Classic nonketotic hyperglycinemia and symmetrical intrauterine growth retardation, diagnostic challenges, and fatal outcome: a case report and review of the literature

Abstract

Background

Nonketotic hyperglycinemia is a rare metabolic disorder caused by glycine accumulation due to defects in the glycine cleavage system. While severe metabolic disorders can theoretically affect fetal growth, nonketotic hyperglycinemia is not recognized as a common or typical cause of symmetric intrauterine growth retardation.

Case presentation

This case report describes a Iranian 36-week male neonate with symmetrical intrauterine growth restriction, born to consanguineous parents with a history of preeclampsia and prior fetal demise. Despite initial stabilization, the infant developed metabolic acidosis, recurrent apnea, and seizures. Laboratory findings revealed elevated glycine levels (2560 µmol/L), confirming nonketotic hyperglycinemia. Despite seizure management and antibiotic therapy, the infant deteriorated and died on day 11.

Narrative review and conclusion

Nonketotic hyperglycinemia typically presents with lethargy, hypotonia, seizures, and apnea, often fatal in the neonatal period. Glycine’s dual role as an excitatory and inhibitory neurotransmitter explains the seizures and hypotonia seen in nonketotic hyperglycinemia. While acute symptoms may resolve, survivors face severe neurological impairment. Early recognition of nonketotic hyperglycinemia is critical for genetic counseling and palliative care. This case highlights the diagnostic challenge of nonketotic hyperglycinemia, particularly when presenting with intrauterine growth restriction, which can mimic other neonatal conditions such as sepsis or hypoxic-ischemic encephalopathy. Consanguinity and prior fetal loss should raise suspicion for metabolic disorders, and according to this case presentation, symmetric intrauterine growth restriction in high-risk pregnancies should prompt metabolic screening. Despite advances, nonketotic hyperglycinemia remains a devastating condition with high mortality and neurodevelopmental morbidity, emphasizing the importance of further research and early intervention strategies.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13256-025-05764-4.

Background

Classic nonketotic hyperglycinemia (NKH) is a rare metabolic disorder characterized by an accumulation of glycine, an amino acid, due to deficiencies in the glycine cleavage system (GCS). This condition presents unique diagnostic challenges, particularly in the context of prenatal and neonatal care [1]. Symmetrical intrauterine growth restriction (IUGR) is often associated with various genetic and environmental factors, complicating the clinical picture when NKH is present. The intersection of these two conditions can lead to significant morbidity and mortality, underscoring the importance of early and accurate diagnosis [2]. This case report highlights a tragic outcome in a patient with classic NKH and symmetrical IUGR, illustrating the complexities faced by healthcare providers in managing such case [3]. Additionally, a narrative review of the literature will be presented to contextualize the diagnostic hurdles and clinical implications of this metabolic disorder, aiming to enhance understanding and improve outcomes for affected individual [4]. Understanding the multifaceted relationship between IUGR and NKH is crucial for developing targeted interventions and optimizing management strategies in clinical practice. A comprehensive approach that incorporates genetic counseling, nutritional support, and early intervention strategies may significantly improve the prognosis for these patient [5].

While severe metabolic disorders can theoretically affect fetal growth, NKH is not recognized as a common or typical cause of symmetric IUGR [6]. Most metabolic disorders associated with IUGR involve mitochondrial dysfunction or energy metabolism disruptions, which are distinct from NKH’s pathophysiology. In this paper we report a case of NKH and IUGR.

Case presentation

We present the case of an Iranian 36-week-old male neonate born by caesarean section to a mother with a history of preeclampsia and Hemolysis, Elevated Liver enzyme levels, and Low Platelet levels (HELLP) syndrome. The infant was born to consanguineous parents and had symmetric IUGR with a birth weight of 1780 g, birth height of 46, and a head circumference of 31 cm. The pregnancy was complicated by a previous intrauterine fetal demise (IUFD) at 26 weeks’ gestation. At birth, Apgar scores were 7 at 1 minute and 9–10 at 5 minutes. The neonate required positive pressure ventilation (PPV) for 15 seconds due to initial respiratory distress, but spontaneous breathing resumed promptly.

Following stabilization, the neonate was transferred to the neonatal intensive care unit (NICU) for close monitoring and further evaluation of potential complications associated with IUGR and prematurity.

