Nonketotic Hyperglycinemia: Two Case Reports and Review

The Neurodiagnostic Journal ISSN: 2164-6821 (Print) 2375-8627 (Online) Journal homepage: https://www.tandfonline.com/loi/utnj20 Nonketotic Hyperglycinemia: Two Case Reports and Review Rajesh P. Poothrikovil, Khalid Al Thihli, Amna Al Futaisi & Fathiya Al Murshidi To cite this article: Rajesh P. Poothrikovil, Khalid Al Thihli, Amna Al Futaisi & Fathiya Al Murshidi (2019): Nonketotic Hyperglycinemia: Two Case Reports and Review, The Neurodiagnostic Journal, DOI: 10.1080/21646821.2019.1645549 To link to this article: https://doi.org/10.1080/21646821.2019.1645549 Published online: 21 Aug 2019. Submit your article to this journal View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=utnj20 The Neurodiagnostic Journal, 0: 1–10, 2019 © 2019 ASET – The Neurodiagnostic Society ISSN: 2164-6821 print / 2375-8627 online DOI: https://doi.org/10.1080/21646821.2019.1645549 Nonketotic Hyperglycinemia: Two Case Reports and Review Rajesh P. Poothrikovil, R. EEG/EP T., RPSGT, RST1; Khalid Al Thihli, M.D., FRCPC, FCCMG2; Amna Al Futaisi, M.D., FRCPC, FRCPCH3; Fathiya Al Murshidi, M.D., FRCPC2 1 Department of Clinical Physiology Sultan Qaboos University Hospital Muscat, Sultanate of Oman 2 Department of Clinical Genetics Sultan Qaboos University Hospital Muscat, Sultanate of Oman 3 Department of Child Health Sultan Qaboos University Hospital Muscat, Sultanate of Oman ABSTRACT. Nonketotic hyperglycinemia (NKH) or glycine encephalopathy is an autosomal recessive disorder of glycine metabolism resulting in an excessive accumulation of glycine in all body tissues, including the central nervous system. It is caused by a biochemical defect in the glycine cleavage system and considered as a rare disorder with an estimated prevalence of 1:60,000. The neonatal form presents in the first few days of life with progressive encephalopathy, hypotonia, myoclonic jerks, hiccups, seizures, rapid progression to coma and often death due to central apnea. Surviving infants often have severe developmental delay and refractory seizures. Atypical forms of NKH present with heterogeneous and nonspecific disease course. Classical glycine encephalopathy usually carries a very poor prognosis. We describe two neonates who presented with neonatal encephalopathy, apnea, and progressive lethargy. Increased CSF glycine level along with an elevated CSF to plasma glycine ratio was suggestive of classic NKH. Burst suppression EEG and agenesis of the corpus callosum were supportive findings. Evolution of the EEG patterns and course of the disease are discussed in detail. Transient phases of clinical stabilization and normalized plasma biochemical results may not necessarily reflect the actual encephalopathic process. Serial Corresponding Author’s E-mail: [email protected] Received: May 4, 2019. Accepted for publication: July 16, 2019. Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/utnj. 1 2 NONKETOTIC HYPERGLYCINEMIA EEGs are helpful to assess the efficacy of treatment and to modify the therapeutic approach. KEY WORDS. Burst-suppression, EEG, epileptic encephalopathy, nonketotic hyperglycinemia (NKH), refractory seizures. INTRODUCTION Nonketotic hyperglycinemia (NKH) or glycine encephalopathy is an autosomal recessive disorder of glycine metabolism resulting in an excessive accumulation of glycine in all body tissues, including the central nervous system. The primary biochemical defect in glycine encephalopathy is in the glycine cleavage system, which consists of a mitochondrial enzyme complex. It is considered a rare disorder with an estimated prevalence of 1:60,000 (Applegarth et al. 2000; Hamosh and Johnston 2001). Four forms of glycine encephalopathy have been identified: neonatal, infantile, transient and late (Rezvani 2004). The neonatal form presents in the first few days of life with progressive encephalopathy, hypotonia, myoclonic jerks, hiccups, and seizures. Death due to central apnea occurs early in the disease course. Surviving infants often have severe developmental delay and refractory seizures. The infantile form presents in the first few months of life and is also characterized by hypotonia, developmental delay, and seizures. An increased cerebrospinal fluid (CSF) glycine level along with an elevated glycine index (CSF/plasma glycine ratio >0.08) suggests the diagnosis of NKH (Gallagher et al. 2017). EEG typically shows a burstsuppression pattern at the presentation that evolves into multifocal spikes and hypsarrhythmia. MRI can be normal or may show hypoplastic corpus callosum. Although no effective treatment exists for this condition, therapy is focused on managing seizures using antiepileptic medications, reducing the plasma concentration