- Email: [email protected]
Neurologic sequelae in transient nonketotic hyperglycinemia of the neonate
Clinical and laboratory observations Neurologic sequelae in transient nonketotic hyperglycinemia of the neonate F. J. M. Eyskens, MD, J. W. D. V a n Doorn, MD, a n d P. Marien, MD From the Divisionsof Neonatology, Departments of Pediatrics of the University Hospital of Antwerp and of St. Augustin Hospital, Antwerp, Belgium
We report a neonate with the transient form of nonketotic hyperglycinemia manifested by extreme hypotonia, lethargy, a p n e a , and myoclonic and generalized convulsions in early neonatal life. Despite normalization of the biochemical values, severe neurologic sequelae were observed. This case suggests that the transient form of nonketotic hyperglycinemia sometimes causes severe brain d a m a g e , (J PEDIATR1992;121:620-1) Nonketotic hyperglycinemia is an inherited metabolic disease caused by a defect of the glycine cleavage system. 1 According to the age at onset, three clinical forms may be distinguished. The neonatal form almost invariably has an early fatal outcome; the few patients who have survived have had intractable convulsions and severe psychomotor retardation.2, 3 Recently four neonates have been described with only transiently elevated glycine levels in plasma, urine, and cerebrospinal fluid and with normal psychomotor development. 4, 5 W e report another neonate with transient N K H who had severe neurologic sequelae. CASE REPORT A male neonate was the second child of young, unrelated parents. There were no known inherited disorders in this family. Pregnancy and delivery were uncomplicated. Fetal monitoring during delivery showed no abnormalities. Birth weight was 3800 gm, length 55 cm, and head circumference 36.6 em. Immediately after birth, extreme hypotonia, absence of archaic reflexes, apnea, and myoclonic jerks were noted; the Apgar scores were 5 and 6 after 1 and 5 minutes, respectively. Normal breathing resumed after administration of caffeine, but hypotonia persisted. Capillary blood gas analysis, performed within 1 hour after birth, gave the following results: pH, 7.23; partial pressure of oxygen, 61 mm Hg; partial pressure of carbon dioxide, 35 mm Hg; base deficit, 11:4 mEq/L; and bicarbonate, 14 mEq/L. The metabolic acidosis was corrected with biSubmitted for publication Jan. 6, 1992; accepted April 22, 1992. Reprint requests: F. M. J. Eyskens, MD, University Hospital of Antwerp, Wilrijkstraat 10, B-2650 Antwerpen, Belgium. 9/22/38813
620
carbonate. Other blood gas analysis, performed every 2 to 4 hours, yielded normal results. Serum creatine kinase levels reached a maximum of 688 I U / L (cutoff value for neonates: 500 IU/L). Six hours after birth, generalized convulsions occurred that were resistant to phenobarbital, phenytoin, and pyridoxine treatment but responded partially to clonazepam. Tracheal intubation and artificial respiration were started after 18 hours because of increasing episodes of apnea and bradycardia. Myoclonic convulsions, hypotonia, and absence of archaic reflexes persisted, and lethargy and frequent hiccups were observed. Routine studies of blood, urine, and CSF revealed no abnormalities. There was no ketoacidosis, and blood ammonia levels were within normal limits. Findings of ultrasound examination of the brain were normal; an electroencephalogram showed suppression of brain activity. Column chromatographic
I
CSF NKH
Cerebrospinal fluid Nonketotic hyperglycinemia
I
determination of amino acids showed normal values in plasma and urine but increased glycine levels in the CSF; on the fourth and fifth days a nearly 10-fold increase to 125 and 144 gmol/L, respectively, was found (normal value: 4.5 to 13 ttmol/L). The glycine CSF/ plasma ra~io was increased to 0.4 (normal value: less than 0.04). Organic acid analysis with gas chromatography-mass spectrometry on plasma and urine revealed a normal pattern. On the basis of these findings, the diagnosis of the neonatal form of NKH was made. After 3 days, convulsions and episodes of apnea occurred less frequently and extubation could be performed, but lethargy and hypotonia persisted. Because of the generally accepted poor prognosis of neonatal NKH, no further investigations or lifesaving therapeutic procedures were performed. The child received gavage
Volume 121 Number 4
