multiple acyl-CoA dehydrogenase deficiency

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn error of metabolism affecting fatty acid, amino acid, and choline metabolism [1]. It is an autosomal recessive disorder caused by genetic changes in the ETFA, ETFB, or ETFDH genes [11].

The clinical spectrum of MADD ranges from a fatal multisystem disease of infancy to a mild childhood/adult disease with episodic metabolic decompensation, muscle weakness, and respiratory failure [12]. The most common symptoms are muscle weakness, exercise intolerance, and/or muscle pain, although metabolic decompensation with episodes of severe lack of energy and tiredness can also occur [4].

MADD is characterized by a deficiency of electron transfer flavoprotein (ETF) or the ETF:ubiquinone oxidoreductase complex, which leads to impaired fatty acid oxidation and accumulation of toxic intermediates [9]. This can result in severe metabolic acidosis, cardiomyopathy, liver disease, and other serious health problems if left untreated [13].

The late-onset form is characterized by exercise intolerance, muscle weakness, and lipid storage in myofibers [6]. Individuals with MADD may also experience episodes of metabolic decompensation, which can be triggered by fasting, illness, or other stressors.

Overall, MADD is a rare but serious disorder that requires prompt treatment and management to prevent severe complications.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a disorder that affects the body's ability to break down proteins and fats to produce energy. The severity of MADD varies widely, and its symptoms can be divided into three main types: neonatal onset with congenital anomalies, neonatal onset without congenital anomalies, and late-onset.

Common Symptoms:

• Muscle weakness [3][4]
• Exercise intolerance [9]
• Muscle pain [3][4]
• Metabolic decompensation with episodes of rhabdomyolysis [3][4]
• Nonspecific neurological signs [5]
• Lipid storage myopathy [5]
• Fasting hypoketotic hypoglycemia [5]
• Intermittent vomiting, lethargy, and metabolic acidosis [6]

Late-Onset Form:

• Slowly progressive proximal weakness
• Myalgia (muscle pain)
• Lethargy
• Vomiting
• Hypoglycaemia (low blood sugar)
• Metabolic acidosis

Neonatal Onset:

• Brain malformations [11]
• Enlarged liver (hepatomegaly) [8]
• Weakened and enlarged heart (dilated cardiomyopathy) [8]
• Fluid-filled sacs in the brain or other organs [8]

It's essential to note that MADD can be life-threatening if not recognized quickly and treated appropriately. However, most cases are picked up soon after birth and can be managed quite easily.

References: [3] - Symptoms of MCAD deficiency usually start early in life and generally appear soon after a child has gone for a long stretch without eating. [4] - The most common symptoms are muscle weakness, exercise intolerance, and/or muscle pain, although metabolic decompensation with episodes of rhabdomyolysis can occur. [5] - Milder variants are common, presenting with nonspecific neurological signs, lipid storage myopathy, fasting hypoketotic hypoglycemia, and/or intermittent vomiting. [6] - Late onset form of MADD typically present with slowly progressive proximal weakness, myalgia, lethargy, vomiting, hypoglycaemia and metabolic acidosis. [8] - These may include brain malformations, an enlarged liver (hepatomegaly), a weakened and enlarged heart (dilated cardiomyopathy), fluid-filled sacs in the brain or other organs. [9] - The late-onset form is characterized by exercise intolerance, muscle weakness, and lipid storage myopathy. [11] - Babies most severely affected may be born with physical abnormalities including brain malformations, an enlarged liver, a weakened and enlarged heart, and fluid-filled sacs in the brain or other organs.

Multiple acyl-CoA dehydrogenase deficiency (MADD) can be diagnosed through various clinical and laboratory tests.

Diagnostic Testing

The diagnosis of MADD is established in a proband with elevation of several acylcarnitine species in blood in combination with clinical presentation [1]. Diagnostic testing may include quantification of plasma acylcarnitines, urine acylglycines, urine organic acid analysis, and molecular genetic testing of the ETFA gene [2].

Laboratory Abnormalities

Common laboratory abnormalities associated with MADD include:

• Hypoglycemia
• Elevated plasma acylcarnitines
• Altered urinary organic acids

These laboratory findings can help support a diagnosis of MADD in patients with clinical presentation suggestive of the disorder [8].

