Nonketotic Hyperglycinemia Research Articles

Benzoate treatment and the glycine index in nonketotic hyperglycinaemia

High-dose benzoate treatment aimed at reducing plasma glycine levels to normal reduces seizures and increases wakefulness in patients with nonketotic hyperglycinaemia (NKH). Since benzoate metabolism is dependent on the available glycine pool, and since the glycine pool is variably affected by the deficiency in the glycine cleavage enzyme system, we examined the importance of interpatient variability in benzoate requirement. To correct for the dietary glycine contribution, the glycine index was introduced as the molar requirement of benzoate dose necessary to normalize plasma glycine levels and subtracting from that the dietary glycine intake, both corrected for weight. The glycine index varied between 3.62 and 4.87 mmol/kg per day in five patients with a poor neurodevelopmental outcome and between 0.92 and 1.90 mmol/kg per day in four patients with a better neurodevelopmental outcome, and was 2.54 mmol/kg per day in a single patient with an intermediate outcome. The glycine index was stable over time within each patient. Exceeding the balance by either increasing food glycine intake or decreasing the benzoate dose resulted in increased glycine levels. Exceeding the glycine tolerance by increasing benzoate resulted in elevated and toxic levels of benzoate. The glycine index is a stable, individually specific parameter in patients with NKH. It has clinical consequences for the dose of benzoate required and the role of dietary management. Through its correlation with neurodevelopmental outcome, the glycine index points to potential genetic factors that could contribute to the psychomotor retardation in NKH.

Nonketotic hyperglycinemia in Suleimaniah Children’s Hospital, Riyadh, Saudi Arabia

Nonketotic hyperglycinemia in Suleimaniah Children’s Hospital, Riyadh, Saudi Arabia

Neonatal Movement Disorders

After completing this article, readers should be able to: 1. Delineate the characteristics that differentiate hyperkinetic neonatal movement disorders from neonatal seizures. 2. Describe the primary characteristics of and treatment for hyperekplexia. 3. Explain the relationship between gastroesophageal reflux and movement disorders in neonates. 4. Describe the primary ocular movement disorders in neonates. Neonates often exhibit paroxysmal behaviors that are nonepileptic in nature, such as oral-buccal-lingual movements, pedaling, stepping, and rotatory arm movements. The electroencephalogram (EEG) is of particular value for distinguishing these nonepileptic behaviors from subtle seizures. EEG and video-EEG studies in such movement disorders do not exhibit seizure discharges during the events. This distinction is important because nonepileptic events do not require treatment with anticonvulsants. Although the absence of surface ictal activity does not exclude entirely the possibility of seizures arising from deeper structures, it generally is accepted that these disorders are not epileptic. For the purposes of this review, we include common nonepileptic paroxysmal (episodic) movements that occur from birth to early infancy (onset between birth and 3 months of age). Many of these movement disorders may persist during infancy or early childhood. We do not discuss more persistent motor problems, such as spasticity, hypotonia, or myotonia. Also, disorders that occur after 3 months of age are not included. We have classified the movement disorders into two major categories: 1) hyperkinetic movements and 2) dystonic or extrapyramidal type of movements. Because the pathophysiologic mechanisms underlying neonatal movement disorders often are unknown, they are categorized on the basis of phenomenology, rather than presumed cause. Some of these disorders may have overlapping symptomatology. A third category encompasses “ocular movement disorders.” ### Jitteriness of the Newborn Jitteriness may be due to many factors, including metabolic disturbance, hypoxic-ischemic encephalopathy, drug withdrawal, hypoglycemia, and hypocalcemia. Although jitteriness may be mistaken for neonatal seizures, a distinguishing feature of jitteriness is that the …

The value of autopsy in determining the cause of failure to respond to resuscitation at birth

