Abnormalities of tetrahydrobiopterin metabolism
Apr. 07, 2024
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Multiple acyl-CoA dehydrogenase deficiency, also known as glutaric aciduria type II, is an inborn error of metabolism with a spectrum of clinical presentations that range from a severe, life-threatening neonatal-onset form with profound metabolic acidosis, hypoketotic hypoglycemia, hyperammonemia, cardiomyopathy, and liver disease to a later-onset form predominantly characterized by chronic musculoskeletal symptoms, exercise intolerance, and recurrent episodes of rhabdomyolysis as well as episodes of metabolic decompensation with acidosis and hypoglycemia in the setting of precipitating stressors (11). Patients with the early-onset form may also present with congenital anomalies.
• Multiple acyl-CoA dehydrogenase deficiency is a disorder of fatty acid, amino acid, and choline metabolism caused by defects in the ETF–ETF:QO complex that impair the transfer of electrons to the mitochondrial respiratory chain. | |
• The disease course is highly variable, ranging from a severe neonatal-onset presentation with or without congenital malformations to later-onset forms with intercurrent metabolic decompensations and chronic musculoskeletal symptoms. | |
• Plasma acylcarnitine profile and urine organic acids are diagnostic but may be normal in asymptomatic patients with later-onset forms. Glutaric aciduria type II is also detected by newborn screening. | |
• Diets low in fat and protein, supplementation with riboflavin and carnitine, and avoidance of catabolism are the therapeutic strategies in milder or late-onset disease. Severe neonatal forms are mostly lethal. | |
• Disorders of riboflavin metabolism can also present with clinical features and biochemical abnormalities suggestive of MADD. |
MADD was initially described in 1976 in a male neonate of Turkish descent who was born via vaginal delivery at term following an uncomplicated pregnancy (30). The family’s first child had died within a few hours of life of an undetermined cause. The next child developed tachypnea at 2 hours of life and was found to have metabolic acidosis and profound hypoglycemia at 16 hours of life (24 mg/dl). He was given dextrose 10% and sodium bicarbonate; however, he developed worsening hypoglycemia (5 mg/dl) and cardiorespiratory arrest at 32 hours of life that required intubation. He subsequently developed hypothermia, seizures, and persistent hypoglycemia despite infusion of dextrose 20%. He died at 70 hours of life. His skin, urine, and blood had a sweaty feet odor. Metabolic studies in blood, urine, and fibroblasts revealed abnormal metabolites suggestive of a pathway affecting multiple acyl-CoA dehydrogenases. Due to an abundance of glutaric acid, the authors proposed the designation “glutaric aciduria II,” to differentiate this disease from glutaric aciduria I, which had been described the year before.
MADD represents a clinical spectrum classically described as type I, associated with neonatal presentation and congenital anomalies; type II, associated with neonatal presentation without congenital anomalies; and type III, associated with late-onset disease (29). Milder, later-onset disease forms are also referred to as “ethylmalonic-adipic aciduria” (25). In reality, it is a clinical spectrum ranging from mild to severe disease.
Clinical phenotypes. The clinical presentations comprise a spectrum and can be grouped into three categories: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without anomalies (type II), and a mild and/or later-onset form presenting anytime beyond the neonatal period with metabolic decompensations or with chronic musculoskeletal symptoms and exercise intolerance (type III). The first two groups of patients are sometimes said to have multiple acyl-CoA dehydrogenation deficiency–severe (MADD:S) and the third to have multiple acyl-CoA dehydrogenation deficiency–mild (MADD:M), or ethylmalonic-adipic aciduria (11).
Neonatal onset with congenital anomalies (type I). Neonatal-onset patients with congenital anomalies are typically born premature and develop symptoms within a few hours of life, often before newborn screening results are available (09). The typical presentation includes lethargy, vomiting, severe metabolic acidosis with associated tachypnea and respiratory distress, and profound hypoglycemia and hyperammonemia. Other features can include hypotonia, hepatomegaly, and liver dysfunction. Often, patients have a "sweaty feet" odor. Seizures can occur in the setting of hypoglycemia, hyperammonemia, and electrolyte imbalances. Congenital anomalies include renal anomalies, commonly enlarged polycystic kidneys that can be detected prenatally (21), genital anomalies (hypospadias, chordee in males), and brain anomalies (02). Some patients also have single palmar creases and rocker-bottom feet.
