Late-onset multiple acyl-CoA dehydrogenase deficiency: an insidious presentation

  1. Naini Nishita Rao 1 , 2,
  2. Kharis Burns 1 , 2,
  3. Catherine Manolikos 1 , 3 and
  4. Samantha Hodge 1 , 3
  1. 1 Department of Endocrinology and Diabetes, Royal Perth Hospital, Perth, Western Australia, Australia
  2. 2 School of Medicine, The University of Western Australia, Perth, Western Australia, Australia
  3. 3 Department of Dietetics and Nutrition, Royal Perth Hospital, Perth, Western Australia, Australia
  1. Correspondence to Dr Naini Nishita Rao; n.nishita.rao@gmail.com

Publication history

Accepted:04 May 2023
First published:22 May 2023
Online issue publication:22 May 2023

Case reports

Case reports are not necessarily evidence-based in the same way that the other content on BMJ Best Practice is. They should not be relied on to guide clinical practice. Please check the date of publication.

Abstract

Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare inborn error of metabolism that results in impairment of mitochondrial β-oxidation of fatty acids. It is inherited in an autosomal recessive manner and impairs electron transfer in the electron transport chain. The clinical manifestations of MADD are highly variable and include exercise intolerance, myopathy, cardiomyopathy, encephalopathy, coma and death. Early-onset MADD is often associated with a high mortality with significant number of patients presenting with severe metabolic acidosis, non-ketotic hypoglycaemia and/or hyperammonaemic presentations. While late-onset MADD is suggested to have a lower mortality, the severe encephalopathic presentations may well be under-reported as a diagnosis of MADD may not be considered.

MADD is treatable with riboflavin and appropriate nutrition with a focus on prevention and early management of metabolic decompensation. The neonatal phenotype differs significantly from late-onset MADD, where diagnosis may be delayed due to heterogeneity in clinical features, atypical presentation and confounding comorbidities, together with lower awareness among physicians.

This report describes a woman in her 30s who presented with acute-onset ataxia, confusion and hyperammonaemic encephalopathy requiring intubation. Subsequent biochemical investigation revealed a diagnosis of MADD. At present, there are no national guidelines in Australia for the management of MADD. This case highlights the investigation and treatment of late-onset MADD.

Background

Multiple acyl-CoA dehydrogenase deficiency (MADD), previously referred to as glutaric acidemia type 2, is a rare inborn error of metabolism (IEM) that is inherited in an autosomal recessive manner and has clinically heterogeneous phenotypes. MADD has a prevalence of 1 in 200 000 births with estimates varying between countries.1–3 MADD occurs due to failure of the mitochondrial β-oxidation of fatty acids most commonly due to a mutation in the genes encoding the electron transfer flavoprotein dehydrogenase (ETFDH) or the electron transfer flavoprotein (ETF) which is made up of an alpha (ETFA) and beta subunit (ETFB).1 4 5 The first step of fatty acid β-oxidation involves the removal of an electron via an acyl-CoA dehydrogenase from an acyl-CoA, converting it to a β-enoyl-CoA.6 Both ETF and ETFDH are vital in transferring the electrons derived from the dehydrogenation reaction to the electron transport chain on the inner mitochondrial membrane, thereby linking β-oxidation to oxidative phosphorylation.6 7 When this electron transfer process is disrupted, oxidative phosphorylation and ATP production is diminished.

