Non-Ketotic Hyperglycinemia: A Rare Presentation with Neurological and Skeletal Abnormalities.

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Ketogenic diet as a glycine lowering therapy in nonketotic hyperglycinemia and impact on brain glycine levels.

BACKGROUND: Nonketotic hyperglycinemia (NKH) is a severe neurometabolic disorder characterized by increased glycine levels. Current glycine reduction therapy uses high doses of sodium benzoate. The ketogenic diet (KD) may represent an alternative method of glycine reduction. AIM: We aimed to assess clinical and biochemical effects of two glycine reduction strategies: high dose benzoate versus KD with low dose benzoate. METHODS: Six infants with NKH were first treated with high dose benzoate therapy to achieve target plasma glycine levels, and then switched to KD with low dose benzoate. They were evaluated as clinically indicated by physical examination, electroencephalogram, plasma and cerebral spinal fluid amino acid levels. Brain glycine levels were monitored by magnetic resonance spectroscopy (MRS). RESULTS: Average plasma glycine levels were significantly lower with KD compared to benzoate monotherapy by on average 28%. Two infants underwent comparative assessments of brain glycine levels via serial MRS. A 30% reduction of brain glycine levels was observed in the basal ganglia and a 50% reduction in the white matter, which remained elevated above normal, and was equivalent between the KD and high dose benzoate therapies. CSF analysis obtained while participants remained on the KD showed a decrease in glycine, serine and threonine levels, reflecting their gluconeogenetic usage. Clinically, half the patients had seizure reduction on KD, otherwise the clinical impact was variable. CONCLUSION: KD is an effective glycine reduction method in NKH, and may provide a more consistent reduction in plasma glycine levels than high-dose benzoate therapy. Both high-dose benzoate therapy and KD equally reduced but did not normalize brain glycine levels even in the setting of low-normal plasma glycine.

Integrative Approach to Predict Severity in Nonketotic Hyperglycinemia.

OBJECTIVE: Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inherited neurometabolic disorder with variable clinical course and severity, ranging from infantile epileptic encephalopathy to psychiatric disorders. A precise phenotypic characterization and an evaluation of predictive approaches are needed. METHODS: Longitudinal clinical and biochemical data of 25 individuals with NKH from the patient registry of the International Working Group on Neurotransmitter Related Disorders were studied with in silico analyses, pathogenicity scores, and molecular modeling of GLDC and AMT variants. RESULTS: Symptom onset (p < 0.01) and diagnosis occur earlier in life in severe NKH (p < 0.01). Presenting symptoms affect the age at diagnosis. Psychiatric problems occur predominantly in attenuated NKH. Onset age ≥ 3 months (66% specificity, 100% sensitivity, area under the curve [AUC] = 0.87) and cerebrospinal fluid (CSF)/plasma glycine ratio ≤ 0.09 (57% specificity, 100% sensitivity, AUC = 0.88) are sensitive indicators for attenuated NKH, whereas CSF glycine concentration ≥ 116.5µmol/l (100% specificity, 93% sensitivity, AUC = 0.97) and CSF/plasma glycine ratio ≥ 0.15 (100% specificity, 64% sensitivity, AUC = 0.88) are specific for severe forms. A ratio threshold of 0.128 discriminates the overlapping range. We present 10 new GLDC variants. Two mild variants resulted in attenuated, whereas 2 severe variants or 1 mild and 1 severe variant led to severe phenotype. Based on clinical, biochemical, and genetic parameters, we propose a severity prediction model. INTERPRETATION: This study widens the phenotypic spectrum of attenuated NKH and expands the number of pathogenic variants. The multiparametric approach provides a promising tool to predict disease severity, helping to improve clinical management strategies. ANN NEUROL 2022;92:292-303.

Nonketotic Hyperglycinemia in Tunisia. Report upon a Series of 69 Patients.

