Variant Nonketotic Hyperglycinemia Presenting with Elevated Lactate and Pyruvate: A Diagnostic and Management Challenge

Variant Nonketotic Hyperglycinemia Presenting with Elevated Lactate and Pyruvate: A Diagnostic and Management Challenge | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Variant Nonketotic Hyperglycinemia Presenting with Elevated Lactate and Pyruvate: A Diagnostic and Management Challenge Shreya Sinha, Leslie Lewis This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6771023/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Non-ketotic hyperglycinemia (NKH) is a rare autosomal recessive metabolic disorder resulting from a defect in the glycine cleavage system, leading to accumulation of glycine in the central nervous system. The classic neonatal form presents as a life-threatening metabolic encephalopathy within the first few days of life. Case Presentation: We report a term neonate, born to a 36-year-old multigravida via third-degree consanguineous marriage, who presented on day 4 of life with poor respiratory effort and shock. There was a history of neonatal seizures on day 3. The infant was intubated and commenced on inotropic support. Recurrent seizures on day 5 necessitated initiation of anticonvulsants (levetiracetam and phenytoin). Given the clinical suspicion of an inborn error of metabolism (IEM), metabolic evaluation revealed significantly elevated plasma glycine levels. Cerebrospinal fluid (CSF) analysis confirmed elevated glycine with an increased CSF-to-plasma glycine ratio (0.19), supporting a diagnosis of NKH. Brain MRI demonstrated features of subacute infarct; MR spectroscopy was unremarkable. Treatment included initiation of high-dose vitamins, with clinical improvement observed. The family was counselled regarding home-based physiotherapy, which was demonstrated and reinforced prior to discharge. Conclusion NKH should be considered in neonates presenting with early-onset seizures and encephalopathy. Diagnosis is supported by elevated CSF glycine levels and an increased CSF/plasma glycine ratio. While definitive diagnosis involves liver biopsy to assess glycine cleavage enzyme activity, supportive treatment with sodium benzoate and NMDA receptor antagonists may help reduce glycine levels and improve outcomes. Early recognition and multidisciplinary support are critical for management. Introduction Non-ketotic hyperglycinemia (NKH) is a rare autosomal recessive metabolic disorder caused by defects in the glycine cleavage enzyme system, leading to excessive accumulation of glycine, particularly in the central nervous system. The classic neonatal form is the most severe, typically presenting within the first few days of life with lethargy, hypotonia, apnea, hiccups, and intractable seizures. A related variant, hyperglycinemia with lactic acidosis and seizures (HGCLAS), also referred to as pyruvate dehydrogenase lipoic acid synthetase deficiency (PDHLD), results from pathogenic variants in the LIAS gene. This condition is characterized by persistent metabolic acidosis, elevated glycine levels, and refractory seizures. Glycine exerts both inhibitory and excitatory effects through its action on glycine and NMDA receptors, respectively, contributing to the neurotoxicity seen in these disorders. This case report underscores the diagnostic complexity and clinical progression of HGCLAS in the neonatal period, emphasizing the importance of early metabolic evaluation in infants presenting with unexplained encephalopathy and seizures. Case Presentation A term male neonate, birth weight 2500 g, was born to a 36-year-old multigravida mother following a non-consanguineous pregnancy with no antenatal complications. The infant was delivered via spontaneous vaginal delivery following a third-degree consanguineous union. Family history was notable for one stillbirth and a neonatal death of unknown cause. Two older siblings had a history of neonatal seizures but were developmentally normal at ages 4 and 8. The infant presented on day 4 of life with respiratory distress, circulatory shock, and a prior history of seizures on day 3. On admission, he was apnoeic with absent spontaneous respiration, generalized hypotonia, cyanosis, diminished peripheral pulses, and generalized anasarca. Neurological examination revealed three episodes of subtle multifocal clonic seizures involving all limbs. Initial investigations revealed compensated metabolic acidosis (pH 7.39, bicarbonate 