Clinical Diagnosis

Neonates or infants presenting with hypotonia, unexplained coma, and seizures and children with seizures, hypotonia, and developmental delay should be suspected of having glycine encephalopathy (nonketotic hyperglycinemia, NKH).

Testing

For laboratories offering biochemical testing, see .

Enzyme Testing: Glycine Cleavage Enzyme (GCS) Activity

Affected individuals. The diagnosis of glycine encephalopathy may be confirmed on a clinical basis only by measurement of glycine cleavage enzyme (GCS) activity in liver. In its major degradative pathway, glycine is metabolized by GCS (see Figure 1).

Figure

Figure 1. Metabolism of glycine by glycine cleavage enzyme (GCS). Glycine enters the four-protein enzyme complex at the lower left, where it is decarboxylated by the P-protein (also known as glycine decarboxylase). A defect of the P-, H-, or T-proteins (more...)

Reliable enzymatic confirmation of the diagnosis of glycine encephalopathy requires 80 mg of liver to measure the activity of the glycine cleavage enzyme GCS. Liver is usually obtained by surgical endoscopy as a wedge biopsy or as soon as possible at autopsy. The enzyme is labile and rapid processing and deep freezing are essential for proper enzyme assay.

• The vast majority of affected individuals have no detectable enzyme activity.

• Patients with a T-protein defect tend to have activity up to 25% of normal values.

• Patients with a P-protein defect do not tend to have residual activity [Toone et al 2000] except for some very mildly affected patients. The highest residual activity of an affected individual tested in one series is 0.4 units (normal 2.1-11.9) [Steiner et al 1996].

Note: Although enzymatic confirmation of glycine encephalopathy using Epstein-Barr virus cultured lymphoblasts from peripheral blood samples was reported in six individuals with P-protein defects, others have obtained overlapping GCS enzyme activity in both controls and individuals with glycine encephalopathy, making this method unreliable [Applegarth et al 2000b].

Carriers

• The initial report of measurement of GCS enzyme activity in lymphoblasts included ten obligate heterozygotes for P-protein deficiency. A subsequent report showed overlap of GCS enzyme activity in lymphoblasts in normals and carriers [Kure et al 1999], making this assay unreliable.

• No attempts have been made to measure GCS enzyme activity in liver biopsies from obligate heterozygotes.

Molecular Genetic Testing

Genes. Three genes are currently known to be associated with glycine encephalopathy:

• GLDC (encoding the P-protein component of the glycine cleavage system [GCS] complex). Mutations in this gene account for approximately 70%-75% of glycine encephalopathy [Toone et al 2000, Kure et al 2006a].

• AMT (encoding the T-protein component of the GCS complex). Mutations in this gene account for approximately 20% of glycine encephalopathy.

• GCSH (encoding the H-protein component of the GCS complex). Only one individual was identified with deficient H-protein enzyme activity in 1981; however, no mutation was identified in the comprehensive analysis of mutations by Kure et al [2006a].

Other genes. Up to 5% of persons with deficient glycine cleavage enzyme activity do not have a mutation in any of the three genes known to cause glycine encephalopathy. These patients are candidates for mutations in genes encoding proteins involved in the addition of the cofactors lipoyl (lipoyltransferase II and lipoyl-CoA synthase) and pyridoxal-P (see Differential Diagnosis) and in the transport of glycine into the astrocyte (GLYT1) where the enzyme is located.

Clinical testing

• Sequence analysis. Mutations are identified in one of the three known genes associated with glycine encephalopathy in about 95% of individuals with this clinical diagnosis.

  • GLDC. The clinical experience to date suggests that in non-consanguineous families the affected individual is likely to be a compound heterozygote.

• Deletion/duplication analysis. Approximately 20% of GLDC mutant alleles have exonic/multiexonic deletions or duplications [Kanno et al 2007]. These occur on various haplotypes and in different ethnic groups. They appear to arise as a result of nonhomologous allelic recombination of Alu repeats. Current methods used for the detection of deletions include heterozygosity testing (the analysis of intragenic SNPs in the affected child and his/her biological parents), which detects half of the known deletions, and MLPA (multiplex ligation-dependent probe amplification).