Neonatal onset without congenital anomalies (type II). These patients present with lethargy, poor feeding, and hypotonia within the first few days of life and are found to have metabolic acidosis, hypoglycemia, hyperammonemia, hypotonia, hepatomegaly and liver dysfunction (02). If they survive the acute neonatal episode, they have increased risk for additional severe episodes of metabolic decompensation and hypertrophic cardiomyopathy.
Mild or later onset (type III). This is the most common presentation, with variable age of onset from infancy to adulthood (12). In countries that have established expanded newborn screening, affected individuals may be detected early on but remain asymptomatic in the newborn period and early infantile life. Most patients present with chronic muscular symptoms, including fatigue, exercise intolerance, muscle weakness, proximal myopathy, and myalgias, with or without episodes of metabolic decompensation (38). Episodes of metabolic decompensation are typically triggered by metabolic stressors, such as infection or fasting. During that time, patients present with vomiting; nonketotic hypoglycemia; metabolic acidosis; and liver dysfunction with transaminitis, hyperbilirubinemia, and coagulopathy (39). Hepatic steatosis can also occur (31). Recurrent pancreatitis has been reported in MADD (17). Rhabdomyolysis can happen in the setting of acute metabolic decompensation (28). Progressive muscle weakness can also involve the respiratory muscles, causing respiratory failure (10). Severe axonal sensory neuropathy has rarely been described in late-onset disease (36). There are case reports of patients who presented with symptoms initially indicating Guillain-Barre syndrome, without consistent electrophysiologic studies (15). Cardiac arrhythmias and ventricular wall thickness have been reported in late-onset forms in the setting of metabolic decompensation (04).
Patients with neonatal-onset disease, with or without congenital anomalies, have poor prognosis (type I worse than type II). Despite prompt intervention, most of them die within the first week of life. Infants with type II disease who survive beyond the first week of life usually die later in infancy, either due to severe cardiomyopathy or during an episode of metabolic decompensation.
A review of all 350 cases of late-onset MADD reported in the literature found that the mean age at disease onset was 19.2 years (12). Chronic muscular symptoms were more than twice as common as acute metabolic decompensations (85% versus 33% of patients, respectively). Twenty percent of affected individuals presented with both acute and chronic symptoms; 5% of patients died at a mean age of 5.8 years, whereas 3% of patients remained asymptomatic until a maximum age of 14 years. Almost all patients with late-onset MADD (98%) were clearly responsive to riboflavin.
Medical history. A 56-year-old man presented with progressive proximal myopathy of unknown origin. His previous medical history and family history were unremarkable (16). His family and previous medical history were unremarkable. Before the onset of symptoms, his exercise tolerance was unimpaired. At age 42 years he started having intermittent weakness and pain predominantly of the proximal limbs that was precipitated by physical exercise. The symptomatology slowly progressed until age 55 years and rapidly within the following year. During this year, elevated creatine kinase (1511 U/L; normal 10 to 171 U/L) was found, and EMG showed a myopathic pattern. In addition, serum lactate was elevated at rest and massively increased following physical exercise, suggesting a metabolic disorder. Precautionary supplementation of oral L-carnitine (50 mg/kg/day) resulted in no improvement. At the age of 56 years, he was referred to a specialist hospital.
Physical examination. On admission he was awake and fully oriented. He could walk a maximum of 15 meters. He developed profuse sweating and severe pain during physical exercise, such as chewing or walking. Severe muscle atrophy was found in proximal limbs and muscle tone was severely reduced, whereas muscle strength was unaffected. Deep tendon reflexes were diminished or absent. Babinski sign was negative. In contrast to motor dysfunction, examination of the sensory system revealed no abnormalities. MRI scans of the lower limbs confirmed severe muscular atrophy of musculus quadriceps femoris.
