Tools
Nonketotic Hyperglycinemia
Introduction
Nonketotic hyperglycinemia (NKH) is a rare genetic disease secondary to an inborn error in glycine metabolism.[1] Due to a mutation in the glycine cleavage enzyme system, the patient cannot break down glycine, ultimately accumulating it throughout the body.[2][3][4] The buildup of glycine primarily occurs within the spinal cord and brain; thus, this condition's initial clinical manifestations and long-term sequelae are more often of neurological origin.[1][2][5] No known interventions are effective in altering the natural history of nonketotic hyperglycinemia, but whatever therapeutic strategies are applied can potentially reduce the comorbidities associated with this condition. It is essential that the clinician recognizes this disease and initiates early evaluation and treatment to attain the best possible outcome.[4]
Etiology
Register For Free And Read The Full Article
Search engine and full access to all medical articles- 10 free questions in your specialty
- Free CME/CE Activities
- Free daily question in your email
- Save favorite articles to your dashboard
- Emails offering discounts
Learn more about a Subscription to StatPearls Point-of-Care
Etiology
Classic nonketotic hyperglycinemia commonly occurs due to defects in the genes (GLDC and AMT) that encode the protein components of the glycine cleavage enzyme system, resulting in decreased enzyme activity.[6] Newer mutations were also reported in recent studies from Chinese and Turkish patients.[7] This autosomal recessive hereditary disease usually presents at a very early age.
Epidemiology
Classic nonketotic hyperglycinemia is a rare disorder with a global incidence of 1 in 76,000.[8] The incidence may range between 1 in 12,000 to 1 in 63,000 cases in newborn babies in certain geographic areas.[9][10] This disease can occur in any population, but it is reportedly seen more frequently in individuals of Finnish descent.[10]
Pathophysiology
Glycine is an amino acid that is primarily an inhibitory neurotransmitter but also serves as a co-agonist (excitation modulator) of N-methyl-D-aspartate (NMDA) (glutamatergic) receptors.[11][12] Excessive activation of N-methyl-D-aspartate receptors can result in neuronal and axonal injury and potential impairment of neurogenesis.[13][14] Nonketotic hyperglycinemia occurs due to decreased activity of the glycine cleavage enzyme system, which is the system tasked with maintaining the appropriate glycine concentration.[2][3] This results in accumulating a significant quantity of glycine throughout the body, primarily within the brain and the spinal cord.[1][5] The pathophysiologic process of nonketotic hyperglycinemia likely begins as early in utero; thus, irreversible glycine-induced brain damage is also likely to have already occurred by the time of the patient symptom presentation.[15]
History and Physical
When a patient presents with signs and symptoms that cause concern for an inborn error of metabolism, the usual systematic approach of good history and physical examination are required.[16] Particular historical features that the clinician should investigate for nonketotic hyperglycinemia include a past medical history and a review of systems that focus on the presence of lethargy, poor feeding, hypotonia, refractory seizures, encephalopathy (particularly if there are unexplained episodes), and apnea (if the patient presents during the neonatal period). It is essential for the clinician to fully investigate the patient's dietary history, growth, and development.[16]
Additional questions should focus on developmental delays (expressive language impairment), hyperactivity, and the progression of the patient's clinical manifestations as they become older children.[4][16] It is important to review a patient's family history, particularly for any evidence of stillbirth, unexplained neonatal death, and consanguinity.[16] Nonketotic hyperglycinemia is a disorder that begins in utero and commonly presents with abnormalities that are already present at birth; thus, the maternal history should be thoroughly reviewed. Inquiries regarding fetal movement, particularly neonatal hiccups, are suspicious for nonketotic hyperglycinemia and should be asked directly.[1][17]
Physical examination findings that are suspicious for nonketotic hyperglycinemia are nonspecific but include lethargy and impaired mental status (like encephalopathy).[16] A complete neurologic examination should be performed on these patients. The exam should also focus on the respiratory system (evaluating for apnea, hiccuping, or irregular breathing, placing the patient at risk for respiratory failure), a motor exam, and an evaluation of muscle tone since patients may be hypotonic.[16] Nonketotic hyperglycinemia is divided into 2 forms: severe and attenuated. Patients with severe NKH usually have intractable seizures and present no developmental progress, whereas those with the attenuated form of the disease present with varied developmental progress and no epilepsy (or easily controlled seizures).[18]
Evaluation
