Carnitine palmitoyltransferase 1A deficiency
Nov. 30, 2021
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This article includes discussion of multiple acyl-CoA dehydrogenase deficiency, MADD, MAD deficiency, glutaric aciduria type II, ethylmalonic-adipic aciduria, electron transfer flavoprotein deficiency, electron transfer flavoprotein dehydrogenase deficiency, electron transfer flavoprotein: ubiquinone oxidoreductase deficiency, ETF deficiency, ETFDH deficiency, and ETFQO deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Multiple acyl-CoA dehydrogenase deficiency, also known as glutaric aciduria type II, can result in a variety of clinical manifestations. Characteristic phenotypes include the neonatal-onset (lethal) form with congenital abnormalities (type I), the neonatal-onset form with hypoketotic hypoglycemia without congenital abnormalities (type II), and the late-onset form presenting with progressive proximal myopathy (type III). The authors present novel insights in pathophysiology and genetics of Multiple acyl-CoA dehydrogenase deficiency.
• Multiple acyl-CoA dehydrogenase deficiency, also known as glutaric aciduria type II, is a mitochondrial fatty acid oxidation disorder caused by defects of electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase, or by disturbance of riboflavin metabolism.
• The disease course is highly variable, ranging from severe neonatal-onset fatal disease with congenital malformations to late-onset and treatable forms in adulthood with myopathy.
• Multiple acyl-CoA dehydrogenase deficiency has a typical biochemical pattern of organic acids in urine and especially acylcarnitines in dried blood spots or plasma.
• A fat-restricted diet, avoidance of catabolism, and supplementation with riboflavin and carnitine are the therapeutic strategies.
• Acylcarnitine profiling should always be included in the diagnostic work-up of infantile lactic acidemia.
Multiple acyl-CoA dehydrogenase deficiency (MADD, MIM 231680), also known as glutaric aciduria type II, is an autosomal recessive inherited disorder of fatty acid, amino acid, and choline metabolism (25). Przyrembel and colleagues described the first patient in 1976 (68). In most cases, the disorder is due to a defect in either the alpha or beta subunit of electron transfer flavoprotein (ETFA, OMIM 608053; ETFB, OMIM 130410) or ETF dehydrogenase (ETFDH, OMIM 231675), but in some patients the disorder appears to be due to some as yet only partially identified disturbances of riboflavin metabolism. Brown-Vialetto-Van Laere syndrome (OMIM 211530) and Fazio-Londe syndrome (OMIM 211500) were shown to be allelic with a riboflavin transporter defect, biochemically resulting in mild MADD (08).
Przyrembel and colleagues reported a Turkish patient with fatal neonatal acidosis, hypoglycemia, and a strong “sweaty feet” odor (68). Large amounts of glutaric acid were found in blood and urine. The defect was tentatively located to the metabolism of a range of acyl-CoA compounds, and the name “glutaric aciduria type II” was proposed (68).
Clinical phenotypes. The clinical presentations are highly variable and can be grouped into three categories including intermediate phenotypes: 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 with progressive proximal myopathy (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 (25).
Type I/II. Neonatal-onset patients with congenital anomalies are often born prematurely and present during the first 24 to 48 hours of life with hypotonia, hepatomegaly, severe nonketotic hypoglycemia, hyperammonemia, and metabolic acidosis, often associated with an odor of “sweaty feet.” Neonatal MADD differs from most inborn errors of intermediary metabolism in that prominent congenital malformations can be present: (type I) kidney malformations with subcortical renal glomerular cysts, renal medullary dysplasia, glomerulopathy (15), congenital polycystic kidneys (48), facial dysmorphism with a high forehead, macrocephaly, low-set ears, hypertelorism, hypoplastic midface (88), rocker-bottom feet, muscular defects of the anterior abdominal wall, anomalies of the external genitalia, including hypospadia and chordee (25), brain anomalies like cerebral pachygyria (15), and symmetric warty dysplasia of the cerebral cortex (48). Newborns without congenital anomalies usually develop hypotonia, tachypnea, metabolic acidosis, hepatomegaly, hypoglycemia, and a “sweaty feet” odor within the first few days of life. Many have had hepatomegaly (06).
