National Taiwan University Hospital from 1996 to 2003 once the diagnosis and treatment or to assist the treatment of the six babies suffering from this disease. First they start the performance, including sleepiness and apnea, age at onset in about 1-3 days, especially all of the patients had neonatal hiccup phenomenon, and soon after birth can be observed. These patients will be gradually shown, in part or in whole body clonic cramps or muscle, anti-epileptic drugs on the control of these movements ineffective and usually required the use of several drugs at the same time can slow down the case of myoclonus. The diagnosis of all patients are in compliance with the non-ketone high glycine hyperlipidemia, including cerebrospinal fluid glycine values have increased, blood glycine values have increased, and cerebrospinal fluid glycine value on the blood values of the ratio of glycine greater than 0.08. These patients have specific changes in brain waves, in line with the non-ketone high glycine hyperlipidemia diagnosis.
These patients are at about one month beginning accepted for non-ketone high glycine Hyperlipemia rare drug treatment, including Sodium benzoate and Dextromethorphan. Sodium benzoate glycine concentration in order to reduce the special drug, but in these patients, the use of Sodium benzoate, although the blood glycine values returned to normal, but cerebrospinal fluid in glycine minimal value dropped to normal range inside.
Dextromethorphan (commonly known as merchandise Medicon) generally used to cough, but in these patients, the use of high doses of Dextromethorphan (per kilogram of body weight 20-35 mg) can effectively reduce muscle tension and spasm cramp slowed phenomenon. In addition, these patients in the neonatal period, both the phenomenon of intractable spasticity, you may need to simultaneously use several kinds of anti-epileptic drugs. In the after-effects, these patients have serious head, stiffness of limbs, paralysis, and severe developmental delay phenomenon. Since one of the three patients with aspiration pneumonia or related complications, respectively, died a year and a half, three-year-old and five-year-old. A patient's younger brother, but also the performance of 3-day-old when the symptoms begin, after adequate genetic counseling, the parents decided to give up aggressive treatment, so we do not have kids for intubation and the use of respirators, only to give oxygen therapy. The patient died five days. As regards the remaining two patients, the current three-year-old and a half years and separately for the two-year-old, brain MRI showed severe brain atrophy and white matter lesions, neurological development in babies less than four months.
Current non-ketone high neonatal glycine treatment of hyperlipidemia, although there is Sodium benzoate and Dextromethorphan such as medicine, but the outcome of treatment is still unsatisfactory. Even if early treatment, but also save the damaged nerve cells. As remnants of nerve cells, due to high concentration of glycine caused by sustained stimulation of intractable spasticity. Therefore, for such patients, whose prognosis is not very optimistic.
As for prenatal diagnosis, the current use of someone abroad enzyme test for human chorionic cells, but there are false positive and false negative of the question have to be overcome. If there were children at home and have found genetic mutation point, they may make use of genetic testing, to do prenatal diagnosis. But did not find mutations point home, they can only rely on an enzyme test to diagnose. Based on these difficulties, we give the parents of these six patients adequate genetic counseling, they must face their own future reproductive choices.
(Original published in the Journal of Child Neurology)
Wednesday
Nonketotic Hyperglycinemia；NKH
English synonym name: Glycine Encephalopathy; GCE
English translation: Non-ketone high glycine Hyperlipemia
Commonly known as:
Genetic model: AR
Gene name: AMT, GCSP, GCSH
Address: 3p21.2-p21.1, 9p22, 16q24
Author: Chung Shan Medical University Hospital physician Pen-Hua Su
Author Date: 2007-12-04
Validation date: 2007-12-04
Upgrading Date: 2008-01-07
Review date: 1998-07-12
Updated: 2007-12-04
Notice rare disease
ICD-9-CM coding: 270.7
Foreword etiology │ │ │ genetic model of the incidence of clinical │ │ │ Diagnosis Treatment Case Report │ │
Relevant groups to read │ │ the extension of domestic inspection unit
Preface:
Non-keto high glycine hyperlipidemia (Nonketotic Hyperglycinemia) is a congenital metabolic disease. Decomposition of the system because of glycine (glycine cleavage system, GCS) A lack of enzymes, resulting in glycine metabolism can not make body fluids glycine increased, leading to severe brain lesions, and then generate a series of combined disease, prognosis of considerable well, giving up a treatment, most patients will be dead.
Etiology:
Glycine (NH2-CH2-COOH) in vivo metabolism of decomposition required to glycine cleavage system (GCS), there is at tetrahydrofolate (THF) circumstances will glycine decomposed into ammonia and carbon dioxide. GCS is an enzyme complex, including four enzymes, namely P protein, H protein, T protein and L protein (P-protein, a pyridoxal phosphate-dependent glycine decarboxylase; H-protein, lipoic acid containing; T-protein, tetrahydrofolate-requiring aminomethyltransferase; L-protein, lipoamide dehydrogenase), if the system has flaws will result in the body can not be normal glycine decomposed into ammonia and carbon dioxide, thus producing a series of lesions. One high in the non-glycine in patients with hyperlipidemia, most are protein, P or T proteins lack. At present, Taiwan has no formal genetic analysis of the report.
Incidence:
Non-keto high glycine Hyperlipemia belong to a rare disease, its incidence is extremely low, all over the world apart from outside Finland, there is no incidence of the statistical report. As for Finland, regional, national incidence of approximately 50,000 live births per ㄧ, at Finland's northern region, has reported its incidence as high as 12,000 live births. So all over the world the incidence of other ethnic groups will be lower than in Finland. In Taiwan, according to recent statistics, about a dozen patients have discovered, some of which patients have died.
Genetic model:
Non-keto high glycine Hyperlipemia belong to autosomal genetic stealth (Autosomal recessive, AR), both parents carry the defective gene there is one, each child then has 1 / 4 chance of cancer, both sexes have the potential.
Parents are most concerned about the majority of patients with prenatal diagnosis, there are still restrictions exist Detect abroad have studied the feasibility of using human chorionic cells make an enzyme test, but there are false positive and false negative of the issues to be resolved, and therefore if used as a Prenatal diagnosis of instrument is still very risky, there is no domestic provision of prenatal diagnosis.
Clinical presentation:
Non-keto high glycine levels, depending on age of onset can be divided into neonatal and late-onset type, one of the most common type in the newborn. Patient incidence of about 1-3 at the first day, according to foreign statistics, its onset may occur as early as 6 hours after birth, more than two-thirds of patients within 48 hours will be the incidence. The performance of the incidence of drowsiness and one start apnea, and then gradually shown to reduce tension, reflection is also reduced, and then show, in part or in whole body clonic convulsions or muscle, in particular, is sick of all newborns have the hiccups phenomenon.because of a very early time, and change fast, health care workers about the disease must be very alert. Convulsive movements of these patients are very stubborn, anti-epileptic drugs are generally difficult to control, most of them will need a number of drugs used simultaneously in order to slow down muscle clonus sick phenomenon. Spend patients if the neonatal period, after all there is much still together disease, such as serious head syndrome, intractable spasticity, rigidity of limbs, paralysis and severe developmental delay. Prognosis is poor.
Diagnosis:
When a newborn at birth of all good, but in hours or days there drowsiness, apnea, tension reduction, partial or generalized clonic convulsions or muscle, if the exclusion of neonatal infection and postnatal hypoxic brain lesions such circumstances, must take into account the congenital metabolic diseases, rather than one high hyperlipidemia is also important reasons之ㄧ. To the diagnosis of non-ketone with high glycine levels, must be detected simultaneously in plasma and cerebrospinal fluid amino acid value. If the cerebrospinal fluid increased the value of glycine, plasma glycine increased the value, and cerebrospinal fluid glycine values of plasma glycine ratio values greater than 0.08, you can diagnose this disease. As required by the diagnosis of liver puncture (Liver biopsy), determination of liver tissues of the activity of glycine cleavage system, glycine cleavage system to verify whether the lack of activity. In this category of patients with neonatal-type, the liver tissues of the glycine cleavage system activity is very low, almost close to 0.
High in the non-ketone glycine hyperlipidemia in patients with brain waves will show a special change, such as: burst-suppression pattern, can also provide a diagnosis of this disease to help, this change in brain waves will gradually disappear, and then transformed into hypsarrythmia, if timely ventilator support apnea patients will gradually improve the situation.
Treatment:
The disease mainly in order to reduce the value of glycine in vivo, because sustained high glycine values will cause serious harm to the brain. These methods reduce the glycine include: limiting the uptake of glycine, voted with ursodeoxycholic acid, with a view to combining with glycine, and then glycine by bile discharged; also voted with the sodium benzoate in order to promote Gan amine acid from the urine discharged, but such methods or can reduce the blood of the value of glycine, it can not be cerebral spinal fluid in the value of glycine decreased to normal, so the impact of brain injury patients may assist limited. On the other hand, previous studies have shown that drugs commonly used for cough Dextromethorphan (merchandise called Medicon) patients in this category have to mitigate the effects of spasticity, and its machines to Dextromethorphan pharmacology metabolites dextrophan for N-methyl -D-aspartate (NMDA)-receptor-channel complex of the inhibitor.
Non-keto high glycine in patients with hyperlipidemia in the cerebrospinal fluid will stimulate glycine glutaminergic NMDA receptor, therefore the use of high doses of Dextromethorphan (20-25mg/kg/day), can slow disease cramp spasm phenomenon. While another NMDA-channel inhibitor, Ketamine ((8mg/kg/day), has also been reported for use in the treatment of patients to control also the effect of apnea, with the exception of the special drug outside, because the patients have many refractory spasm phenomenon, while the use of several anti-epileptic drugs also its necessity.
