Nonketotic Hyperglycinemia

Article Author:
Conrad Krawiec
Article Editor:
Amandeep Goyal
Updated:
3/24/2020 6:07:54 AM
PubMed Link:
Nonketotic Hyperglycinemia

Introduction

Nonketotic hyperglycinemia is a rare, genetic, inborn error of glycine metabolism.[1] Due to a mutation in the glycine cleavage enzyme system, the patient is unable to breakdown glycine, resulting in its accumulation throughout the body.[2][3][4] The buildup of glycine primarily occurs within the spinal cord and brain; thus, the initial clinical manifestations and long-term sequelae from this condition are often neurological.[1][2][5] 

There are no known interventions effective in altering the natural history of nonketotic hyperglycinemia, but there are therapeutic strategies that can reduce the co-morbidities associated with this condition. Thus, the clinician needs to recognize this disease and initiate early evaluation and treatment to try to attain the best possible outcome.[4]

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]

Epidemiology

Classic nonketotic hyperglycinemia is a rare disorder with a global incidence of 1:76,000.[7] In certain geographic areas, the incidence may range between 1:12,000 to 1:63,000 in newborn babies.[8][9] This disease can occur in any population but is reportedly seen more in individuals with Finnish descent.[9]

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.[10][11] Excessive activation of N-methyl-D-aspartate receptors can result in neuronal and axonal injury as well as potentially impair neurogenesis.[12][13] Nonketotic hyperglycinemia occurs due to decreased activity of the glycine cleavage enzyme system; it is a system tasked with maintaining appropriate glycine concentration.[2][3] This results in an accumulation of a significant quantity of glycine throughout the body, primarily within the brain and spinal cord.[1][5] The pathophysiologic process of nonketotic hyperglycinemia likely begins in utero; thus, irreversible glycine-induced brain damage likely has already occurred by the time of patient presentation.[14]

History and Physical

When a patient presents with signs and symptoms concerning for an inborn error of metabolism, the usual systematic approach to history and physical examination are required.[15] Particular historical features that clinician should investigate for nonketotic hyperglycinemia include a past medical history and 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.[15] In older children, additional questions should focus on developmental delays (expressive language impairment), hyperactivity, and progression of the patient's clinical manifestations.[4][15] It is important to review a patient's family history, particularly for any evidence of stillbirth, unexplained neonatal death, and consanguinity.[15] Nonketotic hyperglycinemia is a disorder that begins in utero and commonly presents with abnormalities often 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 directly asked.[1][16]

Physical examination findings that are suspicious for nonketotic hyperglycinemia are nonspecific but include the presence of lethargy and impaired mental status (encephalopathy).[15] A full neurologic examination should be performed in these patients along with particularly focusing on the respiratory system (evaluating for apnea, hiccuping, and/or irregular breathing placing the patient at risk for respiratory failure), motor exam, and tone (which may be hypotonic in patients with nonketotic hyperglycinemia).[15]

Evaluation

For patients with nonketotic hyperglycinemia, a systematic laboratory and diagnostic approach are 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.[15] These tests are often followed by specialized testing in consultation with a metabolic specialist. For nonketotic hyperglycinemia, measurement of glycine within the plasma and cerebral spinal fluid (evaluating for an abnormal CSF-to-plasma glycine ratio), magnetic resonance imaging of the brain (evaluating for diffusion restriction in the infratentorial regions (posterior limb of the internal capsule, anterior brain stem, posterior tegmental tracts, cerebellum) before the age of 3 months and generalized diffusion restriction of the supratentorial white matter after 3 months; brain magnetic resonance spectroscopy; molecular genetic testing; and rarely, analysis of enzymatic activity.[15][17][18] If the patient has a seizure activity, additional testing may include an electroencephalogram.[15]

Treatment / Management

There are no effective treatment strategies that alter the natural history of nonketotic hyperglycinemia.[1][19] Treatment is thus focused on reducing plasma glycine concentration by initiating sodium benzoate and utilizing N-methyl-D-aspartate receptor site antagonists (i.e., dextromethorphan, oral ketamine) to reduce glycinergic stimulation.[19][20] These therapies have resulted in an improvement in seizure control and neurodevelopmental outcomes in selected populations with nonketotic hyperglycinemia.[4]

After establishing the diagnosis of nonketotic hyperglycinemia, the patient will require routine developmental assessments, orthopedic evaluation for scoliosis and hip dislocation as they age, and routine ophthalmologic evaluation to determine the presence of cortical blindness.[21][22][23] The patient may develop pulmonary hypertension, thus requiring cardiology evaluation to determine if the patient requires pharmacological therapy.[24][25] A gastrointestinal referral may be necessary to determine if enteral access is needed for nutrition.[21] These patients often need long-term antiepileptic maintenance therapy with antiepileptic therapy, diet, and surgical interventions (i.e., vagal nerve stimulator).[24]