Type III. The disease course and age at presentation of late-onset MADD is variable (31). The first patient to be described with this form of the disease had intermittent episodes of vomiting, hypoglycemia, and acidosis beginning at seven weeks of age (78); another patient was totally symptom-free during childhood, presenting in adult life with episodic vomiting, hypoglycemia, hepatomegaly, and proximal myopathy (21). Mongini and colleagues reported on a similar patient, a 25-year-old woman who complained of episodes of muscle weakness, nausea, and vomiting from the age of 10 years (54). Muscle biopsy showed lipid storage, and a low-lipid diet reduced the episodes. Progressive lipid storage myopathy and systemic carnitine deficiency are often described (45). Olsen and colleagues reported a patient with lipid storage myopathy due to ETFDH mutations who developed respiratory insufficiency at the age of 14 years (64). A 14-year-old boy with a background of autism spectrum disorder initially presented with severe muscle weakness and rhabdomyolysis (67). Lipid-storage myopathy may be an isolated finding in mild forms of MADD in childhood or adulthood (09). Izumi and colleagues reported an adult patient with MADD who presented with recurrent rhabdomyolysis and acute renal failure (39). A few patients developed a progressive extrapyramidal movement disorder (14). Uziel and colleagues described a boy with gradually progressive spastic ataxia and leukodystrophy without ever having experienced episodic metabolic crises (80). An adult patient with riboflavin-responsive MADD due to electron transfer flavoprotein ubiquinone oxidoreductase (ETFQO) deficiency presented with an acute encephalopathy with vomiting 10 years before the onset of muscular symptoms (53). One adult patient presented for several years with cyclic vomiting and was initially diagnosed with cyclic vomiting syndrome (24). In six patients with adult-onset multiple acyl-CoA dehydrogenase deficiency, severe axonal sensory neuropathy was diagnosed (85). A depressive state and intermittent nausea were the first symptoms of an adolescent patient (38). Brain magnetic resonance imaging of this patient showed disseminated high-intensity areas in the periventricular white matter and in the splenium of the corpus callosum on T2-weighted images and fluid-attenuated inversion-recovery images before starting the treatment. Another 7-month-old patient with MADD had a T2-weighted prolongation in the corpus striatum, putamen, caudate nucleus, middle cerebral peduncles, and splenium of the corpus callosum (55).
Recurrent pancreatitis has been recorded in MADD, and this possibility must be specifically investigated when abdominal symptoms of unknown origin occur (49). Chronic digestive disease even before the occurrence of muscle symptoms may also occur in late-onset MADD (26).
In summary, late-onset MADD is characterized by a progressive myopathy of varying degrees and time course, risk of acute muscular deteriorations and metabolic decompensation, and, occasionally, additional neurologic, digestive and other nonspecific symptoms.
The prognosis of MADD, except for cases that are responsive to riboflavin treatment, is usually severe because of multiorgan failure and/or progressive encephalopathy that develops during acute episodes and cardiac complications. Neonatal-onset patients with or without congenital anomalies are often premature, and most of them die within the first week of life (25). Infants who have survived beyond the first week of life because of prompt diagnosis and treatment have died within a few months, usually with severe decompensated cardiomyopathy. A few infants have been hypoglycemic in the newborn period and only later developed episodes of Reye-syndrome-like illness; these patients have survived somewhat longer (06; 25).
Most patients with late-onset MADD (also termed as riboflavin-responsive MADD [RR-MADD]) are well responsive to treatment with riboflavin, which often improves muscular weakness and fatigability dramatically and long-term (90).
Medical history. The authors reported a 56-year-old man with progressive proximal myopathy of unknown origin. 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. Probatory 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 at proximal limbs and muscle tone was strongly 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 all 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 MAD deficiency, although subtle. The diagnosis was confirmed by organic acid analysis in urine and 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 again able to walk a distance of one kilometer and to walk upstairs. Furthermore, analysis of organic acids and acylcarnitines showed normalization of biochemical abnormalities. There were no adverse effects of therapy (45).
Etiology and pathogenesis. Mutations in electron transfer flavoprotein (ETF) and in ETF ubiquinone oxidoreductase (ETFDH) are the molecular basis of disease in most patients with MADD, resulting in deficiency of all mitochondrial flavoprotein dehydrogenases and, thus, most importantly, impairment of energy metabolism. Other less frequent potential causes of MADD are variants in the riboflavin (32) and mitochondrial FAD transporter (75) genes. FLAD1 variants causing a disturbed riboflavin metabolism have been identified in several individuals with riboflavin-responsive and nonresponsive MADD (72).