of glycine via administration of sodium benzoate, and N-methyl-D-aspartate (NMDA) receptor antagonism using ketamine injections or oral dextromethorphan. Classical glycine encephalopathy usually carries a very poor prognosis. CASE REPORT The first patient is a female born to consanguineous parents at 37 weeks of gestation via spontaneous vaginal delivery with a birth weight of 2.1 kg (i.e., 4.6 lbs.). Pregnancy was clinically uneventful and there were no antenatal concerns. Apgar scores were 8 at 1 min and 10 at 5 min. She barely cried after birth and her cry was very weak with poor muscle tone (sucking effort). She was discharged on the second day of life but was brought back 2 days later in view of increasing lethargy and poor feeding. She had frequent hiccups, and had respiratory acidosis (pH 7.1) with type II respiratory failure and had to be intubated. NONKETOTIC HYPERGLYCINEMIA 3 There was no family history of sudden unexplained death or metabolic/neurologic disorder. The patient was encephalopathic with an overall Glasgow Coma Scale (GCS) of 5/15. Amino acids analysis of CSF and plasma samples showed markedly increased glycine levels in CSF (147 µmol/L; reference interval 3.2–16.3) and plasma (1286 µmol/ Reference interval, 102–395) with an elevated CSF/plasma glycine ratio (0.11). These results are consistent with the neonatal form of NKH. First EEG was recorded on the ninth day of life. Background of this record showed excessive discontinuity of cerebral activity in the form of burst-suppression pattern. Intermittent high amplitude bursts of delta slowing (up to 400 µV) were noted intermixed with sharp waves on a low amplitude background. Inter-burst interval was varying with a maximum of up to 30 s (18–30 s). At times, these bursts show mild asymmetry and asynchrony (Figure 1). Plasma glycine lowered to almost half its previous levels with a mild improvement in GCS (7/15) after 24 h of sodium benzoate administration. Brain MRI done on the twelfth day showed agenesis of the corpus callosum (Figure 2). The patient was also started on an N-methyl-D-aspartate (NMDA) receptor antagonist and ketamine to reduce the cerebral cortex excitability. A second EEG was done on the thirteenth day which showed burst suppression pattern with paroxysmal high amplitude spike, polyspike and wave bursts on a low voltage suppression period. Compared to the previous record, the inter-burst interval was reduced from 18–30 s to about 10 s (Figure 3). FIG. 1. EEG of patient 1 at an age of 9 days. A 30-second epoch at 20 µV/mm shows burstsuppression pattern with an inter-burst interval of 23 s. (LFF-1 Hz and HFF-70Hz). 4 NONKETOTIC HYPERGLYCINEMIA FIG. 2. Brain MRI of patient 1 at 12 days old showing agenesis of corpus callosum. FIG. 3. EEG of patient 1 at an age of 13 days. A 20 s epoch at 20 µV/mm showing burst suppression pattern with an inter-burst interval of about 10 s. (LFF-1 Hz and HFF-70Hz). NONKETOTIC HYPERGLYCINEMIA 5 Despite the persistence of EEG abnormalities, the patient’s general condition improved, and muscle tone improved (feeding well), moving and crying loudly. Intermittent myoclonic jerks continued only while handling the baby. Treatment continued for a few more days and a third EEG was recorded on the twenty-third day. Burst suppression pattern continued throughout the record with more asynchrony (Figure 4). The inter-burst interval was less than 10 s in this record (4–8 s). In the next few months, the patient was admitted to the hospital due to aspiration pneumonia and seizures. At an age of 14 weeks, the patient was noted to have significant failure to thrive with constipation despite adequate feeding and absence of vomiting or signs of malabsorption. The patient barely reached 3 kg (6.6 lbs.) at the age of 3 months. A videoEEG was performed at this age (fifth) due to frequent short-lasting seizures and staring episodes. This record showed a very frequent spike, polyspike, and wave discharges over both hemispheres with marked asynchrony during sleep (Figure 5). Suppressive epochs were very rare in this record. Two electrographic seizures were recorded in this 2-h long recording from the right hemisphere, during which the patient had extended extremities and a vacant stare. She was started on antiepileptic drugs in order to control the seizures. During her next visit at 11 months old, the patient was presented with hypotonia, poor feeding, and a weak cry. Flash VEP with LED goggles was normal bilaterally. Another EEG (sixth) was performed which showed a hypsarrhythmic pattern throughout the record with mild asymmetry in cerebral activity (increased slowing over left hemisphere). Intermittent spikes and sharp waves were noted over the left hemisphere. Frequent electro-clinical seizures were recorded from the left hemisphere in the form of theta build-up followed by abrupt FIG. 4. EEG of patient 1 at an age of 23 days. A 20 s epoch at 20 µV/mm showing asynchronous burst-suppression pattern with an inter-burst interval of 2–5 s. (LFF-1 Hz and HFF-70Hz). 