feedings during the followingmonths. No further overt seizure activity occurred, and a slight but undeniable improvement of the neurologic condition was noted. When the child was 3 months of age, short eye contact and reaction to sounds were present. Feeding with a spoon was possibleat 4 months, although the sucking reflex remained poor. The psychomotordevelopmentwas grossly retarded: at the age of 9 months, archaic reflexes were still present and there was a relative macrocephaly and a generalized hypotonia with absence of head control. Glycinelevelsin CSF, serum, and urine at the age of 2 months were within normal limits. Except for some slow brain activity, a second electroencephalogram also showed no abnormalities. Magnetic resonance imagingof the brain when the child was 3 months of age revealed bilateral broad subarachnoidal spaces caused by subcortical atrophy and deficient myelinization of the inner white matter. DISCUSSION Nonketotic hyperglycinemia is an autosomal recessive disorder of glycine metabolism. The defect has been located at the glycine cleavage system, which consists of four proteins, the P, H, T, and L proteins. Defects of the P, H, and T proteins but not of the L protein have been demonstrated in patients with NKH. 1 Clinically a distinction is made among the neonatal form, which occurs early with myoclonic jerks, hypotonia, respiratory insufficiency, and coma, the infantile form, characterized by arrest of psychomotor development, and the late-onset form with. mild neurologic symptoms. The biochemical hallmark of NKH is the 10- to 30-fold increase of the CSF glycine level, resulting in a glycine CSF/plasma ratio greater than 0.04. Plasma and urine glycine levels are inconstantly elevated. 3, 6 The mitochondrial glycine cleavage enzyme can be measured in brain and liver tissue and in chorionic villi.7 The main differential diagnosis is with ketotic hyperglycinemia, which is accompanied by ketoacidosis and an abnormal organic acid pattern in the urine. The electroencephalogram in the neonatal type of NKH typically shows burst suppression during the first months; later, hypsarrhythmia is frequently observed. Until recently the neonatal form was considered to have a fatal outcome. The few patients who survived have had, in addition to the persisting biochemical abnormalities, severe psychomotor retardation and intractable convulsions.2, 3 In 1989, however, Luder et al. 4 and Schiffmann et al. 5 reported four patients with the neonatal form of N K H in whom the biochemical as well as the clinical symptoms disappeared within 1 to 8 weeks; no sequelae were observed. It was hypothesized that a delay in the maturation of the glycine cleavage system, which normally functions from the twelfth fetal week onward, may have caused the transient hyperglycinemia.5 Our patient is comparable to those described by Luder et al. and by Schiffmann et al. in that
Clinical and laboratory observations
621
our patient's CSF glycine levels returned to normal by 2 months of age. In contrast, however, our patient's pronounced psychomotor retardation remained after normalization of the biochemical abnormalities. Other causes of brain damage, mainly hypoxemia caused by respiratory or circulatory failure, were highly improbable in this patient. An explanation may be that our patient's brain was exposed to high glycine levels during a prolonged period of intrauterine life. That the fetal nervous system can be affected by a disturbed glycine metabolism is suggested by the delayed myelinization found in neonates who died of NKH during the first weeks of life.8 Furthermore, it is known from experiments in rats that the damage to the brain caused by high glycine levels is most pronounced during early postnatal life, when the glycine neurosynaptic system is still immature. 9 Further studies are needed to determine the role of glycine and other neurotransmitters in the development of the nervous system. The existence of transient forms of neonatal NKH has implications for our approach to neonates with this disorder, especially regarding a decision to withhold treatment. This problem can be solved only if the transient form of the disease can be differentiated from the classic type; one possibility is the identification of specific mutations at the site of the glyeine cleavage system for each clinical variant. As exemplified by our patient, however, the prognosis is not good in all patients with the transient form of NKH. REFERENCES
1. Tada K. Nonketotic hyperglyeinemia: clinical and metabolic aspects. Enzyme 1987;38:27-35. 2. Carson NAJ. Non-ketotic hyperglycinemia:a reviewof 70 patients. J Inher Metab Dis 1982;5(suppl 2):126-8. 3. Tada K, Hayasaka K. Non-ketotic hyperglycinemia:clinical and biochemical aspects. Eur J Pediatr 1987;146:221-7. 4. Luder AS, Davidson A, Goodman SI, Green CL. Transient nonketotic hyperglycinemia in neonates. J PEDIATR 1989; 114:1013-5. 5. Schiffmann R, Kaye EM, Willis JK, Africk D, Ampola M. Transient neonatal hyperglycinemia. Ann Neurol 1989; 25:201-3. 6. Tada K. Nonketotie hyperglyeinemia.In: Fernandes J, Saudubray J-M, Tada K, eds. Inborn metabolic diseases: diagnosis and treatment. Berfin: Springer-Verlag, 1990:323-9. 7. Hayasaka K, Tada K, Fueki N, Aikawa J. Prenatal diagnosis of nonketotic hyperglyeinemia:enzymatic analysis of the glycine cleavage system in chorionic villi. J PEDIATR 1990; 116:444-5. 8. Brun A, B6rjesonH, Multberg B. Neonatal nonketotic hyperglycinemia: a clinical, biochemical and neuropathological study including eleetronmicroscopyfindings. Neurop/idiatrie 1979;10:195-205. 9. De Groot CJ, Everts RS. The age-dependent toxicity of glyeine. J Inher Metab Dis 1982;5(suppl 2):124-5.