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 (i.e., hypoglycemia), hypoxia, intracranial hemorrhage, sepsis, thrombosis, neonatal epilepsy syndromes, congenital brain malformations.[26][27][28][29][30]

During 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:

  1. Medications (particularly valproate which is known to decrease glycine cleavage enzyme system activity) [31]
  2. Artificial elevation due to laboratory sampling technique [31]
  3. Starvation [31]
  4. Use of glycine-containing fluids (i.e., bladder irrigation fluid) [31]
  5. Transient glycine encephalopathy due to intracerebral hemorrhage or hypoxic-ischemic injury [31][32]
  6. Transient glycine encephalopathy due to immaturity of the glycine cleavage enzyme system [33]
  7. Hyperglycinuria (due to defects in the renal transport of glycine including familial iminoglycinuria or benign hyperglycinuria) [31]

There are inherited metabolic conditions that resemble nonketotic hyperglycinemia, but have different pathophysiologic mechanisms and may require different treatment strategies. These include: 

  1. Organic acidurias [34]
  2. Pyridoxine dependent epilepsy [35]
  3. Disorders of intracellular cobalamin metabolism [36]
  4. GLYT1 encephalopathy [37]
  5. Lipoate deficiency [38]

Prognosis

Prognosis is dependent on the amount of glycine cleavage enzyme system activity.[39] Severe deficiencies in this enzyme result in the presentation during the neonatal period, which is associated with a poor prognosis due to life-threatening apnea.[39][40] In neonates where spontaneous breathing is reestablished, these patients may develop progressive lethargy, encephalopathy, and death. Others are marred by a lifetime of severe developmental impairment and intractable epilepsy.[41][42] Patients who present later in life (3 months or later) likely have attenuated glycine cleavage enzyme activity.[39] There developmental progress and severity of epilepsy vary depending on when it is recognized and if early treatment is initiated.[4]

Complications

When this disease presents in neonates, the patient may develop severe apnea resulting in acute hypoxemic respiratory failure requiring respiratory support.[39][41] In patients where respiratory failure resolves, the patient will likely develop progressive lethargy, encephalopathy. Some patients may live for several years though death can occur depending on the severity of the disease.[25][39][41] In those that survive or present later in life (3 months or later), the severity of the disease varies.[39][41] They may be marred by a lifetime of no or limited developmental progress, intractable epilepsy, pulmonary hypertension, dysphagia, and dysmotility requiring surgical enteral access, scoliosis, and hip dislocation due to spasticity, cortical blindness.[21][22][24][25]

Deterrence and Patient Education

Parents should be counseled on the prognosis of nonketotic hyperglycinemia, particularly the possibility of neurologic impairments in patients who survive.[25]

In patients who develop long-term epilepsy, the parents should have higher vigilance in situations (i.e., ensure adequate supervision) where if seizure activity occurs, the dangers can be compounded.[43]

Genetic counseling may be required to help parents and siblings of a child with nonketotic hyperglycinemia understand the genetic risks to help make informed future medical and personal decisions.[44]

Enhancing Healthcare Team Outcomes

The diagnosis and management of nonketotic hyperglycinemia require an interprofessional approach to avoid the complications from underrecognition of clinical seizures and ensuring 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.[45] [Level 4]

Pediatric neurology should be consulted to evaluate the patient and confirm the diagnosis of seizures.[45] [Level 4]

A metabolic specialist should be consulted to ensure the patient receives an appropriate evaluation and initiation of therapy.[46] [Level 4]

The patient’s parents should be referred to genetic counseling to determine the genetic risk for medical and personal reasons.[44] [Level 4]

Finally, patients with severe nonketotic hyperglycinemia should be referred to a pediatric palliative care specialist as these children have a poor neurologic prognosis, and families may let to withdraw critical care support.[25] [Level 4] 


