Decoding the Enigma of Multiple Neonatal Deaths

A female neonate is born at 35 weeks gestation to a mother with pregestational hypothyroidism and a past history significant for 2 neonatal deaths. Both were male infants with an uneventful delivery and postnatal period until 4 days after birth when they developed lethargy, refusal to feed, and loose stools. By 21 to 26 days, their condition worsened with fever seizures and severe metabolic acidosis in the second infant with elevated lactate (pH of 6.6, pCO2 of 39, pO2 of 77, bicarbonate of 3.9, and lactate levels >20). Both infants died because of this suspected metabolic disorder without a final diagnosis.Additionally, there is a history of early infant death in a male child in the mother’s extended family at 40 days; however, there is no history of seizures or developmental delay in the family. The family pedigree is as shown in Figure 1.The index neonate, a girl, is delivered via cesarean section with a birth weight of 2436 g (50th centile as per Modified Fenton chart) at 35 weeks of gestation. Anthropometric parameters at birth are appropriate for age with a head circumference measuring 32.5 cm (50th percentile) and a length measuring 46 cm (50th percentile). Initially, she breastfeeds well, but she experiences excessive weight loss of 11.4% on day 3 without signs of dehydration. There is no history of vomiting, reduced feeding, jaundice, seizures, abnormal body odor, dysmorphism, or involuntary movements. Neurological examination shows appendicular and axial hypotonia. Additionally, the infant is noted to have intractable hiccups not associated with abnormal limb or eye movements.Blood glucose at the time of intractable hiccups is 36 mg/dl. Laboratory investigations completed on admission to the neonatal intensive care unit are listed in Table 1. Further history is elicited from the family that reveals that the other 2 babies also had intractable hiccups from birth that were observed by the parents but not reported to the doctors. These hiccups persist throughout the day and resolve spontaneously. Amplitude electroencephalogram shows a discontinuous background pattern without seizures.The following are the preliminary investigations of the neonate:Urea cycle defectFatty acid oxidation defectNonketotic hyperglycinemiaMaple syrup urine diseaseOrganic aciduriasWhole exome sequencing of the neonate reveals a homozygous nonsense variant in exon 2 of the BOLA3 gene (chr2.74145222G>A), c.136C>T, resulting in a stop codon and premature truncation of the protein at codon 46. This mutation is pathogenic for multiple mitochondrial dysfunctions syndrome 2 (MMDS2).The neonate requires a peak glucose infusion rate of 8 mg/kg/min during an episode of hypoglycemia associated with intractable hiccups and is transitioned to full feeds after 2 days.She is discharged with a regimen that includes specialized amino acid-free formula, sodium benzoate (200 mg/kg/d), and early intervention therapy on the 20th day of life. Parents are offered genetic counseling to explain disease prognosis, lack of definitive therapy for MMDS2 disease, recurrence risk, and future reproductive options.At 2 months, the neonate shows remarkable improvement. She is growing well, seizure-free, and has reduced hiccups. Neurologically, the baby has spasticity of all limbs. At 3 months of age, abnormal movement of all 4 limbs is noted by her mother that lasts for around 5 minutes, after which the baby is found nonresponsive and dies on arrival at a nearby hospital.Multiple mitochondrial dysfunction syndrome type 2 (MMDS2) is a very rare autosomal recessive genetic disorder caused by severe mitochondrial dysfunction that affects multiple organ systems.1 The hallmark of the disease is the mutation in the BOLA3 gene, which orchestrates the synthesis of iron sulfur clusters necessary for mitochondrial and cytosolic proteins.2 MMDS2 with hyperglycinemia is a specific subtype of MMDS2 in which hyperglycinemia is a prominent feature. The disorder is a variant form of nonketotic hyperglycinemia (NKH) and is distinct from classic NKH that is characterized by very high cerebrospinal fluid glycine levels.3The diseased neonates typically present in early infancy or in the neonatal period, usually with a history of consanguinity. The affected neonate will have marked hypotonia, encephalopathy in the form of slight to moderate stupor, seizures, and delayed attainment of developmental milestones. Some infants may experience severe respiratory distress due to weakness of the respiratory muscles and diaphragm.1,2 Our patient had all the cardinal signs that indicated the presence of a metabolic disease; she was born into a third-degree consanguineous marriage, had deaths of 2 elder siblings in late neonatal period because of unknown causes, severe metabolic acidosis, unphysiological weight loss, abnormal sensorium, and appendicular hypotonia. She had a characteristic feature of persistent hiccups that her mother had thought to be normal, but that were present in her previous 2 infants, as well.These intractable hiccups, which presented at 24 to 48 hours of life, pointed to central nervous system and/or diaphragmatic involvement. Asymptomatic hypoglycemia that required glucose infusion for 2 days was an uncommon feature noted in the neonate that later resolved on its own. Transient hyperammonemia was another uncommon feature noted. The neonate did not have any dysmorphic features and organomegaly. Lactic acidosis due to impaired mitochondrial function that is usually noted in mitochondrial disorders was not observed in this infant, possibly because of the earlier presentation. Infants with this condition can have multisystem involvement characterized by cardiomyopathy, liver dysfunction, hematological problems like anemia, bone marrow failure, and endocrine dysfunction causing adrenal insufficiency and hypoglycemia.3 The quality of life of affected for neonates is severely impaired because of neurological morbidity, frequent hospitalization, and need for intensive care. Their life expectancy is significantly short and most of patients die in early childhood.4Multidisciplinary care involving neonatologists, pediatricians, geneticists, dieticians, neurologists, and cardiologists is crucial for the effective care of such patients.2,3 Although the disease is life-limiting, the treatment of acute issues, seizures, metabolic derangements, and the nutrition and symptomatic management of specific organ system involvement can assist in symptomatic management of the affected individuals.Eliciting presence of unusual symptoms such as intractable hiccups can lead to the correct diagnosis.Phenotypic spectrum of rare diseases like MMDS2 is often incompletely defined and may have overlapping manifestations with other disorders in the same biochemical pathway such as nonketotic hyperglycinemia.Comprehensive biochemical and molecular evaluation with advanced genetic testing assists establish a diagnosis and providing genetic counseling for future pregnancies.American Board of Pediatrics Neonatal–Perinatal Content SpecificationUnderstand common chromosome deletion or insertion syndromes presenting in the neonatal period.Know the signs of neonatal seizures.The authors thank Dr Sangeeta Ravat and the Dean of Seth Gordhandas Sunderdas Medical College and King Edward Medical Hospital, Mumbai for granting permission for publication.