For patients with nonketotic hyperglycinemia, a systematic laboratory and diagnostic approach is often undertaken when the patient first presents, as the etiology is often unknown. This may include a CBC with differential, blood glucose, electrolytes, blood urea nitrogen, creatinine, uric acid, arterial blood gas, ammonia level, and liver enzymes.[16] These tests are often followed by specialized testing in consultation with a metabolic specialist. For nonketotic hyperglycinemia, measurement of glycine within the plasma and the cerebral spinal fluid (evaluating for an abnormal CSF-to-plasma glycine ratio), a magnetic resonance imaging of the brain (evaluating for diffusion restriction in the infratentorial regions like the posterior limb of the internal capsule, anterior brain stem, posterior tegmental tracts, and cerebellum before the age of 3 months and generalized diffusion restriction of the supratentorial white matter after 3 months), a brain magnetic resonance spectroscopy, molecular genetic testing, and rarely, analysis of enzymatic activity should be performed, and they can help to establish the diagnosis as well as the extent of the systemic damage.[16][19][20] If the patient has a seizure activity, additional testing may include an electroencephalogram.[16]
Treatment / Management
There are no effective treatment strategies that alter the natural history of nonketotic hyperglycinemia.[1][21] Thus, treatment focuses on reducing plasma glycine concentration by initiating sodium benzoate therapy and utilizing N-methyl-D-aspartate receptor site antagonists (ie, dextromethorphan, oral ketamine) to reduce glycinergic stimulation.[21][22][23] These therapies have been shown to improve seizure control and neurodevelopmental outcomes in selected populations with nonketotic hyperglycinemia.[4](B2)
After establishing the diagnosis of nonketotic hyperglycinemia, the patient requires routine developmental assessments, frequent orthopedic evaluation for scoliosis and hip dislocation, especially as they age, and routine ophthalmologic evaluation to determine the presence of cortical blindness.[24][25][26] The patient may develop pulmonary hypertension, thus requiring cardiology evaluation to determine if they would benefit from pharmacological therapy.[27][28] A gastrointestinal referral may be necessary to determine if enteral access is needed for nutrition.[24] These patients often require long-term antiepileptic maintenance therapy with antiepileptic therapy, diet, and special surgical interventions (like vagal nerve stimulator placement).[27](B3)
Differential Diagnosis
The clinical manifestations guide the differential diagnosis of this condition during the presentation. Inborn errors of metabolism do not represent the most common cause of confirmed seizures or encephalopathy. Thus, the clinician should first consider acute metabolic disturbances (for example, hypoglycemia), hypoxia, intracranial hemorrhage, sepsis, thrombosis, neonatal epilepsy syndromes, or congenital brain malformations.[29][30][31][32][33] During the newborn screening, or when a clinician suspects an inborn error of metabolism, laboratory features of nonketotic hyperglycinemia may be present. The following conditions, therefore, must be differentiated from nonketotic hyperglycinemia. These include:
- Medications (particularly valproate, which is known to decrease glycine cleavage enzyme system activity) [34]
- Artificial elevation due to laboratory sampling technique [34]
- Starvation [34]
- Use of glycine-containing fluids (ie, bladder irrigation fluid) [34]
- Transient glycine encephalopathy due to intracerebral hemorrhage or hypoxic-ischemic injury [34][35]
- Transient glycine encephalopathy due to immaturity of the glycine cleavage enzyme system [36]
- Hyperglycinuria (due to defects in the renal transport of glycine, including familial iminoglycinuria or benign hyperglycinuria) [34]
Some inherited metabolic conditions resemble nonketotic hyperglycinemia, but they have different pathophysiologic mechanisms and may require different treatment strategies. These include:
Prognosis
The prognosis depends on the amount of glycine cleavage enzyme system activity.[42] Severe deficiency in this enzyme results in the presentation of the disease during the neonatal period, which is associated with a poor prognosis due to life-threatening apnea.[42][43] In neonates where spontaneous breathing is reestablished, these patients may develop progressive lethargy, encephalopathy, or death. Other patients might be marred by a lifetime of severe developmental impairment and intractable epilepsy.[44][45] Patients who present later in life (3 months or later) are more likely to have attenuated glycine cleavage enzyme activity.[42] In those patients, the developmental progress and severity of epilepsy may vary depending on when the disease is recognized and if early treatment is initiated.[4][46]
Complications
When this disease presents in neonates, the patient may develop severe apnea, resulting in acute hypoxemic respiratory failure requiring respiratory support.[42][44] In patients where respiratory failure resolves, the patient might likely develop progressive lethargy or encephalopathy. Some patients may live for several years, though death can occur at any time, depending on the severity of the disease.[28][42][44] In those patients that survive or present later in life (mostly at 3 months or later), the severity of the disease varies.[42][44] They may be marred by a lifetime of no or limited developmental progress, intractable epilepsy, pulmonary hypertension, dysphagia, gastrointestinal dysmotility requiring surgical enteral access, scoliosis, hip dislocation due to spasticity, and even cortical blindness.[24][25][27][28] Different studies in infants also reported the presence of hydrocephalus [47] that required shunt placement.