We report a neonate with the transient form of nonketotic hyperglycinemia manifested by extreme hypotonia, lethargy, a p n e a , and myoclonic and generalized convulsions in early neonatal life. Despite normalization of the biochemical values, severe neurologic sequelae were observed. This case suggests that the transient form of nonketotic hyperglycinemia sometimes causes severe brain d a m a g e , (J PEDIATR1992;121:620-1) Nonketotic hyperglycinemia is an inherited metabolic disease caused by a defect of the glycine cleavage system. 1 According to the age at onset, three clinical forms may be distinguished. The neonatal form almost invariably has an early fatal outcome; the few patients who have survived have had intractable convulsions and severe psychomotor retardation.2, 3 Recently four neonates have been described with only transiently elevated glycine levels in plasma, urine, and cerebrospinal fluid and with normal psychomotor development. 4, 5 W e report another neonate with transient N K H who had severe neurologic sequelae. CASE REPORT A male neonate was the second child of young, unrelated parents. There were no known inherited disorders in this family. Pregnancy and delivery were uncomplicated. Fetal monitoring during delivery showed no abnormalities. Birth weight was 3800 gm, length 55 cm, and head circumference 36.6 em. Immediately after birth, extreme hypotonia, absence of archaic reflexes, apnea, and myoclonic jerks were noted; the Apgar scores were 5 and 6 after 1 and 5 minutes, respectively. Normal breathing resumed after administration of caffeine, but hypotonia persisted. Capillary blood gas analysis, performed within 1 hour after birth, gave the following results: pH, 7.23; partial pressure of oxygen, 61 mm Hg; partial pressure of carbon dioxide, 35 mm Hg; base deficit, 11:4 mEq/L; and bicarbonate, 14 mEq/L. The metabolic acidosis was corrected with biSubmitted for publication Jan. 6, 1992; accepted April 22, 1992. Reprint requests: F. M. J. Eyskens, MD, University Hospital of Antwerp, Wilrijkstraat 10, B-2650 Antwerpen, Belgium. 9/22/38813
620
carbonate. Other blood gas analysis, performed every 2 to 4 hours, yielded normal results. Serum creatine kinase levels reached a maximum of 688 I U / L (cutoff value for neonates: 500 IU/L). Six hours after birth, generalized convulsions occurred that were resistant to phenobarbital, phenytoin, and pyridoxine treatment but responded partially to clonazepam. Tracheal intubation and artificial respiration were started after 18 hours because of increasing episodes of apnea and bradycardia. Myoclonic convulsions, hypotonia, and absence of archaic reflexes persisted, and lethargy and frequent hiccups were observed. Routine studies of blood, urine, and CSF revealed no abnormalities. There was no ketoacidosis, and blood ammonia levels were within normal limits. Findings of ultrasound examination of the brain were normal; an electroencephalogram showed suppression of brain activity. Column chromatographic
I
CSF NKH
Cerebrospinal fluid Nonketotic hyperglycinemia
I
determination of amino acids showed normal values in plasma and urine but increased glycine levels in the CSF; on the fourth and fifth days a nearly 10-fold increase to 125 and 144 gmol/L, respectively, was found (normal value: 4.5 to 13 ttmol/L). The glycine CSF/ plasma ra~io was increased to 0.4 (normal value: less than 0.04). Organic acid analysis with gas chromatography-mass spectrometry on plasma and urine revealed a normal pattern. On the basis of these findings, the diagnosis of the neonatal form of NKH was made. After 3 days, convulsions and episodes of apnea occurred less frequently and extubation could be performed, but lethargy and hypotonia persisted. Because of the generally accepted poor prognosis of neonatal NKH, no further investigations or lifesaving therapeutic procedures were performed. The child received gavage
Volume 121 Number 4
feedings during the followingmonths. No further overt seizure activity occurred, and a slight but undeniable improvement of the neurologic condition was noted. When the child was 3 months of age, short eye contact and reaction to sounds were present. Feeding with a spoon was possibleat 4 months, although the sucking reflex remained poor. The psychomotordevelopmentwas grossly retarded: at the age of 9 months, archaic reflexes were still present and there was a relative macrocephaly and a generalized hypotonia with absence of head control. Glycinelevelsin CSF, serum, and urine at the age of 2 months were within normal limits. Except for some slow brain activity, a second electroencephalogram also showed no abnormalities. Magnetic resonance imagingof the brain when the child was 3 months of age revealed bilateral broad subarachnoidal spaces caused by subcortical atrophy and deficient