AAV-mediated expression of mouse or human GLDC normalises metabolic biomarkers in a GLDC-deficient mouse model of Non-Ketotic Hyperglycinemia.

Non-Ketotic Hyperglycinemia (NKH) is a rare inborn error of metabolism caused by impaired function of the glycine cleavage system (GCS) and characterised by accumulation of glycine in body fluids and tissues. NKH is an autosomal recessive condition and the majority of affected individuals carry mutations in GLDC (glycine decarboxylase). Current treatments for NKH have limited effect and are not curative. As a monogenic condition with known genetic causation, NKH is potentially amenable to gene therapy. An AAV9-based expression vector was designed to target sites of GCS activity. Using a ubiquitous promoter to drive expression of a GFP reporter, transduction of liver and brain was confirmed following intra-venous and/or intra-cerebroventricular administration to neonatal mice. Using the same capsid and promoter with transgenes to express mouse or human GLDC, vectors were then tested in GLDC-deficient mice that provide a model of NKH. GLDC-deficient mice exhibited elevated plasma glycine concentration and accumulation of glycine in liver and brain tissues as previously observed. Moreover, the folate profile indicated suppression of folate one­carbon metabolism (FOCM) in brain tissue, as found at embryonic stages, and reduced abundance of FOCM metabolites including betaine and choline. Neonatal administration of vector achieved reinstatement of GLDC mRNA and protein expression in GLDC-deficient mice. Treated GLDC-deficient mice showed significant lowering of plasma glycine, confirming functionality of vector expressed protein. AAV9-GLDC treatment also led to lowering of brain tissue glycine, and normalisation of the folate profile indicating restoration of glycine-derived one­carbon supply. These findings support the hypothesis that AAV-mediated gene therapy may offer potential in treatment of NKH.

Use of Perampanel and a Ketogenic Diet in Nonketotic Hyperglycinemia: A Case Report.

BACKGROUND: Nonketotic hyperglycinemia is a severe form of early onset epileptic encephalopathy caused by disturbances in the glycine cleavage system; the neurological damage is mainly attributed to overstimulation of the N-methyl-D-aspartate receptor. CASE: The patient presented with a severe form of nonketotic hyperglycinemia and experienced frequent epileptic spasms and focal seizures, which were resistant to vigabatrin, adrenocorticotropic hormone therapy, and combined dextromethorphan and sodium benzoate treatments. By 9 months of age, perampanel reduced epileptic spasms by >50%. At 14 months of age, the ketogenic diet markedly reduced focal seizures and glycine levels in the cerebrospinal fluid. CONCLUSION: Perampanel reduced fast excitatory neuronal activity, which was induced by an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, followed by prolonged electrical depolarizations due to an N-methyl-D-aspartate receptor. Furthermore, the ketogenic diet may have modulated the excessive neurotoxic cascade through the N-methyl-D-aspartate receptor. Perampanel and ketogenic diet were effective for seizure control in our patient.

Ventilator respiratory graphic diagnosis of hiccupping in non-ketotic hyperglycinaemia.

A neonate presented with early encephalopathy deteriorated and was intubated and ventilated. Ventilator data were monitored and recorded at 100 Hz for 24 hours.The infant had many sudden deep inspirations during this time which were initially thought to be seizures. These were characterised by short, rapid, large inspirations when the airway pressure was reduced well below the positive end expiratory pressure level. Analysis of the ventilator data showed that these were hiccupping episodes misinterpreted by the ventilator as spontaneous breaths and triggering ventilator inflations. The expired tidal volumes during the hiccupping episodes were more than double the set 4.5 mL/kg. During these episodes, there was no change in the level of consciousness or in the amplitude-integrated electroencephalogram signal. Detailed respiratory recording of pathological hiccups has not been reported.Metabolic screening diagnosed non-ketotic hyperglycinaemia. Hiccups commonly occur in this condition and should not be misinterpreted as seizures, spontaneous breaths or gasps.