Consultations
After the diagnosis of NKH has been made, most patients benefit from evaluations by different specialists, including but not limited to a neurologist, a pulmonologist, a gastroenterologist, an orthopedic surgeon, and an ophthalmologist. Genetic counseling is essential in an effort also to help the families that have to take care of these patients. In the long run, for patients who survive, physical medicine and rehabilitation specialists should also be consulted to help recover from complications, particularly physical disability, if any. Due to the need for multiple medical services, these patients benefit from dedicated nursing teams and social workers who can coordinate the care and alleviate some of the burden from parents and families.
Deterrence and Patient Education
Parents should be counseled on the prognosis of nonketotic hyperglycinemia, particularly the possibility of neurologic impairments in those who survive.[28] In patients who develop long-term epilepsy, the parents should have higher vigilance in situations (ie, ensure adequate supervision) where the dangers can be compounded if seizure activity occurs.[48] Genetic counseling may be required to help parents and siblings of a child with nonketotic hyperglycinemia understand the genetic risks to help them make informed future medical and personal decisions.[49]
Enhancing Healthcare Team Outcomes
Diagnosing and managing nonketotic hyperglycinemia require an interprofessional team approach that includes clinicians (including mid-level practitioners), nursing staff, and pharmacists to avoid complications like underrecognition of clinical seizures and ensure that early and proper diagnostic testing is performed. Referral to critical care services (neonatal or pediatric) should be performed early to place the patient under the care of neurocritical care experts and to ensure that the patient is stabilized from a neurocritical care standpoint.[50] Specialists involved in the care of these patients may include:
- The pediatric neurologist should be consulted to evaluate the patient and confirm the diagnosis of seizures.[50]
- A metabolic specialist should be consulted to ensure that the patient receives an appropriate evaluation and initiation of therapy.[51]
- Genetic counseling specialists that the patient’s parents should be referred to determine the genetic risk for medical and personal reasons.[49]
- Pediatric palliative care specialists should be consulted in cases of patients with severe nonketotic hyperglycinemia, as these children have a poor neurologic prognosis, and families might need to get help for a difficult decision to be made about withdrawing critical care support.[28]
Nurses are crucial in coordinating care between the various clinicians. In cases where anti-epileptic medications are necessary, the pharmacist consults with clinicians to determine optimal dosing and agent selection and perform medication reconciliation. With this integrated and interprofessional coordination, timely and directed care coordination can improve patient outcomes.
