March MADDness – A diagnostic dilemma with genotype/phenotype discordance
Biochemical/Metabolic and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
Multiple acyl-coA dehydrogenase deficiency (MADD) refers to an autosomal recessive spectrum of deficient electron transfer flavoprotein (ETF) activity leading to impaired oxidation of fatty acids and amino acid metabolism. Depending on the onset of symptoms and presence of congenital abnormalities, MADD is divided into three subtypes. Types 1 and 2 are marked by neonatal onset of hypoglycemia/hyperammonemia ± congenital anomalies. Type 3 MADD is the most common and generally presents later [4]. Symptoms associated with type 3 MADD are primarily muscular, including myalgia/weakness and are often precipitated by exercise and catabolic demand [4-6].
Pathogenic variants have been described in several ETF genes, as well as other genes encoding accessory proteins in the pathway. The mainstay of therapy includes avoidance of fasting, a low-fat diet, high-dose riboflavin/carnitine and possibly CoQ10 supplementation [4]. Of note, riboflavin therapy is most beneficial in type 3 MADD [6].
Case Presentation
We describe a 7 year-old female evaluated by Clinical Genomics for a 6 month history of recurrent episodes of altered mental status with hypoglycemic metabolic acidosis and mild hyperammonemia in the setting of emesis. Her past medical history is significant for craniopharyngioma s/p partial resection and radiation therapy at age 4 with subsequent adrenal insufficiency, hypothyroidism and growth hormone deficiency.
Diagnostic Workup
Biochemical evaluation included plasma amino acids, plasma acylcarnitine profile and urine organic acids. Urine organic acids revealed elevation of ethylmalonic acid, glutaric acid, 2-hydroxyglutaric acid and methylsuccinic acid. Additionally, isobutyrylglycine, hexanoylglycine and suberylglycine were elevated, which taken together suggested a biochemical MADD phenotype. Molecular testing was pursued with no variants reported in a targeted gene panel including ETFA, ETFB, ETFDH, FLAD1, SLC52A1, SLC52A2, SLC52A3 and TANGO2 genes. Whole genome sequencing was also negative.
Treatment and Management
Patient was started on high dose riboflavin and L-carnitine supplementation. Family was also instructed to avoid fasting and in the importance of medical surveillance during emesis/NPO states.
Outcome and Follow-Up
Soon after riboflavin treatment was started, improvement was noted in the patient’s energy level and appetite. She did require another hospitalization due to recurrence of symptoms once after initial diagnosis. She has not had recurrence of metabolic crisis in the past 6 months.
Discussion
We describe a 7 year-old female with a clinical/biochemical phenotype consistent with MADD type 3 and documented response to riboflavin supplementation. Type 3 MADD is associated with pathogenic variants in the ETFDH gene, which encodes electron transfer flavoprotein:ubiquinone oxidoreductase. Loss-of-function variants in ETFDH impair transfer of electrons formed during β-oxidation, causing intolerance to catabolic stress and lipid storage myopathy [6]. Riboflavin increases FAD levels, stabilizing the ETFDH enzyme and optimizing its activity. Response rates of type 3 MADD to riboflavin have been suggested to be as high as 98.4% [4,5].
However, our patient's molecular testing is negative for risk genes commonly associated with MADD. She also underwent whole genome sequencing with no variants reported. Very few cases of clinical and biochemical presentation consistent with MADD diagnosis but negative per molecular testing have previously been reported. Cotelli et al (2012) describes a 20 year old that presented with an 8 year history of progressive myopathy and biochemical/histological findings consistent with diagnosis of MADD but no variants identified in ETF and ETFDH genes. Furthermore, Maguolo et al (2020), Wen et al (2022) and Grunert (2014) have reported another 5 cases where clinical and biochemical findings are suggestive of MADD type 3 but no genetic cause was identified.
Conclusion
Further research is needed to elucidate risk genes associated with riboflavin-responsive MADD. Low-risk interventions such as riboflavin should be considered in all genotypes of MADD due to favorable risk/benefit profile.