6.4 mmol/L, PaO₂ 103 mmHg, PaCO₂ 32.5 mmHg). Plasma lactate was significantly elevated at 35.9 mg/dL, pyruvate 0.29 mg/dL, and serum ammonia was 92 µg/dL. Serum creatinine was 0.7 mg/dL. MRI brain with MR spectroscopy showed a subacute infarct in the right medial temporal lobe. Metabolic screening via gas chromatography-mass spectrometry (GC-MS) and tandem mass spectrometry (TMS) suggested mitochondrial cytopathy. High-performance liquid chromatography (HPLC) revealed markedly elevated glycine in both plasma and cerebrospinal fluid (CSF), with a CSF/plasma glycine ratio of 0. This biochemical profile was consistent with a glycine metabolism disorder. The infant was managed with immediate resuscitation and supportive therapy, including inotropes (dobutamine, adrenaline), hydrocortisone for refractory hypotension, and anticonvulsants. Metabolic management included correction of acidosis, initiation of sodium benzoate, megavitamin therapy with coenzyme Q10, and a protein-restricted diet. Physiotherapy was commenced during recovery. At 4-month follow-up, the infant had gained 2.9 kg and was achieving age-appropriate developmental milestones. Ongoing megavitamin therapy and regular metabolic follow-up were recommended. Here is a revised version of the Discussion section tailored for BMJ Paediatrics Open submission. It maintains clinical precision, enhances clarity, and includes properly formatted references consistent with BMJ style: Discussion Nonketotic hyperglycinemia (NKH), also known as glycine encephalopathy, is a rare autosomal recessive neurometabolic disorder caused by defects in the glycine cleavage system (GCS). This results in pathological accumulation of glycine, particularly within the central nervous system, leading to severe neurological dysfunction [ 1 , 2 ]. The estimated global incidence is approximately 1 in 250,000 live births [ 3 ]. NKH is broadly classified into four clinical subtypes based on age of onset and progression: classic neonatal, transient neonatal, infantile, and late-onset forms [ 1 ]. The classic neonatal form is the most common and severe presentation, typically manifesting within the first few days of life with lethargy, hypotonia, apnea, poor feeding, hiccups, and intractable seizures [ 1 , 4 ]. If not promptly recognized and managed, neonates can rapidly progress to coma and death. Electroencephalography (EEG) often reveals a burst-suppression pattern, while neuroimaging may demonstrate cerebral atrophy, delayed myelination, or other structural abnormalities [ 2 , 5 ]. Atypical or variant forms of NKH involving defects in mitochondrial lipoate biosynthesis—such as mutations in the LIAS gene—can mimic classic NKH but often present with additional features, including persistent lactic acidemia and elevated pyruvate levels [ 6 ]. In the present case, biochemical findings consistent with hyperglycinemia, elevated lactate, and pyruvate levels suggested a variant form of NKH with mitochondrial involvement. These features are crucial in guiding differential diagnosis, especially when combined with neuroimaging and clinical presentation. Transient neonatal NKH, although rare, has been described and may show spontaneous or treatment-induced clinical and biochemical improvement. Nevertheless, neurodevelopmental outcomes remain variable, and long-term follow-up is warranted [ 7 ]. Diagnostic confirmation of NKH requires elevated glycine levels in both plasma and cerebrospinal fluid (CSF), with a CSF-to-plasma glycine ratio typically exceeding 0.09 [ 1 , 2 ]. Although liver biopsy and enzyme activity assays were historically used, molecular genetic testing—targeting GLDC , AMT , or GCSH —has become the preferred diagnostic modality due to its specificity and non-invasive nature [ 1 ]. Distinguishing NKH from other metabolic disorders, particularly those involving organic acidemias or mitochondrial dysfunction, can be challenging. Features such as persistent metabolic acidosis, refractory seizures, and elevated lactate levels should raise suspicion for mitochondrial variants of NKH [ 6 , 8 ]. The absence of ketoacidosis or abnormal organic aciduria in NKH may help exclude other inborn errors of metabolism. Management of NKH remains primarily supportive. Therapeutic goals include reducing systemic glycine levels and limiting excitotoxic neuronal injury. Sodium benzoate is used to promote glycine conjugation and excretion, while dietary protein restriction helps limit glycine