Multiple Acyl-Coa Dehydrogenase Deficiency
Summary
Clinical characteristics.
Multiple acyl-CoA dehydrogenase deficiency (MADD) represents a clinical spectrum in which presentations can be divided into type I (neonatal onset with congenital anomalies), type II (neonatal onset without congenital anomalies), and type III (late onset).
Individuals with type I or II MADD typically become symptomatic in the neonatal period with severe metabolic acidosis, which may be accompanied by profound hypoglycemia and hyperammonemia. Many affected individuals die in the newborn period despite metabolic treatment. In those who survive the neonatal period, recurrent metabolic decompensation resembling Reye syndrome and the development of hypertrophic cardiomyopathy can occur. Congenital anomalies may include dysmorphic facial features, large cystic kidneys, hypospadias and chordee in males, and neuronal migration defects (heterotopias) on brain MRI.
Individuals with type III MADD, the most common presentation, can present from infancy to adulthood. The most common symptoms are muscle weakness, exercise intolerance, and/or muscle pain, although metabolic decompensation with episodes of rhabdomyolysis can also be seen. Rarely, individuals with late-onset MADD (type III) may develop severe sensory neuropathy in addition to proximal myopathy.
Diagnosis/testing.
The diagnosis of MADD is established in a proband with elevation of several acylcarnitine species in blood in combination with increased excretion of multiple organic acids in urine and/or by identification of biallelic pathogenic variants in ETFA, ETFB, or ETFDH.
Management.
Treatment of manifestations: Routine daily treatment includes limitation of protein and fat in the diet, avoidance of prolonged fasting, high-dose riboflavin (100-300 mg daily), carnitine supplementation (50-100 mg/kg daily in 3 divided doses) in those with carnitine deficiency, and coenzyme Q10 supplements (60-240 mg daily in 2 divided doses). Further treatments include feeding therapy with consideration of gastrostomy tube for those with failure to thrive, as well as standard treatment for developmental delay, cardiac dysfunction, and sensory neuropathy. Emergency outpatient treatment for mild decompensation includes decreasing the fasting interval, administration of antipyretics for fever, and antiemetics for vomiting. Acute treatment includes hospitalization with intravenous fluid containing at least 10% dextrose, and bicarbonate therapy depending on the metabolic status.
Prevention of primary manifestations: Avoidance of fasting and supplementation with riboflavin, L-carnitine, and coenzyme Q10; a diet restricted in fat and protein is prescribed for some affected individuals based on the severity of the disorder.
Prevention of secondary complications: Education of parents and caregivers such that diligent observation and management can be administered expediently in the setting of intercurrent illness or other catabolic stressors. Prompt initiation of dextrose containing intravenous fluids is essential to avoid complications such as liver failure, rhabdomyolysis, encephalopathy, and coma. Written protocols for emergency treatment should be provided to parents and primary care providers/pediatricians, and to teachers and school staff.
Surveillance: Measurement of plasma free and total carnitine, acylcarnitine profile, serum creatine kinase (CK), urine organic acids, head circumference (in infants and children), and growth and developmental milestones at each visit; neuropsychological testing and standardized quality-of-life assessment tools for affected individuals and parents/caregivers as needed; EKG and echocardiogram annually for individuals with severe forms of MADD and less frequently for individuals with milder presentations.
Agents/circumstances to avoid: Inadequate caloric provision during stressors (including following vaccination); prolonged fasting; dehydration; high-fat, high-protein diet; volatile anesthetics and those that contain high doses of long-chain fatty acids; administration of intravenous intralipids during an acute metabolic crisis.
Evaluation of relatives at risk: Testing of all at-risk sibs of any age is warranted (targeted molecular genetic testing if the familial pathogenic variants are known in parallel with plasma acylcarnitine profile, plasma free and total carnitine, and urine organic acid assay) to allow for early diagnosis and treatment of MADD.
Pregnancy management: Successful pregnancy with low-fat, high-carbohydrate diet in late-onset MADD has been published. There is no evidence to suggest that taking supplemental carnitine during pregnancy leads to adverse fetal effects. Riboflavin is a B vitamin and is considered an essential nutrient that is likely eliminated through feces and urine and does not result in excessive tissue absorption.
Genetic counseling.
MADD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% change of being affected, a 50% chance of being unaffected and a carrier, and a 25% change of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member.