Autopsy is invaluable in identifying the causes of severe depression and very low Apgar score after birth and in assessing contributory conditions. Brain scans are increasingly used in the care of neonates who fail to respond to resuscitation at birth but their interpretation depends on the information gained from sound neuropathological studies. Asphyxia, both acute intrapartum asphyxia and chronic asphyxia, is an important cause of low Apgar scores. The gestational age and the nature of the asphyxial insult both have a profound influence on the ultimate pattern of injury. Asphyxia in the preterm brain tends to damage preferentially the white matter but some white matter damage is also seen in many infants who have an hypoxia-ischaemic insult at term though the predominant site of injury is to the central grey matter. The nature of the cellular damage and reactive change seen at autopsy is described. There is an association between low Apgar scores and intrauterine exposure to infection and maternal pyrexia. Detailed autopsy examination should include the search for infection. The placenta, cord and membranes should be examined in view of the mounting evidence of the association between intrauterine infection of the placenta and fetal membranes and prenatal brain damage. Additionally, the presence of placental thrombosis and infarction should be sought in relation to focal and global injury in the full term infant. Acquired prepartum lesions rarely cause the infant to present with a low Apgar score. The exception to this is severe damage to the brainstem and basal ganglia. Traumatic injury to the brain is now much less common than in previous decades. Subdural haemorrhage occurs more frequently than intraventricular or subarachnoid haemorrhage. Instrumental and assisted deliveries are associated with an increased incidence of subdural haemorrhage though these rarely cause significant long term damage. Careful autopsy, particularly of the neck and paravertebral tissues, spinal cord, brainstem and nerve roots is important where trauma is suspected. Tearing of nerve roots or fibre bundles in the spinal cord is readily demonstrated under the microscope using immunocytochemistry to β-amyloid precursor protein. Disorders of the spinal cord, peripheral nerve and muscle as well as some metabolic diseases may cause a baby to be both floppy and weak. Metabolic disease, including peroxisomal disorders, non-ketotic hyperglycinaemia, lipid and glycogen storage disorders and mitochondrial diseases may cause profound hypotonia and respiratory failure at birth or shortly afterwards.

Persistent NKH with transient or absent symptoms and a homozygous GLDC mutation.

Three of four nonketotic hyperglycinemia patients homozygous for a novel GLDC mutation (A802V) were treated by assisted respiration and/or sodium benzoate with or without ketamine and had transient neonatal or absent symptoms and normal developmental outcome, despite persisting biochemical evidence of nonketotic hyperglycinemia. This exceptional outcome may be related to the high residual activity of the mutant protein (32% of wild type) and therapeutic intervention during a critical period of heightened brain exposure and sensitivity to glycine.

Mild variant of nonketotic hyperglycinemia with typical neonatal presentations: mutational and in vitro expression analyses in two patients

In neonatal-onset nonketotic hyperglycinemia, severe psychomotor retardation is the expected uniform outcome. We report two patients with typical neonatal presentation who showed far better developmental outcomes. The in vitro expression analysis of the identified GLDC mutations revealed considerable residual enzyme activity, suggesting prognostic and enzymatic heterogeneity even in neonatal-onset nonketotic hyperglycinemia.

Mild variant of nonketotic hyperglycinemia with typical neonatal presentations: mutational and in vitro expression analyses in two patients*1

<h2>Abstract</h2> In neonatal-onset nonketotic hyperglycinemia, severe psychomotor retardation is the expected uniform outcome. We report two patients with typical neonatal presentation who showed far better developmental outcomes. The in vitro expression analysis of the identified <i>GLDC</i> mutations revealed considerable residual enzyme activity, suggesting prognostic and enzymatic heterogeneity even in neonatal-onset nonketotic hyperglycinemia.

Poor outcome for neonatal-type nonketotic hyperglycinemia treated with high-dose sodium benzoate and dextromethorphan.

Neonatal-type nonketotic hyperglycinemia treatment remains unsatisfactory, even if started early. A review of six patients who underwent treatment for neonatal-type nonketotic hyperglycinemia in our hospital is presented. All patients were treated with a standardized protocol. Medical histories were retrieved from case notes. All six patients had elevated cerebrospinal fluid plasma glycine levels initially. All but one had received sodium benzoate and dextromethorphan from 1 month of age. All suffered from intractable seizures and severe mental retardation, and only two patients remain alive. One patient died at 5 days of age. No resuscitation was attempted in accordance with the family's wish after genetic counseling. The prognosis of neonatal nonketotic hyperglycinemia remains poor with current treatment. Genetic counseling helps parents cope with this devastating genetic disease.