Case Report:
Over the years the author has treated one of two non-glycine hyperlipidemia, and to share in this experience, two patients with a performance beginning at birth are in good condition, but when in one day, appears drowsiness, weakness and apnea cases by the local obstetrics and gynecology clinic evacuation immediately transferred to hospital by one day to rule out the hearts of three days while the infection, birth trauma, hypoxic brain lesions after again to the medical center, and then by the plasma and cerebrospinal fluid amino acid glycine measurements confirmed both an increase in both value and cerebrospinal fluid glycine on plasma glycine ratio of greater than 0.08. Determined not to be one of the high glycine hyperlipidemia after beginning drug therapy given to rare diseases, including Sodium benzoate (250-500 mg / kg / day) and Dextromethorphan (25-35 mg / kg / day), and give the majority of combined use of anti-epileptic drugs to control his intractable spasticity. But the disease can only be controlled, they can not have a good clinical outcome, because even if early treatment of patients earlier in the nerve cells can not respond to the injury. Therefore, such patients have serious head syndrome, intractable spasticity, rigidity of limbs, paralysis and severe developmental delay. Can not be effective because of the prenatal diagnosis of this disease, so patients with many mining Parent born the idea of luck. One of a pair of first child, in patients with the disease of their parents, second child in the development of normal birth-old boy, third child while the baby boy birth incidence because we have already had a detailed genetic counseling, the parents decided to give up aggressive treatment, the third child in a few days after birth, death, and their first child, a rare disease in the patients with medication also around the age of 2 due to aspiration pneumonia and death concurrency.
Another first child patients with the disease is still rare disease drug treatment, is about two years old. His mother a second child in the current pregnancy.
English translation: Non-ketone high glycine Hyperlipemia
Commonly known as:
Genetic model: AR
Gene name: AMT, GCSP, GCSH
Address: 3p21.2-p21.1, 9p22, 16q24
Author: Chung Shan Medical University Hospital physician Pen-Hua Su
Author Date: 2007-12-04
Validation date: 2007-12-04
Upgrading Date: 2008-01-07
Review date: 1998-07-12
Updated: 2007-12-04
Notice rare disease
ICD-9-CM coding: 270.7
Foreword etiology │ │ │ genetic model of the incidence of clinical │ │ │ Diagnosis Treatment Case Report │ │
Relevant groups to read │ │ the extension of domestic inspection unit
Preface:
Non-keto high glycine hyperlipidemia (Nonketotic Hyperglycinemia) is a congenital metabolic disease. Decomposition of the system because of glycine (glycine cleavage system, GCS) A lack of enzymes, resulting in glycine metabolism can not make body fluids glycine increased, leading to severe brain lesions, and then generate a series of combined disease, prognosis of considerable well, giving up a treatment, most patients will be dead.
Etiology:
Glycine (NH2-CH2-COOH) in vivo metabolism of decomposition required to glycine cleavage system (GCS), there is at tetrahydrofolate (THF) circumstances will glycine decomposed into ammonia and carbon dioxide. GCS is an enzyme complex, including four enzymes, namely P protein, H protein, T protein and L protein (P-protein, a pyridoxal phosphate-dependent glycine decarboxylase; H-protein, lipoic acid containing; T-protein, tetrahydrofolate-requiring aminomethyltransferase; L-protein, lipoamide dehydrogenase), if the system has flaws will result in the body can not be normal glycine decomposed into ammonia and carbon dioxide, thus producing a series of lesions. One high in the non-glycine in patients with hyperlipidemia, most are protein, P or T proteins lack. At present, Taiwan has no formal genetic analysis of the report.
Incidence:
Non-keto high glycine Hyperlipemia belong to a rare disease, its incidence is extremely low, all over the world apart from outside Finland, there is no incidence of the statistical report. As for Finland, regional, national incidence of approximately 50,000 live births per ㄧ, at Finland's northern region, has reported its incidence as high as 12,000 live births. So all over the world the incidence of other ethnic groups will be lower than in Finland. In Taiwan, according to recent statistics, about a dozen patients have discovered, some of which patients have died.
Genetic model:
Non-keto high glycine Hyperlipemia belong to autosomal genetic stealth (Autosomal recessive, AR), both parents carry the defective gene there is one, each child then has 1 / 4 chance of cancer, both sexes have the potential.
Parents are most concerned about the majority of patients with prenatal diagnosis, there are still restrictions exist Detect abroad have studied the feasibility of using human chorionic cells make an enzyme test, but there are false positive and false negative of the issues to be resolved, and therefore if used as a Prenatal diagnosis of instrument is still very risky, there is no domestic provision of prenatal diagnosis.
Clinical presentation:
Non-keto high glycine levels, depending on age of onset can be divided into neonatal and late-onset type, one of the most common type in the newborn. Patient incidence of about 1-3 at the first day, according to foreign statistics, its onset may occur as early as 6 hours after birth, more than two-thirds of patients within 48 hours will be the incidence. The performance of the incidence of drowsiness and one start apnea, and then gradually shown to reduce tension, reflection is also reduced, and then show, in part or in whole body clonic convulsions or muscle, in particular, is sick of all newborns have the hiccups phenomenon.because of a very early time, and change fast, health care workers about the disease must be very alert. Convulsive movements of these patients are very stubborn, anti-epileptic drugs are generally difficult to control, most of them will need a number of drugs used simultaneously in order to slow down muscle clonus sick phenomenon. Spend patients if the neonatal period, after all there is much still together disease, such as serious head syndrome, intractable spasticity, rigidity of limbs, paralysis and severe developmental delay. Prognosis is poor.
Diagnosis:
When a newborn at birth of all good, but in hours or days there drowsiness, apnea, tension reduction, partial or generalized clonic convulsions or muscle, if the exclusion of neonatal infection and postnatal hypoxic brain lesions such circumstances, must take into account the congenital metabolic diseases, rather than one high hyperlipidemia is also important reasons之ㄧ. To the diagnosis of non-ketone with high glycine levels, must be detected simultaneously in plasma and cerebrospinal fluid amino acid value. If the cerebrospinal fluid increased the value of glycine, plasma glycine increased the value, and cerebrospinal fluid glycine values of plasma glycine ratio values greater than 0.08, you can diagnose this disease. As required by the diagnosis of liver puncture (Liver biopsy), determination of liver tissues of the activity of glycine cleavage system, glycine cleavage system to verify whether the lack of activity. In this category of patients with neonatal-type, the liver tissues of the glycine cleavage system activity is very low, almost close to 0.
High in the non-ketone glycine hyperlipidemia in patients with brain waves will show a special change, such as: burst-suppression pattern, can also provide a diagnosis of this disease to help, this change in brain waves will gradually disappear, and then transformed into hypsarrythmia, if timely ventilator support apnea patients will gradually improve the situation.
Treatment:
The disease mainly in order to reduce the value of glycine in vivo, because sustained high glycine values will cause serious harm to the brain. These methods reduce the glycine include: limiting the uptake of glycine, voted with ursodeoxycholic acid, with a view to combining with glycine, and then glycine by bile discharged; also voted with the sodium benzoate in order to promote Gan amine acid from the urine discharged, but such methods or can reduce the blood of the value of glycine, it can not be cerebral spinal fluid in the value of glycine decreased to normal, so the impact of brain injury patients may assist limited. On the other hand, previous studies have shown that drugs commonly used for cough Dextromethorphan (merchandise called Medicon) patients in this category have to mitigate the effects of spasticity, and its machines to Dextromethorphan pharmacology metabolites dextrophan for N-methyl -D-aspartate (NMDA)-receptor-channel complex of the inhibitor.
Non-keto high glycine in patients with hyperlipidemia in the cerebrospinal fluid will stimulate glycine glutaminergic NMDA receptor, therefore the use of high doses of Dextromethorphan (20-25mg/kg/day), can slow disease cramp spasm phenomenon. While another NMDA-channel inhibitor, Ketamine ((8mg/kg/day), has also been reported for use in the treatment of patients to control also the effect of apnea, with the exception of the special drug outside, because the patients have many refractory spasm phenomenon, while the use of several anti-epileptic drugs also its necessity.
Case Report:
Over the years the author has treated one of two non-glycine hyperlipidemia, and to share in this experience, two patients with a performance beginning at birth are in good condition, but when in one day, appears drowsiness, weakness and apnea cases by the local obstetrics and gynecology clinic evacuation immediately transferred to hospital by one day to rule out the hearts of three days while the infection, birth trauma, hypoxic brain lesions after again to the medical center, and then by the plasma and cerebrospinal fluid amino acid glycine measurements confirmed both an increase in both value and cerebrospinal fluid glycine on plasma glycine ratio of greater than 0.08. Determined not to be one of the high glycine hyperlipidemia after beginning drug therapy given to rare diseases, including Sodium benzoate (250-500 mg / kg / day) and Dextromethorphan (25-35 mg / kg / day), and give the majority of combined use of anti-epileptic drugs to control his intractable spasticity. But the disease can only be controlled, they can not have a good clinical outcome, because even if early treatment of patients earlier in the nerve cells can not respond to the injury. Therefore, such patients have serious head syndrome, intractable spasticity, rigidity of limbs, paralysis and severe developmental delay. Can not be effective because of the prenatal diagnosis of this disease, so patients with many mining Parent born the idea of luck. One of a pair of first child, in patients with the disease of their parents, second child in the development of normal birth-old boy, third child while the baby boy birth incidence because we have already had a detailed genetic counseling, the parents decided to give up aggressive treatment, the third child in a few days after birth, death, and their first child, a rare disease in the patients with medication also around the age of 2 due to aspiration pneumonia and death concurrency.
Another first child patients with the disease is still rare disease drug treatment, is about two years old. His mother a second child in the current pregnancy.