AIM: The aim of the study is to report on epidemiological, clinical, and biochemical characteristics of nonketotic hyperglycinemia (NKH) in Tunisia. METHODS: Patients diagnosed with NKH in Laboratory of Biochemistry at Rabta hospital (Tunis, Tunisia) between 1999 and 2018 were included. Plasma and cerebrospinal fluid (CSF) free amino acids were assessed by ion exchange chromatography. Diagnosis was based on family history, patient's clinical presentation and course, and increased CSF to plasma glycine ratio. RESULTS: During 20 years, 69 patients were diagnosed with NKH, with 25 patients originating from Kairouan region. Estimated incidences were 1:55,641 in Tunisia and 1:9,684 in Kairouan. Consanguinity was found for 73.9% of the patients and 42% of the families have history of infantile death due to a disease of similar clinical course than the propositus. Clinical symptoms initiated within the first week of life in 75% of the patients and within the first 3 months in 95.7% ones. The phenotype was severe in 76.8% of the patients. Main symptoms were hypotonia, feeding difficulties, coma, apnea, and seizures. Most patients died within few days to months following diagnosis. CSF to plasma glycine ratio was increased in all patients. CSF and plasma glycine levels were negatively correlated with age of disease onset and severity. CONCLUSION: NKH is quite frequent in Tunisia. Kairouan region has the highest NKH incidence rate, worldwide. However, due to lack of confirmatory enzymatic and genetic tests, NKH diagnosis was based on first-line biochemical tests. Characterization of causal mutations is needed for accurate diagnosis and prenatal diagnosis of this devastating life-threatening disease.

Large scale analyses of genotype-phenotype relationships of glycine decarboxylase mutations and neurological disease severity.

Monogenetic diseases provide unique opportunity for studying complex, clinical states that underlie neurological severity. Loss of glycine decarboxylase (GLDC) can severely impact neurological development as seen in non-ketotic hyperglycinemia (NKH). NKH is a neuro-metabolic disorder lacking quantitative predictors of disease states. It is characterized by elevation of glycine, seizures and failure to thrive, but glycine reduction often fails to confer neurological benefit, suggesting need for alternate tools to distinguish severe from attenuated disease. A major challenge has been that there are 255 unique disease-causing missense mutations in GLDC, of which 206 remain entirely uncharacterized. Here we report a Multiparametric Mutation Score (MMS) developed by combining in silico predictions of stability, evolutionary conservation and protein interaction models and suitable to assess 251 of 255 mutations. In addition, we created a quantitative scale of clinical disease severity comprising of four major disease domains (seizure, cognitive failure, muscular and motor control and brain-malformation) to comprehensively score patient symptoms identified in 131 clinical reports published over the last 15 years. The resulting patient Clinical Outcomes Scores (COS) were used to optimize the MMS for biological and clinical relevance and yield a patient Weighted Multiparametric Mutation Score (WMMS) that separates severe from attenuated neurological disease (p = 1.2 e-5). Our study provides understanding for developing quantitative tools to predict clinical severity of neurological disease and a clinical scale that advances monitoring disease progression needed to evaluate new treatments for NKH.

Nonketotic Hyperglycinemia: Two Case Reports and Review.

Nonketotic hyperglycinemia (NKH) or glycine encephalopathy is an autosomal recessive disorder of glycine metabolism resulting in an excessive accumulation of glycine in all body tissues, including the central nervous system. It is caused by a biochemical defect in the glycine cleavage system and considered as a rare disorder with an estimated prevalence of 1:60,000. The neonatal form presents in the first few days of life with progressive encephalopathy, hypotonia, myoclonic jerks, hiccups, seizures, rapid progression to coma and often death due to central apnea. Surviving infants often have severe developmental delay and refractory seizures. Atypical forms of NKH present with heterogeneous and nonspecific disease course. Classical glycine encephalopathy usually carries a very poor prognosis. We describe two neonates who presented with neonatal encephalopathy, apnea, and progressive lethargy. Increased CSF glycine level along with an elevated CSF to plasma glycine ratio was suggestive of classic NKH. Burst suppression EEG and agenesis of the corpus callosum were supportive findings. Evolution of the EEG patterns and course of the disease are discussed in detail. Transient phases of clinical stabilization and normalized plasma biochemical results may not necessarily reflect the actual encephalopathic process. Serial EEGs are helpful to assess the efficacy of treatment and to modify the therapeutic approach.

Inherited metabolic disorders presenting as hypoxic ischaemic encephalopathy: A case series of patients presenting at a tertiary care hospital in Pakistan.

In spite of the efforts and interventions by the Government of Pakistan and The World Health Organization, the neonatal mortality in Pakistan has declined by only 0.9% as compared to the global average decline of 2.1% between 2000 and 2010. This has resulted in failure to achieve the global Millennium Development Goal 4. Hypoxic-ischaemic encephalopathy, still birth, sepsis, pneumonia, diarrhoea and birth defects are commonly attributed as leading causes of neonatal mortality in Pakistan. Inherited metabolic disorders often present at the time of birth or the first few days of life. The clinical presentation of the inherited metabolic disorders including hypotonia, seizure and lactic acidosis overlap with clinical features of hypoxic-ischaemic encephalopathy and sepsis. Thus, these disorders are often either missed or wrongly diagnosed as hypoxicischaemic encephalopathy or sepsis unless the physicians actively investigate for the underlying inherited metabolic disorders. We present 4 neonates who had received the diagnosis of hypoxic-ischaemic encephalopathy and eventually were diagnosed to have various inherited metabolic disorders. Neonates with sepsis and hypoxic-ischaemic encephalopathy-like clinical presentation should be evaluated for inherited metabolic disorders.