Evolución de la hiperglicinemia no cetósica neonatal en tratamiento

Non-ketotic hyperglycinemia is a congenital error in the breakdown of glycine. The most common type is the classical neonatal form, which begins at the age of a few days with symptoms of lethargy, hypotonia, myoclonia, convulsions, apneas and, frequently, ends in death. Survivors usually develop intractable epilepsy and mental retardation. There is no effective treatment for this condition, but trials have been carried out with a therapy that diminishes the levels of glycine, benzoate (BZ), and another that blocks the excitatory effect in N-methyl-D-aspartate receptors: dextromethorphan (DTM). We report on the progress of a classical neonatal case, which began at the age of a few hours with hypotonia and stupor, without myoclonias or seizures, but with a suppression wave trace on the electroencephalogram (EEG). Cerebrospinal fluid (CSF) showed glycine levels of 141 micromol/L (the normal level is 6.66 +/- 2.66 micromol/L), with a CSF/plasma ratio of 0.19 (the normal ratio is < 0.02). Treatment was started on the thirteenth day with BZ and DTM, and alertness and eye fixation improved in just three days; at the same time the EEG readings become normal. The glycine level in plasma returned to normal at two months and that in CSF was considerably reduced, although with CSF/plasma levels that were still high. At present the patient is 4 years old, has never had convulsions, EEG results have always been normal, and continues with BZ, DTM, carnitine and diet. The patient has presented a high degree of hypermotoric behaviour, but is currently more attentive and more sociable, has been walking from the age of 35 months and has a quotient in the different areas of development of 40-50. The clinical progress made by our patient could be said to be anything but negligible, and we therefore recommend that treatment should be started as early as possible after diagnosis.

Inactivation of the Glycine Transporter 1 Gene Discloses Vital Role of Glial Glycine Uptake in Glycinergic Inhibition

The glycine transporter subtype 1 (GlyT1) is widely expressed in astroglial cells throughout the mammalian central nervous system and has been implicated in the regulation of N-methyl-D-aspartate (NMDA) receptor activity. Newborn mice deficient in GlyT1 are anatomically normal but show severe motor and respiratory deficits and die during the first postnatal day. In brainstem slices from GlyT1-deficient mice, in vitro respiratory activity is strikingly reduced but normalized by the glycine receptor (GlyR) antagonist strychnine. Conversely, glycine or the GlyT1 inhibitor sarcosine suppress respiratory activity in slices from wild-type mice. Thus, during early postnatal life, GlyT1 is essential for regulating glycine concentrations at inhibitory GlyRs, and GlyT1 deletion generates symptoms found in human glycine encephalopathy.

Pediatric drug formulations of sodium benzoate:: II. Coated granules with a lipophilic binder

Sodium benzoate is used as a therapeutic agent in the treatment of some rare disorders that predominantly affect children. In preliminary investigations, liquid and semi-solid formulations of sodium benzoate failed because children refuse the oral uptake due to the bad taste of the drug. Recently developed microcapsules with macrogol as a hydrophilic binder raise concern in high-dose treatment regimens because acceptable daily intake limits are exceeded. A novel microcapsule formulation was developed consisting of a lipophilic core with high sodium benzoate load and a saliva-resistant coating. A new powder quality of saturated triglycerides from plant origin was introduced which complies with the Ph. Eur. monograph ‘Hard fat’. Sodium benzoate and the triglyceride were mixed and directly extruded at room temperature. The extrudates were spheronized and coated in a fluidized-bed process. The resulting coated granules are small-sized microcapsules and taste neutrally. They can be mixed with food before administration. As the amount of released sodium benzoate is negligible within the first minutes, children do not recognize the bad taste and accept the medication. Recently, sodium benzoate in this novel formulation has been designated by the European Community as an orphan drug in the treatment of non-ketotic hyperglycinemia.

Molecular genetic and potential biochemical characteristics of patients with T-protein deficiency as a cause of glycine encephalopathy (NKH)

A defect in the P-protein component of the glycine cleavage system has been the most frequent abnormality found in patients with glycine encephalopathy (NKH). In a retrospective study of a more specific group of NKH patients, however, we found that >50% had T-protein mutations. The patients studied had one or more of the following unusual biochemical findings: residual glycine cleavage system activity in liver assayed by the standard method or a newly developed micromethod, residual glycine cleavage system activity in lymphoblasts, and/or increased amniotic fluid glycine/serine ratio with a normal amniotic fluid glycine level in prenatal diagnosis. The selected patients had a much higher incidence of T-protein defects than expected in the general NKH patient population. We report, here, three novel mutations and five polymorphisms in the T-protein gene, PCR/restriction enzyme methods for one mutation (R296H) and two polymorphisms (E211K and R318R), and an estimation of their frequency in normal controls. The co-occurrence of the polymorphism E211K with the mutation R320H in patients with a severe phenotype is discussed.