Flavine adenine dinucleotide (FAD) is an essential cofactor for ETF and ETFDH, and is derived from riboflavin, hence riboflavin deficiency can also mimic MADD and is easily treated with supplementation of riboflavin.1 6 Furthermore, there is a growing body of evidence to demonstrate mutations in genes involved in FAD metabolism, such as FLAD1, also result in MADD like phenotypes.8 9 Certain phenotypes are also responsive to riboflavin supplementation (RR-MADD). Though not clearly understood why, it is theorised that as FAD also plays a role in chaperoning the correct folding of ETF and ETFDH, increasing riboflavin supplies increases mitochondrial FAD availability. This, in turn, enhances FAD binding to flavoproteins thereby promoting correct protein folding and stability of certain mutant variants, and consequentially improving mutant protein activity.10–12

The MADD phenotypes can be broken down into three broad subtypes: in its most severe phenotype, neonates with MADD present in a metabolic crisis state with the aforementioned biochemical abnormalities either with congenital abnormalities (subtype I) or without (subtype II). Both subtype I and II confer a high rate of morbidity and mortality particularly due to progressive cardiomyopathy.1 12 Those with the late-onset MADD (subtype III) tend to have the less severe phenotypes with a higher likelihood of RR-MADD, and only declare themselves with metabolic stressors such as infections, pregnancy, surgery and prolonged fasting.1 5 12

Screening for fatty acid oxidation disorders was only introduced into the Newborn Screening (NBS) programme in Australia in 1998 with the advent of tandem mass spectrometry, and it was not until 2005 that this was implemented in all states.13 An Australian study found that the incidence of fatty acid oxidation disorders (FAOD) increased from 0.9–3.2 in 100 000 births to 8 in 100 000 births post introduction of FAOD in the NBS.14 Patients with MADD may also express normal biochemistry when they are well, thus individuals with later onset MADD are often undiagnosed and can present with acute metabolic decompensation, that if not recognised and adequately addressed, can lead to serious comorbidities and even death. This case report highlights one such rare presentation of previously undiagnosed late-onset MADD.

Case presentation

A woman in her 30s was brought into the emergency department (ED) after she was found in her home, disorientated and confused. On arrival to ED, she was found to have Glasgow Coma Scale (GCS) score of 13, was ataxic and complaining of muscular weakness and nausea. She stated having had 1 week of gastroenteritis prior to her presentation and denied any alcohol consumption or illicit drug use. Her medical history was significant for asthma, Ehlers Danlos syndrome, cervical intraepithelial neoplasia 2 and paranoid schizophrenia. She was 3 months post partum and no longer breast feeding. Regular medications included olanzapine depot, sertraline and as required ondansetron.

On initial assessment vital signs were all within the normal limits. She had a non-blanching rash to her upper and lower limbs, and apart from a GCS of 13, her neurological examination was unremarkable with reflexes intact, preserved power of 5/5 globally and normal sensation with no signs of meningism or photophobia.

Her gastrointestinal, cardiovascular and respiratory examinations were unremarkable. Within 5.5 hours of her presentation, her GCS had deteriorated to 8, necessitating intubation and intensive care management (see table 1).

Table 1

A timeline of the main events with corresponding GCS and key management summarised throughout the course of the clinical presentation

Day Event Relative time* GCS Investigations Management Working diagnosis
1 Arrival to ED 0 hours
2 hours
3.5 hours		 13 (E3, V3, M6) VBG, FBC, UEC, LFT, drug assay
CT head, CXR
LP		 Commenced on D50W infusion intravenous with D5W+insulin to correct blood glucose and ketones Meningitis vs Encephalitis vs Toxic syndrome
Deteriorated GCS 5 hours 8 (E3, V3, M5) VBG, ABG Intubated, arterial line placed
2 Transferred to ICU 6–15 hours 3
(intubated)		 Serial ABG, ammonia Endocrinology team alerted of HAGMA with high ammonia Inborn error of metabolism
Endocrine team first review 15.5 hours Urine organic acid profile+plasma acylcarnitine profile Commenced on riboflavin and high protein NG feeds with ongoing IV insulin/dextrose
3 Extubated 38–40 hours 14 (E3, V5, M6) Serial FBC, UEC, BSL, ammonia Commenced riboflavin 50 mg and L-Carnitine 1 g three times a day, supplemented nutrition with intravenous dextrose given ongoing reduced oral intake Multiple acyl-CoA dehydrogenase deficiency (MADD)
4–7 Recovery GCS 15 Serial FBC, UEC, BSL, ammonia Supplemented diet with fortijuice† three times a day, ongoing education about probable diagnosis of MADD
8 Discharged GCS 15 Sick day plan with SOS 25 glucose polymer‡ arranged for home welfare check, weekly endocrinology clinic follow-up, genetic testing and medic alert bracelet

  • *Time in hours relative to initial presentation which is designated 0 hours.