Genetics. ETFDH mutations are the major causes of riboflavin-responsive and late-onset MADD, whereas mutations in the ETFA and ETFB genes are the exception (31). Over 80 mutations in ETFDH have been reported worldwide. ETFDH mutations can be classified into two groups: mutations affecting protein folding and assembly and mutations affecting enzymatic activity (Fan et al 2018).
Genotype/phenotype correlation. Olsen and colleagues investigated the relationship between ETF/ETFDH genotype and phenotype in nine patients with MADD (59). The molecular genetic investigations of these patients were consistent with the three clinical forms of MADD, showing a clear relationship between the nature of the mutations and the severity of disease. Homozygosity for two null mutations of ETFA, ETFB, or ETFDH was associated with neonatal onset with anomalies (type I), whereas small amounts of residual activity prevent the development of embryonic anomalies (type II). These observations establish a correlation between biochemical and clinical phenotypes. The authors also identified and characterized seven novel mutations in ETF/ETFDH genes (59). By contrast, similar ETFDH genotypes may result in significant clinical heterogeneity (26).
Pathophysiology and implications for treatment. ETF is a mitochondrial matrix protein consisting of alpha (30 kDa) and beta (28 kDa) subunits encoded by ETFA (chromosome 15q23-q25) and ETFB (chromosome 19q13.3) genes (25). ETFDH exists as 64 kDa monomer in the inner mitochondrial membrane, with the cofactors FAD and a [4Fe-4S](+1+2) cluster (86), and is encoded by the ETFDH gene (chromosome 4q32--> qter). Both enzymes are required for electron transfer from at least nine mitochondrial flavin-containing dehydrogenases to the respiratory chain. The disorders resulting from defects in the ETFA, ETFB, or ETFDH genes are referred to as glutaric aciduria IIA, IIB, and IIC, respectively, although there appears to be no difference in the clinical phenotype.
Russell and colleagues studied the metabolic disturbances of riboflavin-responsive MADD (71). Biochemical and molecular tests demonstrated decreases in fatty acid beta-oxidation, in the activities of respiratory chain complexes I/II and an increase of muscle uncoupling protein-3 (UCP3) mRNA and protein expression. All abnormalities were restored by riboflavin treatment. The authors postulated that upregulation of UCP3 in MADD is due to the accumulation of muscle fatty acids/acyl-CoAs, and the effects of fatty acids on UCP3 expression are direct and independent of fatty acid beta-oxidation. An inhibition of mitochondrial fusion with increased fractionation and mitophagy has been observed in riboflavin responsive MADD patient fibroblasts, which was positively influenced by CoQ10 treatment (16).
The induction of a severe mitochondrial dysfunction has been observed for different missense mutations in the ETFDH gene, leading to a vicious cycle between mitochondrial dysfunction and lipid droplet accumulation (13). Riboflavin/flavin cofactors seem to be involved in modulating the level of a number of functionally coordinated polypeptides involved in fatty acyl-CoA and amino acid metabolism, extending the number of enzymatic pathways altered in riboflavin-responsive MADD (28). Wen and colleagues report increased muscle CoQ10 in several riboflavin responsive MADD patients, underlining the possible secondary effect of CoQ10-shifts (87).
Brown-Vialetto-Van Laere syndrome and Fazio-Londe syndrome were shown to be associated with a riboflavin transporter defect, biochemically resulting in mild MADD, which was riboflavin responsive (08).
A large study including 15 patients with riboflavin-responsive MADD revealed that this disease is often caused by defects of electron transfer flavoprotein ubiquinone oxidoreductase (ETFQO) (63). Olsen and colleagues demonstrated that the clinical phenotype of MADD is influenced by environmental factors such as cellular temperature. This was particularly obvious in patients with milder forms of MADD (type III), in whom residual ETF/ETFDH-enzyme activity allowed modulation of the enzymatic phenotype. Overexpression studies of an ETFB-D128N missense mutation identified in a patient with type III disease showed that the residual activity of the mutant enzyme could be restored up to 59% of that of wild-type activity when ETFB-D128N-transformed E coli cells were grown at low temperature. The ETFB-D128N mutant enzyme displayed significantly decreased resistance to thermal inactivation compared to wild-type ETF. The authors concluded that fever may lead to a further decrease in the level of active ETF enzyme activity (59). Henriques and colleagues demonstrated that under stress conditions, such as fever, flavin becomes less tightly bound to the disease-causing ETFbeta-D128N variant protein. The authors concluded that flavinylation is important for the conformational stability and biological activity of this protein variant. The supplementation of riboflavin, the precursor of FAD, may enhance the conformational stabilization of the mutant ETFQO protein (34). Missense mutations of ETF essentially fall into two groups: one in which mutations affect protein folding, assembly, and interplay, and another in which mutations impair catalytic activity and disrupt interactions with partner dehydrogenases (61). In comparison to controls, the mitochondrial proteome of a patient with MADD expressed different proteins associated to binding-folding functions and apoptosis, and mitochondrial antioxidant enzymes (69). Cornelius and colleagues reported folding defects in the variant ETFQO proteins and genotype-phenotype correlations of these defects for the riboflavin responsiveness in MADD (17). The authors observed milder folding defects in riboflavin-responsive MADD than in non- or partially responsive MADD in a human HEK293 cell expression system. Clinical improvement on riboflavin-responsive MADD has been attributed to the removal of an autophagic block associated with p62-positive aggregates, which appears to be reversible in this lipid storage myopathy (02).
