito community by driving meaningful change and funding essential research into the prevention, diagnosis, treatment and cures of mitochondrial disorders.

Metabolic Dietary Disorders Association (MDDA)
Website: https://mdda.org.au/

Metabolic Dietary Disorders Association Inc (MDDA) is the national peak consumer body dedicated to supporting, educating, connecting, and representing all individuals their families and carers living with Inborn Errors of protein Metabolism (IEpM).

Please note that RVA does not monitor or endorse each group/organisation’s operational governance and activities. When engaging with a group, please consider the information on the RARE Portal’s Finding Helpful Peer and Community Supports page.

Glutaric acidaemia type II varies between individuals, and each person’s experience is unique.

If you would like to share your personal story with RVA, please visit the Rare Voices Australia: Share Your Story page. RVA will consider your story for publishing on our website and inclusion on the RARE Portal.

For information on available government and social services that provide support for individuals with a rare disease, please visit the National and State Services pages.

People living with a rare disease often face unique challenges such as diagnostic delays, misdiagnoses, limited treatment options, and limited access to rare disease specialists and support. These challenges may impact people’s emotional wellbeing and quality of life. Many find it helpful to seek mental health and wellbeing support to cope with ongoing stress and uncertainty. Connecting with people who have shared experiences through a support group may also be helpful. Information about relevant mental health and wellbeing support can be found at:

• Mental Health and Wellbeing Support for Australians Living with a Rare Disease
• The National and State Services pages underneath the ‘Mental Health’ sections listed

Further information relevant to glutaric acidaemia type II can be found at:

• Genetic and Rare Diseases (GARD) Information Center: Multiple acyl-coa dehydrogenase deficiency
• National Organization for Rare Disorders (NORD): Glutaric Aciduria Type II
• MedlinePlus Genetics: Glutaric acidemia type II

Orphanet: Multiple acyl-CoA dehydrogenase deficiency

Online Mendelian Inheritance in Man, OMIM^®: #231680 – Multiple acyl-CoA dehydrogenase deficiency; MADD

This page has been developed by Rare Voices Australia (RVA)’s RARE Portal team.

If you are aware of any additional information that may benefit stakeholders with an interest in this page, or if you notice any broken links or inaccurate information, please let us know via the Contribute page.