MRI for neonatal encephalopathy in full-term infants

Encephalopathy in an infant within the first few days of birth often reflects a major neurological disorder with a significant risk of long-term disability. 1 Ellenberg JH Nelson KB Cluster of perinatal events identifying infants at high risk for death or disability. J Pediatr. 1988; 113: 546-552 Summary Full Text PDF PubMed Scopus (113) Google Scholar Determining the cause and prognosis remains challenging. Signs of neonatal encephalopathy include seizures, lethargy or coma, poor tone and feeding, and difficulty maintaining respiration; and early descriptions focused on intrapartum asphyxia as the primary cause. In 1976 Sarnat and Sarnat 2 Sarnat HB Sarnat MS Neonatal encephalopathy following fetal distress. Arch Neurol. 1976; 33: 696-705 Crossref PubMed Scopus (1979) Google Scholar pointed out the importance of staging encephalopathy with behavioural and electroencephalographic criteria, and 10 years later Levene et al 3 Levene MI Grindulis H Sands C Moore JR Comparison of two methods of predicting outcome in perinatal asphyxia. Lancet. 1986; 1: 67-69 Summary PubMed Google Scholar reported that rating the clinical severity of encephalopathy is better than the Apgar score for predicting neurological outcome after asphyxia. Evidence, especially from the Western Australian case-control study by Badawi et al, 4 Badawi N Kurinczuk JJ Keogh JM et al. Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ. 1998; 317: 1549-1553 Crossref PubMed Scopus (750) Google Scholar suggests that a diverse group of disorders, many beginning antenatally, in addition to asphyxia are associated with encephalopathy in newborn babies. These disorders include maternal and fetal infections, maternal thyroid and nutritional deficiencies, placental disorders, and genetic diseases including Prader-Willi and Angelman's syndromes, Rett's syndrome, myotonic dystrophy, non-ketotic hyperglycinaemia, thrombophilic disorders, brain malformations, and family history of epilepsy. 4 Badawi N Kurinczuk JJ Keogh JM et al. Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study. BMJ. 1998; 317: 1549-1553 Crossref PubMed Scopus (750) Google Scholar , 5 Ellis M Manandhar N Manandhar DS Costello AM Risk factors for neonatal encephalopathy in Kathmandu, Nepal, a developing country: unmatched case-control study. BMJ. 2000; 320: 1229-1236 Crossref PubMed Scopus (106) Google Scholar , 6 Grether JK Nelson KB Maternal infection and cerebral palsy in infants of normal birth weight. JAMA. 1997; 278: 207-211 Crossref PubMed Google Scholar , 7 Geerdink N Rotteveel JJ Lammens M et al. MECP2 mutation in a boy with severe neonatal encephalopathy: clinical, neuropathological and molecular findings. Neuropediatrics. 2002; 33: 33-36 Crossref PubMed Scopus (55) Google Scholar , 8 Richer LP Shevell MI Miller SP Diagnostic profile of neonatal hypotonia: an 11-year study. Pediatr Neurol. 2001; 25: 32-37 Summary Full Text Full Text PDF PubMed Scopus (77) Google Scholar , 9 Smith A Wiles C Haan E et al. Clinical features in 27 patients with Angelman syndrome resulting from DNA deletion. J Med Genet. 1996; 33: 107-112 Crossref PubMed Scopus (90) Google Scholar In the Western Australian study, 28% of infants with encephalopathy had birth defects compared with 4% of controls, and these defects were judged to have contributed to the encephalopathy in 37% of these cases. 10 Felix JF Badawi N Kurinczuk JJ Bower C Keogh JM Pemberton PJ Birth defects in children with newborn encephalopathy. Dev Med Child Neurol. 2000; 42: 803-808 Crossref PubMed Google Scholar Origin and timing of brain lesions in term infants with neonatal encephalopathyAlthough our results cannot exclude the possibility that antenatal or genetic factors might predispose some infants to perinatal brain injury, our data strongly suggest that events in the immediate perinatal period are most important in neonatal brain injury. Full-Text PDF

Metabolic disorders and mental retardation.

The metabolic and anatomical substrate of most forms of mental retardation is not known. Because the basis of normal brain function is not sufficiently understood, the basis of abnormal function is understood poorly. Even in disorders where the fundamental biochemical defect is known, such as phenylketonuria (PKU) and other enzyme defects, the exact basis for brain dysfunction is uncertain. The outcome for treated PKU, galactosemia, homocystinuria, and lysosomal disorders is not yet optimal. The various forms of nonketotic hyperglycinemia often respond poorly to current therapy. Less familiar disorders, with or without seizures, such as deficient synthesis of serine or creatine and impaired glucose transport into the brain, and disorders with variable malformations, such as Smith-Lemli-Opitz (SLO) syndrome and the congenital disorders of glycosylation (CDGs), may initially be thought to be a nonspecific form of developmental delay. Less familiar disorders, with or without seizures and disorders with variable malformations may initially be thought to be a nonspecific form of developmental delay. Simple tests of urine, blood, and cerebrospinal fluid may lead to a diagnosis, accurate genetic counseling, and better treatment. Metabolic brain imaging (magnetic resonance spectroscopy (MRS)) has also helped to reveal biochemical abnormalities within the brain.

