Nonketotic Hyperglycinemia: A Life-Threatening Disorder in Saudi Newborns
1996; King Faisal Specialist Hospital and Research Centre; Volume: 16; Issue: 4 Linguagem: Inglês
10.5144/0256-4947.1996.400
ISSN0975-4466
AutoresNasser Haider, Mustafa A. Salih, Soud A. Al-Rasheed, Salih Al-Mofada, Peter M. Krahn, Muslimudin Kabiraj,
Tópico(s)RNA modifications and cancer
ResumoOriginal ArticlesNonketotic Hyperglycinemia: A Life-Threatening Disorder in Saudi Newborns Nasser Haider, MBBS, MRCP, ABDP Mustafa A.M. Salih, MBBS, MPCH, MD Soud Al-Rasheed, MBBS, FRCPC Salih Al-Mofada, MBBS, FRCPC Peter M. Krahn, and PhD, CIH, FCACB Muslimudin KabirajMBBS, M PHIL Nasser Haider From the Department of Pediatrics, King Saud University, Riyadh Search for more papers by this author , Mustafa A.M. Salih Address reprint requests and correspondence to Prof. Salih: Department of Pediatrics (39), College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia. From the Department of Pediatrics, King Saud University, Riyadh Search for more papers by this author , Soud Al-Rasheed From the Department of Pediatrics, King Saud University, Riyadh Search for more papers by this author , Salih Al-Mofada From the Department of Pediatrics, King Saud University, Riyadh Search for more papers by this author , Peter M. Krahn From the Department of Pathology and Laboratory Services, King Faisal Specialist Hospital and Research Centre, Riyadh Search for more papers by this author , and Muslimudin Kabiraj From the Department of Pediatrics, King Saud University, Riyadh Search for more papers by this author Published Online:1 Jul 1996https://doi.org/10.5144/0256-4947.1996.400SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutAbstractNonketotic hyperglycinemia (NKH) is an autosomal recessive disorder due to a fundamental defect in the glycine cleavage system, which leads to neuronal dysfunction caused by two receptor-mediated mechanisms. It is a life-threatening condition in the neonate. Until now, the disease has not been described from Saudi Arabia. We report on three Saudi newborns (two males and one female) who had NKH. Two of these were siblings (male and female). Following uneventful deliveries, they presented between the first and third day of life with progressive lethargy, poor feeding, recurrent apnea and severe hypotonia. Two newborns had myoclonic seizures, whereas electroencephalogram showed burst-suppression pattern in all of them. The diagnosis was confirmed by high cerebrospinal fluid/plasma glycine ratio (0.2 and 1.08) in two patients (normal < 0.03), whereas a sibling of one of the neonates had a high glycine level. Both siblings died during the second month of life despite therapy with dextromethorphan (an N-methyl-D-aspartate [NMDA] receptor antagonist) in one of them. The third baby had ketamine (noncompetitive NMDA receptor antagonist) and sodium benzoate (that conjugates with glycine, forming nontoxic hippuric acid). Although his seizures were controlled, he survived with severe neurological sequelae.IntroductionNonketotic hyperglycinemia (NKH) is an inherited autosomal recessive inborn error of the glycine cleavage system resulting in the presence of a high glycine level (Figure 1) in the body fluids.1–3 Absence of metabolic acidosis serves to distinguish it from the ketotic type, in which hyperglycinemia is secondary to certain organic acidemias such as ß-ketothiolase deficiency, propionic, methylmalonic and isovaleric acidemias.4,5 NKH is a well-recognized metabolic cause of life-threatening illness in the neonate that presents with poor feeding and decreased activity, with or without seizures. This usually progresses to apnea, coma and death. Those who survive are severely handicapped.6 A late-onset form has also been described in which patients develop neurological symptoms of varying degrees after the neonatal period.7Figure 1. Typical HPLC chromatogram of plasma sample from patient with hyperglycinemia. Note the large glycine peak(*) eluting at 7.9 minutes containing 1592 μmol/L (normal 100-500).Download FigureThe pathophysiologic effects of hyperglycinemia were attributed to the resulting neuronal dysfunction caused by two receptor-mediated mechanisms. These are the inhibitory effects of glycine at the postsynaptic strychnine-sensitive receptor,8,9 and overstimulation of the excitatory glycine receptor, which is linked to, and allosterically activates, the N-methyl-D-aspartate (NMDA) receptor. The latter is one of the major subtypes of excitatory amino acid receptors in the brain.10Attempts at treating NKH have included the administration of benzoate to conjugate the glycine forming nontoxic hippuric acid.11 Ketamine, a noncompetitive NMDA receptor antagonist, was also tried and found to improve seizure