Nonketotic hyperglycinemia
Brief introduction
High glycine Hyperlipidemia refers to body fluids of glycine (glycine) high concentration of disease, high glycine has two kinds: non-ketone and ketone sexual. Non-keto high pathogenicity of glycine hyperlipidemia are the main mechanism to split the system because glycine (glycine cleavage system, GCS) of the defect caused by the degradation of glycine. High non-ketone is a glycine Hyperlipemia occur during the neonatal period and there is a very serious biochemical metabolic abnormalities. Another one of the high glycine hyperlipidemia (ketotic hyperglycinemia) is the most lethal symptoms of ketoacidosis are mainly because of organic acid disorders are a result of ketoacidosis and high glycine hyperlipidemia, and such diseases are usually happen early in life.
Clinical symptoms
Non-keto high glycine Hyperlipemia clinical characterization can be divided into two types: type newborn (neonatal type) and late onset (late-onset type).
Newborns are more common type, the majority of cases of this type is quite normal at birth, but shortly after, usually little more than 48 hours, neurological symptoms will appear and the rapid deterioration of the muscles such as low-tension (muscle hypotonic), the Moro Test low response (depressed Moro response), epilepsy (seizure), asphyxia (apnea attack), sleepiness (lethargy) or unconscious (coma). Most of the cases will be dead in a few weeks, after this period of time while still alive there is a serious developmental delay mental exercise phenomenon. In addition, there is also likely to attack various types of cramps, myoclonic epilepsy from the onset of epilepsy Tai may have happened, have hiccups situation is also very common. Neonatal period there will be very clear with low muscle tension, and then will gradually become stiff muscles.
Late onset cases in the neonatal period will not have abnormal symptoms, and then will be gradually developed various degrees of neurological symptoms, their age of onset ranging from infancy to adolescence.
Metabolic degradation
Non-keto high defect Hyperlipemia glycine at glycine are split system (GCS), glycine split system is a multi-enzyme system by combination of four proteins: P protein (a pyridosal phosphate-dependant glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L-protein (lipoamide dehydrogenase). In 30 newborns in the liver of patients who measured the activity of glycine-free or very low, whereas in late onset cases are detected only residual activity, so from the severity of clinical symptoms of view also seems to glycine split system the degree of defect.
Non-keto high hyperlipidemia cases glycine glycine concentration in the brain than one high glycine high hyperlipidemia cases; and non-keto high hyperlipidemia cases glycine glycine brain activity is to split the system Measuring less than one high and hyperlipidemia glycine glycine case of split brain system showed normal activity.
Most of the non-ketone high glycine hyperlipidemia are sick belong to P protein has defects, a small number of proteins for the T defect. Seven patients from the brain and the liver anatomical analysis of that brain and liver glycine split protein system is controlled by the same gene.
Recently, a lot of study and observation of the brain glycine exciting link between agents and some new views. Before glycine has been regarded as a nerve conduction inhibitor, but now it is found that while there is some role in nerve excitability, and high concentrations of glycine on the developing brain damage.
Diagnostic tests
Happen when the baby epilepsy, low muscle tension, and drowsiness when these symptoms are not from infection, trauma, hypoxia, or other common pediatric problem, should be strongly suspected at this time whether the patient is suffering from congenital metabolic diseases. At this point the patient should be analyzed in blood amino acids and urine organic acids, as found in abnormal blood glycine increased, we should then consider the possibility of the disease, the disease takes and one high glycine Hyperlipemia make one distinction. The disease generally have normal blood pH and normal organic acid test results (which may be gas-phase analyzer layer inspection to determine the urine). Second, comparable brain fluid and plasma glycine concentrations, the ratio is as follows:
1. Cerebrospinal fluid of glycine: glycine in plasma of> 0.09 = non-ketone high glycine Hyperlipemia
2. Cerebrospinal fluid of glycine: glycine in plasma of <0.09 and> 0.04 = normal
3. Cerebrospinal fluid glycine: plasma glycine <0.04 = one of the high glycine hyperlipidemia.
Since glycine split systems are present in liver, kidney, and brain, liver anatomy therefore contribute to high non-ketone glycine enzyme diagnosis of hyperlipidemia.
Prenatal genetic diagnosis
Since the current non-ketone high glycine Hyperlipemia no effective method of treatment, so prenatal diagnosis is very necessary. Cultured amniotic fluid cells, glycine-free split system activity and therefore does not apply to prenatal genetic diagnosis, but glycine decomposition of the system exist in the villous placenta, so human chorionic sampling applied to make the non-ketone high glycine Prenatal genetic diagnosis of hyperlipidemia. Moreover, if the family's gene mutation point has been identified, and the gene (DNA) diagnosis is feasible.
Treatment and clinical progress
Patients in order to reduce the concentration of glycine, clinical reports on the use has been a lot of treatment methods including the restriction of the protein diet, this diet is the non-glycine and its precursors serine (serine); use of benzoic acid salt (Benzoate) combined hippuric acid glycine become discharged by the kidneys; injection ursodeoxycholic acid glycine to link out from the bile excretion. These treatments can effectively reduce the plasma concentrations of glycine can not effectively reduce the cerebrospinal fluid concentrations of glycine, but also can not effectively improve the clinical symptoms. The use of tranquillizers (such as Valium), methionine (methionine), Antidote (Leucovorin), or choleretic agents (Choline), such as drugs, while only a slight improvement in clinical symptoms or even no response.
Recent report indicates that there is also another treatment to try, in accordance with glycine are excitatory nerve agents and the use of the hypothesis of NMDA antagonists (such as chlorine Ketamine Security ketone) or blockers (such as Dextromethorphan). Have reported that by a 7-month high with the non-ketone glycine Hyperlipemia baby every day oral non-barbiturate agent of general anesthesia such as chlorine-an-one (Ketamine), every day per kilogram of body weight 8 grams of ketamine four times using it, can improve the part of the neurological symptoms and brain waves. Hamosh et al have combined antitussive agents (dextromethorphan), and NMDA pipeline (NMDA channel) blocking agents and high doses of sodium Benzoin (sodium benzoate) therapy HKH cases, such treatment will be carried out one year after the results were published out. In this case sodium Benzoin (sodium benzoate) initial treatment dose of 500 mg per kg every day (500mg/kg/day), from the fifth day after birth, they start taking it to the first 8 days of each dose was increased to day 750 mg per kilogram. The first 12 days then add the antitussive agents, antitussive agents (dextromethorphan) starting dose was 7.5 mg per kg every day (7.5mg/kg/day). The case was heard up to 12 months of age except values development (developmental quotient) than the slow addition of 60, the physical examination and showed normal growth. The report can be found from the early use of NMDA receptor (NMDA receptor) antagonist, or blocker, may help to improve the patient's brain injury NKH.
Genetic
Non-keto high glycine hyperlipidemia are autosomal recessive inheritance, the next child the chance of recurrence is 25%. Its prevalence has not been one really knows. At the northern part of Finland, it is estimated that the prevalence for each of around 10,002 people in there is a (1:12000). In Taiwan, the prevalence is unknown, only a small number of cases have been discovered.
High glycine Hyperlipidemia refers to body fluids of glycine (glycine) high concentration of disease, high glycine has two kinds: non-ketone and ketone sexual. Non-keto high pathogenicity of glycine hyperlipidemia are the main mechanism to split the system because glycine (glycine cleavage system, GCS) of the defect caused by the degradation of glycine. High non-ketone is a glycine Hyperlipemia occur during the neonatal period and there is a very serious biochemical metabolic abnormalities. Another one of the high glycine hyperlipidemia (ketotic hyperglycinemia) is the most lethal symptoms of ketoacidosis are mainly because of organic acid disorders are a result of ketoacidosis and high glycine hyperlipidemia, and such diseases are usually happen early in life.
Clinical symptoms
Non-keto high glycine Hyperlipemia clinical characterization can be divided into two types: type newborn (neonatal type) and late onset (late-onset type).
Newborns are more common type, the majority of cases of this type is quite normal at birth, but shortly after, usually little more than 48 hours, neurological symptoms will appear and the rapid deterioration of the muscles such as low-tension (muscle hypotonic), the Moro Test low response (depressed Moro response), epilepsy (seizure), asphyxia (apnea attack), sleepiness (lethargy) or unconscious (coma). Most of the cases will be dead in a few weeks, after this period of time while still alive there is a serious developmental delay mental exercise phenomenon. In addition, there is also likely to attack various types of cramps, myoclonic epilepsy from the onset of epilepsy Tai may have happened, have hiccups situation is also very common. Neonatal period there will be very clear with low muscle tension, and then will gradually become stiff muscles.
Late onset cases in the neonatal period will not have abnormal symptoms, and then will be gradually developed various degrees of neurological symptoms, their age of onset ranging from infancy to adolescence.
Metabolic degradation
Non-keto high defect Hyperlipemia glycine at glycine are split system (GCS), glycine split system is a multi-enzyme system by combination of four proteins: P protein (a pyridosal phosphate-dependant glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L-protein (lipoamide dehydrogenase). In 30 newborns in the liver of patients who measured the activity of glycine-free or very low, whereas in late onset cases are detected only residual activity, so from the severity of clinical symptoms of view also seems to glycine split system the degree of defect.
Non-keto high hyperlipidemia cases glycine glycine concentration in the brain than one high glycine high hyperlipidemia cases; and non-keto high hyperlipidemia cases glycine glycine brain activity is to split the system Measuring less than one high and hyperlipidemia glycine glycine case of split brain system showed normal activity.
Most of the non-ketone high glycine hyperlipidemia are sick belong to P protein has defects, a small number of proteins for the T defect. Seven patients from the brain and the liver anatomical analysis of that brain and liver glycine split protein system is controlled by the same gene.