Table 2. Summary of Molecular Genetic Testing Used in Glycine Encephalopathy

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Gene Symbol	Test Method	Mutations Detected	Proportion of Glycine Encephalopathy Attributed to Mutations in This Gene	Mutation Detection Frequency by Gene and Test Method	Test Availability
GLDC	Sequence analysis	Sequence variants	70%-75%	>91% of alleles	Clinical
	Deletion/duplication analysis 1	Exonic and whole gene deletions		~20% 2
AMT	Sequence analysis	Sequence variants	20%	97% of alleles	Clinical
GCSH	Sequence analysis	Sequence variants	<1%	Unknown	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. Testing that identifies deletions not readily detectable by sequence analysis of genomic DNA. A variety of methods may be used; methods in current use include multiplex ligation-dependent probe amplification (MLPA) and heterozygosity testing.

2. Sensitivity is increasing as new test methods (e.g., MLPA) to detect deletions are developed.

Interpretation of test results

• For issues to consider in interpretation of sequence analysis results, click here.

• When two apparent disease-causing alleles have been identified in a proband, parental samples should be obtained in a timely manner to ensure proper identification of both alleles. Patients who seemed to have two GLDC mutations or two AMT mutations have turned out to have both mutations on the same parental allele with an unrecognized deletion on the second allele [Author, personal observation], a situation which can cause serious problems during prenatal testing unless recognized ahead of time.

Testing Strategy

To confirm the diagnosis in a proband who has elevated glycine concentrations in the CSF and plasma consistent with glycine encephalopathy, either (1) molecular genetic testing to identify mutations in GLDC or AMT or (2) enzymatic testing can be performed; molecular genetic testing is often done first because it is noninvasive.

• The glycine exchange assay can guide which gene should be analyzed first. The presence of residual GCS enzyme activity in liver on the glycine cleavage enzyme assay also favors an AMT mutation.

• In the absence of information from the glycine exchange assay, AMT is usually sequenced first (because it comprises only nine exons), followed by sequence analysis of GLDC.

• If no mutation is identified on sequence analysis of either gene, deletion testing of GLDC should be undertaken.

• If only a single mutation is identified in either gene, assay of enzyme activity is necessary to confirm the diagnosis.

Fifty percent of individuals with residual GCS enzyme activity in liver or lymphoblasts on postnatal studies and/or increased amniotic fluid glycine/serine ratio with a normal glycine amniotic fluid concentration on prenatal studies have AMT mutations [Toone et al 2003].

Note: The order in which testing is used in establishing the diagnosis of a symptomatic individual greatly differs according to clinical circumstances. For example, when the patient is deceased and a rapid postmortem liver biopsy is available, the first test is GCS enzyme assay to confirm the diagnosis followed by glycine exchange assay to guide molecular genetic testing.

Carrier testing for at-risk relatives requires identification of the disease-causing mutations in an affected family member.

Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis for at-risk pregnancies is possible by either molecular genetic testing or GCS enzyme assay.

• Molecular genetic testing. Use of molecular genetic testing in prenatal diagnosis requires identification of the two disease-causing mutations in the family.
  
  Note: If the causative gene has been properly assigned but only a single mutation has been identified and if material from the proband and both parents is available, a battery of intragenic SNPs can often be used to provide intragenic linkage analysis.

• GCS enzyme activity. If the causative gene has not been assigned, intragenic SNPs are not informative, or parental samples are not available, prenatal diagnosis is possible by assay of GCS enzyme activity in uncultured CVS material.
  
  Note: Prenatal diagnosis by GCS enzyme assay has at least a 1% false negative rate [Applegarth et al 2000b]. The false negative cases seem particularly to involve T-protein deficiency or mildly affected cases, in which residual GCS enzyme activity is present and overlap has been observed between affected individuals and carriers in the range of enzyme activity.

Preimplantation genetic diagnosis (PGD) requires identification of the disease-causing mutations in the family.

Genetically Related Disorders

No other phenotypes are known to be associated with mutations in the GLDC, AMT, or GCSH genes.

L-protein deficiency. Individuals with L-protein deficiency present with a variant form of branched chain amino acidemia (maple syrup urine disease, or MSUD) rather than glycine encephalopathy.