Laboratory investigations. Creatine kinase (1855 U/L; normal 10 to 171 U/L), lactate dehydrogenase (942 U/L; normal 135 to 225 U/L), and myoglobin (723 µg/L; normal < 100 µg/L) were elevated. Electroneurography of peroneal and median nerves revealed no abnormalities. In contrast to previous investigations, EMG showed no characteristic myopathic pattern of the upper and lower limbs, whereas positive sharp waves were found in deltoid muscles. A muscle biopsy (musculus rectus femoris) demonstrated degenerative changes and lipid storage in type I fibers. ATPase staining revealed no fiber type grouping. Acylcarnitine profiling in dried blood spots (filter cards) using tandem mass spectrometry (MS/MS) showed characteristic biochemical abnormalities of MADD deficiency, although subtle. The diagnosis was supported by organic acid analysis in urine and confirmed by mutation analysis demonstrating compound heterozygosity for two mutations in the ET-FDH gene, specifically c.728T>C and c.881C>T.
Therapeutic management. The patient was treated orally with 100 mg riboflavin per day. To prevent secondary carnitine deficiency, oral carnitine supplementation (50 mg/kg/day) was continued; a low-fat diet was introduced. With this treatment, muscle weakness, pain, and physical exercise capacity significantly improved, and profuse sweating stopped. He became able to walk a distance of one kilometer and to walk upstairs again. Furthermore, analysis of organic acids and acylcarnitines showed normalization of biochemical abnormalities. There were no adverse effects of therapy.
Etiology and pathogenesis. MADD is caused by an impairment of the electron transfer flavoprotein–electron transfer flavoprotein:ubiquinone oxidoreductase (ETF–ETF:QO) system, which disrupts electron flow to the mitochondrial respiratory chain at the level of coenzyme Q10 (CoQ10) and, hence, diminishes ATP production (13). ETF is a heterodimeric protein located in the mitochondrial matrix and is composed of alpha (ETFA) and beta (ETFB) subunits. ETF requires one flavin adenine dinucleotide (FAD) and one AMP as cofactors. ETF accepts electrons from several acyl-CoA dehydrogenases, enzymes involved in fatty acid oxidation, and amino acid and choline metabolism. ETF then transfers its electrons to ETF:ubiquinone oxidoreductase (ETF:QO), which, in turn, relays them to CoQ10 in the inner mitochondrial membrane. FAD is produced from riboflavin (B2), a water-soluble vitamin obtained from dietary sources and, in part, from the intestinal microflora. Individuals with dysfunction in the synthesis or transport of FAD present with a clinical and biochemical phenotype consistent with MADD.
Genetics. MADD is an autosomal recessive disease caused by homozygous or compound heterozygous variants in ETFA, ETFB, and ETFDH genes that encode for ETF and ETF:QO, respectively. Pathogenic variants in genes associated with riboflavin metabolism and transport (FLAD1, SLC52A1, SLC52A2, SLC52A3, SLC25A32) cause autosomal recessive disorders with a MADD-like phenotype and MADD-like biochemical abnormalities.