Recently, a lot of study and observation of the brain glycine exciting link between agents and some new views. Before glycine has been regarded as a nerve conduction inhibitor, but now it is found that while there is some role in nerve excitability, and high concentrations of glycine on the developing brain damage.
Diagnostic tests
Happen when the baby epilepsy, low muscle tension, and drowsiness when these symptoms are not from infection, trauma, hypoxia, or other common pediatric problem, should be strongly suspected at this time whether the patient is suffering from congenital metabolic diseases. At this point the patient should be analyzed in blood amino acids and urine organic acids, as found in abnormal blood glycine increased, we should then consider the possibility of the disease, the disease takes and one high glycine Hyperlipemia make one distinction. The disease generally have normal blood pH and normal organic acid test results (which may be gas-phase analyzer layer inspection to determine the urine). Second, comparable brain fluid and plasma glycine concentrations, the ratio is as follows:
1. Cerebrospinal fluid of glycine: glycine in plasma of> 0.09 = non-ketone high glycine Hyperlipemia
2. Cerebrospinal fluid of glycine: glycine in plasma of <0.09 and> 0.04 = normal
3. Cerebrospinal fluid glycine: plasma glycine <0.04 = one of the high glycine hyperlipidemia.
Since glycine split systems are present in liver, kidney, and brain, liver anatomy therefore contribute to high non-ketone glycine enzyme diagnosis of hyperlipidemia.
Prenatal genetic diagnosis
Since the current non-ketone high glycine Hyperlipemia no effective method of treatment, so prenatal diagnosis is very necessary. Cultured amniotic fluid cells, glycine-free split system activity and therefore does not apply to prenatal genetic diagnosis, but glycine decomposition of the system exist in the villous placenta, so human chorionic sampling applied to make the non-ketone high glycine Prenatal genetic diagnosis of hyperlipidemia. Moreover, if the family's gene mutation point has been identified, and the gene (DNA) diagnosis is feasible.
Treatment and clinical progress
Patients in order to reduce the concentration of glycine, clinical reports on the use has been a lot of treatment methods including the restriction of the protein diet, this diet is the non-glycine and its precursors serine (serine); use of benzoic acid salt (Benzoate) combined hippuric acid glycine become discharged by the kidneys; injection ursodeoxycholic acid glycine to link out from the bile excretion. These treatments can effectively reduce the plasma concentrations of glycine can not effectively reduce the cerebrospinal fluid concentrations of glycine, but also can not effectively improve the clinical symptoms. The use of tranquillizers (such as Valium), methionine (methionine), Antidote (Leucovorin), or choleretic agents (Choline), such as drugs, while only a slight improvement in clinical symptoms or even no response.
Recent report indicates that there is also another treatment to try, in accordance with glycine are excitatory nerve agents and the use of the hypothesis of NMDA antagonists (such as chlorine Ketamine Security ketone) or blockers (such as Dextromethorphan). Have reported that by a 7-month high with the non-ketone glycine Hyperlipemia baby every day oral non-barbiturate agent of general anesthesia such as chlorine-an-one (Ketamine), every day per kilogram of body weight 8 grams of ketamine four times using it, can improve the part of the neurological symptoms and brain waves. Hamosh et al have combined antitussive agents (dextromethorphan), and NMDA pipeline (NMDA channel) blocking agents and high doses of sodium Benzoin (sodium benzoate) therapy HKH cases, such treatment will be carried out one year after the results were published out. In this case sodium Benzoin (sodium benzoate) initial treatment dose of 500 mg per kg every day (500mg/kg/day), from the fifth day after birth, they start taking it to the first 8 days of each dose was increased to day 750 mg per kilogram. The first 12 days then add the antitussive agents, antitussive agents (dextromethorphan) starting dose was 7.5 mg per kg every day (7.5mg/kg/day). The case was heard up to 12 months of age except values development (developmental quotient) than the slow addition of 60, the physical examination and showed normal growth. The report can be found from the early use of NMDA receptor (NMDA receptor) antagonist, or blocker, may help to improve the patient's brain injury NKH.
Genetic
Non-keto high glycine hyperlipidemia are autosomal recessive inheritance, the next child the chance of recurrence is 25%. Its prevalence has not been one really knows. At the northern part of Finland, it is estimated that the prevalence for each of around 10,002 people in there is a (1:12000). In Taiwan, the prevalence is unknown, only a small number of cases have been discovered.
Nonketotic hyperglycinemia, NKH
Detect code ︰
NKH
Pathogenesis ︰
Nonketotic hyperglycinemia (NKH) for autosomal recessive genetic disease, the cause for the glycine cleavage enzyme complex (glycine cleavage enzyme complex, referred to as GCS) abnormalities caused by the enzyme by the P, T, H, L four protein composition, current research shows that nearly 80% NKH patients are caused by abnormal protein because of P and another near 10-15% of the patients due to abnormal T protein. P protein, glycine decarboxylase (GLDC) gene product; and T protein aminomethyltransferase (AMT) gene product.
Clinical symptoms ︰
Non-keto high glycine can be divided into neonatal hyperbilirubinemia type (neonatal type) and late onset (late-onset type) the two types.
Neonatal type more common in a few days after birth, neurological symptoms will appear and rapidly deteriorating, there will be low muscle tone, low Moro test reaction, epilepsy, asphyxia, lethargy or coma. Most of the patients died within a few weeks, after this period of time while still alive there is a serious developmental delay mental exercise phenomenon. In addition, there is also likely to attack various types of cramps, myoclonic epilepsy from the onset of epilepsy Tai may have happened, have hiccups situation is also very common. Neonatal period there will be very clear with low muscle tension, and then will gradually become stiff muscles.
Late onset cases in the neonatal period will not have abnormal symptoms, and then will be gradually developed various degrees of neurological symptoms, their age of onset ranging from infancy to adolescence. [The above information is extracted from the rare disease foundations]
Detected items ︰
GLDC and AMT gene
Detection Method ︰
Coding region sequencing
Sample type / volume ︰
Whole blood 5 ml.
Collection tube ︰
Purple head EDTA mining vessel.
Detect costs ︰
Call contact
Detect Time ︰
2 weeks
Prenatal diagnosis ︰
Can be mined villi (10mg and above) or amniotic fluid (10ml).
Genetic approach ︰
Prevalence ︰
1 / 12, 000 (Finland); Taiwan no statistical data
Gene location ︰
GLDC gene: the region on chromosome 9p
AMT gene: located on chromosome region 3p21.
Genetic testing
Limitations ︰
1. The molecular genetic testing to direct gene sequencing method, detection with a result of patients or persons in GLDC gene and the performance of sub-AMT gene (exon) regions whether pathogenic mutations happen, if for large fragment deletion of sequences or non-detection zone mutation can not be learned from this test.
2. If the cause of patients with this gene caused by non-, they can not be detected by this test.
3. Report of the accuracy rate of 97%, the results of clinical reference for physicians.
NKH
Pathogenesis ︰
Nonketotic hyperglycinemia (NKH) for autosomal recessive genetic disease, the cause for the glycine cleavage enzyme complex (glycine cleavage enzyme complex, referred to as GCS) abnormalities caused by the enzyme by the P, T, H, L four protein composition, current research shows that nearly 80% NKH patients are caused by abnormal protein because of P and another near 10-15% of the patients due to abnormal T protein. P protein, glycine decarboxylase (GLDC) gene product; and T protein aminomethyltransferase (AMT) gene product.
Clinical symptoms ︰
Non-keto high glycine can be divided into neonatal hyperbilirubinemia type (neonatal type) and late onset (late-onset type) the two types.
Neonatal type more common in a few days after birth, neurological symptoms will appear and rapidly deteriorating, there will be low muscle tone, low Moro test reaction, epilepsy, asphyxia, lethargy or coma. Most of the patients died within a few weeks, after this period of time while still alive there is a serious developmental delay mental exercise phenomenon. In addition, there is also likely to attack various types of cramps, myoclonic epilepsy from the onset of epilepsy Tai may have happened, have hiccups situation is also very common. Neonatal period there will be very clear with low muscle tension, and then will gradually become stiff muscles.
Late onset cases in the neonatal period will not have abnormal symptoms, and then will be gradually developed various degrees of neurological symptoms, their age of onset ranging from infancy to adolescence. [The above information is extracted from the rare disease foundations]
Detected items ︰
GLDC and AMT gene
Detection Method ︰
Coding region sequencing
Sample type / volume ︰
Whole blood 5 ml.
Collection tube ︰
Purple head EDTA mining vessel.
Detect costs ︰
Call contact
Detect Time ︰
2 weeks
Prenatal diagnosis ︰
Can be mined villi (10mg and above) or amniotic fluid (10ml).
Genetic approach ︰
Prevalence ︰
1 / 12, 000 (Finland); Taiwan no statistical data
Gene location ︰
GLDC gene: the region on chromosome 9p
AMT gene: located on chromosome region 3p21.
Genetic testing
Limitations ︰
1. The molecular genetic testing to direct gene sequencing method, detection with a result of patients or persons in GLDC gene and the performance of sub-AMT gene (exon) regions whether pathogenic mutations happen, if for large fragment deletion of sequences or non-detection zone mutation can not be learned from this test.
2. If the cause of patients with this gene caused by non-, they can not be detected by this test.
3. Report of the accuracy rate of 97%, the results of clinical reference for physicians.
Nonketotic hyperglycinemia. Glycine accumulation due to absence of glycerine cleavage in brain
Abstract
Glycine concentrations were measured in plasma and cerebrospinal fluid of five patients in different types of hyperglycinemia to determine why severe neurologic deterioration is confined to the so-called nonketotic form of hyperglycinemia. Glycine content and glycine-cleavage enzyme activity were also determined in brain obtained in autopsy from three of these patients. Spinal-fluid glycine concentrations were 15 to 30 times above normal in patients with nonketotic hyperglycinemia, but were normal in those with hyperglycinemias of undetermined type who had comparable elevations of plasma glycine. Glycine content was two to four times above normal in several brain regions, and brain glycine cleavage enzyme activity was absent in two patients dying of nonketotic hyperglycinemia. By contrast, glycine content was normal and glycine cleavage activity present in the brain of an infant who died of hyperglycinemia of unknown cause. These results suggest that elevated glycine levels may be harmless in blood, but lethal in brain.