References

[1] Iqbal M,Prasad M,Mordekar SR, Nonketotic hyperglycinemia case series. Journal of pediatric neurosciences. 2015 Oct-Dec;     [PubMed PMID: 26962342]
[2] Poothrikovil RP,Al Thihli K,Al Futaisi A,Al Murshidi F, Nonketotic Hyperglycinemia: Two Case Reports and Review. The Neurodiagnostic journal. 2019;     [PubMed PMID: 31433733]
[3] Tada K,Narisawa K,Yoshida T,Konno T,Yokoyama Y, Hyperglycinemia: a defect in glycine cleavage reaction. The Tohoku journal of experimental medicine. 1969 Jul;     [PubMed PMID: 5307488]
[4] 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]
[5] Lim YT,Mankad K,Kinali M,Tan AP, Neuroimaging Spectrum of Inherited Neurotransmitter Disorders. Neuropediatrics. 2020 Feb;     [PubMed PMID: 31634934]
[6] 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;     [PubMed PMID: 16450403]
[7] Coughlin 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]
[8] Applegarth DA,Toone JR,Lowry RB, Incidence of inborn errors of metabolism in British Columbia, 1969-1996. Pediatrics. 2000 Jan;     [PubMed PMID: 10617747]
[9] von Wendt L,Hirvasniemi A,Similä S, Nonketotic hyperglycinemia. A genetic study of 13 Finnish families. Clinical genetics. 1979 May;     [PubMed PMID: 445864]
[10] 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;     [PubMed PMID: 25533534]
[11] Subramanian 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]
[12] McDonald JW,Johnston MV, Excitatory amino acid neurotoxicity in the developing brain. NIDA research monograph. 1993;     [PubMed PMID: 8232513]
[13] McDonald JW,Johnston MV, Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain research. Brain research reviews. 1990 Jan-Apr;     [PubMed PMID: 2163714]
[14] Korman 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;     [PubMed PMID: 16404748]
[15] Almannai 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;     [PubMed PMID: 29502914]
[16] 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]
[17] 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;     [PubMed PMID: 30737808]
[18] 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;     [PubMed PMID: 30559706]
[19] 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;     [PubMed PMID: 16151895]
[20] Alemzadeh R,Gammeltoft K,Matteson K, Efficacy of low-dose dextromethorphan in the treatment of nonketotic hyperglycinemia. Pediatrics. 1996 Jun;     [PubMed PMID: 8657542]
[21] 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;     [PubMed PMID: 23814620]
[22] Markand ON,Garg BP,Brandt IK, Nonketotic hyperglycinemia: electroencephalographic and evoked potential abnormalities. Neurology. 1982 Feb;     [PubMed PMID: 6798489]
[23] 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;     [PubMed PMID: 10870920]
[24] Cataltepe 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]
[25] Boneh 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]
[26] Soul JS, Acute symptomatic seizures in term neonates: Etiologies and treatments. Seminars in fetal     [PubMed PMID: 29433814]
[27] 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, Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study. The Journal of pediatrics. 2016 Jul;     [PubMed PMID: 27106855]
[28] 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;     [PubMed PMID: 19663912]
[29] Yamamoto H,Okumura A,Fukuda M, Epilepsies and epileptic syndromes starting in the neonatal period. Brain     [PubMed PMID: 21067877]
[30] Shellhaas RA,Wusthoff CJ,Tsuchida TN,Glass HC,Chu CJ,Massey SL,Soul JS,Wiwattanadittakun N,Abend NS,Cilio MR, Profile of neonatal epilepsies: Characteristics of a prospective US cohort. Neurology. 2017 Aug 29;     [PubMed PMID: 28733343]
[31] Korman SH,Gutman A, Pitfalls in the diagnosis of glycine encephalopathy (non-ketotic hyperglycinemia). Developmental medicine and child neurology. 2002 Oct;     [PubMed PMID: 12418798]
[32] 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;     [PubMed PMID: 21335543]
[33] Aliefendio─člu D,Tana Aslan Ay,Co┼čkun T,Dursun A,Cakmak FN,Kesimer M, Transient nonketotic hyperglycinemia: two case reports and literature review. Pediatric neurology. 2003 Feb;     [PubMed PMID: 12699870]
[34] Hayasaka 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]
[35] Maeda 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]
[36] Scalais 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;     [PubMed PMID: 28363510]
[37] Alfallaj R,Alfadhel M, Glycine Transporter 1 Encephalopathy From Biochemical Pathway to Clinical Disease: Review. Child neurology open. 2019;     [PubMed PMID: 30815509]
[38] 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;     [PubMed PMID: 24334290]
[39] Swanson 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]
[40] 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;     [PubMed PMID: 15032382]
[41] Suzuki Y,Kure S,Oota M,Hino H,Fukuda M, Nonketotic hyperglycinemia: proposal of a diagnostic and treatment strategy. Pediatric neurology. 2010 Sep;     [PubMed PMID: 20691948]
[42] Cusmai 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;     [PubMed PMID: 22261077]
[43] Howard GM,Radloff M,Sevier TL, Epilepsy and sports participation. Current sports medicine reports. 2004 Feb;     [PubMed PMID: 14728909]
[44] 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;     [PubMed PMID: 22532538]
[45] Mulkey SB,Swearingen CJ, Advancing neurologic care in the neonatal intensive care unit with a neonatal neurologist. Journal of child neurology. 2014 Jan;     [PubMed PMID: 23271754]
[46] Sharma S,Prasad AN, Inborn Errors of Metabolism and Epilepsy: Current Understanding, Diagnosis, and Treatment Approaches. International journal of molecular sciences. 2017 Jul 2;     [PubMed PMID: 28671587]