Biochemistry. Due to functional deficiency of multiple flavoprotein dehydrogenases, there is accumulation of multiple upstream substrates and metabolites that can be identified in urine and blood. Urine organic acid analysis shows elevations of glutaric acid, lactic acid, as well as many dicarboxylic acids (ethylmalonic, adipic, suberic, sebacic) and hydroxy acids (2-hydroxybutyric, 2-hydroxyglutaric, 3-hydroxyisovaleric, 2-hydroxyisocaproic acid, 5-hydroxyhexanoic acid). Plasma acylcarnitine analysis shows elevations of multiple esters of organic acids (C4, C5, C5DC, C6, C8, C10, C12, C14:1, C16, and C18:1 species). Urine acylcarnitine assay (acylglycine assay) reveals isobutyrylglycine, isovalerylglycine, hexanoylglycine, and suberylglycine. The concentration of free carnitine in the blood may be low. Sarcosine is frequently found in the serum and urine of patients with milder disease but not in the severe early-onset forms. The enzymes that synthesize and metabolize sarcosine (dimethylglycine dehydrogenase and sarcosine dehydrogenase, respectively) transfer flavin-bound electrons to ETF. In complete ETF or ETFDH deficiency (severe MADD), sarcosine biosynthesis is disrupted. In milder ETF–ETF:QO deficiencies (milder MADD), sarcosine can accumulate if its rate of oxidation is slower than its rate of biosynthesis (Frerman and Goodman 2001). Fibroblast acylcarnitine analysis following incubation with palmitic acid shows significant accumulation of C16 in severe forms and accumulation of downstream acylcarnitines (C14, C12, C10, C8) in milder forms.
Pathophysiology and implications for treatment. ETF is a mitochondrial matrix protein composed of two subunits encoded by the ETFA and ETFB genes (Frerman and Goodman 2001), alpha (30 kDa) and beta (28 kDa), and requires FAD as a cofactor (flavoprotein). ETF:QO (aka ETFDH) is an iron-sulfur flavoprotein of 64 kDa located in the inner mitochondrial membrane (37) and is encoded by the ETFDH gene. Both ETF and ETF:QO are required for electron transfer from multiple mitochondrial flavin-containing dehydrogenases to the respiratory chain at the level of coenzyme Q10. Riboflavin is used for the treatment of patients with MADD. The rationale behind this therapy is that riboflavin, which is a precursor of FAD, increases the concentrations of FAD and allows for stabilization of the defective ETF–ETF:QO complex (Berry 2005).
Coenzyme Q is the ultimate electron acceptor from the ETF–ETF:QO complex. Patients with MADD have a secondary coenzyme Q10 deficiency; thus, CoQ10 supplementation should be tried in all affected individuals (07).
Impairment of the ETF–ETF:QO complex in patients with MADD results in functional deficiency of all acyl-CoA dehydrogenases, with subsequent accumulation of metabolites that are conjugated to carnitine for excretion and subsequent secondary depletion of carnitine stores. Therefore, L-carnitine supplementation is required for patients with MADD. Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for beta oxidation. Presumably, carnitine deficiency is more important in patients with milder MADD disease as they may have marginally adequate rates of beta oxidation; carnitine depletion in these patients would further impair uptake of long-chain fatty acids into the mitochondria, leading to fat accumulation in the liver and muscles (41; 11). In severely affected MADD patients, complete deficiency of the ETF–ETF:QO complex impedes mitochondrial beta oxidation of long-chain fatty acids, even in the presence of normal carnitine stores. Hypoglycemia in the setting of MADD is caused by impaired gluconeogenesis due to limited availability of acetyl-CoA from decreased beta oxidation of fatty acids. Acetyl-CoA activates pyruvate carboxylase, which converts pyruvate to oxaloacetate, a significant substrate in the gluconeogenic pathway. Another possible mechanism for hypoglycemia is reduced generation of NADH, again, due to impaired beta oxidation, which leads to decreased glyceraldehyde phosphate dehydrogenase activity. Glyceraldehyde phosphate dehydrogenase plays an important role in glycolysis and gluconeogenesis. Limited availability of acetyl-CoA from deficient mitochondrial beta oxidation of fatty acids results in decreased ketogenesis. The limited availability of ketone bodies as alternative energy substrates during fasting, as well as reduced activation of pyruvate carboxylase and decreased gluconeogenesis, results in reduced fasting tolerance and hypoketotic hypoglycemia.
The presence of congenital anomalies in MADD type I suggests toxicity of accumulating metabolites, or the necessity of an intact energy metabolism for certain developmental processes, or both. Olsen and colleagues showed that fetal anomalies in MADD can be caused by null variants in the ETFDH or ETFB genes (26). Even small amounts of residual ETF/ETFDH activity seem to be sufficient to prevent the development of congenital anomalies giving rise to a type II disease phenotype, so expression of ETF/ETFDH appears to be essential for normal embryonic development.