Glycine concentrations were measured in plasma and cerebrospinal fluid of five patients in different types of hyperglycinemia to determine why severe neurologic deterioration is confined to the so-called nonketotic form of hyperglycinemia. Glycine content and glycine-cleavage enzyme activity were also determined in brain obtained in autopsy from three of these patients. Spinal-fluid glycine concentrations were 15 to 30 times above normal in patients with nonketotic hyperglycinemia, but were normal in those with hyperglycinemias of undetermined type who had comparable elevations of plasma glycine. Glycine content was two to four times above normal in several brain regions, and brain glycine cleavage enzyme activity was absent in two patients dying of nonketotic hyperglycinemia. By contrast, glycine content was normal and glycine cleavage activity present in the brain of an infant who died of hyperglycinemia of unknown cause. These results suggest that elevated glycine levels may be harmless in blood, but lethal in brain.
Nonketotic Hyperglycinemia (NKH)
Save Babies Through Screening Foundation is comprised of volunteers. Some have children who were helped by newborn screening, and some have children who have died, or suffered brain damage. For many of the Foundation's volunteers, joy comes from knowing that your child was saved. Many hours of hard work have been done to help children, maybe even yours. Please let us hear from you.
What is it?
NKH, also known as glycine encephalopathy, is caused by an inadequate supply of an enzyme necessary to break down glycine in the body. This leads to abnormally high levels of glycine.
Inheritance and Frequency
The gene defect for NKH is an autosomal recessive genetic trait and is unknowingly passed down from generation to generation. This faulty gene usually emerges when two carriers have children together and pass it to their offspring. For each pregnancy of two such carriers, there is a 25% chance that the child will be born with the disease and a 50% chance the child will be a carrier for the gene defect.
Signs & Symptoms
The most common form of NKH occurs in infants. It is characterized by delayed development, feeding difficulties and seizures in infancy.
Long Term Effects
Mental retardation and seizures may result from NKH.
Treatment
History
The occurrence rate of NKH worldwide is unknown. Limited studies suggest approximately 1 in 60,000 newborns is affected..
Screening
Visit the What Does Your State Screen page to learn about your state's newborn screening program.
What is it?
NKH, also known as glycine encephalopathy, is caused by an inadequate supply of an enzyme necessary to break down glycine in the body. This leads to abnormally high levels of glycine.
Inheritance and Frequency
The gene defect for NKH is an autosomal recessive genetic trait and is unknowingly passed down from generation to generation. This faulty gene usually emerges when two carriers have children together and pass it to their offspring. For each pregnancy of two such carriers, there is a 25% chance that the child will be born with the disease and a 50% chance the child will be a carrier for the gene defect.
Signs & Symptoms
The most common form of NKH occurs in infants. It is characterized by delayed development, feeding difficulties and seizures in infancy.
Long Term Effects
Mental retardation and seizures may result from NKH.
Treatment
History
The occurrence rate of NKH worldwide is unknown. Limited studies suggest approximately 1 in 60,000 newborns is affected..
Screening
Visit the What Does Your State Screen page to learn about your state's newborn screening program.
Nonketotic Hyperglycinemia (NKH)
This page is an Internet presence of a network of parents with children with Nonketotic Hyperglycinemia (NKH), a rare and still incurable metabolic disorder.
The Network's History
Karen Carter and MaryLou Chandler were the first parents who made contact with other parents. The Network was founded in early 1996. Judy Clifford is now preparing and distributing newsletters to the members of the network.
To learn more about NKH, the network, the families, and others, please choose from the items on the left hand side.
--------------------------------------------------------------------------------
NKH International Family Network's goal is to network and connect families by means of this website, newsletter, and member list, assist parents with support, advice and information and how to best care for their child/children with NKH, offer emotional and educational support of each other and of new families.
Annual dues to be used for these goals of $20 are requested, however, any affordable amount is acceptable and no one will be denied if not affordable. All dues/donations can be sent to Judy Clifford.
"We are all only a piece of twine in our lives, but together as our NKH family group, we make a rope of hope, faith, and love for one another to hold onto." -by Rita Williams, mom to Kurt Dalton 9/30/92 to 1/1/01
What is NKH? (not complete)
Nonketotic Hyperglycinemia is an inherritted metabolic disorder. Patients suffering from this disorder have elevated level of glycine, a basic amino acid, in blood, cerebrospinal fluid (CSF), and urine. The diagnostic characteristic is the elevated ratio of glycine in CSF/blood. Some patients died in the newborn period after a course characterized by lethargy, weak cry, generalized hypotonia, absent reflexes, and periodic myoclonic jerks. Survivors are subject to various degrees of mental retardation.
NKH has a very wide spectrum of severity. There are two way of classifications: one is based on clinical manifestations, and the other is based on underlying enzymatic causes.
The clinical categorization of NKH falls into four broad groups: classical or neonatal NKH, infantile NKH, late-onset NKH, and the rare transient NKH. Most NKH children are of classical group.
The enzymatic categorization divides NKH into four types, based on the location of deficient sub-enzymes in the glycine cleavage system (GCS), which is the large and complex enzyme that is supposed to gets rid of excessive glycine.
--------------------------------------------------------------------------------
Symptoms (under construction)
--------------------------------------------------------------------------------
Treatment (not complete)
Progress has been made during the past decade for a better treatment of NKH. Unfortunately, due partly to the disorder's heterogenuity, no absolute cure has yet been found. Sodium Benzoate (SB) has long been used to reduce the excessive glycine in both plasma and CSF, and can results in controlled or reduced seizures and increased alertness. Recent trials of higher doses of sodium benzoate succeeded in normalization of plasma glycine and substantial reduction in CSF. In contrast to earlier reservation among medical researchers upon the role of sodium benzoate in promoting mental development, the experiences among many of our parent members seem to indicate the benefit of sodium benzoate. (Exceptions do occur, though). This seems to be true especially when the children start taking sodium benzoate at high enough dose early in life (within the first years of life).
The most serious side effect from SB is its irritation on stomach due to its acidity. At high dose, some children developed inflammations in stomach, duodenum, esophagus. Few suffer from recurrent heartburn and fail to gain weight. Protective medications have been prescibed. These include antacids, H2-blocker (e.g. Zantag), protein pumb inhibitor, and sucralfate. These protective medications work differently, and it is a matter of trial and error to find the most suitable strategy for each child. The SB's side effect is apparently dose dependent. Many medical articles confirm that a dose of 250 mg/kg/day is well tolerated. Some NKH children of our network can take as much as 500-600 mg/kg/day without too much stomach irritation and without any protective medications. Consequently, if a child can poorly tolerate the proper dose, it might be wise to investigate into other possible complication. The author's personal experience has found that a problem of delayed gastric emptying greatly reduces the tolerability, as the sodium benzoate stays in the stomach for too long. Correcting this problem results in much better tolerance of sodium benzoate.
Dextromethorphan (DM or DXM)嚙箠s another principal medication added recently to the treatment of NKH children. It has been found in animal model to prevent neuron death resulting from the brain being exposed to high glycine. Some researches also indicate that DM prevents or reduces seizures. (Personal experience by the author of this webpage seems to confirm both the seizure prevention and the development promotion of DM). However, DM can have relatively strong side effects, especially after long term and regular use. It can cause irritability, involuntary movements, refusal to eat, troubled sleeping and breathing suppression. The side effects are different from child to child, and seem to be caused by substantial difference in the body's metabolism of dextromethorphan into dextrophan. The optimal dose (or practical dose) for each child is therefore quite different. To learn more about DM, there is a FAQ (frequently Asked Questions) on DM which can be found at William E. White's Dextromethorphan FAQ.
--------------------------------------------------------------------------------
Some Case Studies (under construction)
--------------------------------------------------------------------------------
Prenatal Diagnosis (under construction)
Since NKH is an autosomal inherited inborn disorder, the chance that parents who are both carriers of this disease (those who already have or had affected child) will have another NKH child is one in four, a normal child is also one in four, and two in four will be carriers. The question is how we can know during pregnancy if the child is affected for not. Fortunately, prenatal diagnosis has been available for quite some time. The medical literature on this diagnosis come from both Japan and North America. One of the center that has done most prenatal diagnosis is the Biomedical Diseases Laboratory of the Division of Biomedical Diseases at the University of British Columbia, Vancouver, Canada. Dr. Derek Applegarth has done twelve prenatal diagnoses so far (as of January 1997). Out of these twelve pregnancies, the diagnosis can be made with accuracy (that the child was either affected or normal) in nine of them. The result on the other three pregnancies were inconclusive (in "grey area"), as the GCS enzyme activities were detected but were not in normal range. That means the child can be anything from normal to mildly affected (atypical NKH), or even classical NKH.
We have to interpret these number carefully. The good thing is that if the data is strong enough, the diagnosis has been always right so far. And that is nine out of twelve, not a bad number. However, the risk is still there because of the possibility like the three inconclusive cases. It is not possible to make prediction on those cases and the parents still have to make a very tough decision, either to keep or to abort the pregnancy. Also, the total number of twelve diagnoses that has been done is still too small to say that, statistically, these "inconclusive" diagnoses are less likely to happen than the conclusive ones. We can only hope that even more accurate diagnosis will be developed very soon.