6 NONKETOTIC HYPERGLYCINEMIA FIG. 5. EEG of patient 1 at an age of 14 wks. A 10 s epoch at 20 µV/mm showing very frequent, bilaterally asynchronous spike, polyspike and wave discharges. (LFF-1 Hz and HFF-70Hz). arousal from sleep, extending all the extremities with a vacant stare and restlessness for about 1 min. Five seizures were recorded in a 20-min EEG with an index of 15 seizures per hour (Figure 6). At this time, she was on sodium benzoate, daily ketamine injection and FIG. 6. EEG of patient 1 at an age of 11 months. A 10 s epoch at 20 µV/mm showing onset of a seizure from left temporal area on a hypsarrhythmic background. (LFF-1 Hz and HFF-70Hz). NONKETOTIC HYPERGLYCINEMIA 7 multiple anti-epileptic drugs. Treatment continued until the age of 5 years and 2 months. At this age the patient passed away. The second patient is a male born to consanguineous parents at 41 weeks of gestation through induction of labor. The patient had good Apgar scores (nine at 1 min and 10 at 5 min) and birth weight (3.2 kg; 7 lbs.). He was transferred from a peripheral hospital for the management of intractable seizures. Soon after birth, it was reported that the patient was inactive with a poor cry and poor feeding efforts with frequent left-sided twitching of the face and abnormal movements of the left upper limb. Subsequently, prolonged seizures were noted and the patient was put on anti-epileptic medications. The patient had mild dysmorphic features such as down-slanting eyes, micrognathia and prominent long thumbs with a family history of epilepsy and sudden infantile death. On day nine, the patient developed central apnea and cyanosis and required intubation and ventilation for 8 days in the neonatal intensive care unit. First EEG was performed at an age of 8 weeks showed multifocal spikes and polyspikes over both hemispheres with mild to moderate asymmetry and asynchrony. Intermittent suppressive epochs were also noted in this record (Figure 7). Flash VEP with LED goggles and BAEP studies were within normal limits. MRI brain showed agenesis of the corpus callosum. Biochemical genetic study (amino acid analysis) at an age of about 2 months showed an elevated CSF: plasma glycine ratio (0.18), which is suggestive of NKH. The patient was started on sodium benzoate and ketamine. During the next follow-up at an age of 9 months, an EEG was performed and showed status epilepticus pattern in the form of frequent electrographic seizures with a subtle clinical association (Figure 8). The patient presented with frequent jerking of both lower FIG. 7. EEG of patient 2 at an age of 8 weeks. A 10-s epoch at 20 µV/mm showing multifocal spikes and polyspikes bilaterally asynchronous with intermittent suppressive epochs. (LFF-1 Hz and HFF-70Hz). 8 NONKETOTIC HYPERGLYCINEMIA FIG. 8. EEG of patient 2 at an age of 9 months. A 10-s epoch at 20 µV/mm showing an electrographic seizure with onset over right temporal area. (LFF-1 Hz and HFF-70Hz). limbs and intermittent rotator nystagmus. The patient could not follow or respond to sound. Deep tendon reflexes were very brisk and no head control or social smile was noted. During the last visit at the age of 2.5 years, it was noted that the patient did not gain any developmental milestones and no improvements were noted in his clinical condition. DISCUSSION NKH is an inborn error of metabolism caused by mutations in genes encoding protein in the mitochondrial glycine cleavage system. Glycine acts both as an excitatory and an inhibitory neurotransmitter. Large amounts of glycine accumulated in the brain have an excitatory effect at the NMDA receptor channel complex located in hippocampus, cerebral cortex, olfactory bulb, and cerebellum. Overstimulation of these receptors may cause intractable seizures and brain damage (Tada and Kure 1993). Stimulation of the glycinergic receptors located in the spinal cord and the brain stem has an inhibitory effect, causing central apnea, hiccups and diffuse hypotonia seen early in the disease course (Hamosh and Johnston 2001). Most patients with the classic form present to the hospital within the first few days of life and progress to death usually in the first 6 months or develop epileptic encephalopathy with profound neurodevelopment disorder. Though NKH carries a poor prognosis, a subset of patients present in the neonatal or early infancy period may make some developmental progress (Dinopoulos et al. 2005; Hoover-Fong