frequency on the electroencephalogram (EEG).12 Another noncompetitive antagonist at the NMDA receptor is dextromethorphan. This also had documented beneficial effects.13We report on the clinical course, therapeutic management and outcome of three Saudi children who had NKH. To the best of our knowledge, the disease has not been reported until now in Saudi Arabia.METHODSQuantitation of amino acids was performed on a Hewlett Packard Aminoquant HPLC fitted with an automatic sampler, thermostatted column compartment and a programmable fluorescent detector. Samples were deproteinized by filtration in Amicon Centriflo filters and diluted 1:4 with norvaline internal standard (IS) immediately prior to analysis. Chromatographic separation of amino acids, derivatized by precolumn reaction with o-phthaldialdehyde (OPA) by a modified procedure14 was performed using a 2.1 x 200 mm ODS Hypersil reverse phase column and a 2.1 x 20 mm guard column containing the same stationary phase. OPA-derivatized amino acids were eluted at a flow rate of 0.45 mL/minute at a column temperature of 40°C, employing a linear gradient elution technique. Mobile phase A consisted of sodium acetate (13 mmol/L), triethylamine (0.72 mmol/L), tetrahydrofuran (24.6 mmol/L), adjusted to pH 7.2 and Mobile Phase B was a mixture of HPLC grade methanol, acetonitrile and acetic acid in a ratio of 60/40/0.0025 (v/v) respectively. Freshly prepared mobile phases were filtered through a 0.2 micron Nylon 66 membrane and degassed immediately prior to use. The fluorescent OPA-derivatized amino acids were quantitated by measurement of emission at 455 nm using an excitation wavelength of 288 nm. Precision and accuracy of the procedure were monitored with the use of daily normal and elevated plasma pools and proficiency samples from the European Quality Assurance Program.CASE REPORTSCase 1A three-day-old Saudi male was referred to King Khalid University Hospital (KKUH) from one of the regional hospitals with a history of poor feeding, lethargy and generalized myoclonic seizures, mainly involving the right upper and lower limbs. He was the product of a term uncomplicated pregnancy and delivery. Apgar scores were 9 and 10 at one and five minutes, respectively. Birth weight was 3100 g (50th centile), length 54 cm (95th centile). Symptoms were first noted in the second day of life when he became increasingly lethargic and hypotonic. Following his arrival at KKUH, he developed repeated episodes of apnea that progressed to respiratory failure within 24 hours and required assisted ventilation. His parents were first-degree cousins and were of the same age (24 years). They had one healthy son (age one year), and gave a history of another male and female with unexplained deaths during the first month of life.On examination, the neonate had no dysmorphic features, was hypotonic, had absent reflexes, but responded to painful stimuli. Arterial blood gases (ABG) revealed respiratory acidosis on several occasions. Serum urea and electrolytes (U&E), lactate, ammonia, anion gap and creatine kinase were within normal limits. Sepsis work-up was negative. Urine organic acid values were normal. Brain CT scan showed multiple low attenuated areas in the frontal and parietal regions, whereas EEG showed burst-suppression pattern (Figure 2). Electromyography (EMG) and nerve conduction velocity (NCV) were also normal. Plasma amino acid quantitation showed a glycine concentration of 1700 μmol/L (N = 60-310 μmol/L). The glycine CSF/plasma ratio was 0.2 (N < 0.03).15Figure 2. Case 1: A portable EEG showing burst-suppression pattern. There are high voltage generalized discharges of spikes, bispikes, sharp and slow wave complexes followed by periods of flattening that extend for about eight seconds.Download FigureThe patient had supportive management with assisted ventilation and received phenobarbitone, phenytoin and ketamine (1 mg twice daily). The seizures became only occasional after eight days and subsequently stopped. He could be successfully extubated after 17 days and was transferred to the general ward on nasogastric tube feeding. Following his discharge from KKUH, he was lost to follow-up but brought again by his parents, at age 16 months, to the pediatric neurology outpatient clinic. During this time, he had been followed at a different hospital (affiliated to his father's place of work) and was maintained on clonazepam and sodium benzoate (500 mg/kg/day). He had no seizures, but was found to be a spastic quadriplegic with no head control. Tendon jerks were brisk in the upper and lower limbs.Case 2This Saudi girl was admitted at the age of one month to KKUH because of severe lethargy, hypotonia and recurrent episodes of apnea. She was noted to have had a weak cry, poor