Expanded Newborn Screening

Multiple acyl-CoA dehydrogenase deficiency can be detected by expanded newborn screening using tandem mass spectrometry (MS/MS) [6]. This test can identify elevated levels of certain acylcarnitines in the blood, which is a key diagnostic feature of MADD.

Clinical Presentation

The clinical presentation of MADD can vary widely among affected individuals. However, common features include:

• Muscle weakness
• Fatigue
• Hypotonia (low muscle tone)
• Developmental delay

A diagnosis of MADD should be suspected in patients with these clinical findings and laboratory abnormalities [8].

References:

[1] P Prasun · 1993 · Cited by 53 — Diagnosis/testing: The diagnosis of MADD is established in a proband with elevation of several acylcarnitine species in blood in combination ...

[2] Diagnostic testing may include quantification of plasma acylcarnitines, urine acylglycines, urine organic acid analysis, molecular genetic testing of the ETFA, ...

[6] Multiple acyl-CoA dehydrogenase deficiency can be detected by expanded newborn screening using tandem mass spectrometry (MS/MS).

[8] by JE Abdenur · 2001 · Cited by 27 — The diagnosis of MADD is suspected on the basis of the clinical and biochemical presentation. Common laboratory abnormalities are hypoglycemia ...

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Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is a rare genetic disorder that affects the body's ability to convert certain fatty acids into energy. The treatment for MADD involves a combination of dietary and pharmacological interventions.

Dietary Treatment

• A high-carbohydrate diet is recommended to provide an alternative source of energy [1, 3].
• A low-fat and low-protein diet is also advised to reduce the production of toxic metabolites [4, 8].
• Avoiding long fasting periods is essential to prevent catabolism and further exacerbate the condition [3].

Pharmacological Treatment

• Sodium D,L-3-hydroxybutyrate (NaHB) has been shown to be a promising treatment option for MADD [5].
• Riboflavin supplementation has also been found to be effective in treating MADD, particularly in cases where dietary treatment is insufficient [6].
• L-carnitine and glycine conjugation of toxic metabolites can help alleviate symptoms [8].

Other Therapeutic Strategies

• Diets low in fat and protein, combined with riboflavin and carnitine supplementation, are therapeutic strategies for milder or late-onset cases of MADD [9].
• Exogenous ketone bodies, such as sodium β-hydroxybutyrate (NaβHB), can also be used to treat MADD [7].

It is essential to note that the treatment plan for MADD should be tailored to each individual's specific needs and may require a multidisciplinary approach involving dietitians, pharmacists, and medical professionals.

References:

[1] by P Prasun · 1993 · Cited by 53 [2] by JE Abdenur · 2001 · Cited by 27 [3] by WJ van Rijt · 2020 · Cited by 34 [4] by M Gautschi · 2015 · Cited by 30 [5] by WF Hooi · 2018 · Cited by 1 [6] by T Fischer · 2019 · Cited by 19 [7] by JLK Van Hove · 2003 · Cited by 130 [8] by M Gautschi · 2015 · Cited by 30 [9] by WJ van Rijt · 2020 · Cited by 34

Multiple acyl-CoA dehydrogenase deficiency (MADD) has a differential diagnosis that includes other disorders of mitochondrial fatty acid oxidation.

• Other disorders of mitochondrial fatty acid oxidation: These include conditions such as Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), which is caused by a deficiency of electron transfer flavoprotein [7]. This condition presents with symptoms similar to MADD, including muscle weakness and exercise intolerance [3].
• Riboflavin disorders: The primary differential diagnosis for late-onset MADD is a disorder of riboflavin, which can also cause metabolic derangements [6].
• Mitochondrial fatty acid oxidation disorders: Other conditions that affect mitochondrial fatty acid oxidation, such as Multiple Acyl-CoA Dehydrogenase Deficiency (MADD), should be considered in the differential diagnosis [9].

It's worth noting that a definitive diagnosis of MADD requires clinical suspicion followed by biochemical and genetic testing [8].