The Network's History
Karen Carter and MaryLou Chandler were the first parents who made contact with other parents. The Network was founded in early 1996. Judy Clifford is now preparing and distributing newsletters to the members of the network.
To learn more about NKH, the network, the families, and others, please choose from the items on the left hand side.
--------------------------------------------------------------------------------
NKH International Family Network's goal is to network and connect families by means of this website, newsletter, and member list, assist parents with support, advice and information and how to best care for their child/children with NKH, offer emotional and educational support of each other and of new families.
Annual dues to be used for these goals of $20 are requested, however, any affordable amount is acceptable and no one will be denied if not affordable. All dues/donations can be sent to Judy Clifford.
"We are all only a piece of twine in our lives, but together as our NKH family group, we make a rope of hope, faith, and love for one another to hold onto." -by Rita Williams, mom to Kurt Dalton 9/30/92 to 1/1/01
What is NKH? (not complete)
Nonketotic Hyperglycinemia is an inherritted metabolic disorder. Patients suffering from this disorder have elevated level of glycine, a basic amino acid, in blood, cerebrospinal fluid (CSF), and urine. The diagnostic characteristic is the elevated ratio of glycine in CSF/blood. Some patients died in the newborn period after a course characterized by lethargy, weak cry, generalized hypotonia, absent reflexes, and periodic myoclonic jerks. Survivors are subject to various degrees of mental retardation.
NKH has a very wide spectrum of severity. There are two way of classifications: one is based on clinical manifestations, and the other is based on underlying enzymatic causes.
The clinical categorization of NKH falls into four broad groups: classical or neonatal NKH, infantile NKH, late-onset NKH, and the rare transient NKH. Most NKH children are of classical group.
The enzymatic categorization divides NKH into four types, based on the location of deficient sub-enzymes in the glycine cleavage system (GCS), which is the large and complex enzyme that is supposed to gets rid of excessive glycine.
--------------------------------------------------------------------------------
Symptoms (under construction)
--------------------------------------------------------------------------------
Treatment (not complete)
Progress has been made during the past decade for a better treatment of NKH. Unfortunately, due partly to the disorder's heterogenuity, no absolute cure has yet been found. Sodium Benzoate (SB) has long been used to reduce the excessive glycine in both plasma and CSF, and can results in controlled or reduced seizures and increased alertness. Recent trials of higher doses of sodium benzoate succeeded in normalization of plasma glycine and substantial reduction in CSF. In contrast to earlier reservation among medical researchers upon the role of sodium benzoate in promoting mental development, the experiences among many of our parent members seem to indicate the benefit of sodium benzoate. (Exceptions do occur, though). This seems to be true especially when the children start taking sodium benzoate at high enough dose early in life (within the first years of life).
The most serious side effect from SB is its irritation on stomach due to its acidity. At high dose, some children developed inflammations in stomach, duodenum, esophagus. Few suffer from recurrent heartburn and fail to gain weight. Protective medications have been prescibed. These include antacids, H2-blocker (e.g. Zantag), protein pumb inhibitor, and sucralfate. These protective medications work differently, and it is a matter of trial and error to find the most suitable strategy for each child. The SB's side effect is apparently dose dependent. Many medical articles confirm that a dose of 250 mg/kg/day is well tolerated. Some NKH children of our network can take as much as 500-600 mg/kg/day without too much stomach irritation and without any protective medications. Consequently, if a child can poorly tolerate the proper dose, it might be wise to investigate into other possible complication. The author's personal experience has found that a problem of delayed gastric emptying greatly reduces the tolerability, as the sodium benzoate stays in the stomach for too long. Correcting this problem results in much better tolerance of sodium benzoate.
Dextromethorphan (DM or DXM)嚙箠s another principal medication added recently to the treatment of NKH children. It has been found in animal model to prevent neuron death resulting from the brain being exposed to high glycine. Some researches also indicate that DM prevents or reduces seizures. (Personal experience by the author of this webpage seems to confirm both the seizure prevention and the development promotion of DM). However, DM can have relatively strong side effects, especially after long term and regular use. It can cause irritability, involuntary movements, refusal to eat, troubled sleeping and breathing suppression. The side effects are different from child to child, and seem to be caused by substantial difference in the body's metabolism of dextromethorphan into dextrophan. The optimal dose (or practical dose) for each child is therefore quite different. To learn more about DM, there is a FAQ (frequently Asked Questions) on DM which can be found at William E. White's Dextromethorphan FAQ.
--------------------------------------------------------------------------------
Some Case Studies (under construction)
--------------------------------------------------------------------------------
Prenatal Diagnosis (under construction)
Since NKH is an autosomal inherited inborn disorder, the chance that parents who are both carriers of this disease (those who already have or had affected child) will have another NKH child is one in four, a normal child is also one in four, and two in four will be carriers. The question is how we can know during pregnancy if the child is affected for not. Fortunately, prenatal diagnosis has been available for quite some time. The medical literature on this diagnosis come from both Japan and North America. One of the center that has done most prenatal diagnosis is the Biomedical Diseases Laboratory of the Division of Biomedical Diseases at the University of British Columbia, Vancouver, Canada. Dr. Derek Applegarth has done twelve prenatal diagnoses so far (as of January 1997). Out of these twelve pregnancies, the diagnosis can be made with accuracy (that the child was either affected or normal) in nine of them. The result on the other three pregnancies were inconclusive (in "grey area"), as the GCS enzyme activities were detected but were not in normal range. That means the child can be anything from normal to mildly affected (atypical NKH), or even classical NKH.
We have to interpret these number carefully. The good thing is that if the data is strong enough, the diagnosis has been always right so far. And that is nine out of twelve, not a bad number. However, the risk is still there because of the possibility like the three inconclusive cases. It is not possible to make prediction on those cases and the parents still have to make a very tough decision, either to keep or to abort the pregnancy. Also, the total number of twelve diagnoses that has been done is still too small to say that, statistically, these "inconclusive" diagnoses are less likely to happen than the conclusive ones. We can only hope that even more accurate diagnosis will be developed very soon.
Nonketotic Hyperglycinemia in a Neonate
Hyperglycinemia represents a group of
disorders characterized by elevated concentrations
of glycine in body fluids. Two
types exist, the ketotic and non ketotic. In
the ketotic type, the most striking feature is
ketoacidosis, which begins early in life and
in which hyperglycinemia is secondarily
associated with organic acidemias.
Nonketotic hyperglycinemia (NKH) is a
disorder of glycine metabolism due to a
molecular defect in the glycine cleavage
system (GCS)(1,2). Though NKH is a well
documented entity, to the best of our
knowledge there are no reports of this disorder
from India, the result of inadequate
diagnostic facilities. We report a case of
NKH in a neonate, with a review of its recent
therapeutics.
Case Report
A male baby weighing 2490 g was born
at term, after an uneventful antenatal period,
to a 25-year-old fifth gravida mother.
He was the product of a non-consanguineous
marriage. There was history of early
neonatal deaths of previous 3 male term infants.
They had no history of birth asphyxia
From the Neonatal Division, Department of
Pediatrics, Maulana Azad Medical College,
New Delhi 110 002
Reprint requests: Dr. S. Ramji, Professor,
Department of Pediatrics, Maulana Azad
Medical College, New Delhi 110 002.
Manuscript Received: April 21,1997;
Initial review completed: June 2,1997;
Revision Accepted: ]uly 21,1997
and followed an identical course of lethargy
and floppiness soon after birth, with inability
to suck on the breast, followed by
seizures, progressive sensorial deterioration
and death. One female sibling, 8 years
old, is alive and apparently healthy.
This neonate presented at 11 hours of
age with lethargy, weak cry and inability to
feed. On examination the baby was normothermic,
pink with a heart rate of 136/min,
respiratory rate of 48/min and normal peripheral
perfusion. There were no gross
congenital anomalies. The sensorium was
depressed with minimal spontaneous eye
opening and limb movements. Response to
painful stimuli was decreased. Neonatal reflexes
were sluggish. There were no focal
neurological deficits. In view of the clinical
presentation and similar history in earlier
siblings, possibility of an inborn error of
metabolism was kept and the baby accordingly
investigated.
Hematological investigations revealed:
TLC 8400 /cumm (polymorphonuclears
70%, lymphocytes 30%, immature to total
neutrophil ratio 0.07) and (μESR 1 mm fall
in 1st hour. Initial and subsequent blood
sugars ranged between 45 to 90 mg/dl.
Arterial blood gas analysis yielded pH
7.34, bicarbonate 18.2 mmol/L, base excess
3.4 mmol/L, paO2 90 mmHg, and paCO2
32 mmHg. Blood ammonia was 56 (μg/dl
(normal : 90-150 mg/dl) and serum creatinine
0.5 mg/dl. Ultrasound of cranium was
within normal limits.
The baby was initially started on expressed
breastmilk by nasogastric tube,
which he tolerated well. By 36 hours of life,
the baby's sensorium was completely
obtunded and respiration became shallow.
At this juncture, enteral feeding was discontinued
and the child provided intravenous
fluids and oxygen by hood. At 70
hours of age, the baby had recurrent
myoclonic seizures, which did not respond
278
INDIAN PEDIATRICS VOLUME 35-MARCH 1998
to phenobarbitone and phenytoin. At this
stage, the baby was provided assisted mechanical
ventilation. Inspite of adequate
supportive management, the baby died on
the fifth day of life.
The results of gas chromatographicmass
spectroscopy analysis of urine and
blood for organic and aminoacids revealed
markedly elevated levels of glycine. Glycine
levels in blood were 8.2 mg/dl (normal
: 3.1 ± 0.8 mg/dl) and in urine 18.4
umol/mg creatinine (normal : 2.3 ± 1.4
umol/mg creatinine). The other organic
and aminoacids were within normal limits.