production [ 9 ]. NMDA receptor antagonists such as dextromethorphan or ketamine have shown some benefit in reducing glycine-mediated excitotoxicity [ 2 , 10 ]. In patients with suspected mitochondrial involvement, empiric use of mitochondrial cofactors—such as thiamine, folinic acid, and coenzyme Q10—has been attempted, although evidence supporting their efficacy is limited and largely anecdotal [ 6 ]. Despite aggressive management, the prognosis of NKH remains guarded. Many survivors experience profound global developmental delay, refractory epilepsy, spasticity, and feeding challenges [ 1 , 5 ]. Hence, early diagnosis and individualized treatment plans are essential for optimizing outcomes. Conclusions Recognition of variant NKH presentations, including those associated with mitochondrial dysfunction, is critical for accurate diagnosis and management. In this case, elevated plasma and CSF glycine levels supported the diagnosis of NKH, while concomitant metabolic derangements (elevated lactate and pyruvate) suggested mitochondrial involvement. Differentiating NKH subtypes through integrated clinical, biochemical, and genetic approaches is vital for guiding appropriate therapy and prognostication. Abbreviations NKH: Nonketotic Hyperglycinemia CSF: Cerebrospinal Fluid MRI: Magnetic Resonance Imaging MRS: Magnetic Resonance Spectroscopy GC-MS: Gas Chromatography–Mass Spectrometry TMS: Tandem Mass Spectrometry HPLC: High-Performance Liquid Chromatography Declarations Ethics approval and consent to participate Ethics approval was obtained from the institutional ethics committee at Kasturba Medical College, Manipal. Written informed consent for participation was obtained from the parents of the patient. Consent for publication Written informed consent was obtained from the patient’s parents for publication of clinical details and diagnostic images. Availability of data and materials All data generated or analysed during this study are included in this published article and its supplementary files. Competing interests The authors declare no competing interests. Funding This study received no specific funding. Authors’ contributions Dr. Shreya Sinha conceptualized the case and drafted the manuscript. Dr. Leslie Lewis supervised the clinical management, contributed to manuscript revisions, and approved the final version. Acknowledgements The authors thank the patient’s family for their cooperation. We also acknowledge the NICU team and laboratory staff at Kasturba Medical College, Manipal, for their support. Ethics declaration : not applicable Consent to Participate : not applicable References van Hove JL, Coughlin CR II, Swanson MA, et al. Nonketotic hyperglycinemia (NKH). In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews® . University of Washington, Seattle; 2000. Updated 2023. Gahl WA, Tuchman M. Nonketotic Hyperglycinemia. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024. Orphanet. Glycine encephalopathy. Available at: https://www.orpha.net/en/disease/detail/407. Accessed May 2025. Boneh A, Applegarth DA, Coulter-Mackie MB, et al. Clinical, biochemical and molecular findings in patients with nonketotic hyperglycinemia. J Pediatr . 2008;153(1):99-104. Dinopoulos A, Matsoukas K, Tzetis M, et al. Nonketotic hyperglycinemia: clinical and laboratory findings. Brain Dev . 2005;27(7):473-476. Baker PR II, Friederich MW, Swanson MA, et al. Variant nonketotic hyperglycinemia due to mutations in LIAS . Mol Genet Metab . 2014;111(3):371-377. Hamosh A, Johnston MV. Transient neonatal hyperglycinemia: a benign disorder with characteristic laboratory findings. Pediatrics . 1991;88(6):1193-1196. Bindu PS, Nagappa M, Taly AB, et al. Nonketotic hyperglycinemia: Clinical and metabolic profile of 22 Indian patients. JIMD Rep . 2018;42:91–98. Korman SH, Boneh A, Ichinohe A, et al. Outcome of glycine encephalopathy: dependence on age at onset and biochemical phenotype. J Inherit Metab Dis . 2004;27(6):845–854. Shchelochkov OA, Carrillo N, Venditti CP. Dextromethorphan as an NMDA receptor antagonist in nonketotic hyperglycinemia. Mol Genet Metab . 