Nonketotic hyperglycinemia case series

Abstract

To present three cases who presented with neonatal hiccups and who were later diagnosed with nonketotic hyperglycinemia (NKH). Case series. We present three babies who presented in neonatal life with hiccups who later were diagnosed with NKH. Two babies presented on the 2^nd day of life with hypotonia, poor feeding, and abnormal movements including jitteriness, hiccups, and twitching. The third baby only had transient hiccups lasting for a couple of days in the 1^st week of life but later presented at 3 months of age with poor feeding, drowsiness, and jerky movements. All three cases needed extensive investigations before reaching the diagnosis including metabolic screen, lumbar puncture, electroencephalography, and computed tomography/magnetic resonance imaging. The first two babies needed intubation on their 2^nd day of life because of apneas in whom later, the care was withdrawn after reaching the diagnosis of NKH because of poor prognosis. The third baby was discharged home on oral dextromethorphan and ketogenic diet. We discuss the importance of early recognition of symptoms (frequent hiccups) and investigation needed to reach the diagnosis early as it helps in making decision to either carry on treatment or withdraw care because of poor prognosis. It also helps in genetic counseling and prenatal diagnosis can be offered at the subsequent pregnancy.

Introduction

Hiccups are fairly common in the neonatal period and sometimes also occur in late fetal life. It is caused by an intense synchronous contraction of the diaphragmatic and inspiratory intercostal muscles followed by glottal closure, which causes the characteristic inspiratory sound and discomfort. It can continue in sleep, and may cease in response to emotional shock. Increasing PaCO₂ and breath holding reduce hiccup frequency (and may eliminate it); but a low PaCO₂ increases the amplitude but not frequency,[1] the characteristics suggest a gastrointestinal nature; its function (if any) is unknown.

Neonatal hiccups are nonpathological in the majority of the cases; however, the physicians should be aware of the conditions associated with symptomatic hiccups, brainstem infarction, tumor, encephalitis, and rare metabolic conditions such as nonketotic hyperglycinemia (NKH).

Glycine encephalopathy also known as NKH is a rare autosomal recessive metabolic encephalopathy usually presenting in the neonatal period. It is an inborn error of glycine metabolism caused by deficiency in the glycine cleavage system (GCS)[2] and characterized by the accumulation of glycine in all body tissues, especially in cerebrospinal fluid. Most infants appear normal at birth and remain asymptomatic for a brief period. The infants present with rapidly progressive neurological symptoms such as poor feeding, lethargy, seizures, and generalized hypotonia. Hiccups are also frequently observed. Most patients deteriorate very quickly into coma and die within a few weeks.[3] NKH is associated with poor outcome with mortality up to 50% during the 1^st week of life.[4] Survivors usually have severe psychomotor retardation, microcephaly, spasticity, and uncontrolled seizures. The classical neonatal form of NKH presents within a few days of life with poor feeding, lethargy, hypotonia, hiccups, apnea, convulsion, and coma. The infantile form usually presents after 6 months and infants are symptoms free and have normal development until 6 months of age. Late onset and a transient form of NKH have been reported in literature.[5] In late onset, NKH patients usually have normal intellectual functions and present with spastic diplegia and optic atrophy.[6]

These patients present like classical form of NKH, but the levels of glycine in plasma and cerebrospinal fluid (CSF) normalizes over time and often have a few or no neurological sequelae.

We present 3 cases of NKH, 2 presented with classical NKH type, and 1 intermediate between classical and infantile form of NKH. There was a history of neonatal hiccups in all three cases.

Case Reports

Case 1

Following an uneventful pregnancy, and normal delivery a 2-day-old baby boy presented with lethargy, poor feeding, and frequent hiccups. His birth weight was 3.2 kg, and head circumference was 35 cm which were both on 50^th centile.

Examination revealed gross hypotonia with poor suck and weak cry and no dysmorphic features. Within few hours of presentation, he was noted to have apneic episodes requiring ventilatory support. No spontaneous breathing was observed while on ventilator despite not being on sedation. He was noted to have some abnormal movements including jitteriness, hiccups, and twitching of his limbs for which he was treated with phenobarbitone.

His blood did not show any evidence of infection, acidosis, or ketosis and had normal lactate and ammonia levels. Extensive metabolic investigations were carried out including CSF. His serum glycine levels were high 754 (normal range: 200–600 µmol/l), CSF glycine levels of 423 (normal range: 0–10 micro m/l), and CSF/plasma glycine ratio 0.56 which is diagnostic of NKH. His electroencephalography (EEG) showed myoclonic epileptic seizures with burst suppression pattern. Magnetic resonance imaging (MRI) showed hypoplasia of cerebellar vermis.