et al. 2004). Atypical forms of NKH present with heterogeneous and nonspecific disease course making the diagnosis more difficult. Transient forms of NKH usually resolve partially or completely NONKETOTIC HYPERGLYCINEMIA 9 within a few months and are attributable to the delay in the maturation in the glycine cleavage system (Applegarth and Toone 2001). As the outcome is excellent in transient form, it is important to distinguish it from the classical form of NKH (Aliefendioglu et al. 2003). Several studies reported that presence of severe cerebral malformations such as hypoplasia of the corpus callosum is always consistent with a poor outcome (Fletcher et al. 1995; Hennermann et al. 2012; Hoover-Fong et al. 2004; Yis et al. 2009). In a recent study about the long-term outcome in a large cohort of NKH patients, authors suggest that an early brain MRI is extremely useful in predicting disease severity (Hennermann et al. 2012). They also state that typical EEG patterns such as burst-suppression in neonates and hypsarrhythmia in infants are often, but not always, associated with a poor outcome. According to some reports, the irreversible glycine-induced brain damage in utero is the responsible factor for the poor long-term outcome in NKH patients regardless of the structural brain anomalies (Hamosh and Johnston 2001). In another study of 65 patients with neonatal NKH, two-thirds of infants were ventilated during the neonatal period and 40% died. Ninety percent had seizures, 75% during the first month of life (Hoover-Fong et al. 2004). They also found that boys had more extended survival and better developmental progress than girls. The treatment of convulsions in NKH is challenging and mostly requires multiple medications. Treatment is a combination of glycine lowering agents, NMDA receptor antagonists, and multiple anti-epileptic medications. The patients in our cases have a classical form of neonatal NKH which showed signs of clinical stabilization in some stages of disease course. The first patient in this case report was born in our hospital, which allowed for a timely and extensive neurophysiological work-up; i.e., the EEG series showed some improvement along with the treatment progress and clinical improvement. Continued burst-suppression pattern was noted even after the clinical improvement and normalization of plasma glycine. This is suggestive of an irreversible brain injury, and may suggest the possibility of unrecognized pathophysiologic mechanisms in this disorder that are not addressed with the current therapeutic interventions. EEG can be used to assess the efficacy in each stage of therapy and to provide guidance regarding the modification of therapeutic agents and its dosages. Evolution of EEG patterns in this patient is classical. The burst-suppression pattern in neonatal stage evolved into frequent and totally asynchronous spike, polyspike discharges from both hemispheres, followed by hypsarrhythmia. The last EEG in this series demonstrated the presence of frequent subtle seizures which remained intractable and demanded further modification in treatment. Later, the child passed away due to recurrent infections and failure to thrive. CONCLUSION NKH should be considered in neonates with neonatal encephalopathy, recurrent apneas, and hiccups. Serial EEGs are helpful to assess the treatment response and to modify the therapy. Clinical improvement and biochemical results may not always 10 NONKETOTIC HYPERGLYCINEMIA reflect the actual encephalopathic process and disease course. EEG in encephalopathy due to NKH may show almost all types of epileptic encephalopathic patterns and should be distinguished from other etiologies for the correct treatment plan. ACKNOWLEDGMENTS This article was partly published as a poster presentation at the ASET conference in 2014 in Asheville, NC. We wish to thank Mrs. Susan Margaratte Al Nabhani for reviewing our article. DISCLOSURE STATEMENT No potential conflict of interest was reported by the authors. REFERENCES Aliefendioglu D, Aslan AT, Coskun T, Dursun A, Cakmak FN, Kesimer M. 2003. Transient nonketotic hyperglycinemia: two case reports and literature review. Pediatr Neurol. 28:151–155. Applegarth DA, Toone JR. 2001. Nonketotic hyperglycinemia (glycine encephalopathy): laboratory diagnosis. Mol Genet Metab. 74:139–146. Applegarth DA, Toone JR, Lowry RB. 2000. Incidence of inborn errors of metabolism in British Columbia, 1969–1996. Pediatrics. 105:e10. Dinopoulos A, Matsubara Y, Kure S. 2005. Atypical variants of nonketotic hyperglycinemia. Mol Genet Metab. 86:61–69. Fletcher JM, Bye AM, Nayannar V, Wilcken B. 1995. Non-ketotic hyperglycinaemia presenting as pachygyria. 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