  • †Fortijuice is a 200 mL high calorie (300 kcal) supplemental drink with 8 g of protein and 28 vitamins and minerals.

  • ‡SOS 25 glucose polymer is a sachet of carbohydrate mix containing 200 calories, 50 g carbohydrates and 4.7 g sugars, and no protein or fats, that needs to be added to 200 mL of water.

  • ABG, arterial blood gas; BSL, blood sugar level; CXR, chest X-ray; D5W, dextrose 5% water; D50W, dextrose 50% water; ED, emergency department; FBC, full blood count; GCS, Glasgow Coma Scale; HAGMA, high anion gap metabolic acidosis; ICU, Intensive Care Unit; LFT, liver function test; LP, lumbar puncture; NG, nasogastric; UEC, urea electrolytes and creatinine; VBG, venous blood gas.

Investigations

Full blood count and renal function tests were within normal limits, and toxicology and urine drug screen were negative for tested substances. Plasma ketones were elevated to 5 mmol/L (normal range <0.5 mmol/L), ammonia was elevated to 145 mmol/L (see table 2 for trend) and normalised by day 3. Creatine kinase was elevated at 2030 U/L initially, but serial trend was not done. Plasma glucose decreased from 3.2 mmol/L initially to 1.9 mmol/L at its nadir, which was 2 hours prior to intubation. Blood gas analysis demonstrated high anion gap metabolic acidosis (table 3).

Table 2

Values of significantly altered pathology with trend demonstrated where available

Test—normal range Day 1
18:00		 Day 2 Day 3
02:00
01:20 3:29 09:55 15:45 20:00
Liver function test
 Bilirubin <20 µmol/L 4 2 2 <2
 ALT <35 U/L 42 38 36 35
 ALP 35–135 U/L 116 98 82 80
 GGT <55 U/L 26 24 27 25
 Albumin 35–59 g/L 46 38 33 32
 Protein 60–80 g/L 75 60 51 50
 Globulin 25–42 g/L 29 22 18 18
Ammonia <60 mmol/L 145 65 61 62 31
Creatine kinase 30–170 U/L 2030
β-OH butyrate 0.4–0.5 mmol/L 5
Serum drug assay
 Carbamazepine <1
 Valproic acid <5
 Salicylate <20
 Paracetamol <10
 Ethanol <0.01

  • Serum drug assay was compared with a reference range that corresponds to a therapeutic range if the patient was taking it at therapeutic doses.

  • ALP, Alkaline Phosphatase; ALT, Alanine Transaminase; GGT, Gamma-glutamyltransferase.

Table 3

Trend of blood gases demonstrating high anion gap metabolic acidosis

Normal
Range for
venous
blood gas		 Venous blood gas Normal range
for arterial
blood gas		 Arterial blood gas
Day 1
18:04		 Day 2
22:17		 00:23 Day 2
03:54		 07:50 10:30
pH 7.32–7.43 7.26 7.22 7.12 7.35–7.45 7.42 7.42 7.36
pCO2 37–50 mm Hg 27 23 17 36–45 mm Hg 17 23 31
pO2 36–44 mm Hg 32 84 65 85–110 mm Hg 153 148 140
Bicarbonate 22–28 mmol/L 12 9 9 21–28 mmol/L 11 15 17
Base excess −3 to 3 mmol/L −14 −17 −19 −3 to 3 mmol/L −13 −9 −8
Anion gap 7–17 mmol/L 24 22 7–17 mmol/L 19 16 14
Blood glucose level 3–5.4 mmol/L 3.2 19.4 10 3–5.4 mmol/L 8.4 8.4 4.7
Lactate <2 mmol/L 0.5 0.7 0.6 <2 mmol/L 0.5 0.9 0.7

  • Patient was intubated after first venous blood gas reading and remained for all subsequent blood gas values. Values below the reference range are shaded in red while those above are shaded blue.

