Hyperglycinemia Nonketotic

The study's purpose was to delineate the genetic mutations that cause classic nonketotic hyperglycinemia (NKH). Methods: Genetic results, parental phase, ethnic origin, and gender data were collected from subjects suspected to have classic NKH. Mutations were compared with those in the existing literature and to the population frequency from the Exome Aggregation Consortium (ExAC) database. Results: In 578 families, genetic analyses identified 410 unique mutations, including 246 novel mutations. 80% of subjects had mutations in GLDC. Missense mutations were noted in 52% of all GLDC alleles, most private. Missense mutations were 1.5 times as likely to be pathogenic in the carboxy terminal of GLDC than in the aminoterminal part. Intragenic copy-number variations (CNVs) in GLDC were noted in 140 subjects, with biallelic CNVs present in 39 subjects. The position and frequency of the breakpoint for CNVs correlated with intron size and presence of Alu elements. Missense mutations, most often recurring, were the most common type of disease-causing mutation in AMT. Sequencing and CNV analysis identified biallelic pathogenic mutations in 98% of subjects. Based on genotype, 15% of subjects had an attenuated phenotype. The frequency of NKH is estimated at 1:76,000. Conclusion: The 484 unique mutations now known in classic NKH provide a valuable overview for the development of genotype-based therapies.

Introducción. La Hiperglicinemia no Cetósica (HNC) es un error innato del metabolismo de herencia autosómica recesiva, cuya principal característica es la acumulación de glicina en los fluidos corporales, producido por una falla en el complejo de clivaje enzimático de este aminoácido. Presentación del caso. Presentamos el caso de un recién nacido de 36 semanas, con adaptación neonatal espontánea, sin historia de noxa perinatal ni hipoglicemia documentada, quien tras un corto período de 24 horas presentó deterioro neurológico progresivo, rápida alteración del estado de conciencia hasta el coma y falla ventilatoria. Llamó la atención al ingreso la hipotonía severa generalizada, hiporreflexia, ausencia de reflejos primitivos, con episodios de hipo aislado y movimientos oculares anormales. Ante la sospecha de un error innato del metabolismo se realizó el perfil de aminoácidos donde se evidenció elevación significativa de la glicina, 1417 mmol/L (referencia 94-553 umol/L). Se solicitaron aminoácidos en líquido cefalorraquídeo, glicina muy elevada 1263 mmol/L (referencia 3-7 umol/L), con lo que se confirma la sospecha de hiperglicinemia no cetósica. Se decidió iniciar manejo con benzoato de sodio y dextrometorfano. La resonancia magnética inicial fue normal, en estudio control se encontraron al igual que en el electroencefalograma hallazgos reportados previamente en la literatura para esta patología. Discusión. La mayoría de los niños con HNC se presentan en el período neonatal o en la primera infancia, y solo los casos más leves se presentan al final de la infancia o la niñez. En las presentaciones de inicio neonatal, el 85% tiene HNC grave y el 15% tiene forma atenuada, como este caso. El diagnóstico de la HNC se hace con base en la sospecha clínica, confirmada por los hallazgos de laboratorio, con la alteración característica de la glicina tanto en plasma como en el LCR y soportada por los hallazgos de las neuroimágenes y electroencefalograma (EEG). Conclusiones. La HNC no es una condición tan inusual, aunque sí posiblemente subdiagnosticada por la forma de presentación tan catastrófica, además porque no produce grandes desarreglos metabólicos de rápido diagnóstico. Por este motivo, ante un paciente con cuadro clínico sugestivo, con coma, alteración respiratoria y convulsiones de difícil manejo, y muy característicamente hipo, debe solicitarse el estudio de aminoácidos en plasma, neuroimágenes y EEG, con el fin de instaurar un manejo temprano.

Introduction. Nonketotic hyperglycinemia (NKH) is an autosomal recessive innate error of metabolism, whose main characteristic is the accumulation of glycine in body fluids, produced by a failure in the enzymatic cleavage complex of this amino acid. Case Presentation. We present the case of a 36-week-old newborn, with spontaneous neonatal adaptation, no history of perinatal noxa or documented hypoglycemia, who after a short period of 24 hours presented progressive neurological deterioration, rapid alteration of consciousness to coma and ventilatory failure. At admission the patient was noted for severe generalized hypotonia, hyporeflexia, absence of primitive reflexes, with episodes of isolated hiccups and abnormal eye movements. In view of the suspicion of an innate error of metabolism, an amino acid profile was performed, showing a significant elevation of glycine, 1417 umol/L (reference 94-553 umol/L). Amino acids were requested in cerebrospinal fluid, glycine very elevated 1263 umol/L (reference 3-7 umol/L), confirming the suspicion of nonketotic hyperglycinemia. It was decided to start treatment with sodium benzoate and dextromethorphan. The initial MRI was normal; in the control study, findings previously reported in the literature for this pathology were found, as well as in the electroencephalogram. Discussion. Most children with NKH will display it in the neonatal period or early infancy, with only the mildest cases presenting in late infancy or childhood. In neonatal-onset cases, 85% have severe NKH and 15% have attenuated form, as in this case. The diagnosis of NKH is made based on clinical suspicion, confirmed by laboratory findings, with the characteristic alteration of glycine in both plasma and CSF and supported by neuroimaging and electroencephalogram (EEG) findings. Conclusions. NKH is not such an unusual condition, although it is possibly underdiagnosed because of its catastrophic presentation and because it does not produce major metabolic disorders that are quickly diagnosed. For this reason, in a patient with a suggestive clinical condition, with coma, respiratory alteration and unmanageable seizures, and very characteristically hiccups, the study of amino acids in plasma, neuroimaging and EEG should be requested, in order to establish early treatment.