Discussion
NKH is a relatively frequent metabolic
cause of overwhelming illness in infancy(
l). Over 150 cases have been reported^).
The exact prevalence is not known,
though it is estimated to be 1 in 250,000. It
is common in northern Finland, where the
prevalence is 1 in 12,000 (1) and is transmitted
as an autosomal recessive trait. In the
present family, only the male children
manifested clinically, suggesting that a sexlinked
mode of inheritance may also exist.
NKH classically presents as a life
threatening metabolic encephalopathy in
the neonatal period. Most infants appear
normal at birth and remain asymptomatic
for a brief period, seldom longer than 48
hours(2). They present with rapidly progressive
neurological symptoms such as
lethargy, poor feeding, seizures, high
pitched cry and generalized hypotonia.
Hiccups are frequently observed. Most
patients lapse into coma and die within a
few weeks. Survivors usually have severe
psychomotor retardation, spasticity, microcephaly
and uncontrolled seizures(l,2). The
present case had a clinical presentation
consistent with the classical type of NKH
and the history in the earlier siblings also
suggests that they too probably had the
same disorder. During the first few weeks
of life, a characteristic electroencephalogram
(EEG) pattern is seen with
bursts of large amplitude sharp waves,
arising periodically from a hypoactive
background. The so called burst-suppression
pattern changes by the end of the first
month to hypsarrhythmia(l,2). Cortical
atrophy and delayed or deficient rnyelination
may be seen on CT or MRI scan(4).
The late onset or infantile type of NKH
has a variable onset from "infancy to adolescence,
the patient usually remaining
asymptomatic in the neonatal period(2).
The presentations include seizures, delayed
development or mental retardation,
spinocerebeller degeneration and optic atrophy(
5,6). Transient NKH is also reported,
which has a variable prognosis(7).
Diagnosis is based on the findings of
hyperglycinemia and hyperglycinuria in
the absence of an organic acid disorder.
Absence of ketoacidosis and exclusion of
organic acidemias is crucial. During the investigation
of neonatal seizures due to a
suspected inborn error of metabolism,
absence of common biochemical abnormalities
evaluated (hyperammonemia, lactic
acidosis, ketoacidosis) should suggest the
possibility of classical NKH. Glycine levels
in cerebrospinal fluid (CSF) are also elevated,
the ratio of CSF and plasma glycine
characteristically being greater than 0.09,
whereas under normal circumstances and
in ketotic hyperglycinemia, it is below
0.04(1,2). CSF examination was not done in
the present case as neither an infective condition
nor this specific metabolic disorder
was suspected at presentation. Liver biopsy
can be performed for the enzymatic diagnosis
of NKH, as GCS is expressed in the
liver(3). GCS is also induced in B lymphocytes
in the peripheral blood by Epstein
Barr virus (EBV) and enzymatic assay can
be performed. This method is useful for
279
CASE REPORTS
differentiating NKH from ketotic hyperglycinemia
and for detection of carriers(8).
Prenatal diagnosis is possible by chorionic
villus sampling to estimate GCS activity between
8th-12th week of gestation(9).
The pathophysiologic effects of hyperglycinemia
are attributed to the inhibitory
property of glycine at post synaptic strychnine
sensitive receptors particularly in the
spinal cord and brain stem, and over stimulation
of the excitatory gluta-minergic NMethyl-
D-aspartate (NMDA) receptors,
particularly in the forebrain(lO). Measures
to lower the glycine concentration in NKH
patients have included protein restriction,
synthetic diet devoid of glycine and it's
precursor serine, promotion of renal excretion
by benzoate, administration of ursodeoxycholic
acid, strychnine and benzodiazepines.
The response has generally remained
unsatisfactory(l,2).
Recently, NMDA receptor antagonists
have been used with modest success. Oral
administration of ketamine (8 mg/kg/day,
in four divided doses)(ll), tryptophan
(100-150 mg/kg/day)(12) and dextromethorphan
(5-35 mg/kg/day in three to
four divided gradually increased doses) in
combination with benzoate (500-750 mg/
kg/day)(10,13) have brought about a partial
improvement of neurological symptoms
and EEG findings. Though aggressive
management employing assisted ventilation,
exchange transfusions and peritoneal
dialysis along with the aforementioned
therapeutic approaches has decreased the
mortality, the long term morbidity due to
NKH has remained unacceptably poor.
Acknowledgment
We wish to acknowledge Sapporo City
Institute of Public Health, Japan for carrying
out the GC-MS analysis for organic and
amino-acids.
REFERENCES
1. Nyhan WL. Nonketotic hyperglycinemia.
In; The Metabolic Basis of Inherited Diseases,
6th edn. Eds. Scriver CR, Beaudet
AL, Sly WS, Valle D. New York, Me Graw
Hill Inc., 1989; pp 743-753.
2. Tada K. Nonketotic hyperglycinemia. In:
Inborn Metabolic Diseases, 2nd edn. Eds.
Fernandes J, Saudubray, Van den Berghe
G. Berlin, Springer Verlag, 1995; pp 191-
196.
3. Hayasaka K, Tada K, Fueki N, Nakamura
Y, Nyhan WL, Schmidt K, et al.
Nonketotic hyperglycinemia: Analysis of
glycine cleavage system in typical and
atypical cases. J Pediatr 1987; 110: 873-
877.
4. Dobyns WB. Agenesis of corpus callosum
and gyral malformations are frequent
manifestations of nonketotic
hyperglycinemia. Neurology 1989; 39:
817-820.
5. Flannery DB, Pellock J, Bousounis D,
Hunt P, Nance C, Wolf B. Nonketotic
hyperglycinemia in two retarded adults:
A mild form of infantile nonketotic
hyperglycinemia. Neurology 1983; 33:
1064-1066.
6. Trauner DA, Page T, Greco C, Sweetman
L, Kulorich S, Nyhan WL. Progressive
neurodegenerative disorder in a patient
with nonketotic hyperglycinemia. J
Pediatr 1981; 98: 272-275.
7. Eyskens FJM, Van Door JWD, Marien P.
Neurologic sequelae in transient
nonketotic hyperglycinemia of the neonate.
J Pediatr 1992; 121: 620-621.
8. Christodoulou J, Kure S, Hayasaka K,
Clarke JTR. Atypical nonketotic
hyperglycinemia confirmed by assay of
glycine cleavage system in lymphoblasts.
J Pediatr 1993; 123:100-102.
9. Hayasaka K, Tada K, Fueki N, Sikawa J.
Prenatal diagnosis of nonketotic
hyperglycinemia: Enzymatic analysis of
the glycine cleavage system in chorionic
willi. J Pediatr 1990; 116: 444-445.
280
INDIAN PEDIATRICS VOLUME 35-MARCH 1998
10. Hamosh A, Me Donald JW, Valle D.
Francomano CA, Niedermeyer E,
Johnston MV. Dextromethorphan and
high-dose benzoate therapy for nonketotic
hyperglycinemia in an infant. J
Pediatr 1992; 121:131-135.
11. Ohya Y, Ochi N, Mizutani N, Hayakawa
C, Watanabek. Nonketotic hyperglycinemia:
treatment with NMDA antagonist
and consideration of neuropathogenesis.
Pediatr Neurol 1991; 7: 65-68.
12. Matsuo S, Inoue F, Takeuchi Y, Yoshioka
H, Kinusasa A, Sawada T. Efficacy of
tryptophan for the treatment of
nonketotic hyperglycinemia: A new therapeutic
approach for modulating N-Methyl-
D-aspartate receptor. Pediatrics 1995;
95:142-146.
14. Schmitt B, Steinmann B. Thun-Honestein
L, Mascher H, Dumermuth G. Nonketotic
hyperglycinemia: Clinical and electrophysiologic
effects of dextromethorphan, an
antagonist of the NMDA receptor. Neurology
1993; 43: 421-424.
disorders characterized by elevated concentrations
of glycine in body fluids. Two
types exist, the ketotic and non ketotic. In
the ketotic type, the most striking feature is
ketoacidosis, which begins early in life and
in which hyperglycinemia is secondarily
associated with organic acidemias.
Nonketotic hyperglycinemia (NKH) is a
disorder of glycine metabolism due to a
molecular defect in the glycine cleavage
system (GCS)(1,2). Though NKH is a well
documented entity, to the best of our
knowledge there are no reports of this disorder
from India, the result of inadequate
diagnostic facilities. We report a case of
NKH in a neonate, with a review of its recent
therapeutics.
Case Report
A male baby weighing 2490 g was born
at term, after an uneventful antenatal period,
to a 25-year-old fifth gravida mother.
He was the product of a non-consanguineous
marriage. There was history of early
neonatal deaths of previous 3 male term infants.
They had no history of birth asphyxia
From the Neonatal Division, Department of
Pediatrics, Maulana Azad Medical College,
New Delhi 110 002
Reprint requests: Dr. S. Ramji, Professor,
Department of Pediatrics, Maulana Azad
Medical College, New Delhi 110 002.
Manuscript Received: April 21,1997;
Initial review completed: June 2,1997;
Revision Accepted: ]uly 21,1997
and followed an identical course of lethargy
and floppiness soon after birth, with inability
to suck on the breast, followed by
seizures, progressive sensorial deterioration
and death. One female sibling, 8 years
old, is alive and apparently healthy.
This neonate presented at 11 hours of
age with lethargy, weak cry and inability to
feed. On examination the baby was normothermic,
pink with a heart rate of 136/min,
respiratory rate of 48/min and normal peripheral
perfusion. There were no gross
congenital anomalies. The sensorium was
depressed with minimal spontaneous eye
opening and limb movements. Response to
painful stimuli was decreased. Neonatal reflexes
were sluggish. There were no focal
neurological deficits. In view of the clinical
presentation and similar history in earlier
siblings, possibility of an inborn error of
metabolism was kept and the baby accordingly
investigated.