Muscle involvement in MADD is correlated with the decrease of ETFDH protein and the dysregulation of circulating muscle-specific miRNAs (myomiRs) in serum; the latter might be a promising biomarker for muscle disorders (23).
Preliminary data from expanded newborn screening programs have estimated a prevalence of 1 in 750,000 to 2,000,000 newborns (19). There appears to be a highly increased incidence in the Turkish population. Riboflavin-responsive MADD is the most common cause of lipid storage myopathy in China, but its exact prevalence remains unclear (18).
Prevention of episodes of metabolic decompensation is similar to other long-chain fatty acid oxidation disorders: avoidance of prolonged fasting, a diet lower in protein/fat and higher in carbohydrates, and prompt management of intercurrent illness with adequate supplementation of calories orally or through administration of intravenous glucose if oral intake is not appropriate.
MADD can be detected by expanded newborn screening using tandem mass spectrometry (MS/MS). Although newborn screening for MADD results in the early and timely detection critical for reducing the risks of morbidity and mortality associated with this disease, adverse outcomes of promptly treated patients with MADD identified via newborn screening illustrate the significant challenges in the management of patients with this disorder (04).
Preimplantation genetic diagnosis is possible for families at risk once the pathogenic variants in ETFA, ETFB, and ETFDH genes have been identified in a previously affected family member. If the familial variants are known, prenatal genetic testing can identify affected fetuses and initiate management at birth.
Disorders of riboflavin transport and metabolism. Riboflavin (vitamin B2) is a precursor for the synthesis of flavin adenine dinucleotide (FAD). If FAD biogenesis is impaired, electron transfer by the ETF–ETF:QO complex is compromised, which can result in a clinical and biochemical presentation mimicking that of MADD (05). Riboflavin ingested in diets exists as either free riboflavin or its protein-bound form as flavoproteins, including FAD and flavin mononucleotide (FMN), which must be released from the carrier proteins to which they are bound. Three human plasma membrane riboflavin transporters have been characterized, RFVT1, RFVT2 and RFVT3, encoded by the SLC52A1, SLC52A2, and SLC52A3 genes, respectively. These three transporters have different subcellular locations and tissue specificities. Free riboflavin is transported into enterocytes via carrier-mediated uptake by RFVT3. After cellular uptake, riboflavin is converted into its catalytically active cofactors FMN and FAD by the action of two enzymes, riboflavin kinase (RFK) and FAD synthase (FADS), respectively. Riboflavin can then be released into the portal blood and to the liver in its free form or as FMN after being transported by RFVT1 and RFVT2, which are embedded within the basolateral membrane of enterocytes. RFVT2-mediated transport allows riboflavin uptake into the brain where it is highly expressed. RFVT2 is also expressed in the pancreas, liver, and muscle. Another transporter (encoded by the SLC25A32 gene) is embedded in the inner mitochondrial membrane and facilitates FAD import from cytosol to the mitochondria, where it facilitates many FAD-dependent enzymatic reactions (05).
Brown-Vialetto-Van Laere syndromes 1 and 2 are autosomal recessive disorders caused by pathogenic variants in the SLC52A3 and SLC52A2 genes, respectively. They are characterized by progressive peripheral and cranial neuronopathy that causes muscle weakness, vision loss, deafness, sensory ataxia, and respiratory insufficiency due to diaphragmatic weakness. Onset is usually in infancy or in childhood. High-dose oral supplementation of riboflavin between 10 and 50 mg/kg/day improves symptoms and objective testing (vital capacity, brainstem evoked potentials, nerve conduction studies) and normalizes acylcarnitine levels in affected individuals (06). Haploinsufficiency of the SLC52A1 riboflavin transporter associated with maternal riboflavin deficiency has been reported in two neonates who developed transient severe symptoms resembling MADD, which resolved with riboflavin supplementation (05).