The neonate was admitted to the NICU due to tachypnea, grunting, and signs of respiratory distress. Surfactant therapy was administered under intubation; however, metabolic acidosis persisted despite bicarbonate supplementation (4.5 mEq stat and 4.5 mEq in daily serum). After extubation on day 1, the infant was started on dopamine infusion, total parenteral nutrition (TPN), and caffeine. Initial investigations included brain and abdominal ultrasound, cardiac consultation, and intrauterine infectious diseases serology, all of which were unremarkable except for the persistent metabolic acidosis. No brain magnetic resonance imaging (MRI) was done because of unstable situation; instead of it, for evaluation of the brain structure, brain sonography was done on days 0, 7, and 11. It showed no structural abnormalities and also no intracranial bleeding.

The clinical team continued to monitor the infant’s vital signs closely, while adjusting the treatment plan on the basis of ongoing lab results and response to therapies.

Laboratory findings on admission included marked initial metabolic acidosis and hypoglycemia. Serum lactate and ammonia levels were slightly elevated (lactate: 47 mg/dL, ammonia: 186 µmol/L). Urinalysis showed trace proteinuria, while urine culture and urine ketone were negative. Lumbar puncture (LP) performed on day 3 showed elevated cerebrospinal fluid (CSF) protein (178 mg/dL), low glucose (13 mg/dL with simultaneous blood glucometer 76), and red blood cells (RBC; 20), with negative CSF culture (Table 1). Intrauterine infectious diseases serology, human immunodeficiency virus (HIV) antibodies, and herpes simplex virus (HSV) polymerase chain reaction (PCR) tests were negative.

Table 1.

Laboratory results of neonate with nonketotic hyperglycinemia

Tests	Day 1	Day 3	Day 8	Day 11
Blood sugar (mg/dL)	20	46	9
Urea (mg/dL)	40	–	70	27
Creatinine (mg/dL)	1.2	0.7	0.7	0.5
Calcium (mg/dL)	9.5	7.3	7.5	8.7
pH	7.18	7.43	7.32	7.38
PCO₂ (mmHg)	18.5	33.7	34.9	41
HCO3 (mEq/L)	11	23	19.7	23.9
White blood cell count	10.8	–	4.9	2.8
Hemoglobin (g/dL)	16.2	–	13.8	11.7
Platelet count (×103/µL)	173	–	51	177
CRP (mg/L)	3.4	9.1	1	8.1
Sodium (mEq/L)			135	128
Potassium (mEq/L)			3	3.4
Urine sodium (mEq/L)	–	–	11.3	–
Urine potassium (mEq/L)	–	–	12.5	–
CSF glucose (simultaneous BS glucometer)	13 (76)
CSF protein	178
CSF WBC	0
CSF RBC	20
CSF culture	Negative

During hospitalization, the neonate developed recurrent apnea, recurrent hypoglycemia, and several bouts of hypocalcemia and hyponatremia that compensated after serum and electrolytes therapy. Levetiracetam was initiated for suspected seizures. Endocrinology consultation was sought for genital ambiguity (enlarged clitoris), recurrent hypoglycemia, and initial elevation in ammonia and lactate levels. Pediatric endocrinologist assessed the adrenal functional tests [cortisol, adrenocorticotropic hormone (ACTH), aldosterone] and ultrasound, as well as uterine and ovary ultrasounds, which were all normal. High-performance liquid chromatography (HPLC) analysis of amino acids revealed markedly elevated glycine levels (2560 µmol/L), in addition to no ketone in urine, consistent with a diagnosis of nonketotic hyperglycinemia (NKH).

Repeat imaging studies, including renal, pelvic, and brain ultrasonography, showed mild renal pelvic fullness (anteroposterior diameter: 1.5 mm) but no other abnormalities. Antibiotic therapy was adjusted to include vancomycin, meropenem, and amikacin due to concern for sepsis. Despite aggressive supportive care, the neonate’s condition progressively worsened. On day 8, the infant became oliguric, developed generalized edema, and required shock therapy with normal saline and hydrocortisone. On day 11, the neonate experienced cardiorespiratory arrest and died despite prolonged resuscitation efforts. Written informed consent was obtained from the parents for publication of this case report.

Narrative review

A 36-week neonate with symmetric IUGR (1780 g) was born to consanguineous parents with prior fetal demise. Despite initial stabilization (Apgar 7/9), respiratory distress required NICU admission. Persistent metabolic acidosis, seizures, and elevated glycine (2560 µmol/L) confirmed NKH. Despite aggressive care (ventilation, antibiotics, anticonvulsants), the infant developed oliguria, edema, and cardiorespiratory arrest by day 11. This case highlights NKH’s rapid progression and poor prognosis despite intensive management.