  • pCO2, Partial Pressure of Carbon Dioxide; pO2, Partial Pressure of Oxygen.

On microbiology, COVID-19 swab was negative and blood and urine cultures yielded no growth. Cerebrospinal fluid analysis, including culture and PCR, was only significant for low glucose of 2.1 mmol/L.

On imaging, both CT brain and chest X-ray were unremarkable. Plasma acylcarnitine profile demonstrated elevations of short, medium and long chain fatty acids (table 4) and urine organic acid screen showed elevated urine organic acids and ketone bodies (table 5).

Table 4

Plasma acylcarnitine profile pre- and post- riboflavin supplementation

Acylcarnitine Abbreviation Value day 2 (µmol/L) Value 2 hours postriboflavin (µmol/L) Reference range (µmol/L)
Total carnitine – 54 21 21–70
Free carnitine – 22 16 13–56
Acetylcarnitine C2 17 3 <17
Propionylcarnitine C3 0.23 0.12 <0.76
Malonylcarnitine C3DC 0.02 0.00 <0.10
Butyrylcarnitine C4 0.63 0.14 <0.50
3-hydroxybutyrylcarnitine C4OH 0.09 0.01 <0.50
2-methylbutyryl or isovalerylcarnitine C5 1.07 0.17 <0.30
Tiglyl or 3-methylcrotonyl-L-carnitine C5:1 0.01 0.00 <0.04
Glutarylcarnitine C5DC 0.09 0.24 <0.08
Methylglutarylcarnitine C6DC 0.23 0.03 <0.16
3-hydroxyisovalerylcarnitine C5OH 0.04 0.00 <0.15
Hexanoylcarnitine C6 0.44 0.03 <0.22
Octanoylcarnitine C8 0.49 0.07 <0.31
Decanoylcarnitine C10 0.65 0.09 <0.44
Decenoylcarnitine C10:1 0.11 0.02 <0.23
Dodecanoylcarnitine C12 0.81 0.06 <0.34
Tetradecanoylcarnitine C14 1.30 0.07 <0.20
Tetradecenoylcarnitine C14:1 1.78 0.14 <0.69
Hexadecanoylcarnitine C16 2.78 0.19 <0.32
3-hydroxyhexadecanoylcarnitine C16OH 0.04 0.01 <0.05
Octadecanoylcarnitine C18 1.00 0.07 <0.09
3-hydroxyoctadecenoylcarnitine C18:1OH 0.05 0.02 <0.06
Octadecenoylcarnitine C18:1 2.96 0.22 <0.45
3-hydroxyoctadecanoylcarnitine C18OH 0.02 0.02 <0.02

  • There is near normalisation of the acylcarnitine profile in just 2 hours post riboflavin supplementation. Values highlighted in beige are borderline elevated, while those in red are above the reference range.

Table 5

Urine organic acid profile pre-riboflavin and post-riboflavin supplementation

Organic substance Value detected Value detected
Day 1 post Riboflavin		 Normal reference
Range
Ketones Undetectable Undetectable
 3-hydroxybutyrate +++
 Acetoacetate +++
Amino acid Undetectable Undetectable Undetectable
Glucose Undetectable Undetectable Undetectable
Organic acids Undetectable
 Adipate +++ Undetectable
 Hexanoylglycine +++ Undetectable
 Suberylglycine +++ Undetectable
 Isobutyrylglycine +++ +
 2-methylbutyrylglycine ++ Undetectable
 Isovalerylglycine + Undetectable
 Glutarate +++ +
 2-hydroxyglutarate + ++

  • There is near normalisation of the acylcarnitine profile by day 1 post-riboflavin supplementation.