PNPO deficiency. Patients with deficiency in the PNPO gene, encoding the pyridox(am)ine 5’-phosphate oxidase gene, have deficient glycine cleavage enzyme activity as a result of insufficient cofactor pyridoxal-5-phosphate for the P-protein. They present in the neonatal period with severe seizures, burst suppression pattern, coma, and sometimes apnea, providing a phenotypic overlap. They respond clinically to treatment with pyridoxal-5’-phosphate (but not to pyridoxine). Biochemically, patients can have elevated glycine, but they also have elevated threonine concentration in plasma and CSF and may have decreased monoamine metabolites [Clayton et al 2003, Mills et al 2005, Hoffmann et al 2007]. Levels of pyridoxal-5’-phosphate in CSF are low.

Natural History

Glycine encephalopathy, also known as nonketotic hyperglycinemia (NKH), is an inborn error of glycine metabolism in which large quantities of glycine accumulate in all body tissues, including the brain. Children with typical disease can present in the neonatal period or in infancy. They can progress to develop a severe form of the disease (developmental quotient [DQ] <20) or a milder form of the disease (DQ >20). Classification of the typical disease is thus based on both age at initial presentation and ultimate clinical outcome and includes the following categories: neonatal severe, neonatal mild, infantile mild, and infantile severe [Hennermann 2006, Hennermann et al 2006]. Several atypical forms exist, usually with later presentation.

The majority of individuals with glycine encephalopathy present as neonates. Of those presenting as neonates, 85% have the neonatal severe form and 15% have the neonatal mild form. Of those presenting in infancy, 50% have the infantile mild form and 50% have the infantile severe form. Overall, 20% of all infants presenting in either the neonatal or the infantile period have a mild outcome [Hoover-Fong et al 2004, Hennermann et al 2006].

Neonatal (classic) presentation. The neonatal form of glycine encephalopathy manifests in the first hours to days of life with progressive lethargy, hypotonia, and myoclonic jerks leading to apnea and often death if not supported by intubation and ventilation. The vast majority of infants regain spontaneous respiration within the first three weeks of life. Many, but not all, show some spontaneous improvement in alertness in the first month of life. They develop further intellectual disability and seizures (see Severe outcome, Mild outcome). The initial EEG usually shows a burst-suppression pattern that evolves into hypsarrhythmia and/or multifocal spikes by about age three months.

Infantile presentation. These infants do not have lethargy and coma in the neonatal period, but often have a history of hypotonia from early on. They present with developmental delay and infantile-onset seizures that can be mild or increasingly difficult to treat.

Severe outcome. Affected individuals do not make developmental progress or at most learn to sit with very limited interaction with their environment (DQ <20). They develop increasingly difficult-to-treat seizures over the first year of life, usually requiring multiple anticonvulsants. They develop progressive and early spasticity with positive Babinski sign before age six months. They have a tendency to develop scoliosis, and often have swallowing dysfunction requiring tube feeding. Some have club feet [Hennermann et al 2006].

Mild outcome. Affected individuals make developmental progress to a variable degree (DQ 20-65). They can learn to walk, have sign language, and interact with caregivers and attend special education classes. In a recent retrospective study of 65 individuals with NKH, up to 20% of surviving children learned to walk and say or sign words [Hoover-Fong et al 2004]. They have little spasticity. They develop a seizure disorder, which is often relatively easy to treat with either benzoate or dextromethorphan alone or with the addition of a single anticonvulsant [Van Hove et al 2005] (see Management). Patients tend to be hyperactive [Wiltshire et al 2000, Hennermann 2006]. They usually have choreic movements, which is a good prognostic sign [Hall & Ringel 2004, Hennermann 2006, Hennermann et al 2006].

Note: The clinical spectrum of the condition is continuous and occasionally patients have an outcome intermediate between severe and mild. The best outcome ever reported is normal intelligence, only observed in persons with a genotype associated with residual enzyme activity (Ala802Val) who received early and aggressive treatment in the first two years of life [Korman et al 2004].

