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.