Diagnosis
Formal clinical diagnostic criteria for multiple acyl-CoA dehydrogenase deficiency (MADD) have not been established.
Suggestive Findings
Scenario 1. Abnormal Newborn Screening (NBS) Result
NBS for MADD is primarily based on quantification of the analytes C4, C5, and C8 with or without other higher acylcarnitine species on dried blood spots.
Multiple acylcarnitine species (C4, C5, C8, and other higher acylcarnitine) values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing, including plasma acylcarnitine and urine organic acid profiles (see Supportive Laboratory Findings, Specific findings).
If follow-up biochemical testing supports the likelihood of MADD, additional testing is required to establish the diagnosis (see Establishing the Diagnosis).
Medical interventions (see Management) need to begin immediately on receipt of an abnormal NBS result while additional testing is being performed to confirm the diagnosis.
Note: The most severe neonatal-onset form of MADD presents in the newborn period despite initiation of treatment. A newborn may become symptomatic before NBS is sent or resulted.
Scenario 2. Symptomatic Individual
Supportive – but often nonspecific – clinical findings, supportive laboratory findings, and other studies can include the following.
Clinical Findings
Neonatal onset
- Encephalopathy
- Tachypnea
- Hepatomegaly
- Hypotonia
Neonatal-onset form can present with or without congenital anomalies. When present, the main congenital anomalies are:
- Dysmorphic facial features (See Clinical Characteristics.)
- Dysplastic kidneys
- Rocker-bottom feet
- Hypospadias with or without chordee in males
Late onset (onset of signs and/or symptoms at any age beyond the neonatal period)
- Episodic vomiting with hypoglycemia and metabolic acidosis
- Muscle weakness and/or exercise intolerance
- Reye syndrome-like illness
- Rhabdomyolysis
- Acute respiratory failure
Supportive Laboratory Findings
Nonspecific findings
- Hypoglycemia (nonketotic or hypoketotic) with blood glucose often less than 45 mg/dL
- Urinalysis that demonstrates the absence of ketones in the setting of hypoglycemia
- Metabolic acidosis
- Hyperammonemia; blood ammonia level may be more than 200 µmol/L in newborns and more than 100 µmol/L after the neonatal period.
- Elevated liver transaminases (AST, ALT)
- Elevated creatine kinase (CK), particularly in the late-onset myopathic form
- A CK value greater than five times the upper limit of reference (range 1,000-100,000 IU/L) is suggestive of rhabdomyolysis.
- A CK value of greater than 15,000 IU/L at presentation increases the risk for acute kidney injury [Bosch et al 2009].
Specific findings. The elevation of multiple acylcarnitine species of different length size in blood in combination with increased excretion of multiple organic acids in urine is highly suggestive of MADD.
- Plasma acylcarnitine profile typically shows elevations of C4, C5, C5DC, C6, C8, C10, C12, C14:1, C16, and C18:1.
- Urine organic acid analysis shows elevations of multiple organic acids, including:
- Lactic acid
- Glutaric acid
- 2-hydroxyglutaric acid
- 2-hydroxybutyric acid
- 2-hydroxyisocaproic acid
- 3-hyroxyisovaleric acid
- 5-hydroxyhexanoic acid
- Ethylmalonic acid
- Adipic acid
- Suberic acid
- Sebacic acid
- Other dicarboxylic acids
- Urine acylglycine assay shows elevations of:
- Isobutyrylglycine
- Isovalerylglycine
- Hexanoylglycine
- Suberylglycine
Note: Because elevations of these metabolites individually are not entirely specific to MADD and can be intermittent, follow-up testing is required to establish the diagnosis of MADD (see Establishing the Diagnosis).
Other Studies
Brain MRI may show increased signal intensity of periventricular white matter, basal ganglia, and corpus callosum in T2-weighted images [Nyhan et al 2012, Vieira et al 2017]. In the most severe neonatal forms, subcortical heterotopias may be seen.
Muscle imaging, biopsy, and enzymology
- MRI of affected muscle group typically shows fatty infiltration and edema [Zhao et al 2018].
- Muscle biopsy outside an episode of rhabdomyolysis, in the late-onset form with myopathic presentation, shows extramitochondrial lipid accumulation characteristic of lipid storage myopathy, which may be accompanied by coenzyme Q10 deficiency [Liang & Nishino 2011, Whitaker et al 2015].