Chew and colleagues reported a Caenorhabditis elegans homolog of human electron flavoprotein dehydrogenase in order to establish a tractable model system for further exploration of ETFDH structure and function (10). Potential model organisms for MADD may be a Drosophila ETFQO mutant with a MADD-like severe phenotype and a zebrafish model of MADD (01). Similar to MADD patients, the knock-out zebrafish had a wide spectrum of phenotypes from mild to severe and showed multi-organ abnormalities (43).
Biochemistry. Inherited deficiency of ETF or ETFDH results in functional deficiency of several flavoprotein dehydrogenases and an accumulation of upstream substrates and metabolites in body fluids and tissues, such as the organic acids glutaric acid, ethylmalonic acid, D-2-hydroxyglutaric acid, and dicarboxylic acids (eg, dodecanoic acid, sebacic acid), resulting in metabolic acidosis and accumulation of different glycine esters (eg, isovalerylglycine) as well as carnitine esters (eg, butyryl-, isovaleryl-, glutaryl-, octanoyl-, myristoleylcarnitine). Sarcosine is frequently found in serum and urine of less severely affected patients but not in patients with acute neonatal onset. Sarcosine is synthesized by dimethylglycine dehydrogenase and metabolized by sarcosine dehydrogenase. Both enzymes transfer flavin-bound electrons to ETF. In complete ETF or ETFDH deficiency, sarcosine biosynthesis might be blocked, which is in contrast to less severe deficiency of ETF or ETFDH, in which sarcosine would accumulate if its rate of oxidation was slower than its rate of biosynthesis (25).
Complications. Secondary carnitine deficiency is a characteristic sequel of enhanced formation and urinary loss of acylcarnitines. It further impairs uptake of long-chain fatty acids into mitochondria of skeletal muscle and hepatocytes, leading to fat accumulation (fatty infiltration of liver, lipid storage myopathy of type I muscle fibers) and organ dysfunction (hepatopathy, myopathy). Carnitine deficiency is more likely to be of significance in patients with milder disease because a complete deficiency of ETF or ETFDH would preclude mitochondrial beta-oxidation of fatty acids in severely affected children, even in the presence of normal carnitine stores. Limited availability of acetyl-CoA from deficient mitochondrial beta-oxidation of fatty acids results in decreased ketogenesis and hyperammonemia (decreased synthesis of N-acetylglutamate), which may trigger encephalopathy and Reye-like syndrome during metabolic decompensation. The limited availability of ketone bodies as alternative energy substrates during fasting as well as reduced allosteric activation of pyruvate carboxylase and decreased gluconeogenesis results in reduced fasting tolerance and hypoketotic hypoglycemia (25). Decreased formation of ketone bodies may favor the manifestation of cardiomyopathy. The presence of congenital anomalies suggests a specific toxicity of at least one accumulating metabolite, or the necessity of an intact energy metabolism for certain developmental processes, or both. The similarity of the renal lesions (cystic dysplasia) to those seen in riboflavin deficiency, Zellweger syndrome, and neonatal carnitine palmitoyltransferase II deficiency has been noted but remains unexplained. Olsen and colleagues showed that congenital anomalies in MADD can be caused by null mutations in the ETFDH or ETFB gene. 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 that regulated expression of ETF/ETFDH appears essential for normal embryonic development (59). Onkenhout and colleagues determined the fatty acid composition of liver, skeletal muscle, and heart obtained postmortem from patients with medium-chain acyl-CoA dehydrogenase deficiency, multiple acyl-CoA dehydrogenase deficiency, and very long-chain acyl-CoA dehydrogenase deficiency and could demonstrate that the pattern of accumulation of intermediates from unsaturated fatty acid oxidation is characteristic for each disease (66).