The case of pyridoxine dependent epilepsy misdiagnosed as non-ketotic hyperglycinemia.

Gazeteci-Tekin H, Demir M, Aktan G, Tekgül H, Gökben S. The case of pyridoxine dependent epilepsy misdiagnosed as non-ketotic hyperglycinemia. Turk J Pediatr 2019; 61: 599-603. Pyridoxine-dependent epilepsy (PDE) is a rare but an important condition, since early diagnosis and treatment result in normal or near normal psychomotor development. It is caused by mutations in the Antiquitin (ALDH7A1) gene. Different clinical findings may appear in the deficiency of pyridoxine, which is the cofactor of many enzymes. A wide variety of clinical and laboratory findings can cause confusion during diagnosis. We present a male with neonatal convulsions; structural brain anomaly, hyperglycinemia in CSF/plasma, with ALDH7A1 Compound heterozygote mutation.

Glycine decarboxylase deficiency-induced motor dysfunction in zebrafish is rescued by counterbalancing glycine synaptic level.

Glycine encephalopathy (GE), or nonketotic hyperglycinemia (NKH), is a rare recessive genetic disease caused by defective glycine cleavage and characterized by increased accumulation of glycine in all tissues. Here, based on new case reports of GLDC loss-of-function mutations in GE patients, we aimed to generate a zebrafish model of severe GE in order to unravel the molecular mechanism of the disease. Using CRISPR/Cas9, we knocked out the gldc gene and showed that gldc-/- fish recapitulate GE on a molecular level and present a motor phenotype reminiscent of severe GE symptoms. The molecular characterization of gldc-/- mutants showed a broad metabolic disturbance affecting amino acids and neurotransmitters other than glycine, with lactic acidosis at stages preceding death. Although a transient imbalance was found in cell proliferation in the brain of gldc-/- zebrafish, the main brain networks were not affected, thus suggesting that GE pathogenicity is mainly due to metabolic defects. We confirmed that the gldc-/- hypotonic phenotype is due to NMDA and glycine receptor overactivation, and demonstrated that gldc-/- larvae depict exacerbated hyperglycinemia at these synapses. Remarkably, we were able to rescue the motor dysfunction of gldc-/- larvae by counterbalancing pharmacologically or genetically the level of glycine at the synapse.

Diagnóstico bioquímico de la hiperglicinemia no cetósica en Cuba / Biochemical diagnosis of nonketotic hyperglycinemia in Cuba

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Nonketotic hyperglycinemia: Clinical range and outcome of a rare neurometabolic disease in a single-center.

BACKGROUND: Nonketotic hyperglycinemia (NKH) is an autosomal recessive severe life-threatening catostrophic metabolic disorder. MATERIALS AND METHODS: The present study was conducted in a tertiary reference center in Turkey for six years period. The accurate diagnosis of six NKH patients was based on clinical history of the patients, neurological examinations, seizure semiology, serial electroencephalography (EEG) recordings, neuroimaging findings, metabolic tests and genetic analysis. RESULTS: The common clinical findings were hypotonia with severe head lag, poor feeding, poor sucking, and intractable seizures. The starting age of the symptoms was between birth and 45 days of age (median: 8 days). The starting age of the seizures was between 30 min of age and 45 days of age (median: 18 days). The age of accurate diagnosis was between 1 month of age and 5.5 months of age (mean: 3.75 ±â€¯1.69 months). The cerebrospinal fluid (CSF) to plasma GLY ratio of the patients was between 0.031 and 0.21 (median: 0.16). The EEG patterns of the patients were suppression-burst, hypsarrhythmia, multifocal epileptic activity, and right centro-occipital epileptic activity on admission. The neuroimaging findings were diffuse hypomyelination, corpus callosum (CC) hypoplasia, CC agenesis and brainstem hypoplasia on the magnetic resonance imaging and glycine peak was evidenced on magnetic resonance spectroscopy. Four of the patients were mutation-positive. CONCLUSIONS: If a child is encephalopathic and/or hypotonic with severe head lag, early evaluation of the EEG records should be made even without a history of clinical seizures. The disease has a heterogenous course and the clinical outcome depends on the mutation type.

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.

[MR spectroscopy in metabolic disorders of the brain]. / MR-Spektroskopie bei Stoffwechselerkrankungen des Gehirns.