- Diminished activity of mitochondrial respiratory chain complexes has also been reported [Angelini et al 2018].
Note: Muscle imaging, biopsy, and enzymology are not required to establish the diagnosis of MADD.
Establishing the Diagnosis
The diagnosis of MADD is established in a proband with elevation of several acylcarnitine species in blood in combination with increased excretion of multiple organic acids in urine AND/OR by identification of biallelic pathogenic variants in ETFA, ETFB, or ETFDH (see Table 1).
Molecular Genetic Testing Approaches
Scenario 1. Abnormal NBS result. When NBS results and other laboratory findings suggest the diagnosis of MADD, molecular genetic testing approaches can include serial single-gene testing or use of a multigene panel:
- Serial single-gene testing. Sequence analysis detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.
- 1.
Perform sequence analysis of ETFDH first. If only one pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- 2.
Perform sequence analysis of ETFA or ETFB second. If only one pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- 3.
Lastly, perform sequence analysis of the remaining gene. If only one pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
- A multigene panel that includes ETFA, ETFB, ETFDH, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Scenario 2. Symptomatic individual
- For a symptomatic individual who has findings associated with late-onset MADD or untreated neonatal-onset MADD (resulting from symptoms before NBS is resulted, NBS not performed, or false negative NBS result), molecular genetic testing approaches can include serial single-gene testing or use of a multigene panel.
- When the diagnosis of MADD has not been considered, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is an option. Exome sequencing is most commonly used; genome sequencing is also possible.For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Multiple Acyl-CoA Dehydrogenase Deficiency
| Gene 1, 2 | Proportion of MADD Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3, 4 Detectable by Method | |
|---|---|---|---|
| Sequence analysis 5 | Gene-targeted deletion/duplication analysis 6 | ||
| ETFA | 5% 7 | ~90% 8 | 1 reported 9 |
| ETFB | 2% 7 | ~90% 10 | None reported 4 |
| ETFDH | 93% 7 | ~94% 11 | 3 reported 12 |
| Unknown 13 | NA | ||
- 1.
Genes are listed in alphabetic order.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 3.
See Molecular Genetics for information on allelic variants detected in these genes.
- 4.
Of note, many studies of ETFA, ETFB, and ETFDH did not include analysis for large deletions or duplications; therefore, deletions and duplications may be more common than reported. Sequencing studies do not routinely test for pathogenic variants deep in introns or in the promoter region.
- 5.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Although sequence analysis is sensitive in detecting the pathogenic variants mentioned here, it is important to remember that often only one pathogenic variant is detected, suggesting deep intronic or promoter region variants. For issues to consider in interpretation of sequence analysis results, click here.
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
The proportion of pathogenic variants listed here are specific for late-onset variant MADD (type III) (see also Phenotype Correlations by Gene). There is no database to determine what percentage of MADD is attributable to pathogenic variants in each gene. In a few case series, pathogenic variants in ETFDH accounted for approximately half of MADD cases, while those in ETFA and ETFB accounted for the remaining half with almost equal shares [Olsen et al 2003, Yotsumoto et al 2008].
- 8.
Freneaux et al [1992], Purevjav et al [2002], Olsen et al [2003], Schiff et al [2006], Yotsumoto et al [2008], Stals et al [2018]
- 9.
A deletion of exon 11 has been reported [Stals et al 2018].
- 10.
Curcoy et al [2003], Olsen et al [2003], Schiff et al [2006], Yotsumoto et al [2008], Sudo et al [2015], Alfares et al [2017], Navarrete et al [2019]
- 11.
Goodman et al [2002], Wen et al [2010], Wen et al [2013], Xi et al [2014]
- 12.
A 312-bp deletion and two multiexon deletions have been reported [Wen et al 2010, Kim et al 2018].
- 13.
Sometimes no pathogenic variant is found after sequencing all three genes, which may indicate other unidentified genetic etiologies for MADD.
