Multiple Acyl CoA dehydrogenase deficiency: Uncommon yet treatable disorder
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.198186
Source of Support: None, Conflict of Interest: None
Multiple acyl CoA dehydrogenase deficiency (MADD), a rare metabolic disorder, presents with chronic muscle-related symptoms in childhood as well as adulthood. Recognizing this entity is important because it is a treatable cause of exercise intolerance and muscle pain. We report a case of a 24-year-old gentleman who presented with exercise intolerance and myoglobinuria. His muscle biopsy was consistent with lipid storage myopathy and the biochemical assays confirmed the diagnosis of MADD. There was a dramatic and sustained response to treatment with riboflavin, carnitine, and coenzyme Q.
A 24-year-old man presented with exertion-induced weakness of upper and lower limbs. Since the age of 12 years, he had difficulty in chewing. He also experienced discomfort in his limbs after running for a while and had difficulty in running. His condition worsened since the last 6 months. After walking for a distance of approximately 800 meters, he would experience difficulty in continuing his activity and had to take a break of around 5 minutes. This worsened gradually, and at the time of presentation, he could only walk for 50 meters before stopping for a break. He also needed to stop for a few minutes after climbing each flight of stairs. He was unable to hold up his arm for more than 30 seconds. He had to stop chewing for a few minutes after taking hard food, such as 'roti', before he could start on his next one.
The patient reported 10–15 episodes of passage of cola-colored urine after prolonged exertion in the past 6 months. He also reported breathlessness and palpitation on exertion since the past 6 months. There was no history of muscle pain, cramps, or twitching. There was no history of double vision, drooping of eyelids, difficulty in swallowing, or voice change. There was no family history suggestive of any neuromuscular illness. For the same complaints, he was evaluated at a local hospital and started on pyridostigmine but had no improvement with this treatment.
The neurological examination revealed no deficits. Laboratory tests revealed normal hemogram and renal functions. The liver enzymes were mildly elevated (serum glutamate pyruvate transaminase: 69 IU/L, serum glutamic oxaloacetic transaminase: 63 IU/L) as were plasma ammonia and serum lactate (77 μmol/L and 40.9 mg/dL, respectively). The thyroid function tests were normal. Creatinine kinase was high (3852 U/L). Forearm exercise test, electromyogram, repetitive nerve stimulation, and neostigmine tests revealed no abnormality. Tandem mass spectroscopy showed elevated medium and long-chain acyl carnitines in the blood, and urine organic acidogram revealed elevated 2-hydroxy glutaric acid, 2-hydroxy adipic acid, and palmitic acid [Figure 1]a and [Figure 1]b. The left quadriceps muscle, subjected to a battery of enzyme stains, revealed preserved architecture, polygonal fibers, and a few regenerating fibers. The predominant finding in hematoxylin and eosin (H and E) and modified Gomori's trichrome (MGT) stains was the presence of multiple fine vacuoles giving a sieve-like appearance [Figure 2]a and [Figure 2]b. The vacuoles intensely stained for oil red O stain that was suggestive of lipid storage [Figure 2]c. A few ragged red fibers were noted. On electron microscopy, multiple lipid vacuoles and aggregation of mitochondria with abnormal cristae, were observed [Figure 2]d.
Genetic studies could not be carried out in our patient. The treatment was initiated with riboflavin (100 mg/day), coenzyme Q (60 mg/day), and carnitine (500 mg/day). The patient reported a dramatic response in exercise tolerance, which was sustained at a follow-up after 6 months.
MADD, an autosomal recessive disorder, is caused by deficiency of electron transfer flavoprotein or electron transfer flavoprotein dehydrogenase, resulting in impaired metabolism of fatty acids. The late onset forms commonly present with chronic muscular symptoms. The genes implicated are the electron transfer flavoprotein A (ETF A), ETF B, and ETF dehydrogenase (ETF DH). ETF DH mutations have been found to be responsible for riboflavin responsive MADD.
The biochemical diagnosis is established by the analysis of urine organic acids and plasma acyl carnitine profiles. The elevation of 2-hydroxyglutaric acid along with glutaric, adipic, butyric, lactic, ethylmalonic, and isovaleric acids in urine is considered pathognomonic. The plasma acyl carnitine profile in MADD typically shows elevated short, medium, and long-chain acyl carnitines. These patients are likely to have secondary carnitine deficiency as well. The muscle biopsy findings gives a clue to the diagnosis of lipid storage myopathy.
In a review of 350 patients with late-onset MADD, Grunert reported a chronic presentation with weakness, muscle pain, and exercise intolerance in 85% of the patients. Urine organic acid analysis revealed the pathognomonic pattern in 92% of the patients. More than 98% of the patients reported a good improvement by treatment with riboflavin.
The presence of exercise intolerance and myoglobinuria suggested the diagnosis of a metabolic myopathy in this patient. The presence of 2-hydroxyl glutaric acid, 2-hydroxyl adipic acid, and palmitic acid in the urine, elevated medium and long-acyl carnitines in plasma, and the biopsy suggestive of lipid storage myopathy, confirmed the diagnosis of MADD. Education regarding the triggering factors and their avoidance is imperative for the prevention of acute metabolic exacerbations. The treatment includes the administration of a low fat, low protein, and a high carbohydrate diet. Riboflavin, carnitine, and CoQ are the specific pharmacological agents.
There are only two case reports of MADD from India. One reported the magnetic resonance imaging finding of a 7-month-old child who presented with encephalopathy  and the other described the association of MADD with bipolar disorder. To the best of our knowledge, this is first case report of MADD presenting as a lipid storage myopathy from India. Though it is rare, the diagnosis of this disease is important in view of the management issues involved.
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[Figure 1], [Figure 2]