Introdução. A hiperglicinemia não-cetótica (HNC) é um erro inato do metabolismo de herança autossômica recessiva, cuja principal característica é o acúmulo de glicina nos fluidos corporais, produzido por uma falha no complexo de clivagem enzimática deste aminoácido. Apresentação do caso. Apresentamos o caso de um recém-nascido de 36 semanas, com adaptação neonatal espontânea, sem história de noxa perinatal nem hipoglicemia documentada, que após um curto período de 24 horas apresentou deterioração neurológica progressiva, alteração rápida de consciência até coma e falha ventilatória. Na admissão,  eran notáveis a hipotonia grave generalizada, hiporreflexia, ausência de reflexos primitivos, com episodios de soluços isolados e movimentos oculares anormais. Diante da suspeita de erro inato no metabolismo, foi realizado o perfil de aminoácidos, onde foi constatada elevação significativa da glicina, 1417umol/L (referência 94-553 umol/L). Foram solicitados aminoácidos no líquido cefalorraquidiano, glicina muito alta 1263umol/L (referência 3-7 umol/L), confirmando a suspeita de hiperglicinemia não-cetótica. Foi decidido iniciar o tratamento com benzoato de sódio e dextrometorfano. A ressonância magnética inicial foi normal, tanto em estudo controle quanto no eletroencefalograma, foram encontrados achados previamente relatados na literatura para esta patologia. Discussão. A maioria das crianças com HNC estão no período neonatal ou na primeira infância, e apenas os casos mais leves ocorrem na infancia ou na infância tardia. Nas apresentações de início neonatal, 85% têm HNC grave e 15% têm forma atenuada, como neste caso. O diagnóstico de HNC é feito com base na suspeita clínica, confirmada por achados laboratoriais, com alteração característica da glicina tanto no plasma quanto no LCR e apoiado por achados de neuroimagem e eletroencefalograma (EEG). Conclusões. A HNC não é uma condição tão incomum, embora possivelmente seja subdiagnosticada por sua apresentação catastrófica, também por não produzir grandes distúrbios metabólicos que possam ser diagnosticados rapidamente. Por ese motivo, em um paciente com quadro clínico sugestivo, com coma, distúrbios respiratórios e convulsões de difícil manejo, e soluços muito característicos, deve ser solicitado um estudo de aminoácidos no plasma, neuroimagem e EEG a fim de estabelecer um tratamento rápido.

Serial diffusion-weighted (DWI) and diffusion tensor imaging (DTI) were performed in a patient with neonatal onset nonketotic hyperglycinemia (NKH). At 3 weeks areas that are normally myelinated at this time showed increased T2-signal intensity and restricted diffusion, consistent with vacuolating myelinopathy. At 3 months, these areas had increased in the topographic pattern of normal myelination, whereas fractional anisotropy was compatible with axonal sparing. At 17 months, diffusion restriction had disappeared, likely because of coalescence of myelin vacuoles. A decrease of fractional anisotropy was observed in the previously myelinated areas indicative of axonal loss. We conclude that DWI and DTI can be used to identify and characterize white matter tract abnormalities in patients with NKH.

Non-ketotic hyperglycinaemia (NKH) is an autosomal recessive inborn error of glycine metabolism characterized by accumulation of glycine in body fluids and various neurological symptoms. This study describes the first screening of NKH in cataract captive-bred vervet monkeys (Chlorocebus aethiops). Glycine dehydrogenase (GLDC), aminomethyltransferase (AMT) and glycine cleavage system H protein (GCSH) were prioritized. Mutation analysis of the complete coding sequence of GLDC and AMT revealed six novel single-base substitutions, of which three were non-synonymous missense and three were silent nucleotide changes. Although deleterious effects of the three amino acid substitutions were not evaluated, one substitution of GLDC gene (S44R) could be disease-causing because of its drastic amino acid change, affecting amino acids conserved in different primate species. This study confirms the diagnosis of NKH for the first time in vervet monkeys with cataracts.

The neonatal period has the greatest incidence of seizures in life, with 1.8-3.5 per 1,000 live births 1. Seizures in the newborn are associated with high morbidity and mortality, which make their detection and treatment essential 2,3. Seizure activity in neonates is often difficult to observe, making the detection of seizures particularly challenging. Clinical observation alone can lead to underdiagnosis of neonatal seizures, as nearly 80% of seizures can be occult 4. It is for these reasons that effective methods for seizure detection are of fundamental importance in neonatal care.

Panton-Valentine leukocidin (PVL) is an exotoxin that is produced by many strains of Staphylococcus aureus, and an important virulence factor. A PVL-positive S. aureus infection leads to rapid and severe infections of soft tissue and necrotizing pneumonia in healthy adolescents, and has a high mortality. This case report included a 12-year-old male patient who admitted for fever, respiratory distress and hip pain and was identified with necrotizing pneumonia with septic pulmonary embolism, psoas abscess, cellulitis and osteomyelitis. The PVL positive methicillin-sensitive S. aureus (MSSA) was isolated in the patient blood culture.

Rare inheritable conditions may present without warning in the neonatal period and thus lead curious staff to institute expansive clinical investigations. Non-ketotic hyperglycaemia (NKH) in a normal fully grown male infant following an essentially eventful pregnancy associated with unrelated condition provoked much clinical curiosity. NKH should therefore be included as a differential diagnosis in an unwell neonate presenting with hiccoughs, seizures, myotonic jerks, and hypotonia as our very unique case clearly demonstrated.