References
Iqbal M, Prasad M, Mordekar SR. Nonketotic hyperglycinemia case series. Journal of pediatric neurosciences. 2015 Oct-Dec:10(4):355-8. doi: 10.4103/1817-1745.174445. Epub [PubMed PMID: 26962342]
Level 2 (mid-level) evidencePoothrikovil RP, Al Thihli K, Al Futaisi A, Al Murshidi F. Nonketotic Hyperglycinemia: Two Case Reports and Review. The Neurodiagnostic journal. 2019:59(3):142-151. doi: 10.1080/21646821.2019.1645549. Epub 2019 Aug 21 [PubMed PMID: 31433733]
Level 3 (low-level) evidenceTada K, Narisawa K, Yoshida T, Konno T, Yokoyama Y. Hyperglycinemia: a defect in glycine cleavage reaction. The Tohoku journal of experimental medicine. 1969 Jul:98(3):289-96 [PubMed PMID: 5307488]
Bjoraker KJ,Swanson MA,Coughlin CR 2nd,Christodoulou J,Tan ES,Fergeson M,Dyack S,Ahmad A,Friederich MW,Spector EB,Creadon-Swindell G,Hodge MA,Gaughan S,Burns C,Van Hove JL, Neurodevelopmental Outcome and Treatment Efficacy of Benzoate and Dextromethorphan in Siblings with Attenuated Nonketotic Hyperglycinemia. The Journal of pediatrics. 2016 Mar; [PubMed PMID: 26749113]
Lim YT, Mankad K, Kinali M, Tan AP. Neuroimaging Spectrum of Inherited Neurotransmitter Disorders. Neuropediatrics. 2020 Feb:51(1):6-21. doi: 10.1055/s-0039-1698422. Epub 2019 Oct 21 [PubMed PMID: 31634934]
Kure S, Kato K, Dinopoulos A, Gail C, DeGrauw TJ, Christodoulou J, Bzduch V, Kalmanchey R, Fekete G, Trojovsky A, Plecko B, Breningstall G, Tohyama J, Aoki Y, Matsubara Y. Comprehensive mutation analysis of GLDC, AMT, and GCSH in nonketotic hyperglycinemia. Human mutation. 2006 Apr:27(4):343-52 [PubMed PMID: 16450403]
Ning JJ, Li F, Li SQ. Clinical and genetic analysis of nonketotic hyperglycinemia: A case report. World journal of clinical cases. 2022 Aug 6:10(22):7982-7988. doi: 10.12998/wjcc.v10.i22.7982. Epub [PubMed PMID: 36158497]
Level 3 (low-level) evidenceCoughlin CR 2nd,Swanson MA,Kronquist K,Acquaviva C,Hutchin T,Rodríguez-Pombo P,Väisänen ML,Spector E,Creadon-Swindell G,Brás-Goldberg AM,Rahikkala E,Moilanen JS,Mahieu V,Matthijs G,Bravo-Alonso I,Pérez-Cerdá C,Ugarte M,Vianey-Saban C,Scharer GH,Van Hove JL, The genetic basis of classic nonketotic hyperglycinemia due to mutations in GLDC and AMT. Genetics in medicine : official journal of the American College of Medical Genetics. 2017 Jan; [PubMed PMID: 27362913]
Applegarth DA, Toone JR, Lowry RB. Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. 2000 Jan:105(1):e10 [PubMed PMID: 10617747]
von Wendt L, Hirvasniemi A, Similä S. Nonketotic hyperglycinemia. A genetic study of 13 Finnish families. Clinical genetics. 1979 May:15(5):411-7 [PubMed PMID: 445864]
Kawai N, Sakai N, Okuro M, Karakawa S, Tsuneyoshi Y, Kawasaki N, Takeda T, Bannai M, Nishino S. The sleep-promoting and hypothermic effects of glycine are mediated by NMDA receptors in the suprachiasmatic nucleus. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2015 May:40(6):1405-16. doi: 10.1038/npp.2014.326. Epub 2014 Dec 23 [PubMed PMID: 25533534]
Level 3 (low-level) evidenceSubramanian V,Kadiyala P,Hariharan P,Neeraj E, A rare case of glycine encephalopathy unveiled by valproate therapy. Journal of pediatric neurosciences. 2015 Apr-Jun; [PubMed PMID: 26167219]
Level 3 (low-level) evidenceMcDonald JW,Johnston MV, Excitatory amino acid neurotoxicity in the developing brain. NIDA research monograph. 1993; [PubMed PMID: 8232513]