2010;100(2):121–126. Picture 1 and 4 Picture 1 and 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Picture1.jpg Picture4.jpg Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6771023","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":486318403,"identity":"4aca2ae9-ae12-4c83-ab95-c49449655268","order_by":0,"name":"Shreya Sinha","email":"data:image/png;base64,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","orcid":"","institution":"Kasturba Medical College, Manipal","correspondingAuthor":true,"prefix":"","firstName":"Shreya","middleName":"","lastName":"Sinha","suffix":""},{"id":486318404,"identity":"c9773752-d7d9-4de0-af72-cec57441c8fd","order_by":1,"name":"Leslie Lewis","email":"","orcid":"","institution":"Kasturba Medical College, Manipal","correspondingAuthor":false,"prefix":"","firstName":"Leslie","middleName":"","lastName":"Lewis","suffix":""}],"badges":[],"createdAt":"2025-05-28 20:53:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6771023/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6771023/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88961447,"identity":"368867d2-0c2d-4171-8334-edb8bc6df9a0","added_by":"auto","created_at":"2025-08-13 08:10:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":398447,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6771023/v1/81fa8307-e6fb-4c0a-a4d6-3a984fcb5185.pdf"},{"id":86967922,"identity":"f0c77ea2-2754-45ee-87ec-f150ce919809","added_by":"auto","created_at":"2025-07-17 17:59:35","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":108534,"visible":true,"origin":"","legend":"","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6771023/v1/6f0f52c0cca7419fc73cc57f.jpg"},{"id":86967927,"identity":"72dbdc23-0d41-45c3-9185-3234ed1d070c","added_by":"auto","created_at":"2025-07-17 17:59:35","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":161018,"visible":true,"origin":"","legend":"","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6771023/v1/79e3ec818de9dd17f552b710.jpg"}],"financialInterests":"No competing interests reported.","formattedTitle":"Variant Nonketotic Hyperglycinemia Presenting with Elevated Lactate and Pyruvate: A Diagnostic and Management Challenge","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNon-ketotic hyperglycinemia (NKH) is a rare autosomal recessive metabolic disorder caused by defects in the glycine cleavage enzyme system, leading to excessive accumulation of glycine, particularly in the central nervous system. The classic neonatal form is the most severe, typically presenting within the first few days of life with lethargy, hypotonia, apnea, hiccups, and intractable seizures.\u003c/p\u003e\u003cp\u003eA related variant, hyperglycinemia with lactic acidosis and seizures (HGCLAS), also referred to as pyruvate dehydrogenase lipoic acid synthetase deficiency (PDHLD), results from pathogenic variants in the \u003cem\u003eLIAS\u003c/em\u003e gene. This condition is characterized by persistent metabolic acidosis, elevated glycine levels, and refractory seizures.\u003c/p\u003e\u003cp\u003eGlycine exerts both inhibitory and excitatory effects through its action on glycine and NMDA receptors, respectively, contributing to the neurotoxicity seen in these disorders. This case report underscores the diagnostic complexity and clinical progression of HGCLAS in the neonatal period, emphasizing the importance of early metabolic evaluation in infants presenting with unexplained encephalopathy and seizures.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA term male neonate, birth weight 2500 g, was born to a 36-year-old multigravida mother following a non-consanguineous pregnancy with no antenatal complications. The infant was delivered via spontaneous vaginal delivery following a third-degree consanguineous union. Family history was notable for one stillbirth and a neonatal death of unknown cause. Two older siblings had a history of neonatal seizures but were developmentally normal at ages 4 and 8.\u003c/p\u003e\u003cp\u003eThe infant presented on day 4 of life with respiratory distress, circulatory shock, and a prior history of seizures on day 3. On admission, he was apnoeic with absent spontaneous respiration, generalized hypotonia, cyanosis, diminished peripheral pulses, and generalized anasarca. Neurological examination revealed three episodes of subtle multifocal clonic seizures involving all limbs.\u003c/p\u003e\u003cp\u003eInitial investigations revealed compensated metabolic acidosis (pH 7.39, bicarbonate 6.4 mmol/L, PaO₂ 103 mmHg, PaCO₂ 32.5 mmHg). Plasma lactate was significantly elevated at 35.9 mg/dL, pyruvate 0.29 mg/dL, and serum ammonia was 92 \u0026micro;g/dL. Serum creatinine was 0.7 mg/dL. MRI brain with MR spectroscopy showed a subacute infarct in the right medial temporal lobe.