feeding and lethargy from the third day of life and had been evaluated and admitted to hospital at the age of 10 days, treated with antibiotics and discharged after confirming a negative sepsis work-up. The pregnancy and delivery were uncomplicated. The birth weight was 2900 g, length 44 cm and head circumference 33.0 cm. She had no history of seizures and her parents, who were not consanguineous, revealed a history of a male who died of a similar illness at the age of 40 days (Case 3).On admission, she was lethargic, and had central hypotonia associated with exaggerated tendon jerks. She had no dysmorphic features, normal anterior fontanel and no organomegaly. Due to progressively increasing episodes of apnea evolving into respiratory failure, she required assisted ventilation.Results of the laboratory investigations were either negative or within normal limits for liver function tests, blood glucose, serum calcium, phosphorus and alkaline phosphatase, ammonia, lactate, anion gap and urinary organic acids. Blood and CSF microscopy and cultures were negative. On admission, and one hour later, she showed hyponatremia and hyperkalemia (Na 126 and 127 mmol/L, K 6.6 and 5.7 mmol/L, respectively). She received hydrocortisone and the appropriate intravenous fluids, in addition to broad spectrum antibiotic coverage. An EEG showed burst-suppression pattern, whereas cranial ultrasound was normal.Amino acid analyses revealed high serum glycine of 1062 μmol/L (N = 120-553 μmol/L) and markedly elevated CSF glycine of 1146 μmol/L (N = 9-18 μmol/L). The CSF/plasma glycine ratio was 1.08 (N < 0.03), which confirmed the diagnosis of NKH. Hence, she was started on dextromethorphan (35 mg/kg/day in four divided doses) and had full supportive management. However, she progressed to deep coma associated with pinpoint pupils and died at the age of 40 days.Case 3The brother of Case 2 was a full-term infant who was delivered in June of 1989 at KKUH. Pregnancy was uneventful, apart from decreased fetal movements that were suspected during the last four weeks of pregnancy, and associated with no gain in the mother's weight. The baby did not cry immediately after birth, but needed minimal resuscitation. Apgar scores were recorded as 8 and 9 at one and five minutes, respectively. He was returned to his mother after six hours and was discharged from hospital six hours later.From the first day of life, the mother noticed him to be listless and to have a weak cry. This evolved into progressive lethargy and towards the end of the first month, he started to have frequent apnea associated with recurrent erratic myoclonic seizures lasting for a few seconds and associated with staring of the eyes.He was admitted at the age of 39 days and was found to be lethargic with axial hypotonia associated with hypertonia of the limbs and brisk tendon jerks. The seizures could be controlled with phenobarbitone. However, on the second day of admission, his ABGs revealed features of respiratory acidosis and he required mechanical ventilation. The anion gap was normal, whereas sepsis work-up was negative. An EEG showed burst-suppression pattern. Ultrasound of the brain revealed echogenic areas around the ventricles, suggestive of periventricular leukomalacia. Brain CT scan showed hypodense foci within the periventricular white matter.Three days later, the baby went into deep coma associated with pinpoint pupils, similar to his sister. He received supportive management and was maintained on phenobarbitone (5 mg/kg/day). Shortly before his death at the age of 54 days, arrangements could be fixed for amino acid chromatography of urine. The results later revealed a high glycine level of 33,970 μmol/24 hours (N = 140 − 560 (μmol/24 hours).DISCUSSIONThe clinical features in the three patients were typical of neonatal NKH; namely, a short, symptom-free interval followed by rapid onset of decreased activity, lethargy and recurrent apneic attacks associated with severe hypotonia, rapidly progressing to coma and respiratory failure. Two patients had myoclonic jerks, whereas the EEG in all of them showed the burst-suppression pattern, a classic abnormality in NKH.16–18 The disease could be finally documented in Cases 1 and 2 by the presence of an elevated CSF/plasma glycine ratio with normal urinary organic acids.19 Case 3, a sibling of Case 2, had a clinical course similar to his sister's and other reported cases of NKH.20 Although his CSF and plasma glycine levels were not assayed, amino acid chromatography of a urine specimen revealed a very high glycine level in the absence of metabolic acidosis and a normal anion gap.It is noteworthy that the initial laboratory findings in Cases 1 and 2 revealed hyponatremia (Na level ranging between 123 and 126 