The clinical presentation of classic NKH is characterized by lethargy, coma, hiccups, hypotonia, hypotension, and myoclonic seizures, often culminating in central apnea requiring ventilatory support. Mortality rates during this critical period can be as high as 50% [7]. A comprehensive review of clinical data indicates that seizures, apnea, and hiccups are observed in 85%, 79%, and 95% of patients with severe neonatal NKH, respectively, while hypotonia remains the most consistent finding, present in 100% of cases [8]. Seizures in affected neonates typically manifest within the first hours to days of life. Glycine, which functions as both an excitatory and inhibitory neurotransmitter, plays a dual role in the pathophysiology of NKH. It stimulates N-methyl-d-aspartate (NMDA) receptors in the hippocampus, cerebral cortex, and cerebellum, contributing to seizure activity. At the same time, glycine binds to inhibitory glycine receptors in the brainstem and spinal cord, resulting in apnea, hypotonia, and persistent hiccups [9].

Although acute symptoms such as lethargy, coma, hiccups, hypotension, and myoclonic seizures may resolve spontaneously after 1–3 weeks, surviving infants invariably develop severe neurological sequelae within 6 months, including epileptic encephalopathy, growth retardation, and global developmental delay [10]. In contrast to the classic form, atypical NKH is rare and presents with a heterogeneous and nonspecific course, making diagnosis challenging. This subtype should be considered in infants who present with milder symptoms such as hypotonia, growth retardation, and epilepsy compared with the severe phenotype of classical NKH. Transient NKH is even rarer and typically resolves spontaneously within a few months due to increased activity of the GCS [11].

The definitive diagnosis of NKH is based on the measurement of GCS activity in a liver biopsy, which serves as the gold standard. However, this invasive procedure is not widely available in clinical practice [12]. Genetic testing has shown that more than 80% of NKH cases result from mutations in the GLDC gene, which encodes the P-protein of the glycine cleavage enzyme complex located on the short arm of chromosome 9 [13]. Advances in prenatal diagnosis now allow early detection of NKH by chorionic villus sampling (CVS) and enzymatic assays of GCS activity [14].

The initial presentation of NKH may mimic other neonatal conditions such as hypoxic-ischemic encephalopathy (HIE), sepsis, or other metabolic and infectious causes of central nervous system involvement. Initial laboratory studies, including blood gases, lactate, ammonia, liver function tests, and infectious disease screening, are usually unremarkable in NKH. In contrast, the neonate described in this case presented with metabolic acidosis and developed seizures within the first 10 days of life, prompting the initiation of antiepileptic therapy. Unlike the typical neonatal form of NKH, which usually manifests after 6 months of age with seizures as the predominant feature, the patient in this report presented with symmetric IUGR and early onset seizures, highlighting the variability in clinical presentation [15].

In cases of suspected neonatal asphyxia, metabolic disorders should be considered as part of the differential diagnosis, especially in the context of consanguinity, a history of intrauterine fetal demise (IUFD), or progressive clinical deterioration. These factors prompted further investigation into metabolic disorders, which ultimately led to the diagnosis of NKH in this patient.

Currently, there is no curative treatment for NKH, and management focuses on reducing glycine load and antagonizing its neurotransmitter effects. Therapeutic strategies include dietary protein restriction, administration of a glycine-free synthetic diet, and pharmacologic interventions such as sodium benzoate to enhance renal excretion of glycine. In addition, NMDA receptor antagonists, including dextromethorphan, ketamine, and topiramate, are used to attenuate the excitotoxic effects of glycine in the central nervous system [16]. Despite these measures, the prognosis remains poor, highlighting the need for further research into novel therapeutic approaches.

Symmetric IUGR is not directly related to NKH. While rare metabolic disorders might theoretically contribute to IUGR, NKH has no well-documented association with growth restriction in utero. Clinical evaluation for IUGR should prioritize more common causes (genetic, infectious, or placental), while NKH warrants specific metabolic and genetic testing postnatally and seems not to contribute with symmetric IUGR.

Conclusion

While NKH is not a typical cause of IUGR, this case underscores the need for metabolic screening in high-risk pregnancies with unexplained growth restriction, particularly in consanguineous families. Prompt cerebrospinal fluid (CSF) glycine analysis and genetic testing are essential for timely diagnosis and informed decision-making.

Author contributions

PM and RA collected the data; SM and PM wrote the paper; and RA, SM, and PM revised the manuscript.

Funding

No fund was received.

Data availability

Data are available on demand.

Declarations

Ethics approval and consent to participate

Informed consent was obtained from parents of the neonate.

Consent for publication

Written informed consent was obtained from the patient’s legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

None of the authors had any conflict of interest.