\u003c/p\u003e\u003cp\u003eMetabolic screening via gas chromatography-mass spectrometry (GC-MS) and tandem mass spectrometry (TMS) suggested mitochondrial cytopathy. High-performance liquid chromatography (HPLC) revealed markedly elevated glycine in both plasma and cerebrospinal fluid (CSF), with a CSF/plasma glycine ratio of 0. This biochemical profile was consistent with a glycine metabolism disorder.\u003c/p\u003e\u003cp\u003eThe infant was managed with immediate resuscitation and supportive therapy, including inotropes (dobutamine, adrenaline), hydrocortisone for refractory hypotension, and anticonvulsants. Metabolic management included correction of acidosis, initiation of sodium benzoate, megavitamin therapy with coenzyme Q10, and a protein-restricted diet. Physiotherapy was commenced during recovery.\u003c/p\u003e\u003cp\u003eAt 4-month follow-up, the infant had gained 2.9 kg and was achieving age-appropriate developmental milestones. Ongoing megavitamin therapy and regular metabolic follow-up were recommended.\u003c/p\u003e\u003cp\u003eHere is a revised version of the \u003cb\u003eDiscussion\u003c/b\u003e section tailored for \u003cb\u003eBMJ Paediatrics Open\u003c/b\u003e submission. It maintains clinical precision, enhances clarity, and includes properly formatted references consistent with BMJ style:\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eNonketotic hyperglycinemia (NKH), also known as glycine encephalopathy, is a rare autosomal recessive neurometabolic disorder caused by defects in the glycine cleavage system (GCS). This results in pathological accumulation of glycine, particularly within the central nervous system, leading to severe neurological dysfunction [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The estimated global incidence is approximately 1 in 250,000 live births [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eNKH is broadly classified into four clinical subtypes based on age of onset and progression: classic neonatal, transient neonatal, infantile, and late-onset forms [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The classic neonatal form is the most common and severe presentation, typically manifesting within the first few days of life with lethargy, hypotonia, apnea, poor feeding, hiccups, and intractable seizures [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. If not promptly recognized and managed, neonates can rapidly progress to coma and death. Electroencephalography (EEG) often reveals a burst-suppression pattern, while neuroimaging may demonstrate cerebral atrophy, delayed myelination, or other structural abnormalities [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAtypical or variant forms of NKH involving defects in mitochondrial lipoate biosynthesis\u0026mdash;such as mutations in the \u003cem\u003eLIAS\u003c/em\u003e gene\u0026mdash;can mimic classic NKH but often present with additional features, including persistent lactic acidemia and elevated pyruvate levels [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In the present case, biochemical findings consistent with hyperglycinemia, elevated lactate, and pyruvate levels suggested a variant form of NKH with mitochondrial involvement. These features are crucial in guiding differential diagnosis, especially when combined with neuroimaging and clinical presentation.\u003c/p\u003e\u003cp\u003eTransient neonatal NKH, although rare, has been described and may show spontaneous or treatment-induced clinical and biochemical improvement. Nevertheless, neurodevelopmental outcomes remain variable, and long-term follow-up is warranted [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDiagnostic confirmation of NKH requires elevated glycine levels in both plasma and cerebrospinal fluid (CSF), with a CSF-to-plasma glycine ratio typically exceeding 0.09 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Although liver biopsy and enzyme activity assays were historically used, molecular genetic testing\u0026mdash;targeting \u003cem\u003eGLDC\u003c/em\u003e, \u003cem\u003eAMT\u003c/em\u003e, or \u003cem\u003eGCSH\u003c/em\u003e\u0026mdash;has become the preferred diagnostic modality due to its specificity and non-invasive nature [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDistinguishing NKH from other metabolic disorders, particularly those involving organic acidemias or mitochondrial dysfunction, can be challenging. Features such as persistent metabolic acidosis, refractory seizures, and elevated lactate levels should raise suspicion for mitochondrial variants of NKH [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The absence of ketoacidosis or abnormal organic aciduria in NKH may help exclude other inborn errors of metabolism.