No accurate figures exist on the prevalence of MADD. More than 50 cases of MADD have been reported to date (29) since its first description in 1976 (68). Preliminary data from expanded newborn screening programs have estimated a prevalence of 1 in 750,000 to 2,000,000 newborns (51). There appears to be a highly increased incidence in the Turkish population (19).
Prevention of metabolic decompensation in fatty acid oxidation disorders, in general as in MADD, consists of avoiding prolonged fasting periods, a continuous treatment with a high-caloric and fat-reduced diet, and prompt management of intercurrent illness. Fasting periods should be limited; during intercurrent illness, carbohydrate feeding should be provided every four to six hours. With gastroenteritis or the development of early signs of unusual lethargy, it is necessary to intervene promptly with intravenous glucose infusion.
Prenatal diagnosis is, at present, the only available tool to prevent MADD.
The clinical features of multiple acyl-CoA dehydrogenase deficiency are heterogenous and can overlap with those of patients with deficiencies of other enzymes of the beta-oxidation pathway. Infants with deficiency of the medium-chain or long-chain acyl-CoA dehydrogenases, in particular, often present with episodes of fasting-induced lethargy, vomiting, and coma beginning in the first two years of life.
The urinary profile of organic acids in MADD combines the features of different organic acid disorders (glutaric aciduria type I, isovaleric aciduria) and mitochondrial fatty acid oxidation defects (short-, medium-, and very long-chain acyl-CoA dehydrogenase deficiencies). The hyperammonemia seen in MADD may suggest a urea cycle disorder, but elevation of blood ammonia is usually milder, and attacks of illness are often provoked by prolonged fasting rather than by protein feeding. An increase of all chain length acylcarnitines in plasma acylcarnitine profile can also be seen in patients with renal insufficiency or rhabdomyolysis. A mutation in the mtDNA MT-CO2 gene may mimic the acylcarnitine profile of MADD (84). Lactic acidosis may be mistaken for a primary respiratory chain disorder or pyruvate dehydrogenase or carboxylase deficiencies. In addition, severe asphyxia in neonates can present with lactic acidosis. A plasma acylcarnitine profile should always be included in the diagnostic work-up of infantile lactic acidemia. 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. The clinical presentation of later-onset MADD with intermittent episodes of vomiting, hypoglycemia, and acidosis may resemble Jamaican vomiting disease induced by the toxin hypoglycin (77). The symptoms of skeletal muscle involvement (lipid storage myopathy and recurrent rhabdomyolysis) in the milder form of MADD (type III) are also observed in the following metabolic disorders: SCADD, VLCADD, LCHADD, primary carnitine deficiency (82; 47), and carnitine palmitoyltransferase 2 deficiency (CPTII) (46). Other lipid storage myopathies include neutral lipid storage disease that may be associated with ichthyosis (57). The clinical picture of cardiomyopathy may also develop in other disorders of fatty acid oxidation, in particular those involving long-chain fatty acids (very long-chain acyl-CoA dehydrogenase deficiency, long-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency, trifunctional protein deficiency), in carnitine palmitoyl-CoA transferase II deficiency, in carnitine-acylcarnitine translocase deficiencies, in electron chain deficiencies, in D-2-hydroxyglutaric aciduria, in congenital muscular dystrophy, and in storage diseases (glycogenosis type II/III, mucopolysaccharidoses). The occurrence of multiple congenital anomalies in the neonatal-onset form of MADD (type I) leads to a broad spectrum of differential diagnoses. Polycystic kidneys are a typical clinical feature of hereditary polycystic kidney diseases. Other inborn errors of metabolism that can present with polycystic kidneys are Zellweger syndrome and congenital disorders of glycosylation (CDG). Brain anomalies can overlap with several diseases, particularly macrocephaly, which occurs in a number of inborn errors of metabolism (eg, glutaric aciduria type I, D-2- and L-2-hydroxyglutaric acidurias, etc.). The neurologic symptoms, including extrapyramidal movement disorder, spastic ataxia, leukodystrophy, and autism spectrum disorder, which have been described in some patients with MADD (14; 80), have an especially broad differential diagnosis. As these patients are mostly well responding to specific therapy, at least determination of acylcarnitines should be performed generously. Brown-Vialetto-Van Laere syndrome and Fazio-Londe syndrome were shown to be associated with a riboflavin transporter defect, resulting biochemically in mild MADD (08). Finally, because MADD can lead to sudden death or Reye-like symptoms, a wide range of causes with these similar presentations has to be considered with at least determination of acylcarnitines.