CLINICAL ISSUE: Metabolic disorders of the brain often present a particular challenge for the neuroradiologist, since the disorders are rare, changes on conventional MR are often non-specific and there are numerous differential diagnoses for the white substance lesions. STANDARD RADIOLOGICAL METHODS: As a complementary method to conventional brain MRI, MR spectroscopy may help to reduce the scope of the differential diagnosis. Entities with specific MR spectroscopy patterns are Canavan disease, maple syrup urine disease, nonketotic hyperglycinemia and creatine deficiency.

d-Glyceric aciduria does not cause nonketotic hyperglycinemia: A historic co-occurrence.

Historically, d-glyceric aciduria was thought to cause an uncharacterized blockage to the glycine cleavage enzyme system (GCS) causing nonketotic hyperglycinemia (NKH) as a secondary phenomenon. This inference was reached based on the clinical and biochemical results from the first d-glyceric aciduria patient reported in 1974. Along with elevated glyceric acid excretion, this patient exhibited severe neurological symptoms of myoclonic epilepsy and absent development, and had elevated glycine levels and decreased glycine cleavage system enzyme activity. Mutations in the GLYCTK gene (encoding d-glycerate kinase) causing glyceric aciduria were previously noted. Since glycine changes were not observed in almost all of the subsequently reported cases of d-glyceric aciduria, this theory of NKH as a secondary syndrome of d-glyceric aciduria was revisited in this work. We showed that this historic patient harbored a homozygous missense mutation in AMT c.350C>T, p.Ser117Leu, and enzymatic assay of the expressed mutation confirmed the pathogeneity of the p.Ser117Leu mutation. We conclude that the original d-glyceric aciduria patient also had classic NKH and that this co-occurrence of two inborn errors of metabolism explains the original presentation. We conclude that no evidence remains that d-glyceric aciduria would cause NKH.

[A stroke mimic: hemichorea associated with non-ketotic hyperglycaemia].

An 85-year-old man with a history of diabetes was admitted with acute onset hemichorea. Laboratory findings confirmed poorly controlled diabetes. A brain computed tomography (CTC) revealed contralateral striatal hyperdensity. The findings were compatible with hyperglycaemia-induced hemichorea, and antidiabetic and symptomatic treatment was initiated. The symptoms remitted completely after six days, and a follow-up CTC showed partial resolution of the striatal changes. This case illustrates the importance of considering if hyperglycaemia is the cause of hemichorea, as early diagnosis and treatment yield an excellent prognosis.

X-Linked Cobalamin Disorder (HCFC1) Mimicking Nonketotic Hyperglycinemia With Increased Both Cerebrospinal Fluid Glycine and Methylmalonic Acid.

BACKGROUND: Autosomal recessive or X-linked inborn errors of intracellular cobalamin metabolism can lead to methylmalonic aciduria and homocystinuria. In neonates, both increased cerebrospinal fluid glycine and cerebrospinal fluid/plasma glycine ratio are biochemical features of nonketotic hyperglycinemia. METHODS: We describe a boy presenting in the neonatal period with hypotonia, tonic, clonic, and later myoclonic seizures, subsequently evolving into refractory epilepsy and severe neurocognitive impairment. RESULTS: Increased cerebrospinal fluid glycine and cerebrospinal fluid to plasma glycine ratio were indicative of nonketotic hyperglycinemia. Early magnetic resonance imaging showed restricted diffusion and decreased apparent diffusion coefficient values in posterior limb of internal capsules and later in entire internal capsules and posterior white matter. Sequencing did not show a mutation in AMT, GLDC, or GCSH. Biochemical analysis identified persistently increased cerebrospinal fluid levels of glycine and methylmalonic acid and increased urinary methylmalonic acid and plasma homocysteine levels, which improved on higher parenteral hydroxocobalamin dose. Exome sequencing identified a known pathogenic sequence variant in X-linked cobalamin (HCFC1), c.344C>T, p. Ala115Val. In addition, a hemizygous mutation was found in the ATRX (c. 2728A>G, p. Lys910Glu). Retrospective review of two other patients with X-linked cobalamin deficiency also identified increased cerebrospinal fluid glycine levels. CONCLUSIONS: This boy had X-linked cobalamin deficiency (HCFC1) with increased cerebrospinal fluid glycine and methylmalonic acid and increased cerebrospinal fluid to plasma glycine ratio suggesting a brain hyperglycinemia. Putative binding sites for HCFC1 and its binding partner THAP11 were identified near genes of the glycine cleavage enzyme, providing a potential mechanistic link between HCFC1 mutations and increased glycine.