Clinical Characteristics
Clinical Description
Multiple acyl-CoA dehydrogenase deficiency (MADD) represents a clinical spectrum in which individuals at the most severe end present with severe decompensation in the neonatal period either with or without congenital anomalies. Those on the milder end may present anytime beyond the neonatal period. They may present with metabolic decompensations when challenged by metabolic stressors, or with chronic symptoms of myopathy and exercise intolerance. Newborn screening (NBS) has enabled identification of asymptomatic newborns with late-onset forms. Early diagnosis and treatment may prevent complications in such cases. The clinical presentation can be divided into three categories according to severity – from most to least severe:
- Type I. Neonatal onset with congenital anomalies and metabolic decompensation
- Type II. Neonatal onset with metabolic decompensation without congenital anomalies
- Type III. Late onset with progressive or fluctuating muscle weakness and episodes of rhabdomyolysis
Neonatal Onset with Congenital Anomalies (Type I)
This group represents the most severe spectrum of MADD.
Metabolic decompensation. Newborns become symptomatic within a few hours after birth, often before NBS has been sent or results have become available. The most common presentation is severe metabolic acidosis leading to tachypnea and respiratory distress. This may be accompanied by profound hypoglycemia and hyperammonemia. Other features may include hypotonia and hepatomegaly. Often, there is a "sweaty feet" odor. The clinical condition typically deteriorates despite intervention and prognosis is very poor: most of these affected newborns have died in the first week of life.
Dysmorphic facial features. Often there are associated dysmorphic facial features. The most typical features:
- High anterior hairline
- Wide nasal bridge
- Short nose with anteverted nares and long philtrum
- Tented upper lip
- Midface retrusion
- Low-set ears
Renal. The characteristic renal malformation seen in affected newborns is large cystic kidneys. The kidneys may be huge and easily palpable. Antenatal oligohydramnios leading to Potter sequence may also be seen.
Genital. Both hypospadias and chordee have been described in affected males.
Musculoskeletal. Some affected infants have been found to have single palmar creases and/or rocker-bottom feet.
Neurologic. Affected newborns present with metabolic encephalopathy. Seizures secondary to profound hypoglycemia, electrolyte imbalances, or hyperammonemia may occur. Neuronal migration defects manifesting as heterotopia may be seen on brain MRI or autopsy.
Neonatal Onset Without Congenital Anomalies (Type II)
Newborns usually present within a few days after birth with metabolic decompensation as described above. The prognosis is very poor: most affected individuals do not survive the initial episode. Those who do survive usually die later in infancy either due to hypertrophic cardiomyopathy or recurrence of metabolic decompensation resembling Reye syndrome.
Late Onset (Type III)
This is the most common presentation. Signs and symptoms of late-onset MADD may become apparent any time from infancy to adulthood. In a cohort of 350 individuals with late-onset MADD, the mean age at diagnosis was 17.6 years with a range of 0.13 years to 69 years [Grünert 2014]. In this cohort, 33.1% of affected individuals had acute metabolic decompensation and 85.3% had chronic musculoskeletal symptoms consisting of muscle weakness, exercise intolerance, or muscle pain. About 20% of affected individuals had both acute metabolic decompensation episodes and chronic symptoms. Individuals with late-onset MADD frequently are detected as asymptomatic newborns through NBS. However, they may not have a known diagnosis of MADD at presentation because either NBS was not performed or was falsely negative.
Metabolic decompensation. Affected individuals may present with recurrent episodes of vomiting accompanied by nonketotic hypoglycemia, metabolic acidosis, and liver dysfunction, which is usually precipitated by metabolic stressors such as infection or fasting. Liver dysfunction, which manifests as liver enzyme elevations, hyperbilirubinemia, and coagulopathy, is reversible. If untreated, individuals may become encephalopathic.
Musculoskeletal. A majority of affected individuals develop chronic muscular symptoms such as muscle weakness, fatigue, myalgia, and exercise intolerance that responds to riboflavin treatment (see Management).
- The most common myopathic presentation is progressive or fluctuating proximal myopathy. Weakness of neck muscles and masseter is also commonly seen [Xi et al 2014].
- Progressive weakness may involve respiratory muscles leading to acute or subacute respiratory failure [Ersoy et al 2015].
- Rapidly progressive proximal myopathy and respiratory failure may mimic Guillain-Barre syndrome (GBS) [Hong et al 2018]. It is important to consider MADD in such scenarios, as early initiation of treatment with riboflavin may lead to complete resolution of symptoms in individuals with MADD.Electrophysiologic studies such as electromyography and nerve conduction velocity (NCV) are helpful in differentiating MADD from GBS, as these studies typically show evidence of peripheral nerve demyelination in GBS. However, further differentiation by plasma acylcarnitine profile and urine organic acid assay should be done promptly.