After confirming the diagnosis and due to the poor prognosis of NKH, the case was extensively discussed between the medical team and the parents and an agreement of withdrawal of care was reached, and he passed away peacefully shortly afterward. Parents were referred to a geneticist for genetic counseling.

Case 2

A 2-day-old baby girl presented with poor feeding, hiccups, and shallow breathing. She was born at full term by vaginal delivery in good condition. Antenatally, mother noticed some increased fetal movements from 20 weeks of gestation, but otherwise it was an uneventful pregnancy. After discharge from the hospital, mother noticed frequent hiccups at home from day 1 onward.

On examination, she was noted to be hypotonic with shallow breathing and was having frequent apneic episodes requiring ventilatory support for her breathing. Soon she developed frequent myoclonic jerks necessitating treatment with phenobarbitone to good effect.

In view of gross hypotonia, myoclonic jerks, and frequent hiccups, a clinical impression of likely glycine encephalopathy was discussed with parents and was confirmed later with metabolic investigations including plasma/CSF amino acids.

The plasma glycine level was 1751 (normal range: 200–600 µmol/l), CSF glycine level of 416 (normal range: 0–10 µmol/l), and CSF/plasma glycine ratio of 0.238, the rest of metabolic investigations were unremarkable.

The computed tomography (CT) head scan did not show any obvious abnormalities, but EEG showed burst suppression pattern consistent with NKH diagnosis.

After discussion with parents, care was withdrawn on day 6 of life. Parents were referred to a geneticist for genetic counseling.

Case 3

A 3-month-old boy was admitted with 1-week history of poor feeding, drowsiness, and jerky movements of his limbs. This was on a background of back arching episodes from 6 weeks of age which was being treated as gastroesophageal reflux. On reviewing the history, mother did report that he started having frequent hiccups in the 1^st week of life which she thought were normal but has continued since then. On admission, he had a focal seizure with deviation of his eye and head toward the right side. He was hypotonic and noted to have poor fixing and following. Parents also reported a loss of social smile in the last 1 week. There were no dysmorphic features, and his head circumference was 40.1 cm (50^th centile).

An urgent EEG was requested which was noted to be very abnormal with frequent epileptiform discharges with a left-sided temporal emphasis. His ophthalmology assessment under GA as well as MRI brain scan was normal. He continued to have right focal as well as prolonged generalized tonic-clonic seizures necessitating rescue medications (buccal midazolam) and intravenous phenytoin loading dose.

Detailed neurometabolic investigations demonstrated a high CSF/plasma glycine level of 0.19, diagnostic of nonketotic hyperglycinemia with CSF glycine of 123, and plasma glycine of 649. The diagnosis and implications, as well as prognosis, were discussed with parents.

After confirming the diagnosis of NKH, he was started on oral dextromethorphan and ketogenic diet by the metabolic team with partial improvement in his seizure control.

Subsequent examination after starting treatment showed improvement in his level of alertness and interaction with parents along with improvement in feeding. On his most recent follow-up at 3 years of age, he has a global developmental delay and poorly controlled epilepsy despite being on ketogenic diet and 2 antiepileptic medications.

Discussion

The incidence of NKH is underestimated as most of the patients die in early life before the condition is recognized, so that is why it is important to keep in mind inborn errors of metabolism when dealing with babies in the neonatal period who presents with seizures and altered consciousness. The worldwide incidence of NKH is unknown. Its incidence has been studied in only a few regions: affecting about 1 in 55,000 newborns in Finland, and about 1 in 63,000 newborns in British Columbia and Canada.

Diagnosis depends on the findings of hyperglycinemia and elevated CSF glycine levels in the absence of an organic acid disorder. Exclusion of organic acidemias and the absence of ketoacidosis are crucial for diagnosing NKH. The absence of common biochemical abnormalities including hyperammonemia, lactic acidosis, and ketoacidosis should suggest the possibility of NKH. CSF and plasma glycine measurements are essential for the diagnosis of NKH, so should be performed at outset when metabolic encephalopathy is suspected. Glycine levels in CSF are also elevated, the ratio of CSF and plasma glycine characteristically being >0.08.