\u003c/p\u003e\u003cp\u003eManagement of NKH remains primarily supportive. Therapeutic goals include reducing systemic glycine levels and limiting excitotoxic neuronal injury. Sodium benzoate is used to promote glycine conjugation and excretion, while dietary protein restriction helps limit glycine production [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. NMDA receptor antagonists such as dextromethorphan or ketamine have shown some benefit in reducing glycine-mediated excitotoxicity [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In patients with suspected mitochondrial involvement, empiric use of mitochondrial cofactors\u0026mdash;such as thiamine, folinic acid, and coenzyme Q10\u0026mdash;has been attempted, although evidence supporting their efficacy is limited and largely anecdotal [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eDespite aggressive management, the prognosis of NKH remains guarded. Many survivors experience profound global developmental delay, refractory epilepsy, spasticity, and feeding challenges [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Hence, early diagnosis and individualized treatment plans are essential for optimizing outcomes.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eRecognition of variant NKH presentations, including those associated with mitochondrial dysfunction, is critical for accurate diagnosis and management. In this case, elevated plasma and CSF glycine levels supported the diagnosis of NKH, while concomitant metabolic derangements (elevated lactate and pyruvate) suggested mitochondrial involvement. Differentiating NKH subtypes through integrated clinical, biochemical, and genetic approaches is vital for guiding appropriate therapy and prognostication.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eNKH: Nonketotic Hyperglycinemia\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CSF: Cerebrospinal Fluid\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;MRI: Magnetic Resonance Imaging\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;MRS: Magnetic Resonance Spectroscopy\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;GC-MS: Gas Chromatography\u0026ndash;Mass Spectrometry\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;TMS: Tandem Mass Spectrometry\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;HPLC: High-Performance Liquid Chromatography\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthics approval was obtained from the institutional ethics committee at Kasturba Medical College, Manipal. Written informed consent for participation was obtained from the parents of the patient.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient\u0026rsquo;s parents for publication of clinical details and diagnostic images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article and its supplementary files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received no specific funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDr. Shreya Sinha conceptualized the case and drafted the manuscript. Dr. Leslie Lewis supervised the clinical management, contributed to manuscript revisions, and approved the final version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the patient\u0026rsquo;s family for their cooperation. We also acknowledge the NICU team and laboratory staff at Kasturba Medical College, Manipal, for their support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics\u003c/strong\u003e \u003cstrong\u003edeclaration\u003c/strong\u003e: not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e: not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col start=\"1\" type=\"1\"\u003e\n\u003cli\u003evan Hove JL, Coughlin CR II, Swanson MA, et al. Nonketotic hyperglycinemia (NKH). In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. \u003cem\u003eGeneReviews\u0026reg;\u003c/em\u003e. University of Washington, Seattle; 2000. Updated 2023.\u003c/li\u003e\n\u003cli\u003eGahl WA, Tuchman M. Nonketotic Hyperglycinemia. In: \u003cem\u003eStatPearls\u003c/em\u003e [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.\u003c/li\u003e\n\u003cli\u003eOrphanet. Glycine encephalopathy. Available at: https://www.orpha.net/en/disease/detail/407. Accessed May 2025.