Hemichorea associated with nonketotic hyperglycemia in a female.

A case of a 61-year-old woman with hemichorea associated with nonketotic hyperglycemia is reported. The typical presentation of this disease is nonketotic hyperglycemia, hemichorea, hyper-intense signal on T1-weighted magnetic resonance imaging (MRI) and high-density on computed tomography (CT) in the contralateral striatum. With good glycemic control, the clinical symptoms disappeared.

Prediction of long-term outcome in glycine encephalopathy: a clinical survey.

OBJECTIVE: Glycine encephalopathy (GE) is a rare autosomal recessive inborn error of glycine degradation resulting in severe encephalopathy with ensuing poor outcome. Attenuated variants with a significantly better outcome have been reported. Early prediction of long-term outcome is not yet possible. METHODS: We compared the clinical and biochemical features of 45 children, each with a different course of the disease, to help determine predictors of long-term outcome. RESULTS: The most common presenting symptoms were hypotonia, seizures, and coma. In this study, 85% of the patients presented within the first week of life, and 15% presented after the neonatal period up to the age of 12 months. Developmental progress was made by 19% of those children presenting during the neonatal period and by 50% of those presenting in infancy. Initial CSF and plasma glycine concentrations were not useful in differentiating severe and attenuated outcome. A severe outcome was significantly associated with early onset of spasticity, frequent hiccupping, EEG burst-suppression or hypsarrhythmia patterns, microcephaly, and congenital or cerebral malformations, e.g. corpus callosum hypoplasia. An attenuated outcome was significantly associated with hyperactivity and choreiform movement disorders. We describe a severity score which facilitates the prediction of the outcome in patients with GE. CONCLUSION: Prediction of the outcome of GE may be facilitated by recognizing selected clinical parameters and early neuroimaging findings.

Nonketotic hyperglycinemia: proposal of a diagnostic and treatment strategy.

Early myoclonic encephalopathy presents neonatally with fragmented myoclonus and a suppression-burst electroencephalography pattern. We describe a newborn boy with early myoclonic encephalopathy caused by nonketotic hyperglycinemia. He presented with severe hypotonia, progressive apneic episodes, and erratic myoclonus. Screening of deletions in GLDC, using the multiplex ligation-dependent probe amplification method, and a (13)C breath test confirmed the diagnosis of nonketotic hyperglycinemia. Treatment with the N-methyl-d-aspartate receptor antagonist ketamine exerted dramatic suppressive effects on his seizures, and ameliorated his clinical status.

Early myoclonic encephalopathy and nonketotic hyperglycinemia.

Early myoclonic encephalopathy is an epileptic syndrome with different etiologies. Nonketotic hyperglycinemia is one cause. We describe two cases of early myoclonic encephalopathy, secondary to nonketotic hyperglycinemia, with fatal evolution in the neonatal period. These two cases may better clarify clinical findings that can be associated with impairment of glycine metabolism. Distinguishing features include agenesis of the corpus callosum in patient 1, and weight loss exceeding 10%, associated with metabolic acidosis, in patient 2. The burst-suppression electroencephalography pattern is relatively common in neonatal encephalopathies, and is frequently associated with seizures. Nonketotic hyperglycinemia is an inborn error of metabolism caused by mutations in genes encoding protein in the mitochondrial glycine cleavage system. The neonatal form is a severe, frequently lethal neurologic disease. When associated with electro-clinical features, progressive lethargy and hypotonia occur in the first days of life, progressing to apnea and often death. Prospective treatment with oral sodium benzoate, the N-methyl-d-aspartate receptor antagonist ketamine, and dextromethorphan can favorably modify the early neonatal course of severe nonketotic hyperglycinemia, but does not prevent poor long-term outcomes.

Reversible hyperglycemic homonymous hemianopia.