MRI may be normal. In infants with neonatal presentation and severe outcome, brain malformations may be observed, the most common of which is thinning or agenesis of the corpus callosum. Delayed myelination and atrophy are later findings. Less common findings include retrocerebellar cyst with subsequent development of hydrocephalus [Van Hove et al 2000], gyral simplification [Van Hove, unpublished observations], and rarely, gyral malformations. In most cases, diffusion-weighted MR showed high-signal lesions in symmetric weight matter consistent with vacuolating myelin. The lesions are present in myelin that is already myelinated at birth, such as the posterior limb of the internal capsule and long tracts in the brain stem [Khong et al 2003, Seo et al 2003, Sener 2003].

MRS can show an elevated peak consistent with glycine on long echo time, usually present in those with a severe outcome.

Atypical forms range from milder disease, with onset from late infancy to adulthood, to rapidly progressing and severe disease with late onset.

The mild episodic form was reported in four children with mild intellectual disability and episodes of chorea, agitated delirium, and vertical gaze palsy associated with febrile illness [Steiner et al 1996]. One individual had confirmed GCS deficiency [Steiner et al 1996]. An adult with the mild-episodic form experienced acute decompensation while on valproate (which is contraindicated in this disorder because it raises serum glycine concentration) [Hall & Ringel 2004].

The late-onset form has been described in seven individuals: four had spastic paraparesis and optic atrophy without seizures or cognitive impairment, two had mild intellectual disability with choreoathetosis, and one had severe intellectual disability and rare seizures.

Progressive neurologic deterioration with pulmonary hypertension. Two unrelated children who developed pulmonary hypertension with progressive neuronal deterioration and vacuolating leukoencephalopathy died before age 18 months. Both had normal EEGs and no seizures. GCS enzyme activity in frozen liver was abnormal, but no mutations in GLDC, AMT, or GCSH were identified [Riudor et al 2001, del Toro et al 2006].

Intrafamilial variability. Discordance between affected children in the same family was reported for age at presentation, the clinical severity of disease, and/or CSF glycine concentration [Applegarth et al 2000b]; however, more recently a retrospective study showed a consistent phenotype within seven families with two or more affected children [Hoover-Fong et al 2004]. The familial concordance for outcome has been observed in several additional families [Wiltshire et al 2000; Van Hove, Scharer, Hennermann, unpublished observations].

Genotype-Phenotype Correlations

Preliminary data suggest that the severity of the mutation is predictive for the outcome of the disease, but not for the age at presentation. Mutations associated with residual enzyme activity seem to be associated with mild outcome, and two mutations with no residual enzyme activity seem to be associated with severe outcome. However, the usually private nature of many mutations and the early demise without evaluation of ultimate neurodevelopmental outcome makes genotype-phenotype correlations difficult.

Prevalence

The birth incidence of glycine encephalopathy is1:55,000 newborns in Finland (1:12,000 in an area of Northern Finland) and 1:63,000 in British Columbia, Canada [Applegarth et al 2000a].

Because it is often the finding of an increased plasma glycine concentration that triggers the request for measurement of CSF glycine concentration, glycine encephalopathy may be underdiagnosed.

Several different mutations in GLDC and AMT account for the high incidence of glycine encephalopathy in several small consanguineous Arab villages in Israel [Boneh et al 2005, Korman et al 2005]. A recurrent mutation is present in New Zealand Maori [Van Hove et al 2007, Wilson et al 2007] and in southern part of the Netherlands [Van Hove et al 2007].

The calculated carrier frequency is approximately 1:125 in the British Columbia, Canada population (a predominantly Caucasian population at the time of data collection for disease incidence).

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with glycine encephalopathy, the following evaluations are recommended:

• MRI of the brain in neonates. The presence of brain malformations is a prognostic indicator of severe outcome. Abnormalities in the posterior fossa should raise suspicion for the development of hydocephalus. In a single case study, Mourmans et al [2006] showed that serial follow-up of the diffusion weighted images/apparent diffusion coefficient (ADC) and the diffusion tensor images can provide evidence for the progressive loss of axonal structures seen in children with severe outcome.