MADD is the likely diagnosis in newborns with hypoketotic hypoglycemia and metabolic acidosis (with or without congenital anomalies) in the presence of a characteristic organic acid pattern in urine detected by gas chromatography-mass spectrometry and/or a characteristic acylcarnitine profile in dried blood spots or plasma detected by MS/MS (eg, expanded newborn screening) (51).
Laboratory tests. The typical urinary pattern of organic acid excretion is often critical for the diagnosis of MADD and shows various combinations of short-chain partially volatile acids such as isovaleric, isobutyric, 2-methylbutyric, glutaric, ethylmalonic, 3-hydroxyisovaleric, 2-hydroxyglutaric, 5-hydroxyhexanoic, adipic, suberic, sebacic, and dodecanoic acids, as well as isovalerylglycine, isobutyrylglycine, and 2-methylbutyrylglycine. Plasma acylcarnitine profile is also characteristic, showing an increase of acylcarnitines of all chain lengths. This technique has been adapted for newborn screening, leading to early diagnosis in some countries (51).
Ombrone and colleagues established the analysis of urinary acylglycines by liquid chromatography coupled with tandem mass spectrometry for the diagnosis of inborn errors of metabolism, such as multiple acyl-CoA dehydrogenase deficiency (65).
The biochemical pattern found in MADD is also found in Jamaican vomiting sickness, which occurs after ingestion of unripe ackees, inducing severe riboflavin deficiency (77); however, this condition is usually easy to exclude by history. Further laboratory findings may be a mild hyperammonemia, low carnitine concentration in plasma, and an elevation of sarcosine in serum and urine.
Diagnosis in late-onset patients (type III) is often more difficult because metabolic acidosis may be absent and the characteristic pattern of organic acids and acylcarnitines may be less pronounced or only intermittently detectable, ie, during acute metabolic crises (20). Endo and colleagues report an in vitro probe acylcarnitine profiling assay using cultured fibroblasts with various fatty acids as substrates that distinguishes severe neonatal-onset forms from mild late-onset forms of MADD (22). The finding of 2-hydroxyglutaric aciduria in such patients is a useful diagnostic marker, serving to distinguish the condition from glutaric acidemia type I, in which 3-hydroxyglutaric acid is excreted. Confirmation of diagnosis should be performed by mutation and enzyme analysis. The diagnosis can also be ascertained by evaluating the specific activity of ETF/ETFDH in fibroblasts. The activity can be measured by following spectrophotometrically the reduction of dichlorophenol indophenol by tissue supernatants, in the presence of octanoyl-CoA and purified medium-chain acyl-CoA dehydrogenase (74). The defect can also be identified by Western blot analysis (52) or immunoprecipitation demonstrating deficient ETF or ETFDH in fibroblasts or other appropriate tissue, eg, liver. Molecular analysis of the patient’s tissues, eg, fibroblasts, confirms the diagnosis (74).
Patients with myopathies of unknown origin, metabolic acidosis, or hypoglycemia should be carefully screened for inherited metabolic disorders. Because not only MADD, but also other fatty acid oxidation defects can be simultaneously detected by MS/MS screening, an acylcarnitine profiling in dried blood spots or plasma should be performed (05).
Diagnostic procedures. Additionally, 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 MRI.
Family history is also important for these diseases to determine if prior siblings have died, sometimes categorized as sudden unexplained (infant) deaths. Some families with these disorders have already suffered the loss of at least one other child. The original newborn screening card of dead siblings may still be available and can be utilized for acylcarnitine profile or molecular analysis.
Patients with metabolic diseases should be supplied with an emergency card, letter, or bracelet containing instructions for emergency measures and phone numbers (35).
Treatment goals. The management of MADD is similar to the management of the other fatty acid oxidation disorders and includes avoiding fasting by frequent feeding in order to prevent the use of fatty acids as a fuel, maintaining high carbohydrate and low fat intake, and treating intercurrent episodes of illnesses with intravenous glucose.
