|Year : 2021 | Volume
| Issue : 4 | Page : 240-243
Compound heterozygous mutation of SLC25A1 gene in glutaric aciduria type 2
Karthikeyan Kadirvel, Adarsh Bagali, Sumathisri Ramachandran
Department of Pediatrics, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth (Deemed to be University), Puducherry, India
|Date of Submission||20-Apr-2021|
|Date of Decision||20-Oct-2021|
|Date of Acceptance||11-Nov-2021|
|Date of Web Publication||29-Nov-2021|
Dr. Karthikeyan Kadirvel
Department of Pediatrics, Mahatma Gandhi Medical College and Research Institute, Sri Balaji Vidyapeeth (Deemed to be University), Puducherry
Source of Support: None, Conflict of Interest: None
Background: Sudden unexplained postnatal collapse (SUPC) is a condition in which a newborn born at term or near term, and an Apgar score >8 at 5 min and deemed healthy, presents with sudden unexpected cardiorespiratory collapse within the 1st week of life. This can be due to multiple, heterogeneous causes. Clinical Description: A term male neonate developed lethargy and refusal to feed at 56 h of life. The baby was cyanosed, apneic, in peripheral circulatory failure and normothermic. Supportive management was started. Sepsis and congenital heart disease were ruled out. The presence of hypoglycemia, metabolic acidosis and hyperammonemia prompted us to think of a metabolic disorder. Metabolic profile was suggestive of glutaric acuduria (GA). Exome sequencing showed heterozygous missense variants in in exon 7 and 8 of SLC25A1 gene indicative of GA II but reported as of uncertain significance. Both parents were carriers. Management: The final diagnosis was neonatal onset GA II without congenital anomalies. He was started on riboflavin and carnitine. Mechanical ventilation and inotropes were gradually withdrawn and breastfeeding started. Genetic counseling was done. The baby was doing well at the 4-month follow-up visit. Conclusions: Identifying and managing a newborn with SUPC is critical for the outcome. An individualized and rational approach should be used to identify the cause. The management of GA II is primarily supportive with tiding over of metabolic crises and dietary modifications.
Keywords: Compound heterozygote, hyperammonemia, hypoglycemia, metabolic acidosis, sudden unexpected postnatal collapse
|How to cite this article:|
Kadirvel K, Bagali A, Ramachandran S. Compound heterozygous mutation of SLC25A1 gene in glutaric aciduria type 2. Indian Pediatr Case Rep 2021;1:240-3
|How to cite this URL:|
Kadirvel K, Bagali A, Ramachandran S. Compound heterozygous mutation of SLC25A1 gene in glutaric aciduria type 2. Indian Pediatr Case Rep [serial online] 2021 [cited 2022 Jan 20];1:240-3. Available from: http://www.ipcares.org/text.asp?2021/1/4/240/331364
Sudden unexplained postnatal collapse (SUPC) is a condition in which a newborn born at term or near term, and an Apgar score >8 at 5 min and deemed healthy, presents with sudden unexpected cardiorespiratory collapse within the 1st week of life, which requires resuscitation, and may result in death, or encephalopathy. Most occur within the first 3 days (36% within 2 h, 29% between 2 and 24 h, and 24% between 25 and 72 h), while 9% occur between 4 and 7 days of life. The common causes of SUPC include congenital infections, congenital anomalies (especially cardiac), respiratory disorders, anemia, hypoglycemia, congenital adrenal hyperplasia, neurological/neuromuscular disorders, and inborn errors of metabolism (IEM)., Electron transfer flavoprotein (ETF) serves as the electron acceptor for flavoprotein dehydrogenases which are important in fatty acid beta-oxidation and amino acid catabolism. Impaired beta-oxidation result from defects in ETF and manifest as hypoglycemia, hyperammonemia, and metabolic acidosis.
We report a case of SUPC who was diagnosed with an IEM, by keeping a high index of suspicion, and following an individualized, rational, diagnostic approach that included simultaneous clinical, biochemical and genetic evaluation, while stabilizing a sick neonate.
| Clinical Description|| |
A 2-day-old boy was shifted from the postnatal ward to the intensive care unit at 56 h of life with a history of acute-onset lethargy, poor responsiveness, and not being able to suckle. Breast feeding had been established successfully within an hour of birth and the baby had been feeding well, crying, and moving all limbs spontaneously, prior to these events. There was no history of any trauma, vomiting, loose motions, or being fed anything, besides breast milk. The baby was born at term gestation by a normal vaginal, institutional delivery. There was no history of any maternal or environmental risk factors for sepsis. The birth weight was 2660 g. The Apgar scores were 8 and 9, at 1 and 5 min, respectively. The antenatal period had been uneventful, with no history of substance abuse, and whatever health records were available, were normal. He was the second issue of a nonconsanguineous union. There was no significant family history.
On examination, the baby had peripheral cyanosis, poor respiratory efforts, bradycardia, low volume peripheral pulses, delayed capillary refill time, nonrecordable blood pressure, and normothermia. No abnormalities were detected on the general physical examination. The baby was limp with minimal spontaneous movement and absent neonatal reflexes. The pupils were normal. The cardiovascular, respiratory, and abdominal examinations were normal. Hypoglycemia and severe metabolic acidosis (arterial bool gas analysis-pH 7.1, base deficit-16, normal lactate and anion gap) were present. Serum electrolytes, liver, and renal function tests were within the normal range. The clinical and metabolic profile led us to consider differential diagnoses of a critical congenital heart disease, early onset neonatal sepsis, or an IEM.