• EEG. The presence of a burst suppression pattern, rather than multifocal seizures, is a poor prognostic indicator. Preliminary evidence indicates that in children with a genotype associated with some residual enzyme activity, treatment of the glycine encephalopathy to prevent or correct burst suppression and hypsarrhythmia results in improved outcome [Korman et al 2004; Dyack, personal communication].

• Developmental assessment should be performed throughout the first years of life.

• Neurologic assessment in the first year can identify early development of spasticity in severely affected patients and of chorea in more mildly affected patients.

Treatment of Manifestations

No effective treatment for severe glycine encephalopathy exists. Circumstantial evidence is however accumulating that in patients with mutations associated with residual enzyme activity, but not in patients with two severe mutations [Korman et al 2006], early and aggressive treatment (benzoate and NMDA receptor blockade) in the first two years of life results in improved neurodevelopmental outcome as compared to late-treated or untreated controls (e.g., siblings) [Korman et al 2004; Flusser et al 2005; Dyack, personal communication].

Current treatment of glycine encephalopathy consists of reduction of plasma concentration of glycine through treatment with sodium benzoate and blocking of glycinergic receptors, most commonly at the N-methyl D-aspartate (NMDA) receptor site.

Sodium benzoate. Oral administration of sodium benzoate at doses of 250-750 mg/kg/day can reduce the plasma glycine concentration into the normal range (see Table 1); however, this treatment does not normalize CSF glycine concentration. Lowering the plasma glycine concentration into the low normal range (between 120 and 300 µmol/L) is often required in order to observe beneficial effects. Benzoate is also a useful anticonvulsant agent in this disorder; it increases alertness. In more mildly affected individuals, it may also improve behavior.

The dose of sodium benzoate required varies and thus must be tailored to the individual patient. The dose should be gradually increased (usually by 50 mg/kg/day) until the plasma glycine concentration is within treatment range. The higher dose of this range (500-750 mg/kg/day) is frequently associated with gastritis, which may require oral administration of antacids, H2 antagonists, or proton pump inhibitors.

• Patients with a mild form of the disease require a lower dose (200-450 mg/kg/day)

• Patients with a severe form of the disease require a higher dose (between 550 and 750 mg/kg/day) [Van Hove et al 2005].

Overdosing with more than the sodium benzoate required for an individual is dangerous [Van Hove et al 2005]. Hypocalcemia and low plasma glycine concentration (<150 µmol/L) are frequent early signs of benzoate overdose. Measurement of plasma benzoate concentration can be helpful in evaluating potential toxicity.

NMDA receptor site antagonists. Antagonists at the NMDA receptor site include dextromethorphan, ketamine, and felbamate. Use of each has resulted in improved seizure control. Antagonism of a presumably overstimulated N-methyl-D-aspartate (NMDA) receptor channel complex with use of dextromethorphan, ketamine, or felbamate has been of limited benefit to the ultimate neurodevelopmental outcome of severely affected children; this may be different in mildly affected children.

Dextromethorphan doses commonly range from five to 15 mg/kg/day, but individual variability is substantial. Blood concentration can be monitored; the therapeutic level is not defined, but should be greater than 0 and lower than 100 nmol/L. Overdose of dextromethorphan causes increased sleepiness and while awake, more movement.

Note: Cimetidine slows the metabolism of dextromethorphan and should not be used in dextromethorphan slow metabolizers (a separate pharmacogenetic phenotype) as it may cause toxicity.

Antiepileptic drugs. Seizure control is important for symptomatic benefit. Control of severe seizure disorders such as burst suppression pattern or hypsarrhythmia tends to favor developmental progress. Children with myoclonic seizures, such as newborns and infants, may benefit from benzodiazepines. Standard antiepileptic drugs (AEDs) such as phenobarbital or phenytoin have limited efficacy for control of the seizures of glycine encephalopathy by themselves in neonates with this condition. However, because the nature of the epilepsy changes in late infancy, phenobarbital is often useful in seizures in older affected children. Various antiepileptic drugs have been used with variable success. Felbamate has been successfully used in some children with hard to treat seizures. This treatment must be closely monitored for signs of liver or hematopoietic toxicity.

Other. Gastrostomy tube placement should be considered early on in the management of patients with swallowing dysfunction associated with severe disease.