Hematological investigations revealed:
TLC 8400 /cumm (polymorphonuclears
70%, lymphocytes 30%, immature to total
neutrophil ratio 0.07) and (μESR 1 mm fall
in 1st hour. Initial and subsequent blood
sugars ranged between 45 to 90 mg/dl.
Arterial blood gas analysis yielded pH
7.34, bicarbonate 18.2 mmol/L, base excess
3.4 mmol/L, paO2 90 mmHg, and paCO2
32 mmHg. Blood ammonia was 56 (μg/dl
(normal : 90-150 mg/dl) and serum creatinine
0.5 mg/dl. Ultrasound of cranium was
within normal limits.
The baby was initially started on expressed
breastmilk by nasogastric tube,
which he tolerated well. By 36 hours of life,
the baby's sensorium was completely
obtunded and respiration became shallow.
At this juncture, enteral feeding was discontinued
and the child provided intravenous
fluids and oxygen by hood. At 70
hours of age, the baby had recurrent
myoclonic seizures, which did not respond
278
INDIAN PEDIATRICS VOLUME 35-MARCH 1998
to phenobarbitone and phenytoin. At this
stage, the baby was provided assisted mechanical
ventilation. Inspite of adequate
supportive management, the baby died on
the fifth day of life.
The results of gas chromatographicmass
spectroscopy analysis of urine and
blood for organic and aminoacids revealed
markedly elevated levels of glycine. Glycine
levels in blood were 8.2 mg/dl (normal
: 3.1 ± 0.8 mg/dl) and in urine 18.4
umol/mg creatinine (normal : 2.3 ± 1.4
umol/mg creatinine). The other organic
and aminoacids were within normal limits.
Discussion
NKH is a relatively frequent metabolic
cause of overwhelming illness in infancy(
l). Over 150 cases have been reported^).
The exact prevalence is not known,
though it is estimated to be 1 in 250,000. It
is common in northern Finland, where the
prevalence is 1 in 12,000 (1) and is transmitted
as an autosomal recessive trait. In the
present family, only the male children
manifested clinically, suggesting that a sexlinked
mode of inheritance may also exist.
NKH classically presents as a life
threatening metabolic encephalopathy in
the neonatal period. Most infants appear
normal at birth and remain asymptomatic
for a brief period, seldom longer than 48
hours(2). They present with rapidly progressive
neurological symptoms such as
lethargy, poor feeding, seizures, high
pitched cry and generalized hypotonia.
Hiccups are frequently observed. Most
patients lapse into coma and die within a
few weeks. Survivors usually have severe
psychomotor retardation, spasticity, microcephaly
and uncontrolled seizures(l,2). The
present case had a clinical presentation
consistent with the classical type of NKH
and the history in the earlier siblings also
suggests that they too probably had the
same disorder. During the first few weeks
of life, a characteristic electroencephalogram
(EEG) pattern is seen with
bursts of large amplitude sharp waves,
arising periodically from a hypoactive
background. The so called burst-suppression
pattern changes by the end of the first
month to hypsarrhythmia(l,2). Cortical
atrophy and delayed or deficient rnyelination
may be seen on CT or MRI scan(4).
The late onset or infantile type of NKH
has a variable onset from "infancy to adolescence,
the patient usually remaining
asymptomatic in the neonatal period(2).
The presentations include seizures, delayed
development or mental retardation,
spinocerebeller degeneration and optic atrophy(
5,6). Transient NKH is also reported,
which has a variable prognosis(7).
Diagnosis is based on the findings of
hyperglycinemia and hyperglycinuria in
the absence of an organic acid disorder.
Absence of ketoacidosis and exclusion of
organic acidemias is crucial. During the investigation
of neonatal seizures due to a
suspected inborn error of metabolism,
absence of common biochemical abnormalities
evaluated (hyperammonemia, lactic
acidosis, ketoacidosis) should suggest the
possibility of classical NKH. Glycine levels
in cerebrospinal fluid (CSF) are also elevated,
the ratio of CSF and plasma glycine
characteristically being greater than 0.09,
whereas under normal circumstances and
in ketotic hyperglycinemia, it is below
0.04(1,2). CSF examination was not done in
the present case as neither an infective condition
nor this specific metabolic disorder
was suspected at presentation. Liver biopsy
can be performed for the enzymatic diagnosis
of NKH, as GCS is expressed in the
liver(3). GCS is also induced in B lymphocytes
in the peripheral blood by Epstein
Barr virus (EBV) and enzymatic assay can
be performed. This method is useful for
279
CASE REPORTS
differentiating NKH from ketotic hyperglycinemia
and for detection of carriers(8).
Prenatal diagnosis is possible by chorionic
villus sampling to estimate GCS activity between
8th-12th week of gestation(9).
The pathophysiologic effects of hyperglycinemia
are attributed to the inhibitory
property of glycine at post synaptic strychnine
sensitive receptors particularly in the
spinal cord and brain stem, and over stimulation
of the excitatory gluta-minergic NMethyl-
D-aspartate (NMDA) receptors,
particularly in the forebrain(lO). Measures
to lower the glycine concentration in NKH
patients have included protein restriction,
synthetic diet devoid of glycine and it's
precursor serine, promotion of renal excretion
by benzoate, administration of ursodeoxycholic
acid, strychnine and benzodiazepines.
The response has generally remained
unsatisfactory(l,2).
Recently, NMDA receptor antagonists
have been used with modest success. Oral
administration of ketamine (8 mg/kg/day,
in four divided doses)(ll), tryptophan
(100-150 mg/kg/day)(12) and dextromethorphan
(5-35 mg/kg/day in three to
four divided gradually increased doses) in
combination with benzoate (500-750 mg/
kg/day)(10,13) have brought about a partial
improvement of neurological symptoms
and EEG findings. Though aggressive
management employing assisted ventilation,
exchange transfusions and peritoneal
dialysis along with the aforementioned
therapeutic approaches has decreased the
mortality, the long term morbidity due to
NKH has remained unacceptably poor.
Acknowledgment
We wish to acknowledge Sapporo City
Institute of Public Health, Japan for carrying
out the GC-MS analysis for organic and
amino-acids.
REFERENCES
1. Nyhan WL. Nonketotic hyperglycinemia.
In; The Metabolic Basis of Inherited Diseases,
6th edn. Eds. Scriver CR, Beaudet
AL, Sly WS, Valle D. New York, Me Graw
Hill Inc., 1989; pp 743-753.
2. Tada K. Nonketotic hyperglycinemia. In:
Inborn Metabolic Diseases, 2nd edn. Eds.
Fernandes J, Saudubray, Van den Berghe
G. Berlin, Springer Verlag, 1995; pp 191-
196.
3. Hayasaka K, Tada K, Fueki N, Nakamura
Y, Nyhan WL, Schmidt K, et al.
Nonketotic hyperglycinemia: Analysis of
glycine cleavage system in typical and
atypical cases. J Pediatr 1987; 110: 873-
877.
4. Dobyns WB. Agenesis of corpus callosum
and gyral malformations are frequent
manifestations of nonketotic
hyperglycinemia. Neurology 1989; 39:
817-820.
5. Flannery DB, Pellock J, Bousounis D,
Hunt P, Nance C, Wolf B. Nonketotic
hyperglycinemia in two retarded adults:
A mild form of infantile nonketotic
hyperglycinemia. Neurology 1983; 33:
1064-1066.
6. Trauner DA, Page T, Greco C, Sweetman
L, Kulorich S, Nyhan WL. Progressive
neurodegenerative disorder in a patient
with nonketotic hyperglycinemia. J
Pediatr 1981; 98: 272-275.
7. Eyskens FJM, Van Door JWD, Marien P.
Neurologic sequelae in transient
nonketotic hyperglycinemia of the neonate.
J Pediatr 1992; 121: 620-621.
8. Christodoulou J, Kure S, Hayasaka K,
Clarke JTR. Atypical nonketotic
hyperglycinemia confirmed by assay of
glycine cleavage system in lymphoblasts.
J Pediatr 1993; 123:100-102.
9. Hayasaka K, Tada K, Fueki N, Sikawa J.
Prenatal diagnosis of nonketotic
hyperglycinemia: Enzymatic analysis of
the glycine cleavage system in chorionic
willi. J Pediatr 1990; 116: 444-445.
280
INDIAN PEDIATRICS VOLUME 35-MARCH 1998
10. Hamosh A, Me Donald JW, Valle D.
Francomano CA, Niedermeyer E,
Johnston MV. Dextromethorphan and
high-dose benzoate therapy for nonketotic
hyperglycinemia in an infant. J
Pediatr 1992; 121:131-135.
11. Ohya Y, Ochi N, Mizutani N, Hayakawa
C, Watanabek. Nonketotic hyperglycinemia:
treatment with NMDA antagonist
and consideration of neuropathogenesis.
Pediatr Neurol 1991; 7: 65-68.
12. Matsuo S, Inoue F, Takeuchi Y, Yoshioka
H, Kinusasa A, Sawada T. Efficacy of
tryptophan for the treatment of
nonketotic hyperglycinemia: A new therapeutic
approach for modulating N-Methyl-
D-aspartate receptor. Pediatrics 1995;
95:142-146.
14. Schmitt B, Steinmann B. Thun-Honestein
L, Mascher H, Dumermuth G. Nonketotic
hyperglycinemia: Clinical and electrophysiologic
effects of dextromethorphan, an
antagonist of the NMDA receptor. Neurology
1993; 43: 421-424.
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