The gold standard for diagnosis of NKH is glycine cleavage enzyme assays on liver biopsy, but this is not feasible in many cases.[7] More than 80% of patients have a defect in P-protein of glycine cleavage enzyme.[8] The gene of P-protein is located on the short arm of chromosome.[9] Perinatal diagnosis is possible by GCS enzyme assay in chorionic villi.

Clinical presentations of NKH differ with different types of the disease. NKH classically presents in the neonatal period as life-threatening metabolic encephalopathy. During the first few weeks of life, a characteristic EEG pattern is seen with bursts of large amplitude sharp waves called “Burst Suppression pattern.” Cortical atrophy and hypoplasia of vermis along with delayed or deficient myelination is seen on CT/MRI.[10] The initial presentation may be difficult to differentiate from hypoxic ischemic encephalopathy or other causes of CNS depression including metabolic and infective causes. Some patients may have hiccups as our first and second patients. Later, these children develop seizures, which are often of the myoclonic type and quickly progress to coma, respiratory depression, and apnea. The baseline investigations including blood gases, lactate, ammonia, liver function tests, and infection screen are usually normal.

The infantile form of the disease usually presents after 6 months of age and seizures are the common presenting feature. These children usually have normal development until the age of 6 months.

The late onset form may present from 2 to 33 years of age with progressive spastic paraparesis, choreoathetosis, and optic atrophy. Severity of disease varies considerably in different patients of the same variety.

Our first two patients had classical neonatal NKH and the third patient fall in between the classical neonatal and infantile form of NKH. All had a typical presentation with CSF/plasma glycine ratio above the diagnostic value of >0.08 (normal value <0.03).[8] All three cases had abnormal EEG and had a history of hiccups which is an important clinical finding in NKH. Only the first patient had abnormal CT/MRI finding which showed hypoplasia of vermis, second and third patient had normal CT/MRI. Other CNS anomalies associated with NKH include absent corpus callosum, abnormal myelination, gyral malformation, progressive atrophy, and parenchymal volume loss.[10,11,12] The first two patients died after withdrawal of care, and the third patient was discharged home on oral dextromethorphan and ketogenic diet, which reduced his seizures and improved his alertness, interactions with parents and feeding.

The major differential diagnosis of a neonate presenting with encephalopathy without obvious metabolic derangement includes NKH, urea cycle defects, maple syrup urine disease (MSUD), pyridoxine-dependent encephalopathy, and peroxisomal disorders (e.g. Zellweger syndrome). Hyperammonemia in the absence of liver function derangement is a prominent feature in urea cycle defect which were not present in our patients. MSUD is characterized by markedly elevated levels of branch-chain amino acids in plasma and keto acids in urine, and these features were absent in our patients. Pyridoxine-dependent encephalopathy is a rare disorder presenting with seizures in the neonatal period, and the seizures are particularly resistant to conventional anticonvulsants but response dramatically to pyridoxine.[13] Our third patient was started on pyridoxal phosphate which was later stopped after confirming the diagnosis of NKH.

No absolute cure has been found yet for NKH and treatment aims for reduction of glycine burden and antagonism of neurotransmitter effect of glycine. Measures to reduce the glycine concentration include protein restriction, synthetic diet devoid of glycine, and promotion of renal excretion by benzoate, strychnine, and benzodiazepines. No effective treatment exists for NKH and the standard treatment strategies for NKH include sodium benzoate (to reduce the plasma concentration of glycine) and N-methyl D-aspartate receptor antagonists (dextromethorphan, ketamine, and topiramate).[14] Both sodium benzoate and dextromethorphan decrease seizure frequency and improve alertness, and that was demonstrated in our third patient who was started on dextromethorphan. The others main focus in NKH is seizure control with the use of antiepileptic medications. It is to be noted that among AEDs, valproate should be avoided in patients with NKH as it raises blood and CSF glycine concentrations by further inhibiting the GCS and may increase seizure frequency.[15]

Conclusion

The importance of early diagnosis of NKH in neonates with seizures and disturbances in consciousness cannot be overemphasized. Frequent neonatal hiccups are an important diagnostic clue and when associated with myoclonic seizures and altered consciousness should prompt toward the diagnosis and required investigation. Despite the progress in the management of patients with NKH, the long-term morbidity remains poor. It is important to recognize the condition early as genetic counseling, and prenatal diagnosis can be offered at the subsequent pregnancy.

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Nil.

Conflicts of interest

There are no conflicts of interest