Level 3 (low-level) evidenceMcDonald JW, Johnston MV. Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain research. Brain research reviews. 1990 Jan-Apr:15(1):41-70 [PubMed PMID: 2163714]
Level 3 (low-level) evidenceKorman SH, Wexler ID, Gutman A, Rolland MO, Kanno J, Kure S. Treatment from birth of nonketotic hyperglycinemia due to a novel GLDC mutation. Annals of neurology. 2006 Feb:59(2):411-5 [PubMed PMID: 16404748]
Level 3 (low-level) evidenceAlmannai M, El-Hattab AW. Inborn Errors of Metabolism with Seizures: Defects of Glycine and Serine Metabolism and Cofactor-Related Disorders. Pediatric clinics of North America. 2018 Apr:65(2):279-299. doi: 10.1016/j.pcl.2017.11.007. Epub 2017 Dec 28 [PubMed PMID: 29502914]
Alfadhel M,Nashabat M,Qahtani HA,Alfares A,Mutairi FA,Shaalan HA,Douglas GV,Wierenga K,Juusola J,Alrifai MT,Arold ST,Alkuraya F,Ali QA, Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans. Human genetics. 2016 Nov; [PubMed PMID: 27481395]
Adam MP,Everman DB,Mirzaa GM,Pagon RA,Wallace SE,Bean LJH,Gripp KW,Amemiya A,Van Hove JLK,Coughlin C II,Swanson M,Hennermann JB, Nonketotic Hyperglycinemia. GeneReviews(®). 1993 [PubMed PMID: 20301531]
Stence NV, Fenton LZ, Levek C, Tong S, Coughlin CR 2nd, Hennermann JB, Wortmann SB, Van Hove JLK. Brain imaging in classic nonketotic hyperglycinemia: Quantitative analysis and relation to phenotype. Journal of inherited metabolic disease. 2019 May:42(3):438-450. doi: 10.1002/jimd.12072. Epub 2019 Mar 20 [PubMed PMID: 30737808]
van Karnebeek CDM, Sayson B, Lee JJY, Tseng LA, Blau N, Horvath GA, Ferreira CR. Metabolic Evaluation of Epilepsy: A Diagnostic Algorithm With Focus on Treatable Conditions. Frontiers in neurology. 2018:9():1016. doi: 10.3389/fneur.2018.01016. Epub 2018 Dec 3 [PubMed PMID: 30559706]
Van Hove JL, Vande Kerckhove K, Hennermann JB, Mahieu V, Declercq P, Mertens S, De Becker M, Kishnani PS, Jaeken J. Benzoate treatment and the glycine index in nonketotic hyperglycinaemia. Journal of inherited metabolic disease. 2005:28(5):651-63 [PubMed PMID: 16151895]
Alemzadeh R,Gammeltoft K,Matteson K, Efficacy of low-dose dextromethorphan in the treatment of nonketotic hyperglycinemia. Pediatrics. 1996 Jun; [PubMed PMID: 8657542]
Level 3 (low-level) evidenceNowak M,Chuchra P,Paprocka J, Nonketotic Hyperglycinemia: Insight into Current Therapies. Journal of clinical medicine. 2022 May 27 [PubMed PMID: 35683414]
Ramirez N, Flynn JM, Casalduc F, Rodriguez S, Cornier AS, Carlo S. Musculoskeletal manifestations of neonatal nonketotic hyperglycinemia. Journal of children's orthopaedics. 2012 Jul:6(3):199-203. doi: 10.1007/s11832-012-0407-1. Epub 2012 May 25 [PubMed PMID: 23814620]
Markand ON, Garg BP, Brandt IK. Nonketotic hyperglycinemia: electroencephalographic and evoked potential abnormalities. Neurology. 1982 Feb:32(2):151-6 [PubMed PMID: 6798489]
Brazis PW, Lee AG, Graff-Radford N, Desai NP, Eggenberger ER. Homonymous visual field defects in patients without corresponding structural lesions on neuroimaging. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society. 2000 Jun:20(2):92-6 [PubMed PMID: 10870920]
Level 3 (low-level) evidenceCataltepe S,van Marter LJ,Kozakewich H,Wessel DL,Lee PJ,Levy HL, Pulmonary hypertension associated with nonketotic hyperglycinaemia. Journal of inherited metabolic disease. 2000 Mar; [PubMed PMID: 10801055]