- Individuals with MADD are at risk of developing rhabdomyolysis, which may manifest during the acute episode of metabolic decompensation [Prasad & Hussain 2015].
- Bent spine syndrome characterized by progressive forward flexion of the trunk caused by selective involvement of paravertebral muscles has also been reported [Peng et al 2015].
Cardiac. Hypertrophic cardiomyopathy is seen in the severe neonatal-onset presentation. However, cardiac arrhythmias and diastolic dysfunction may occur during the metabolic decompensation in late-onset forms and can be fatal [Angle & Burton 2008, Xi et al 2014].
Neurologic. Rarely, individuals with late-onset MADD may develop severe sensory neuropathy in addition to proximal myopathy [Wang et al 2016]. The main symptoms of neuropathy are numbness of the extremities and sensory ataxia. NCV in these individuals shows severe axonal sensory neuropathy. Sensory neuropathy is not reversible with riboflavin treatment.
Biochemical Features
Elevations of several acylcarnitine species in blood in combination with increased exertion of multiple organic acids in urine are highly suggestive of MADD, as summarized in Supportive Laboratory Findings.
Plasma acylcarnitine profile. Individuals with the late-onset milder form may show a less dramatic profile with elevation of only C6, C8, C10, and C12. Additionally, the acylcarnitine profile may be normal if performed during an asymptomatic phase in individuals with the late-onset form.
Plasma carnitine assay may show a very low free carnitine. In this setting the acylcarnitine profile may be falsely normal. Hence, in the setting of very low plasma free carnitine, the plasma acylcarnitine profile should be repeated after carnitine supplementation [Wen et al 2015].
Urine organic acid profile in those with the late-onset form may be less dramatic, with elevations of only ethylmalonic and adipic acids associated with mild dicarboxylic aciduria. Urine organic acid profile may be normal if performed during the asymptomatic phase in those with the late-onset form.
In vitro probe analysis. An individual's fibroblasts are incubated with palmitic acid and culture medium is assayed for acylcarnitine after 96 hours of incubation. There is substantial accumulation of C16 in severe forms, while the downstream acylcarnitines C14, C12, C10, and C8 are not increased. In contrast, C14, C12, C10, and C8 are increased in milder forms, while C16 is relatively lower [Endo et al 2010].
Phenotype Correlations by Gene
ETFDH. The majority of individuals with late-onset MADD (type III) have pathogenic variants in this gene [Grünert 2014].
ETFA and ETFB pathogenic variants are relatively more common in individuals with a neonatal presentation of MADD (types I and II) [Olsen et al 2003, Yotsumoto et al 2008].
Genotype-Phenotype Correlations
Genotype-phenotype correlation is seen in the three known genes that lead to MADD (ETFA, ETFB, and ETFDH) [Olsen et al 2003]. The information provided here applies to pathogenic variants in all three genes.
- Biallelic pathogenic null variants or pathogenic variants that severely affect mRNA expression or stability and result in total lack of protein cause the most severe form of MADD (i.e., neonatal onset with congenital malformations [type I]).
- Pathogenic variants that affect the active site and/or pathogenic splice site variants giving rise to very low residual enzyme activity more often lead to neonatal presentation without congenital anomalies (type II).
- Affected individuals who have at least one pathogenic missense variant that does not affect the active site, mRNA expression, or mRNA stability typically have relatively high residual enzyme activity with resulting late onset and milder disease (type III).
Nomenclature
MADD was first described in 1976 in an infant with nonketotic hypoglycemia, metabolic acidosis, and strong "sweaty feet" odor [Przyrembel et al 1976]. Urine organic acid analysis revealed excretion of several organic acids including massive amounts of glutaric and lactic acids. This disorder was suspected to be due to abnormal metabolism of several acyl-CoA compounds and was named glutaric aciduria type 2 to distinguish it from glutaric aciduria type 1 due to glutaryl-CoA dehydrogenase deficiency, which was described a year before.
Prevalence
MADD is very rare. Exact prevalence is not known. Incidence at birth is estimated at 1:250,000 [Schulze et al 2003]. It is more common in China, where it is the most common cause of lipid storage myopathy [Xi et al 2014]. The carrier frequency of the pathogenic c.250G>A variant in Han Chinese is estimated at 1.35%, implying a disease prevalence of 1:22,000 in this population [Wang et al 2011].