We report a 67-year-old female diabetic with homonymous hemianopia as the presenting sign of nonketotic hyperglycemia. Magnetic resonance imaging (MRI) was abnormal with diffuse bilateral hyperintense white matter changes. A follow-up MRI scan 15 years later showed persisting abnormality. Her hemianopic visual field loss was reversed after correction of her hyperglycemia. Diabetes mellitus should be considered with the sudden onset of a homonymous hemianopia.

Clinical, ethical and legal considerations in the treatment of newborns with non-ketotic hyperglycinaemia.

Non-ketotic hyperglycinaemia (NKH) is a devastating neurometabolic disorder leading, in its classical form, to early death or severe disability and poor quality of life in survivors. Affected neonates may need ventilatory support during a short period of respiratory depression. The transient dependence on ventilation dictates urgency in decision-making regarding withdrawal of therapy. The occurrence of patients with apparent transient forms of the disease, albeit rare, adds uncertainty to the prediction of clinical outcome and dictates that the current practice of withholding or withdrawing therapy in these neonates be reviewed. Both bioethics and law take the view that treatment decisions should be based on the best interests of the patient. The medical-ethics approach is based on the principles of non-maleficence, beneficence, autonomy and justice. The law relating to withholding or withdrawing life-sustaining treatment is complex and varies between jurisdictions. Physicians treating newborns with NKH need to provide families with accurate and complete information regarding the disease and the relative probability of possible outcomes of the neonatal presentation and to explore the extent to which family members are willing to take part in the decision making process. Cultural and religious attitudes, which may potentially clash with bioethical and juridical principles, need to be considered.

Neonatal nonketotic hyperglycinemia.

Nonketotic hyperglycinemia has variable phenotypic expressions and a poor prognosis. We report a case of severe neonatal nonketotic hyperglycinemia, who started convulsing immediately after birth. His glycine index was 0.38 and he did not respond to treatment with sodium benzoate and dextromethorphan. Hypotonia, transient hyperammonemia and metabolic acidosis were associated findings.

Atypical variants of nonketotic hyperglycinemia.

Clinical symptoms in atypical nonketotic hyperglycinemia (NKH) are heterogeneous, in sharp contrast to uniform severe neurological symptoms in the classical NKH. A review of the literature of atypical NKH cases reveals three forms: neonatal, infantile, and late onset. The presentation in the neonatal form is similar to the classical one but the subsequent outcome is significantly better. Mental retardation and behavioral abnormalities are prevalent in both infantile and late onset forms although the phenotype in late onset atypical NKH is more heterogeneous. Patients with the atypical NKH tend to have a lower CSF/plasma glycine ratio when compared with the classical form, but overlap occurs. Hyperglycinemia in the neonatal and infantile atypical NKH, similar to the classical form, is caused by a deficient glycine cleavage system, whereas the cause of hyperglycinemia in late onset atypical NKH is unknown. A mutation of the T-protein AMT gene and several mutations of P-protein GLDC gene have been identified in homozygous or compound heterozygous state. Some of the GLDC mutations are associated with residual glycine decarboxylase activity when expressed in COS7 cells and early therapeutic intervention may be crucial to improve the outcome in patients harboring such mutations. Identification of more mutations causing atypical NKH and information about the mutations' effect on enzyme activity may help to predict patients with a milder phenotype as well as those who may respond to early therapeutic intervention.

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.

[Non-ketonic hyperglycinemia]. / Niekwasicza hiperglicynemia (NKH)

The author presents the possible pathomechanism of brain damage in NKH and the clinical course of severe - newborn and infants - atypical type of the disease. Characteristic for the newborn type EEG patterns has been discussed. Among the detailed presentation of diagnostic methods it was stressed that besides high concentration of glycine in blood and urine, the necessary parameters are high glycine ratio of cerebro-spinal fluid to blood serum, and the detailed differentiation with many transient and persistent hyperglycinemic states, the most important of them being organic acidurias which need the estimation of urinary organic acids. Possibilities of prenatal diagnostic and molecular identification are presented. All the treatment methods used up to now have been presented with special attention to natrium benzoate and dextrametorphan being used together.