Dietary treatment. It is usually recommended that 65% to 75% of total energy intake comes from carbohydrates, 20% to 25% from fat (including essential fatty acids), and 8% to 10% from proteins (07). The goal is to provide sufficient glucose to stimulate insulin secretion to levels that will suppress fatty acid oxidation in liver and muscle and will block adipose-tissue lipolysis. A fat-restricted diet may put patients at risk of deficiency of essential fatty acids; therefore, supplementation with essential fatty acids can be necessary in order to meet the requirements for age (1% to 4% of energy intake). Some patients may be able to tolerate fasting periods up to 12 hours. Determination of an individually safe fasting tolerance should be done under controlled circumstances and careful clinical supervision, and it should include the determination of plasma acylcarnitine profiles and urinary organic acids in short intervals (35).
Drug treatment. Several patients with mild variants of MADD have been reported to respond to supplementation with high doses of riboflavin (100 to 300 mg per day), the cofactor for these enzymes (37). Riboflavin supplementation (100 to 300 mg per day) in three divided doses should be systematically tested in all patients. Because most patients with MADD have low plasma free carnitine levels secondary to increased excretion of acylcarnitine derivatives, an oral supplementation of carnitine (starting dosage 100 mg/kg per day) is mandatory in order to prevent deficiency and to allow the detoxification process to continue (07). Vieira and colleagues describe riboflavin-responsiveness also in severe MADD presenting with profound hypotonia and hepatomegaly (83).
To reduce energy failure in brain, heart, and muscle due to defective ketogenesis in patients with MADD, oral administration of D,L-3-hydroxybutyrate (100 to 1000 mg/kg per day orally) may be beneficial. Beneficial effects have been observed in four patients with the severe infantile form of MADD who presented with progressive leukodystrophy or with acute heart failure and myolysis that did not respond to classical therapy. Oral administration of D,L-3-hydroxybutyrate in increasing doses has resulted in sustained clinical and biochemical improvement (81; 27).
New treatment strategies. 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 (62).
The outcomes of patients suffering from MADD type I/II are still bleak, and they usually succumb in infancy. This is different from the outcomes in MADD type III, which is highly variable and life-threatening if not recognized and treated. The oldest patient with late-onset MADD described in literature was 69 years old (03). After riboflavin treatment, the patient’s clinical status dramatically improved and morphologic changes in muscle disappeared. Araki and colleagues reported another 62-year-old patient with late-onset MADD who showed a dramatic response to riboflavin in both clinical and biochemical aspects (04). Rosa and colleagues reported a child with MADD who also improved dramatically after riboflavin, carnitine, and ubiquinone treatment (70).
The identification of MADD by expanded newborn screening is, therefore, an important tool to initiate early treatment, to prevent severe manifestations, and to improve the outcomes of these patients (41).
Prenatal diagnosis. Prenatal diagnosis of MADD has been established by molecular testing or by demonstrating increased glutaric acid in amniotic fluid (40), acylcarnitine esters in maternal urine (73), and impaired substrate oxidation by whole cultured amniocytes (06). Schuelke and colleagues demonstrated the difficulties that can arise from prenatal diagnosis based on biochemical results alone (76). They indicated that biochemical tests on cultured chorionic villi may be influenced by maternal cell contamination, which should be excluded by microsatellite marker analysis or, when the fetus is male, by chromosome analysis. Methods measuring ETF or ETFDH antigen or activity require amounts of tissue that are not easily obtained by amniocentesis or chorionic villus sampling. Olsen and colleagues reported a DNA-based prenatal diagnosis from chorionic villus samples in the first trimester for severe and variant forms of MADD (60). The authors used the knowledge of the mutational status in three unrelated families.
In routine ultrasound, enlarged echogenic kidneys can be a sign of fetal MADD. Chisholm and colleagues reported the occurrence of MADD in two consecutive pregnancies in a young patient (12). The maternal serum and amniotic fluid concentration of alpha-fetoprotein were elevated. Both fetuses had growth delay and cystic renal changes. These cases provide additional information regarding the evolution of renal changes in affected fetuses and show a relationship with elevated alpha-fetoprotein, which may be useful in counseling couples at risk.
Pregnancy. Harpey and colleagues described a family with seven perinatal deaths, in which the mother was found to excrete 3-hydroxyisovaleric, glutaric, and C6-C10-dicarboxylic acids in the urine during seven months of the following two pregnancies (33). Cases of successful treatment during pregnancies in patients with MADD have been described (79; 18). Riboflavin therapy was instituted in the last trimester of the pregnancies, and the infants developed normally. A probable disorder of riboflavin metabolism was suggested, resulting in MADD. A transient multiple acyl-CoA dehydrogenation defect in a newborn female caused by maternal riboflavin deficiency has been described by Chiong and colleagues (11).