FAD synthase deficiency is an autosomal disorder caused by pathogenic variants in the FLAD1 gene (27). Symptoms develop in infancy in most patients who present with hypotonia, significant muscle weakness leading to feeding difficulties, and respiratory insufficiency. Cardiomyopathy and arrhythmias can also occur. Later-onset disease presents with exercise intolerance, progressive muscle weakness, and gait difficulties. Riboflavin supplementation results in clinical improvement.
There is limited knowledge regarding mitochondrial FAD transporter deficiency (SLC25A32 gene). So far, five patients have been reported in the literature, two of whom presented with weakness and exercise intolerance and three with hypoketotic hypoglycemia (01). All improved with riboflavin supplementation.
Riboflavin kinase deficiency has not been reported in humans, possibly because it might be incompatible with life (05).
Other conditions with similar presentation. Inborn errors of metabolism that can present with hypoketotic hypoglycemia and metabolic acidosis include other fatty acid oxidation defects, HMG-CoA-lyase deficiency, and glucose-6-phosphatase deficiency. Hyperammonemia and metabolic acidosis are also typical presentations of organic acidemias. However, the characteristic urine organic acid and acylcarnitine profile differentiates MADD from other inborn errors of metabolism. A variant in the mtDNA MT-CO2 gene has been reported to mimic the acylcarnitine profile of MADD (35).
Secondary carnitine depletion occurs in most disorders that interfere with the metabolism of mitochondrial CoA-activated carboxylic acids, including organic acidurias and fatty acid oxidation defects.
Skeletal muscle symptoms of lipid storage myopathy and recurrent rhabdomyolysis are also observed in other fatty acid oxidation disorders (03). Cardiomyopathy can also develop in numerous other inborn errors of metabolism, including fatty acid oxidation, mitochondrial disorders, disorders of cytoplasmic glycogen metabolism, storage disorders, etc.
The occurrence of multiple congenital anomalies in the neonatal-onset form of MADD (type I) raises concerns for other genetic disorders, including hereditary polycystic kidney diseases. Other inborn errors of metabolism that can present with polycystic kidneys at birth are Zellweger spectrum disorders, the neonatal form of carnitine palmitoyltransferase II (CPT II) deficiency, and congenital disorders of glycosylation.
A very similar urine organic acid pattern in the setting of intermittent episodes of vomiting, hypoglycemia, and acidosis occurs in Jamaican vomiting sickness, which is induced by the toxin hypoglycin following ingestion of unripe ackees (32).
Maternal riboflavin deficiency has been reported in newborns with transient clinical and biochemical features of MADD and was responsive to riboflavin (14).
There are no established formal clinical diagnostic criteria for multiple acyl-CoA dehydrogenase deficiency. Newborn screening for MADD is primarily based on quantification of C4, C5, C8, and C14:1 acylcarnitines on dried blood spots. Values above the cutoffs are considered positive and are reported by the screening laboratory. Newborns require follow-up for confirmatory tests, including plasma acylcarnitine and urine organic acid analysis. Neonates with severe forms (type I and II) commonly present with symptoms prior to receiving or even sending newborn screening. Metabolic work-up is recommended for all neonates who present with concerning symptomatology, including metabolic acidosis, tachypnea, hypoketotic hypoglycemia, hyperammonemia, lethargy, encephalopathy, hypotonia, and abnormal odor. For later-onset forms, metabolic work-up should be considered for individuals who present with exercise intolerance, myopathy, recurrent episodes of rhabdomyolysis, cardiomyopathy, liver disease, and episodes of hypoglycemia or metabolic acidosis.
Biochemical testing. The diagnosis of MADD is established in a proband with elevation of several acylcarnitine species in plasma along with increased excretion of multiple organic acids in urine. Plasma acylcarnitine analysis is characteristic, showing an increase of acylcarnitines of all chain lengths (C4, C5, C5DC, C6, C8, C10, C12, C14:1, C16, C18:1). Urinary organic acid analysis shows elevations of multiple organic acids, including glutaric, ethylmalonic, 3-hydroxyisovaleric, 2-hydroxyglutaric, 5-hydroxyhexanoic, 2-hydroxybutyric, 2-hydroxyisocaproic, adipic, suberic, and sebacic.