Differential Diagnosis
Disorders of Riboflavin Metabolism
Disorders of riboflavin metabolism can mimic multiple acyl-CoA dehydrogenase deficiency (MADD) (both biochemically and clinically) or have overlapping phenotypic features with MADD and should be considered as the primary differential diagnoses. With frequent use of exome sequencing, it is postulated that many individuals diagnosed with MADD of unknown genetic etiology will be identified as having a genetic alteration associated with a disorder of riboflavin metabolism.
Cellular uptake of riboflavin is mediated by the transmembrane proteins hRFVT1, hRFVT2, and hRFVT3 (encoded by SLC52A1, SLC52A2, and SLC52A3, respectively). Riboflavin is then converted to the coenzyme flavin mononucleotide by riboflavin kinase and then to flavin adenine dinucleotide (FAD) by FAD synthase (encoded by FLAD1).
FAD is a cofactor for electron transfer by the ETF/ETFDH complex from oxidations of fatty acids and some amino acids to the electron transport chain in the inner mitochondrial membrane [Watmough & Frerman 2010]. If FAD biogenesis is deficient, electron transfer by the ETF/ETFDH complex is compromised, which can result in a clinical presentation mimicking that of MADD (as MADD is caused by impairment of the ETF-ETFDH complex itself; see Molecular Genetics).
Table 2 summarizes disorders of riboflavin metabolism presenting as MADD or with overlapping phenotypic features with MADD that should be considered in the differential diagnosis.
Table 2.
Riboflavin Metabolism Disorders to Consider in the Differential Diagnosis of MADD
| Gene | Disorder | MOI | Clinical Features | |
|---|---|---|---|---|
| Overlapping w/MADD | Distinguishing from MADD | |||
| FLAD1 | MADD-like illness (OMIM 255100) | AR | Presentation is similar to late-onset MADD w/lipid storage myopathy & similar biochemical abnormalities. 1 |
|
| SLC52A1 | Transient MADD-like illness in neonates (OMIM 615026) | AD |
|
|
| SLC52A2 SLC52A3 | Brown-Vialetto-Van Laere syndrome (See Riboflavin Transporter Deficiency Neuronopathy.) | AR | Biochemical profile similar to MADD |
|
AD = autosomal dominant; AR = autosomal recessive; MADD = multiple acyl-CoA dehydrogenase deficiency; MOI = mode of inheritance
- 1.
Olsen et al [2016]
- 2.
Mosegaard et al [2017]
- 3.
Ho et al [2011]
Note: Many other inborn errors of metabolism (in additional to disorders of riboflavin metabolism) can have a very similar clinical presentation to MADD and should be considered in the differential diagnosis.
Neonatal-Onset MADD
Inborn errors of metabolism with neonatal onset and clinical similarities with MADD are summarized in Table 3.
Congenital anomalies. The severe neonatal-onset form of carnitine palmitoyltransferase II deficiency is the only disorder in Table 3 that is associated with congenital anomalies.
Table 3.
Disorders with Neonatal Onset to Consider in the Differential Diagnosis of Multiple Acyl-CoA Dehydrogenase Deficiency
| Gene(s) | Disorder | MOI | Biochemical Profile / Comment |
|---|---|---|---|
| ACADVL | Very long-chain acyl-CoA dehydrogenase deficiency | AR | Profound nonketotic hypoglycemia mimics other FAO defects. |
| ASL | Argininosuccinate lyase deficiency | AR | Marked hyperammonemia mimics urea cycle defects. |
| ASS1 | Citrullinemia type I | AR | |
| CPS1 | Carbamoylphosphate synthetase I deficiency (See Urea Cycle Disorders Overview.) | AR | |
| CPT1A | Carnitine palmitoyltransferase 1A deficiency | AR | Profound nonketotic hypoglycemia mimics other FAO defects. |
| CPT2 | Carnitine palmitoyltransferase II deficiency | AR |
|
| HADHA | Long-chain 3-hydroxyacyl-CoA dehydrogenase (OMIM 609016) | AR | Profound nonketotic hypoglycemia mimics other FAO defects. |
| HADHB | Trifunctional |