Gastroesophageal reflux is common, and a Nissen procedure can be very helpful in reducing the risk of aspiration pneumonia.

Most affected individuals need physical therapy.

Scoliosis is managed with standard techniques.

Prevention of Primary Manifestations

There is no way to prevent primary manifestations of this disorder. Note: The effect of therapy in mildly affected children with mutations that provide residual activity is still under investigation.

Prevention of Secondary Complications

Patients on sodium benzoate should have plasma carnitine concentration monitored. Those with free carnitine below the lower limit of normal should receive supplementation to maintain normal plasma concentrations.

Surveillance

Developmental assessment should be performed throughout the first years of life.

Neurologic assessments in the first year can identify early development of spasticity in severely affected patients and early development of chorea in more mildly affected patients.

Severely affected individuals should be monitored for scoliosis.

Agents/Circumstances to Avoid

Valproate is contraindicated in glycine encephalopathy as an antiepileptic drug (AED). It raises blood and CSF glycine concentrations and may increase seizure frequency. It has resulted in severe lethargy, coma, severe seizures, and chorea particularly in mildly affected patients [Hall & Ringel 2004; Author, personal observation].

Testing of Relatives at Risk

Molecular genetic testing and/or biochemical testing of at-risk symptomatic sibs is recommended to promote early diagnosis and treatment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

New therapies under investigation include early use of felbamate and memantine, another NMDA receptor site antagonist.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Strychnine improves tone and respiration but has been abandoned because of serious side effects on long-term use.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Glycine encephalopathy is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes and therefore carry one mutant allele.

• Heterozygotes are asymptomatic.

• Rarely, de novo mutations have been observed. Where possible, carrier status in parents should be confirmed by testing rather than automatically inferred.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

• Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.

• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Most individuals with glycine encephalopathy do not reproduce. However, some individuals with milder forms may be fertile. Pregnancy has been reported in one patient with mild glycine encephalopathy. There was no obvious teratogenic effect [Ellaway et al 2001].

The offspring of affected individuals are obligate heterozygotes (carriers) for a disease-causing mutation.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing using molecular genetic techniques is available on a clinical basis once the mutations have been identified in the family.

Reliable carrier testing using biochemical methodology is not available.

Related Genetic Counseling Issues

Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Before prenatal testing can be performed, either (1) both disease-causing alleles present in the family or (2) at least one clear-cut mutation and multiple informative intragenic SNPs must be identified

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Biochemical testing. Earlier prenatal testing using measurement of amniotic fluid glycine concentration and the glycine/serine ratio was unreliable because normal and affected values overlapped.

Enzymatic testing. Early prenatal diagnosis by enzyme activity measurement in uncultured CVS is available clinically. It carries a 1% false negative rate. This is most likely in patients with T-protein disease or in mildly affected patients, in which the assay can have residual activity and discrimination from carriers is difficult. Enzymatic testing is the preferred method in cases for which molecular testing is unavailable.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see .

Literature Cited

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Suggested Reading

1. Hamosh A, Johnston MV. Nonketotic hyperglycinemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York: McGraw-Hill. Chap 90. Available at www.ommbid.com. Accessed 11-10-09.

Author History

Derek A Applegarth, PhD, FCCMG; University of British Columbia (2002-2005)
Ada Hamosh, MD, MPH (2002-present)
Gunter Scharer, MD, PhD (2009-present)
Jennifer Toone, BSc, RT; Children's and Women's Health Centre of British Columbia (2002-2005)
Johan Van Hove, MD, PhD (2009-present)

Acknowledgments

The authors thank Julia Hennermann, MD, Berlin, for continuing collaboration on the clinical phenotype and Drs. Rolland, Hutchin, and Kure for collaboration on the molecular basis.

Revision History

• 24 November 2009 (me) Comprehensive update posted live

• 26 July 2005 (ah) Revision: molecular genetic testing clinically available

• 14 December 2004 (me) Comprehensive update posted to live Web site

• 16 May 2003 (cd) Revision: enzymatic prenatal testing no longer available

• 14 November 2002 (me) Review posted to live Web site

• 7 March 2002 (da) Original submission