Molecular testing. Confirmation of diagnosis should be performed by genetic testing to identify variants in MADD-associated genes (ETFA, ETFB, ETFDH) or other genes associated with riboflavin transport and metabolism.
Other studies. Radiologic examinations may show cardiac enlargement on chest x-ray, echocardiography may demonstrate hypertrophic cardiomyopathy, and abdominal ultrasound may indicate renal cysts. Cerebral anomalies may be identified by brain MRI.
Avoidance of prolonged fasting, a diet high in carbohydrates and low in fat and protein, as well as supplementation with riboflavin, L-carnitine, and coenzyme Q10 remain the mainstays of treatment. In the event of planned procedures that require prolonged fasting, the patient should be admitted for IV management with dextrose. Aggressive treatment during illness is critical to prevent a metabolic decompensation. Patients with metabolic diseases should be provided with a written protocol for emergency treatment that summarizes important disease information, acute initial management, and contact information for their primary metabolic physician.
Diet. A metabolic dietician should always be involved in the care of patients with MADD. Fasting should be strictly avoided. Recommendations for fasting are age dependent and are the same as those for other fatty acid oxidation disorders (22). From birth to 3 months old, infants should feed every 3 hours, then 4 hours until 4 months old and thereafter; an additional hour of fasting is allowed per month of age up to 8 hours until 12 months of age. After the age of 1, children should not fast more than 10 to 12 hours overnight. Of note, under certain circumstances (eg, periods of sickness), the interval between feeds should be reduced by 50%. A diet high in carbohydrates, reduced fat (20% to 25% of energy), and reduced protein is recommended. The goal is to provide sufficient glucose to stimulate insulin secretion to levels that will suppress fatty acid oxidation in the liver and muscle and block adipose-tissue lipolysis. A fat-restricted diet puts patients at risk for essential fatty acid deficiency, and supplementation with essential fatty acids may be necessary. Essential fatty acid linoleic acid should comprise 3% of energy intake, and alpha-linolenic acid should comprise 1% of energy intake.
Drug treatment. Riboflavin (100 to 300 mg per day) in three divided doses should be tried in all patients. Oral supplementation of L-carnitine (50 to 100 mg/kg per day) divided TID should be given to patients who are deficient. Coenzyme Q10 (60 to 240 mg/day) in two divided doses should be tried in all patients.
Surveillance. Acylcarnitine profile, carnitine battery, urine organic acids, and CPK levels should be checked at regular follow-up visits. Due to the dietary restrictions, growth should be monitored. Due to the risk of cardiomyopathy, an EKG and echocardiogram should be performed yearly, though they may be performed less frequently for more mildly affected patients.
Future directions. A systematic literature review of patients with MADD summarized evidence from 23 patients and demonstrated the efficacy and safety of orally administered D,L-3-hydroxybutyrate in a dose range of 100 to 2600 mg/kg/day (34). Clinical improvement was reported in 16 patients (70%) for cardiomyopathy, leukodystrophy, liver symptoms, muscle symptoms, and/or respiratory failure. D,L-3-HB appeared ineffective for neuropathy. Survival appeared longer with D,L-3-HB treatment compared with historical controls.
Bezafibrate was shown to improve beta oxidation on skin fibroblasts from 12 patients with MADD (40).
Possible new treatment strategies, such as the enhancement of residual enzyme activity of misfolding proteins by cofactor or chemical chaperones, has been described by Olsen and colleagues (26).
The goal of management in patients with MADD is to prevent episodes of metabolic decompensation. However, if they occur, mild patients can often be managed at home by decreasing the intervals in between feeds by 50% and increasing caloric intake to prevent catabolism. A low threshold for admission is necessary, especially for young children and infants. Patients who are unable to maintain oral intake or who are symptomatic (eg, lethargic) should be taken to the closest emergency department to initiate their emergency treatment protocol. The primary genetics team should be contacted to guide management.