Level 3 (low-level) evidenceBoneh A,Allan S,Mendelson D,Spriggs M,Gillam LH,Korman SH, Clinical, ethical and legal considerations in the treatment of newborns with non-ketotic hyperglycinaemia. Molecular genetics and metabolism. 2008 Jun; [PubMed PMID: 18395481]
Soul JS. Acute symptomatic seizures in term neonates: Etiologies and treatments. Seminars in fetal & neonatal medicine. 2018 Jun:23(3):183-190. doi: 10.1016/j.siny.2018.02.002. Epub 2018 Feb 6 [PubMed PMID: 29433814]
Glass HC, Shellhaas RA, Wusthoff CJ, Chang T, Abend NS, Chu CJ, Cilio MR, Glidden DV, Bonifacio SL, Massey S, Tsuchida TN, Silverstein FS, Soul JS, Neonatal Seizure Registry Study Group. Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study. The Journal of pediatrics. 2016 Jul:174():98-103.e1. doi: 10.1016/j.jpeds.2016.03.035. Epub 2016 Apr 19 [PubMed PMID: 27106855]
Govaert P, Ramenghi L, Taal R, de Vries L, Deveber G. Diagnosis of perinatal stroke I: definitions, differential diagnosis and registration. Acta paediatrica (Oslo, Norway : 1992). 2009 Oct:98(10):1556-67. doi: 10.1111/j.1651-2227.2009.01461.x. Epub 2009 Aug 3 [PubMed PMID: 19663912]
Yamamoto H,Okumura A,Fukuda M, Epilepsies and epileptic syndromes starting in the neonatal period. Brain [PubMed PMID: 21067877]
Level 3 (low-level) evidenceShellhaas RA, Wusthoff CJ, Tsuchida TN, Glass HC, Chu CJ, Massey SL, Soul JS, Wiwattanadittakun N, Abend NS, Cilio MR, Neonatal Seizure Registry. Profile of neonatal epilepsies: Characteristics of a prospective US cohort. Neurology. 2017 Aug 29:89(9):893-899. doi: 10.1212/WNL.0000000000004284. Epub 2017 Jul 21 [PubMed PMID: 28733343]
Korman SH, Gutman A. Pitfalls in the diagnosis of glycine encephalopathy (non-ketotic hyperglycinemia). Developmental medicine and child neurology. 2002 Oct:44(10):712-20 [PubMed PMID: 12418798]
Aburahma S, Khassawneh M, Griebel M, Sharp G, Gibson J. Pitfalls in measuring cerebrospinal fluid glycine levels in infants with encephalopathy. Journal of child neurology. 2011 Jun:26(6):703-6. doi: 10.1177/0883073810389041. Epub 2011 Feb 18 [PubMed PMID: 21335543]
Level 2 (mid-level) evidenceAliefendioğlu D, Tana Aslan Ay, Coşkun T, Dursun A, Cakmak FN, Kesimer M. Transient nonketotic hyperglycinemia: two case reports and literature review. Pediatric neurology. 2003 Feb:28(2):151-5 [PubMed PMID: 12699870]
Level 3 (low-level) evidenceHayasaka K,Tada K, Effects of the metabolites of the branched-chain amino acids and cysteamine on the glycine cleavage system. Biochemistry international. 1983 Feb; [PubMed PMID: 6679320]
Level 3 (low-level) evidenceMaeda T,Inutsuka M,Goto K,Izumi T, Transient nonketotic hyperglycinemia in an asphyxiated patient with pyridoxine-dependent seizures. Pediatric neurology. 2000 Mar; [PubMed PMID: 10734255]
Level 3 (low-level) evidenceScalais E, Osterheld E, Weitzel C, De Meirleir L, Mataigne F, Martens G, Shaikh TH, Coughlin CR 2nd, Yu HC, Swanson M, Friederich MW, Scharer G, Helbling D, Wendt-Andrae J, Van Hove JLK. X-Linked Cobalamin Disorder (HCFC1) Mimicking Nonketotic Hyperglycinemia With Increased Both Cerebrospinal Fluid Glycine and Methylmalonic Acid. Pediatric neurology. 2017 Jun:71():65-69. doi: 10.1016/j.pediatrneurol.2016.12.003. Epub 2017 Jan 7 [PubMed PMID: 28363510]
Alfallaj R, Alfadhel M. Glycine Transporter 1 Encephalopathy From Biochemical Pathway to Clinical Disease: Review. Child neurology open. 2019:6():2329048X19831486. doi: 10.1177/2329048X19831486. Epub 2019 Feb 19 [PubMed PMID: 30815509]