Multiple acyl-coA dehydrogenase deficiency (MADD) refers to an autosomal recessive spectrum of deficient electron transfer flavoprotein (ETF) activity leading to impaired oxidation of fatty acids and amino acid metabolism. Depending on the onset of symptoms and presence of congenital abnormalities, MADD is divided into three subtypes. Types 1 and 2 are marked by neonatal onset of hypoglycemia/hyperammonemia ± congenital anomalies. Type 3 MADD is the most common and generally presents later [4]. Symptoms associated with type 3 MADD are primarily muscular, including myalgia/weakness and are often precipitated by exercise and catabolic demand [4-6].
Pathogenic variants have been described in several ETF genes, as well as other genes encoding accessory proteins in the pathway. The mainstay of therapy includes avoidance of fasting, a low-fat diet, high-dose riboflavin/carnitine and possibly CoQ10 supplementation [4]. Of note, riboflavin therapy is most beneficial in type 3 MADD [6].
Case Presentation
We describe a 7 year-old female evaluated by Clinical Genomics for a 6 month history of recurrent episodes of altered mental status with hypoglycemic metabolic acidosis and mild hyperammonemia in the setting of emesis. Her past medical history is significant for craniopharyngioma s/p partial resection and radiation therapy at age 4 with subsequent adrenal insufficiency, hypothyroidism and growth hormone deficiency.
Diagnostic Workup
Biochemical evaluation included plasma amino acids, plasma acylcarnitine profile and urine organic acids. Urine organic acids revealed elevation of ethylmalonic acid, glutaric acid, 2-hydroxyglutaric acid and methylsuccinic acid. Additionally, isobutyrylglycine, hexanoylglycine and suberylglycine were elevated, which taken together suggested a biochemical MADD phenotype. Molecular testing was pursued with no variants reported in a targeted gene panel including ETFA, ETFB, ETFDH, FLAD1, SLC52A1, SLC52A2, SLC52A3 and TANGO2 genes. Whole genome sequencing was also negative.
Treatment and Management
Patient was started on high dose riboflavin and L-carnitine supplementation. Family was also instructed to avoid fasting and in the importance of medical surveillance during emesis/NPO states.
Outcome and Follow-Up
Soon after riboflavin treatment was started, improvement was noted in the patient’s energy level and appetite. She did require another hospitalization due to recurrence of symptoms once after initial diagnosis. She has not had recurrence of metabolic crisis in the past 6 months.
Discussion
We describe a 7 year-old female with a clinical/biochemical phenotype consistent with MADD type 3 and documented response to riboflavin supplementation. Type 3 MADD is associated with pathogenic variants in the ETFDH gene, which encodes electron transfer flavoprotein:ubiquinone oxidoreductase. Loss-of-function variants in ETFDH impair transfer of electrons formed during β-oxidation, causing intolerance to catabolic stress and lipid storage myopathy [6]. Riboflavin increases FAD levels, stabilizing the ETFDH enzyme and optimizing its activity. Response rates of type 3 MADD to riboflavin have been suggested to be as high as 98.4% [4,5].
However, our patient's molecular testing is negative for risk genes commonly associated with MADD. She also underwent whole genome sequencing with no variants reported. Very few cases of clinical and biochemical presentation consistent with MADD diagnosis but negative per molecular testing have previously been reported. Cotelli et al (2012) describes a 20 year old that presented with an 8 year history of progressive myopathy and biochemical/histological findings consistent with diagnosis of MADD but no variants identified in ETF and ETFDH genes. Furthermore, Maguolo et al (2020), Wen et al (2022) and Grunert (2014) have reported another 5 cases where clinical and biochemical findings are suggestive of MADD type 3 but no genetic cause was identified.
Conclusion
Further research is needed to elucidate risk genes associated with riboflavin-responsive MADD. Low-risk interventions such as riboflavin should be considered in all genotypes of MADD due to favorable risk/benefit profile.