myelinization of the inner white matter. DISCUSSION Nonketotic hyperglycinemia is an autosomal recessive disorder of glycine metabolism. The defect has been located at the glycine cleavage system, which consists of four proteins, the P, H, T, and L proteins. Defects of the P, H, and T proteins but not of the L protein have been demonstrated in patients with NKH. 1 Clinically a distinction is made among the neonatal form, which occurs early with myoclonic jerks, hypotonia, respiratory insufficiency, and coma, the infantile form, characterized by arrest of psychomotor development, and the late-onset form with. mild neurologic symptoms. The biochemical hallmark of NKH is the 10- to 30-fold increase of the CSF glycine level, resulting in a glycine CSF/plasma ratio greater than 0.04. Plasma and urine glycine levels are inconstantly elevated. 3, 6 The mitochondrial glycine cleavage enzyme can be measured in brain and liver tissue and in chorionic villi.7 The main differential diagnosis is with ketotic hyperglycinemia, which is accompanied by ketoacidosis and an abnormal organic acid pattern in the urine. The electroencephalogram in the neonatal type of NKH typically shows burst suppression during the first months; later, hypsarrhythmia is frequently observed. Until recently the neonatal form was considered to have a fatal outcome. The few patients who survived have had, in addition to the persisting biochemical abnormalities, severe psychomotor retardation and intractable convulsions.2, 3 In 1989, however, Luder et al. 4 and Schiffmann et al. 5 reported four patients with the neonatal form of N K H in whom the biochemical as well as the clinical symptoms disappeared within 1 to 8 weeks; no sequelae were observed. It was hypothesized that a delay in the maturation of the glycine cleavage system, which normally functions from the twelfth fetal week onward, may have caused the transient hyperglycinemia.5 Our patient is comparable to those described by Luder et al. and by Schiffmann et al. in that
Clinical and laboratory observations
621
our patient's CSF glycine levels returned to normal by 2 months of age. In contrast, however, our patient's pronounced psychomotor retardation remained after normalization of the biochemical abnormalities. Other causes of brain damage, mainly hypoxemia caused by respiratory or circulatory failure, were highly improbable in this patient. An explanation may be that our patient's brain was exposed to high glycine levels during a prolonged period of intrauterine life. That the fetal nervous system can be affected by a disturbed glycine metabolism is suggested by the delayed myelinization found in neonates who died of NKH during the first weeks of life.8 Furthermore, it is known from experiments in rats that the damage to the brain caused by high glycine levels is most pronounced during early postnatal life, when the glycine neurosynaptic system is still immature. 9 Further studies are needed to determine the role of glycine and other neurotransmitters in the development of the nervous system. The existence of transient forms of neonatal NKH has implications for our approach to neonates with this disorder, especially regarding a decision to withhold treatment. This problem can be solved only if the transient form of the disease can be differentiated from the classic type; one possibility is the identification of specific mutations at the site of the glyeine cleavage system for each clinical variant. As exemplified by our patient, however, the prognosis is not good in all patients with the transient form of NKH. REFERENCES
1. Tada K. Nonketotic hyperglyeinemia: clinical and metabolic aspects. Enzyme 1987;38:27-35. 2. Carson NAJ. Non-ketotic hyperglycinemia:a reviewof 70 patients. J Inher Metab Dis 1982;5(suppl 2):126-8. 3. Tada K, Hayasaka K. Non-ketotic hyperglycinemia:clinical and biochemical aspects. Eur J Pediatr 1987;146:221-7. 4. Luder AS, Davidson A, Goodman SI, Green CL. Transient nonketotic hyperglycinemia in neonates. J PEDIATR 1989; 114:1013-5. 5. Schiffmann R, Kaye EM, Willis JK, Africk D, Ampola M. Transient neonatal hyperglycinemia. Ann Neurol 1989; 25:201-3. 6. Tada K. Nonketotie hyperglyeinemia.In: Fernandes J, Saudubray J-M, Tada K, eds. Inborn metabolic diseases: diagnosis and treatment. Berfin: Springer-Verlag, 1990:323-9. 7. Hayasaka K, Tada K, Fueki N, Aikawa J. Prenatal diagnosis of nonketotic hyperglyeinemia:enzymatic analysis of the glycine cleavage system in chorionic villi. J PEDIATR 1990; 116:444-5. 8. Brun A, B6rjesonH, Multberg B. Neonatal nonketotic hyperglycinemia: a clinical, biochemical and neuropathological study including eleetronmicroscopyfindings. Neurop/idiatrie 1979;10:195-205. 9. De Groot CJ, Everts RS. The age-dependent toxicity of glyeine. J Inher Metab Dis 1982;5(suppl 2):124-5.