Baker PR 2nd, Friederich MW, Swanson MA, Shaikh T, Bhattacharya K, Scharer GH, Aicher J, Creadon-Swindell G, Geiger E, MacLean KN, Lee WT, Deshpande C, Freckmann ML, Shih LY, Wasserstein M, Rasmussen MB, Lund AM, Procopis P, Cameron JM, Robinson BH, Brown GK, Brown RM, Compton AG, Dieckmann CL, Collard R, Coughlin CR 2nd, Spector E, Wempe MF, Van Hove JL. Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Brain : a journal of neurology. 2014 Feb:137(Pt 2):366-79. doi: 10.1093/brain/awt328. Epub 2013 Dec 11 [PubMed PMID: 24334290]
Level 3 (low-level) evidenceSwanson MA,Coughlin CR Jr,Scharer GH,Szerlong HJ,Bjoraker KJ,Spector EB,Creadon-Swindell G,Mahieu V,Matthijs G,Hennermann JB,Applegarth DA,Toone JR,Tong S,Williams K,Van Hove JL, Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia. Annals of neurology. 2015 Oct; [PubMed PMID: 26179960]
Chien YH, Hsu CC, Huang A, Chou SP, Lu FL, Lee WT, Hwu WL. Poor outcome for neonatal-type nonketotic hyperglycinemia treated with high-dose sodium benzoate and dextromethorphan. Journal of child neurology. 2004 Jan:19(1):39-42 [PubMed PMID: 15032382]
Suzuki Y, Kure S, Oota M, Hino H, Fukuda M. Nonketotic hyperglycinemia: proposal of a diagnostic and treatment strategy. Pediatric neurology. 2010 Sep:43(3):221-4. doi: 10.1016/j.pediatrneurol.2010.04.018. Epub [PubMed PMID: 20691948]
Level 3 (low-level) evidenceCusmai R, Martinelli D, Moavero R, Dionisi Vici C, Vigevano F, Castana C, Elia M, Bernabei S, Bevivino E. Ketogenic diet in early myoclonic encephalopathy due to non ketotic hyperglycinemia. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2012 Sep:16(5):509-13. doi: 10.1016/j.ejpn.2011.12.015. Epub 2012 Jan 18 [PubMed PMID: 22261077]
Kuseyri Hübschmann O, Juliá-Palacios NA, Olivella M, Guder P, Zafeiriou DI, Horvath G, Kulhánek J, Pearson TS, Kuster A, Cortès-Saladelafont E, Ibáñez S, García-Jiménez MC, Honzík T, Santer R, Jeltsch K, Garbade SF, Hoffmann GF, Opladen T, García-Cazorla Á. Integrative Approach to Predict Severity in Nonketotic Hyperglycinemia. Annals of neurology. 2022 Aug:92(2):292-303. doi: 10.1002/ana.26423. Epub 2022 Jun 16 [PubMed PMID: 35616651]
Van Hove JL, Kishnani PS, Demaerel P, Kahler SG, Miller C, Jaeken J, Rutledge SL. Acute hydrocephalus in nonketotic hyperglycinemia. Neurology. 2000 Feb 8:54(3):754-6 [PubMed PMID: 10680820]
Level 3 (low-level) evidenceHoward GM, Radloff M, Sevier TL. Epilepsy and sports participation. Current sports medicine reports. 2004 Feb:3(1):15-9 [PubMed PMID: 14728909]
Veríssimo C, Garcia P, Simões M, Robalo C, Henriques R, Diogo L, Grazina M. Nonketotic hyperglycinemia: a cause of encephalopathy in children. Journal of child neurology. 2013 Feb:28(2):251-4. doi: 10.1177/0883073812441063. Epub 2012 Apr 24 [PubMed PMID: 22532538]
Level 3 (low-level) evidenceMulkey SB, Swearingen CJ. Advancing neurologic care in the neonatal intensive care unit with a neonatal neurologist. Journal of child neurology. 2014 Jan:29(1):31-5. doi: 10.1177/0883073812469051. Epub 2012 Dec 26 [PubMed PMID: 23271754]
Level 2 (mid-level) evidenceSharma S, Prasad AN. Inborn Errors of Metabolism and Epilepsy: Current Understanding, Diagnosis, and Treatment Approaches. International journal of molecular sciences. 2017 Jul 2:18(7):. doi: 10.3390/ijms18071384. Epub 2017 Jul 2 [PubMed PMID: 28671587]
Level 3 (low-level) evidence