Transient nonketotic hyperglycinemia: two case reports and literature review

Transient nonketotic hyperglycinemia is characterized by clinical and biochemical findings similar to those seen in classic nonketotic hyperglycinemia. Abnormalities in amino acids are partially or completely resolved in a period ranging from days to months. Almost all patients with the classic form of nonketotic hyperglycinemia survive with severe neurologic sequela, whereas most of the patients with the transient form exhibit normal development. Therefore, distinguishing the transient form of nonketotic hyperglycinemia from classic nonketotic hyperglycinemia is important to predict outcome of the patients. Transient nonketotic hyperglycinemia has been reported in only seven neonates. This article adds two cases to the transient nonketotic hyperglycinemia and reviews the relevant literature. Common clinical features were determined, and presence of miotic pupils was stressed.

Heterozygous GLDC and GCSH gene mutations in transient neonatal hyperglycinemia.

Transient neonatal hyperglycinemia is clinically or biochemically indistinguishable from nonketotic hyperglycinemia at onset. In the case of transient neonatal hyperglycinemia, the elevated plasma and cerebrospinal fluid glycine levels are normalized within 2 to 8 weeks. To elucidate the pathogenesis of transient neonatal hyperglycinemia, we studied three patients by screening mutations in the genes that encode three components of the glycine cleavage system. Heterozygous mutations were identified in all of the three patients, suggesting that transient neonatal hyperglycinemia develops in some heterozygous carriers for nonketotic hyperglycinemia.

Pitfalls in the diagnosis of glycine encephalopathy (non-ketotic hyperglycinemia).

Non-ketotic hyperglycinemia (NKH), also termed glycine encephalopathy (MIM 605899), is an autosomal recessive inborn error of glycine degradation which leads to severe neurological symptoms and profound psychomotor disability. In NKH, glycine accumulates in all body fluids and tissues, including the CNS. The biochemical hallmark of NKH is increased glycine concentration in the plasma and to an even greater extent in the CSF, leading to an elevation of the CSF:plasma glycine ratio (C:PGR) to above 0.08 (normal

Pitfalls in the diagnosis of glycine encephalopathy (non‐ketotic hyperglycinemia)

Pitfalls in the diagnosis of glycine encephalopathy (non‐ketotic hyperglycinemia)

Magnetic Resonance Spectroscopy Study of Glycine Pathways in Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia is a life-threatening disorder in neonates characterized by a deficiency of the glycine cleavage system. We report on four cases of the neonatal form of the disease, which were investigated by in vitro1H magnetic resonance spectroscopy of blood and cerebrospinal fluid, and in vivo1H magnetic resonance spectroscopy of brain. The existence of glycine disposal pathways leading to an increase in lactate in fluids and creatine in fluids and brain was demonstrated. This is the first observation of elevated creatine in brain in nonketotic hyperglycinemia. A recurrent decrease of glutamine and citrate was observed in cerebrospinal fluid, which might be related to abnormal glutamine metabolism in brain. Finally, the cerebral N-acetylaspartate to myo-inositol-glycine ratio was identified as a prognostic indicator of the disease.

Magnetic resonance spectroscopy study of glycine pathways in nonketotic hyperglycinemia.

Nonketotic hyperglycinemia is a life-threatening disorder in neonates characterized by a deficiency of the glycine cleavage system. We report on four cases of the neonatal form of the disease, which were investigated by in vitro(1)H magnetic resonance spectroscopy of blood and cerebrospinal fluid, and in vivo(1)H magnetic resonance spectroscopy of brain. The existence of glycine disposal pathways leading to an increase in lactate in fluids and creatine in fluids and brain was demonstrated. This is the first observation of elevated creatine in brain in nonketotic hyperglycinemia. A recurrent decrease of glutamine and citrate was observed in cerebrospinal fluid, which might be related to abnormal glutamine metabolism in brain. Finally, the cerebral N-acetylaspartate to myo-inositol-glycine ratio was identified as a prognostic indicator of the disease.