\u003c/li\u003e\n\u003cli\u003eBoneh A, Applegarth DA, Coulter-Mackie MB, et al. Clinical, biochemical and molecular findings in patients with nonketotic hyperglycinemia. \u003cem\u003eJ Pediatr\u003c/em\u003e. 2008;153(1):99-104.\u003c/li\u003e\n\u003cli\u003eDinopoulos A, Matsoukas K, Tzetis M, et al. Nonketotic hyperglycinemia: clinical and laboratory findings. \u003cem\u003eBrain Dev\u003c/em\u003e. 2005;27(7):473-476.\u003c/li\u003e\n\u003cli\u003eBaker PR II, Friederich MW, Swanson MA, et al. Variant nonketotic hyperglycinemia due to mutations in \u003cem\u003eLIAS\u003c/em\u003e. \u003cem\u003eMol Genet Metab\u003c/em\u003e. 2014;111(3):371-377.\u003c/li\u003e\n\u003cli\u003eHamosh A, Johnston MV. Transient neonatal hyperglycinemia: a benign disorder with characteristic laboratory findings. \u003cem\u003ePediatrics\u003c/em\u003e. 1991;88(6):1193-1196.\u003c/li\u003e\n\u003cli\u003eBindu PS, Nagappa M, Taly AB, et al. Nonketotic hyperglycinemia: Clinical and metabolic profile of 22 Indian patients. \u003cem\u003eJIMD Rep\u003c/em\u003e. 2018;42:91\u0026ndash;98.\u003c/li\u003e\n\u003cli\u003eKorman SH, Boneh A, Ichinohe A, et al. Outcome of glycine encephalopathy: dependence on age at onset and biochemical phenotype. \u003cem\u003eJ Inherit Metab Dis\u003c/em\u003e. 2004;27(6):845\u0026ndash;854.\u003c/li\u003e\n\u003cli\u003eShchelochkov OA, Carrillo N, Venditti CP. Dextromethorphan as an NMDA receptor antagonist in nonketotic hyperglycinemia. \u003cem\u003eMol Genet Metab\u003c/em\u003e. 2010;100(2):121\u0026ndash;126.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Picture 1 and 4","content":"\u003cp\u003ePicture 1 and 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6771023/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6771023/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eNon-ketotic hyperglycinemia (NKH) is a rare autosomal recessive metabolic disorder resulting from a defect in the glycine cleavage system, leading to accumulation of glycine in the central nervous system. The classic neonatal form presents as a life-threatening metabolic encephalopathy within the first few days of life.\u003c/p\u003e\u003ch2\u003eCase Presentation:\u003c/h2\u003e\u003cp\u003eWe report a term neonate, born to a 36-year-old multigravida via third-degree consanguineous marriage, who presented on day 4 of life with poor respiratory effort and shock. There was a history of neonatal seizures on day 3. The infant was intubated and commenced on inotropic support. Recurrent seizures on day 5 necessitated initiation of anticonvulsants (levetiracetam and phenytoin). Given the clinical suspicion of an inborn error of metabolism (IEM), metabolic evaluation revealed significantly elevated plasma glycine levels. Cerebrospinal fluid (CSF) analysis confirmed elevated glycine with an increased CSF-to-plasma glycine ratio (0.19), supporting a diagnosis of NKH. Brain MRI demonstrated features of subacute infarct; MR spectroscopy was unremarkable. Treatment included initiation of high-dose vitamins, with clinical improvement observed. The family was counselled regarding home-based physiotherapy, which was demonstrated and reinforced prior to discharge.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eNKH should be considered in neonates presenting with early-onset seizures and encephalopathy. Diagnosis is supported by elevated CSF glycine levels and an increased CSF/plasma glycine ratio. While definitive diagnosis involves liver biopsy to assess glycine cleavage enzyme activity, supportive treatment with sodium benzoate and NMDA receptor antagonists may help reduce glycine levels and improve outcomes. Early recognition and multidisciplinary support are critical for management.\u003c/p\u003e","manuscriptTitle":"Variant Nonketotic Hyperglycinemia Presenting with Elevated Lactate and Pyruvate: A Diagnostic and Management Challenge","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-17 17:59:30","doi":"10.21203/rs.3.rs-6771023/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a9414295-471c-47ed-b4b5-4407110e8711","owner":[],"postedDate":"July 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-13T08:09:53+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-17 17:59:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6771023","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6771023","identity":"rs-6771023","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}