mmol/L) associated with raised potassium levels (ranging between 4.9 and 6.6 mmol/L). Adrenal crisis was considered in the differential diagnoses given the clinical setting of the patients. We are not aware of such biochemical presentation of NKH being reported in the literature; and documentation and future research on its pathogenesis might be warranted.The prognosis of neonatal NKH is grim. Of 21 cases followed by Tada and associates,6,21 17 died between six days and five years of life. Recently, there were reports of a transient form of NKH in four neonates with only transiently elevated glycine levels in plasma, urine and CSF, but with subsequent normal psychomotor development.22,23 In yet another report, a neonate presented with a transient form of NKH, but had subsequent neurologic sequelae.24Nonketotic hyperglycinemia is essentially untreatable at present. Various therapies have been tried, including the administration of pyridoxine and tetrahydrofolate (to stimulate residual glycine cleavage activity),11,25,26 strychnine8 or diazepam27 (which compete with glycine for postsynaptic receptor sites). None of these therapies were effective in altering the clinical course.Recently, a beneficial effect of a high dose of sodium benzoate (500-750 mg/kg/day) and dextromethorphan (5-7.5 mg/kg/day) was demonstrated to control seizures and improve EEG findings in neonatal NKH.28 A similar response was also observed following the use of dextromethorphan alone (35 mg/kg/day).29 However, neurodevelopmental outcome was poor in both reports. This has been explained by the disturbed myelin synthesis due to inadequate glycine-to-serine conversion following an imbalance of cytoplasmic amino acids.30 On the other hand, Ohya and associates12 reported partial improvement of neurological symptoms and EEG findings following the administration of ketamine (an NMDA receptor antagonist), similar to our observation in Case 1 of this series. Conversely, Zammarchi et al.18 reported failure of dextromethorphan and Na benzoate treatment in a newborn with NKH. Despite initiation of therapy from the 65th hour of life and initial seizure control associated with EEG improvement, the baby developed flexor spasms and hypsarrhythmia at three months. Thereafter, he deteriorated and died at the age of five months and seven days. They accounted for this failure of therapy by a possible genetic variant of the glycine defect in this baby18 (i.e., absent or minimal residual enzymatic activity) or drug pharmacokinetics variability.7 Similarly, one of our cases (Case 2) died despite therapy with dextromethorphan.Prenatal diagnosis of NKH is possible by determining the glycine cleavage system activity in chorionic villi. Hayasaka and associates31 correctly identified an affected fetus among five pregnancies after sampling chorionic villi between the eighth and 12th weeks of gestation. Tada and Kure7 identified eight affected fetuses in a larger series of 31 pregnancies when villous sampling was performed between the eighth and 16th weeks of gestation. They also confirmed the diagnostic potential of DNA analysis, when the mutant site of the family is known, following examination of chorionic villi at the 12th week of gestation in a suspected pregnancy.Nonketotic hyperglycinemia is an autosomal recessive disorder and is likely to be more common in Saudi Arabia than what is reflected in this communication, considering the high prevalence of consanguineous marriages in the community.32 A high index of suspicion is warranted and the disease should be considered in infants who develop seizures, muscular hypotonia and lethargy, especially when symptoms are not readily explained by hypoxic ischemic insult or infection. Such early diagnosis would guide rational therapy that might help in preventing further brain damage or a fatal outcome.ARTICLE REFERENCES:1. Childs B, Nyhan WL, Borden M, Bard L, Cooke RE. "Idiopathic hyperglycinemia and hyperglycinuria: a new disorder of amino acid metabolism" . I Pediatr. 1961; 27: 522–38. 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Google Scholar Previous article Next article FiguresReferencesRelatedDetailsCited byRoy D, Al-Asmari A, Ghazal Y and Al-Oqiel S (2004) Nonketotic hyperglycinemia in Suleimaniah Children’s Hospital, Riyadh, Saudi Arabia, Annals of Saudi Medicine, 24:5, (378-381), Online publication date: 1-Sep-2004. Volume 16, Issue 4July 1996 Metrics History Accepted10 January 1995Received14 June 1995Published online1 July 1996 ACKNOWLEDGMENTSThe authors would like to thank Mr. Vir Salvador for medical illustration and Ms. Gloria D. Palacay for typing the manuscript.InformationCopyright © 1996, Annals of Saudi MedicinePDF download
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