Differential diagnosis

The initial working diagnosis was sepsis with encephalopathy versus toxidrome given the deteriorating GCS and presence of a non-blanching rash and antibiotic treatment was commenced.

The toxicology screen and blood alcohol level were both negative. The high anion gap metabolic acidosis combined with hypoglycaemia and elevated ammonia prompted investigations into possible IEM. Biochemical abnormalities in the plasma and urine organic acid profiles as outlined above confirm a diagnosis of MADD. Elevated CK is consistent with the myopathy seen in MADD.

Treatment

Initially commenced on dextrose 50% in 50 mL to correct glucose levels with addition of insulin and 5% dextrose infusion after to correct ketones. Once stabilised, the patient was reviewed by endocrine team with confirmation of MADD and commenced on appropriate dietary supplementations; a low protein diet of 0.5 g/kg via nasogastric feeds, riboflavin 150 mg/day and L-carnitine 3 g/day. She was educated on a sick day plan to avoid future metabolic crises and closely followed up.

Outcome and follow-up

Genetic analysis via next-generation sequencing (NGS) was pursued and tested for mutations in the following genes—ETFA, ETFB, ETFDH, FLAD1, SCL52A1, SCL52A2, SCL52A3. There was a 100% coverage of all genes except for SCL52A1 which had 99.7% coverage. Nil significant copy number variants were found in the genetic analysis.

Concomitant mental health diagnoses prevented adherence to diet and medications and intermittent episodes of deterioration were precipitated by restricted eating patterns. These episodes of deterioration demonstrated the same biochemical abnormalities and have been successfully resolved with appropriate dietary intervention.

Discussion

This case highlights metabolic decompensation in the postpartum period as the first presentation of MADD an IEM. Pregnancy and the postpartum period are associated with higher catabolic stress, which can precipitate metabolic crisis15 16 During periods of catabolic stress, fatty acid oxidation increases for ATP production, and this process is compromised in individuals with MADD.1–3 The organs most affected by MADD are those with a high flux of β-oxidation such as the heart, skeletal muscle, brain and liver.2 5 12 Hence, respective manifestations include arrhythmias, cardiomyopathy, muscle weakness, exercise intolerance, myopathies, encephalopathy and liver dysfunction. A diagnosis of metabolic encephalopathy was favoured for the patient in the presence of an acute state of confusion in the context of hyperammonaemia and a normal CT head. Although a hypoglycaemic state offers an alternative explanation for the deterioration in GCS, it seemed less likely given that the patient was given 50 mL of 50% dextrose and subsequently commenced on an insulin+5% dextrose infusion hours prior intubation with VBG minutes postintubation demonstrating a blood glucose level of 19.4 mmol/L. Although an immediate EEG or MRI of the brain was not an available option in this patient’s case, it would be a very useful consideration in such presentations, especially if concomitant seizure activity is present, to further clarify global cerebral dysfunction.

The accumulation of fatty acids and the inability to produce ATP results in metabolic acidosis, while the inability to produce acetyl-CoA impairs gluconeogenesis, ketogenesis and ureagenesis usually leading to hypoketotic hypoglycaemia and hyperammoneamia. However, the residual enzymatic activity of the proteins in those with a less severe phenotype means that they may cope with a metabolic stress initially, then may progress to an inability to meet biological demands.1 Consequently, they may not present in the traditional hypoketotic hyperglycaemic state seen in infancy due to the retention of some compensatory ability to produce ketone bodies in starvation states. Ketone production may still be present, though inappropriately low for the degree of hypoglycaemia. We postulate this as a possible explanation for the patient in this study and should be taken into consideration in future guidelines. Although this patient was no longer breast feeding, in other postpartum breastfeeding women who present with hypoglycaemic ketoacidosis in the context of fatty acid oxidation disorders, a diagnosis of lactation ketoacidosis can be considered.17