IV management. IV fluids with dextrose and appropriate electrolytes should be initiated immediately to provide a glucose infusion rate of 8 to 12 mg/kg/min (typically, 1.5 times the maintenance rate or higher). The IV rate should not be decreased if hyperglycemia develops. Rather, insulin should be administered in that situation.
Drug treatment. Patients should continue their medications if they are on riboflavin, coenzyme Q10, or L-carnitine. Patients unable to tolerate enteral intake should have their daily L-carnitine dose switched to IV administration in three to four divided doses. Bicarbonate administration should be considered in patients with severe metabolic acidosis (PH < 7.10).
Labs. Ammonia level, lactic acid, blood gas, CBC, CMP, and CPK should be obtained acutely. Carnitine battery, acylcarnitine profile, and urine organic acids should be considered, though they might not be rapidly available. Additional laboratory investigation and imaging studies should be considered to identify a triggering illness (eg, urine analysis, urine culture, chest x-ray, etc). If there are significant laboratory abnormalities (hyperammonemia, electrolyte imbalances), admission to the pediatric intensive care unit should be considered for closer monitoring.
Other acute management. Hyperammonemia improves with reversal of catabolism, and, thus, ammonia scavengers are not indicated in MADD. If severe hyperammonemia and altered mental status persist after initial IV treatment, the medical team should consider extracorporeal treatment strategies. Antiemetics can be used as needed if vomiting is present. Antipyretics should be given for fever management.
Patients with presentation within a few days of birth usually succumb in infancy despite appropriate treatment, even if they do not have congenital anomalies There is clinical heterogeneity among patients with later-onset forms (12). Almost all are responsive to riboflavin. However, death can still occur (04).
There are no guidelines for the management of pregnant patients with MADD. General guidelines on pregnancy management in patients with defects in energy metabolism should be applied (24). Pregnant patients should be monitored closely during pregnancy to ensure appropriate metabolic control and adequate supply of nutrients and energy to the fetus. They should continue their medications throughout pregnancy. An acute management protocol should be applied if the pregnancy is complicated by nausea and vomiting. Patients should deliver in an appropriate hospital setting, and a delivery plan should be discussed with the patient’s metabolic physician as early as possible. Labor and delivery are times of increased energy requirement, and pregnant women with MADD should initiate IV fluids with dextrose 10% and appropriate electrolytes at 1.5 times the maintenance rate from initiation of labor until oral intake is reestablished.
Successful treatment of patients with MADD during pregnancy has been described (33; 08). A 19-year-old woman with late-onset MADD was maintained on a high-carbohydrate, low-fat protein diet throughout pregnancy; protein intake was increased at the second and third trimesters to ensure appropriate fetal growth. She had been treated with riboflavin and L-carnitine since her diagnosis at 3 years of age, and her medications were continued throughout the pregnancy.
In preparation for planned procedures and surgeries that require fasting, patients with MADD should be admitted and receive intravenous glucose infusion with dextrose 10% plus appropriate electrolytes at 1.5 times the maintenance rate. Dextrose should be initiated when fasting starts and maintained until adequate oral intake is restored. Ringer’s lactate should be avoided because of the inherent risk for lactic acidosis in patients with MADD. The anesthetic medication propofol is avoided in patients with fatty acid oxidation disorders as it is formulated in a lipid emulsion, and there are reports of severe side effects in some critically ill patients receiving high-dose propofol infusion. However, in the examination of outcomes of eight children with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and trifunctional protein deficiency, propofol was safely used for a short-duration procedure (20).
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Jerry Vockley MD PhD
Dr. Vockley of the University of Pittsburgh School of Medicine has no relevant financial relationships to disclose.
See ProfileEvgenia Sklirou MD FACMG
Dr. Sklirou of UPMC Children's Hospital of Pittsburgh has no relevant financial relationships to disclose.
See ProfileDeepa S Rajan MD
Dr. Rajan of UPMC Children's Hospital of Pittsburgh has no relevant financial relationships to disclose.
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