Response to Ketone Therapy in an Unusual Case of Type 1 Multiple Acyl-CoA Dehydrogenase Deficiency
Biochemical/Metabolic and Therapeutics
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Introduction
Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited disorder of mitochondrial fatty acid oxidation. Type 1 MADD is characterized by a severe, neonatal onset with congenital anomalies associated with significant morbidity and mortality. Treatment is challenging and includes restriction of dietary fat and protein intake. In limited cases, exogenous ketone administration has improved the myopathy, cardiomyopathy, and liver dysfunction but can lead to side effects due to high salt content.
Case Presentation
An infant female, born to consanguineous parents, was prenatally diagnosed with multiple congenital anomalies, including structural brain abnormalities. An amniocentesis was performed, and a karyotype and GCH microarray were unrevealing. Following delivery, she was admitted to the NICU due to respiratory distress requiring intubation. During postnatal evaluation, an MRI revealed mild alobar holoprosencephaly, hydrocephalus, and a Dandy-Walker malformation. An echocardiogram identified mild concentric left ventricular hypertrophy. Imaging of her abdomen showed bilateral enlarged cystic kidneys. Her physical examination was significant for macrocephaly and low-set posteriorly rotated ears.
Diagnostic Workup
The need for a diagnosis to guide management in the setting of multiple congenital anomalies prompted rapid trio exome sequencing. While awaiting these results, the newborn screen returned showing an elevation in long chain acylcarnitine species. A confirmatory acylcarnitine profile revealed a large elevation in C4 while confirming elevations in long chain species. Of note, C5 and C8 were not elevated as would be expected in this condition. Follow-up testing shortly thereafter was more consistent with the final diagnosis. Urine organic acids identified elevations in ethylmalonic, glutaric, and dicarboxylic acids, as well as 3-OH isovalerate and isobutyrlglycine, while ketone levels were unremarkable despite the patient’s illness. After providing updated information regarding abnormal biochemical testing, the exome returned with homozygous pathogenic variants in ETFA (c.746 G>A).
Treatment and Management
Following biochemical test results, the patient was started on carnitine, high-dose riboflavin, and coenzyme Q10 supplements. At initiation of enteral feeds, a low fat and low protein diet was initiated and slowly titrated to reach her goal volume. Riboflavin was discontinued due to limited clinical improvement and gastrointestinal distention. She underwent shunt placement for worsening hydrocephalus. Repeat echocardiogram at 2 weeks of life revealed severe left and mild right ventricular hypertrophy. Beta-hydroxybutyrate treatment was initiated on day 22 of life with close monitoring of her electrolytes and eventual titration of the dose up to 500 mg/kg/day.
Outcome and Follow-Up
Within days of beginning this treatment, she became more alert and feeds were increased. Follow-up echocardiogram showed almost full resolution of cardiomyopathy, and she was extubated. Despite this, the patient passed away due to severe respiratoyry acidosis on day 68 of life.
Discussion
This case presents a unique diagnostic challenge. Initially, the differential diagnosis included ciliopathies and CPTII deficiency given the non-characteristic acylcarnitine profile and her structural phenotype. While neuronal migration defects are common in patients with this condition, the brain malformations in this case were more severe. In addition, while this patient’s clinical findings notably improved following ketone therapy without the expected side effects, this intervention was ultimately unable to prevent ultimate decompensation.
Conclusion
It is imperative to maintain a broad differential diagnosis including inborn errors of metabolism in patients with multiple congenital anomalies and metabolic acidosis. Also, obtaining a biochemical phenotype can guide exome interpretation. In addition, this case emphasizes the need for further clinical trials to determine the efficacy of exogenous ketones in infants diagnosed with MADD type 1, specifically with variants in the ETFA gene.
Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited disorder of mitochondrial fatty acid oxidation. Type 1 MADD is characterized by a severe, neonatal onset with congenital anomalies associated with significant morbidity and mortality. Treatment is challenging and includes restriction of dietary fat and protein intake. In limited cases, exogenous ketone administration has improved the myopathy, cardiomyopathy, and liver dysfunction but can lead to side effects due to high salt content.
Case Presentation
An infant female, born to consanguineous parents, was prenatally diagnosed with multiple congenital anomalies, including structural brain abnormalities. An amniocentesis was performed, and a karyotype and GCH microarray were unrevealing. Following delivery, she was admitted to the NICU due to respiratory distress requiring intubation. During postnatal evaluation, an MRI revealed mild alobar holoprosencephaly, hydrocephalus, and a Dandy-Walker malformation. An echocardiogram identified mild concentric left ventricular hypertrophy. Imaging of her abdomen showed bilateral enlarged cystic kidneys. Her physical examination was significant for macrocephaly and low-set posteriorly rotated ears.
Diagnostic Workup
The need for a diagnosis to guide management in the setting of multiple congenital anomalies prompted rapid trio exome sequencing. While awaiting these results, the newborn screen returned showing an elevation in long chain acylcarnitine species. A confirmatory acylcarnitine profile revealed a large elevation in C4 while confirming elevations in long chain species. Of note, C5 and C8 were not elevated as would be expected in this condition. Follow-up testing shortly thereafter was more consistent with the final diagnosis. Urine organic acids identified elevations in ethylmalonic, glutaric, and dicarboxylic acids, as well as 3-OH isovalerate and isobutyrlglycine, while ketone levels were unremarkable despite the patient’s illness. After providing updated information regarding abnormal biochemical testing, the exome returned with homozygous pathogenic variants in ETFA (c.746 G>A).
Treatment and Management
Following biochemical test results, the patient was started on carnitine, high-dose riboflavin, and coenzyme Q10 supplements. At initiation of enteral feeds, a low fat and low protein diet was initiated and slowly titrated to reach her goal volume. Riboflavin was discontinued due to limited clinical improvement and gastrointestinal distention. She underwent shunt placement for worsening hydrocephalus. Repeat echocardiogram at 2 weeks of life revealed severe left and mild right ventricular hypertrophy. Beta-hydroxybutyrate treatment was initiated on day 22 of life with close monitoring of her electrolytes and eventual titration of the dose up to 500 mg/kg/day.
Outcome and Follow-Up
Within days of beginning this treatment, she became more alert and feeds were increased. Follow-up echocardiogram showed almost full resolution of cardiomyopathy, and she was extubated. Despite this, the patient passed away due to severe respiratoyry acidosis on day 68 of life.
Discussion
This case presents a unique diagnostic challenge. Initially, the differential diagnosis included ciliopathies and CPTII deficiency given the non-characteristic acylcarnitine profile and her structural phenotype. While neuronal migration defects are common in patients with this condition, the brain malformations in this case were more severe. In addition, while this patient’s clinical findings notably improved following ketone therapy without the expected side effects, this intervention was ultimately unable to prevent ultimate decompensation.
Conclusion
It is imperative to maintain a broad differential diagnosis including inborn errors of metabolism in patients with multiple congenital anomalies and metabolic acidosis. Also, obtaining a biochemical phenotype can guide exome interpretation. In addition, this case emphasizes the need for further clinical trials to determine the efficacy of exogenous ketones in infants diagnosed with MADD type 1, specifically with variants in the ETFA gene.