In patients with MADD, precautions should be taken before anesthesia: firstly, patients should avoid prolonged perioperative fasting periods (35). Intravenous glucose infusion (8 to 12 mg/kg per minute in infants) should be given to prevent fatty acid oxidation. Metabolic acidosis should be corrected. Ringer’s lactate should be avoided because of lactic acidosis. Drugs stimulating lipolysis and fatty acid oxidation, like epinephrine and other beta-agonists, might pose a hazard for patients with disorders of fatty acid oxidation. Enflurane was reported to increase free fatty acids during perioperative stress caused by minor elective surgery (44). Premedication with morphine, flunitrazepam, and promethazine had no effect on plasma concentrations of free fatty acids (36). Propofol infusion syndrome, a rare but frequently fatal complication in critically ill children given long-term propofol infusions, results in an impaired fatty acid oxidation and an inhibition of the respiratory chain at several points (89). It should definitively not be used in MADD.
Farag and colleagues reported the anesthetic management of ventricular septal defect in a child with MADD and reviewed the literature about anesthetic management of patients with mitochondrial diseases undergoing cardiopulmonary bypass (23). The anesthetic management included avoidance of inhalation anesthetics, maintenance of blood sugar within the normal limits, and normothermia in order to avoid additional stress by hypothermia. The patient tolerated the procedure well and experienced a good recovery. The anesthesia was performed with ketamine and fentanyl. The relaxation was done with rocuronium, although muscle relaxants are often avoided in mitochondrial cytopathies due to reports of prolonged recovery time (56). In a pediatric patient with acute appendicitis and ETFDH deficiency, the combination of fentanyl, low-dose propofol, and nitrous oxide did not result in an adverse outcome (50). A review of the literature concerning the anesthetic management of patients with ETFDH deficiency was published (50). However, in one case report, a malignant hyperthermia-type episode occurred when inhalation anesthetics and succinylcholine were used (58). Vigilant monitoring of respiratory function should be maintained because several authors report a decreased ventilatory response to hypoxia and hypercarboxia in patients with mitochondrial cytopathies (42). Grice and colleagues described a 31-year-old patient presenting to intensive care with a severe persisting metabolic acidosis without apparent cause. The patient was finally diagnosed to suffer from MADD. The authors discussed the pathophysiology of this condition along with potential treatment options from an anesthesiologic point of view (30).
Marina A Morath MD
Dr. Morath of University Children's Hospital in Heidelberg, Germany, has no relevant financial relationships to disclose.See Profile
Georg F Hoffmann MD
Dr. Hoffmann of the University Center for Child and Adolescent Medicine in Heidelberg has no relevant financial relationships to disclose.See Profile
Jennifer Friedman MD
Dr. Friedman of the University of California San Diego has no relevant financial relationships to disclose.See Profile
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Childhood Degenerative & Metabolic Disorders
Nov. 30, 2021
Childhood Degenerative & Metabolic Disorders
Nov. 12, 2021
Childhood Degenerative & Metabolic Disorders
In this clinical article, the authors describe the different manifestations of this inborn error of leucine catabolism and explain pathophysiology, disease
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Childhood Degenerative & Metabolic Disorders
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Childhood Degenerative & Metabolic Disorders
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Childhood Degenerative & Metabolic Disorders
Leukodystrophies affect the brain, spinal cord, and peripheral nerves, and can cause problems with movement, vision, hearing, balance, ability to eat, memory, behavior, and thought. The various types of leukodystrophies are caused by gene abnormalities leading to destruction of the myelin sheath.
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Childhood Degenerative & Metabolic Disorders
Folate deficiency is characterized by megaloblastic anemia and less frequently by neurologic problems, including forgetfulness, irritability, neuropathy or myelopathy. Maternal folate deficiency early in pregnancy is also a major risk factor for fetal neural tube defects. Deficiency may arise as the result of dietary deficiency, alcoholism, or generalized malabsorption, such as in sprue or celiac disease.
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Childhood Degenerative & Metabolic Disorders
Cerebral folate deficiency can be produced by a specific transport defect resulting in decreased transport of folate across the blood-brain barrier at the choroid plexus. This may be caused by either folate receptor alpha deficiency resulting from mutations of the FOLR1 encoding gene with an autosomal-recessive pattern of transmission, or by production of blocking/binding autoantibodies. Patients may have developmental delay or regression, hypotonia, seizures, visual disturbances, and autistic features.
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