Management and outcome
The baby was resuscitated as per the standard protocol and started on mechanical ventilation. Intravenous fluids were administered by multiple lines including glucose infusion (@10 mg/kg/min), sodium bicarbonate, and inotropes. The hemogram was normal and sepsis screen negative. The baby passed the oxygen saturation test, while a 2-dimensional echocardiogram did not detect any structural or obstructive defects. The abdominal ultrasonogram was normal, ruling out any renal or adrenal abnormalities. First tier metabolic workup showed elevated ammonia levels (515 μm/l). The baby was kept nil per orally and empiric management of hyperammonemia was started with sodium benzoate (250 mg/kg), Carnitine (100 mg/kg/day), and megavitamins; thiamine (10 mg twice a day), biotin (10 mg/day), and riboflavin (20 mg/day). The urinary gas chromatography mass spectrometry analysis revealed an increase in the excretion of 2-hydroxyglutaric acid, glutaric acid, and related organic acids. The tandem mass spectrometry report showed increased levels of C4-C18 acylcarnitines. Both of these biochemical abnormalities were indicative of glutaric aciduria (GA).
A whole exome sequencing test was ordered. This revealed heterozygous missense variants (c.634G>A [p. Asp212Asn] and in exon 7 c.769C>T [p. Arg257Trp] in exon 7) of the SLC25A1 gene, associated with DL-2 hydroxyglutaric aciduria, but of unknown significance. After posttest genetic counseling, the parents underwent Sanger sequencing to segregate and understand the inheritance pattern of these variants. The mother was a carrier for the c.634G>A variant [Figure 1] and the father carrier for the c.769C>T variant [Figure 2], making the baby compound heterozygous for GA II, i.e., the atypical allele inherited from either parent was located at different loci within the same gene. Considering the onset, clinical features, biochemical profile and genotype, the final diagnosis was neonatal onset, GA II without congenital anomalies due to a compound heterozygous mutation in the SLC25A1 gene.
|Figure 1: Sanger sequencing report of the mother showing nucleotide change at chromosome 22: c.634G>A, (p. Asp212Asn) in SLC25A1 gene|
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|Figure 2: Sanger sequencing report of the father showing nucleotide change at chromosome 22: C.769C>T, (p. Arg257Trp) in SLC25A1 gene|
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Inotropes were stopped by the 5th day of admission and he was weaned off ventilation by the 6th day. Megavitamins were stopped once the diagnosis was established (day 7). The baby was allowed breastfeeding on day 8, and he was discharged by the 12th day on oral riboflavin and carnitine. The parents were counseled regarding the disorder, sick day management protocol, and the need for regular follow-up that included monitoring for hypoglycemia, rhabdomyolysis, and liver dysfunction. They were also informed about the option of prenatal diagnostic testing for the next pregnancy. At the 2-month follow-up visit, the baby was well, gaining weight adequately, and had attained a social smile. His neurodevelopmental assessment was normal for age.
| Discussion|| |
Sudden unexpected postnatal collapse in a well newborn is a rare event, with multiple causes [Table 1]., Irrespective of etiology, the consequences are serious; mortality or severe neurological disability among survivors. Rapid identification and initiation of resuscitation are critical. After initial stabilization, evaluation for the underlying cardiac, endocrine, and metabolic causes must be carried out according to clinical clues. In our case, an apparently well baby with acute onset encephalopathy, absence of trauma, sepsis, dyselectrolytemia, and cardiac anomalies, in the presence of hypoglycemia and metabolic acidosis, indicated an IEM.
|Table 1: Differential diagnosis of sudden unexplained postnatal collapse|
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GA II is an autosomal recessive disorder caused by mutations in the α or β subunit of the mitochondrial ETF protein or ETF dehydrogenase (ETFDH) protein. Its prevalence is 1:250.000 and affects both genders. GA II is sub-grouped as IIa, IIb, and IIc according to the defects in the ETFA, ETFB, and ETFDH genes, respectively. The mutations result in deficient or complete absence of enzyme activity of multiple acyl-CoA dehydrogenase that catalyze the breakdown of fats and proteins in the body. Mutations in ETFA and ETFB result in neonatal onset presentation, whereas those in ETFDH result in the type that presents later and with milder severity. Dysfunction of either flavoproteins coded by these genes lead to impaired fatty acid oxidation and amino acid degradation that alters production energy and other molecules needed by the body.
Clinicians should suspect GA in a newborn with vomiting, hypotonia, encephalopathy, and/or hepatopathy, associated with unexplained hypoglycemia and metabolic acidosis. There are three types of presentations depending upon the age of onset. In the neonatal period, GA II may present with congenital anomalies (high-arched palate, craniotabes, dolichocephaly, rocker bottom feet, hypotonic abdominal wall, hypospadias, and renal cysts) which is lethal; or without. Thus, an IEM should still be considered in a neonate with multiple congenital anomalies, especially if there is unexplained clinical deterioration. Late onset GA II manifests later, in infancy, childhood or even adulthood, with progressive myopathy, respiratory failure, acute renal failure and repeated episodes of hypoglycemia with hypoketosis. This form is due to partial defect of ETF/ETF-DH that may respond to riboflavin (100 mg/day).
GA II does not have any specific treatment. The goal of management is supportive medical management (riboflavin and carnitine), and treatment of metabolic crises, and dietary modifications: High carbohydrate, low protein and low fat, and frequent meals avoid the episodes of hypoglycemia.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]