Individuals with late-onset MADD have a lifelong risk of intermittent episodes of acute decompensation which can present with vomiting, dehydration and chronic myopathic symptoms.5 18 Due to vague symptomatology, late-onset MADD is thought to be underdiagnosed.19–21 In a state of decompensation, the accumulated fatty acids undergo alternative pathways of metabolism in the peroxisomes and microsomes, ultimately producing organic acids which are excreted in the urine (table 3).18 Although there are well-established genetic mutations known to cause MADD, a limiting factor is that NGS of specific genes does not always reveal an identifiable mutation as was the case in this patient despite 99.7%–100% coverage of targeted genes (see outcome and follow-up).5 22 However, the patient’s plasma acylcarnitine and urine organic profiles when tested during decompensated periods were consistent with IEM (see tables 4 and 5). Hence, relying solely on genetic testing reduces the diagnostic yield of IEM, especially when whole exome is not done, and it is for this reason that biochemical testing is generally considered first line.

The postpartum state also places our patient at a higher risk of riboflavin deficiency, but the duration of time in which there is a biochemical response to riboflavin supplementation in RR-MADD is not well established.16 The improvement in the plasma acylcarnitine profile and the urine organic acid profile seen in this case 2 hours postriboflavin treatment likely represents a response to combination of the riboflavin, dextrose, nutritional treatment and time. Further work is required to elucidate and harmonise the definition of late-onset RR-MADD, which will be complicated by the likely heterogeneous metabolic disturbances secondary to variable residual enzyme activities and the fact that plasma acylcarnitine and urine organic acid profiles are usually normal when the patients are metabolically well.

A wider literary search did not yield any Australian national guidelines for the recognition or management of MADD in adults. Furthermore, there is a paucity of existing literature available. As with the patient in this study, those with adult-onset MADD often present in a state of crisis with non-specific symptoms in the context of a catabolic stressor as above that can acutely and rapidly deteriorate if not corrected. Biochemical patterns of high anion gap metabolic acidosis, with profound hypoglycaemia and hyperammonaemia, should prompt consideration of IEM. Management in the acute phase centres on primary survey with appropriate resuscitative measures. In addition to basic biochemistry, other diagnostically supportive investigations include plasma acylcarnitine profile, urine organic acids, riboflavin, creatine kinase and other clinically indicated tests. A baseline ECG is recommended due to the risk of cardiomyopathies. Catabolism needs to be ceased with intravenous glucose thus stimulating insulin release and dehydration corrected. Once stable, the mainstay of treatment is dietary modification; higher complex carbohydrate, low protein and low-fat diet and avoidance of fasting with supplementation of riboflavin (100–300 mg/day), carnitine (100–200 mg/kg/day) and if indicated, coenzyme Q10. Although there is limited evidence to support these measures. Long-term treatment should also focus on regular patient education with sick day plans. This case aims to assist clinicians globally in recognising and managing the insidious presentation of MADD.

Learning points

  • Individuals with late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) present with non-specific symptoms in decompensated states (eg, vomiting, myalgia, confusion) and can rapidly deteriorate.

  • A combination of high anion gap metabolic acidosis with hyperammonaemia and profound hypoglycaemia should prompt consideration of inborn errors of metabolism.

  • Those with late-onset MADD can present with hyperketotic hypoglycaemia as opposed to the traditionally expected hypoketotic hypoglycaemia due to residual enzymatic activity of mutated protein.

  • Plasma acylcarnitine and urine organic acid profile can still confirm biochemical diagnosis of MAD or other inborn error of metabolism in context of negative genetic studies.

Ethics statements

Patient consent for publication

Acknowledgments

Thanks also due for Dr Damion Bell, Endocrinologist, who served as a scientific advisor to the article.

Footnotes

  • Contributors NNR, who is responsible for the overall content as guarantor, was involved in the planning and data collection for the report. Both NNR and KB collaboratively were involved in the reporting of the article. SH and CM were the primary dieticians involved in the care of the patient with KB being the primary physician in charge. SH and CM were involved in the critical revision and editing of the article.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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