Pediatrics

Non ketotic hyperglycinemia

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Non-Ketotic Hyperglycinemia? What are the typical findings for this disease?

There are certain signs and symptoms which should raise the question 'does my patient have NKH?'. Patients are typically infants with the following:

  1. Hypotonia

  2. Myoclonic jerks/seizures

  3. Coma

Classic EEG finding: Burst Suppression

Key laboratory findings: Elevated CSF to serum glycine level

What other disease/condition shares some of these symptoms?

Diseases/conditions that can mimic Non-Ketotic Hyperglycinemia:

1. Hypoxic ischemic encephalopathy presenting with seizures and coma.

2. Medications such as valproic acid and barbiturates which cause the elevation of glycine and burst suppression on EEG respectively.

3. Transient glycine encephalopathy in general, as it is a condition with seizures, burst suppression on EEG and transient biochemical features suggestive of NKH. This condition originally described by Boneh in 1996 remains controversial. Some literature reports that patients with this condition are carriers of mutations of the GLDC gene, which is the gene involved in NKH. Patients with this condition have only transient elevations of glycine in the CSF and plasma.

4. Organic acidemias i.e. methylmalonic acidemia, isovalaric acidmia and propionic acidemia may all cause elevations of glycine, however they are seen with a ketosis.

5. Elevations of glycine may be seen in the urine of patients with type I or type II hyperprolinemia, benign hyperglycinuria, or familial iminoglycinuria.

6. Pyridoximine 5' phosphate oxidase deficiency giving rise to seizures produces a burst suppression on EEG, however, seizures respond when pyridoxal-5'-phospate is administered.

7. Other Inborn errors of metabolism giving rise to neonatal seizures such as peroxisome disorders, molybenum cofactor deficiency, Vitamin B6 and B9 dependent seizures, and phosphoglycerate dehydrogenase deficiency.

8. Hypothermia may lead to burst suppression on EEG creating a finding similarly found in glycine encephalopathy.

What caused this disease to develop at this time?

  • Most patients present in the neonatal period. Greater than 80% of patients presenting in this time have a severe form of NKH and approximately 15% have a milder form of the disease. Of those presenting later in infancy roughly half present with the severe form and half with a milder form. Atypical forms of the disease may arise in childhood and adulthood but this form is much less common.

  • Homozygous inheritance of mutations in one of the three known genes associated with glycine encephalopathy and components of the glycine cleavage system [GCS] i.e. GLCD (the P-protein component of GCS), AMT (the T-protein of GCS), and GCSH (the H-protein component of GCS).

  • Potentially, inheritance of mutations in cofactors of the GCS complex i.e. lipolytranserase II, pyridoxal-P, and GLYT1 an enzyme involved in transporting glycine into the astrocyte, may be found.

  • Exposure to valproic acid and barbiturates which may exacerbate the presentation by increasing glycine levels.

  • Epidemiologic studies have revealed the incidence of glycine encephalopathy in Finland is 1/55,000 newborns and a similar study in British Columbia, Canada revealed the incidence to be 1/63,000. Several mutations have been identified in consanguineous Arab and Israeli populations. A distinct mutation is present in New Zealand and the southern part of the Netherlands.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Key laboratory testing to evaluate a patient suspected of NKH include simultaneous CSF and plasma amino acids to determine the glycine ratio. The diagnosis of NKH requires simultaneous (within an hour or two) plasma amino and CSF amino acids.

  • An EEG should also be performed and assessed with the administration of B-complex vitamins B6, B9.

Would imaging studies be helpful? If so, which ones?

  • A head ultrasound should be done to rule out a bleed, ischemia or areas of calcification as potential causes for the clinical presentation. After this is performed a magnetic resonance imaging (MRI) and computed tomography (CT) is necessary to assess for other causes of seizure.

Confirming the diagnosis

  • In any neonate presenting with hypotonia, unexplained coma, and seizures, or in children with seizures, hypotonia, and developmental delay, nonketotic hyperglycinemia should be considered. The first step in this diagnosis is measurement of plasma, CSF and urine for glycine. Individuals with NKH have elevation of glycine. CSF and plasma should be measured as close in time to each other as possible. An isolated elevation of CSF glycine and resulting abnormal CSF to plasma glycine ratio suggests the diagnosis of NKH. A bloody tap invalidates the results and attempts to use correction factors should only be done by a biochemical geneticist (See Table I).

  • Enzymatic activity of the GCS in the liver may confirm the diagnosis on a clinical basis if CSF and plasma findings are abnormal. 80mg of liver are necessary to measure activity of the GCS. 200mg of liver is necessary to perform glycine exchange assay and the glycine cleavage enzyme assay.

  • Mutations in the following genes GLDC, AMT and GCSH are cumulatively found in 95% of patients with glycine cleavage enzyme deficient patients.

  • 13C-glycine breath test is being developed but is not currently available as a clinical test.

If you are able to confirm the patient has Non-Ketotic Hyperglycinemia, what treatment should be initated?

If a diagnosis of NKH is made careful consideration should be given to whether any treatment should be started at all.

There is no effective means of treating severe glycine encephalopathy.

There is some evidence to suggest children with mutations rendering some residual GCS enzyme activity have improved outcome and achieve decreased plasma glycine levels compared to late treated or untreated controls when treated with sodium benzoate.

Sodium benzoate is given by mouth. Doses given range from 250mg/kg/day to 750mg/kg/day and have been shown to reduce the plasma glycine concentration into normal range. Treatment DOES NOT lower CSF glycine concentration. Reflux medications such as proton pump inhibitors and H2 antagonists lead to increased metabolism of benzoate and cause the need for higher dosing.

N-methyl D-aspartate receptor site antagonists also arguably improve outcome when initiated early.

NMDA receptor antagonists such as dextromethorphan, ketamine and felbamate have been used.

Dextromethorophan has been shown to decrease seizures in some patients. Dosing of dextromethorphan ranges from 5 to 15mg/kg/day.

The main intervention which should take place when NKH is highly suspected or confirmed is a family meeting to discuss the natural history of the disease and the option for palliative measures. Effective genetic counseling is crucial and time sensitive.

Other longer term treatments include anti-epileptics (valproic acid should be avoided as it exacerbates symptoms), gastrostomy tube for feeding problems, anti-reflux medications and physical therapy.

What are the adverse effects associated with each treatment option?

NKH is a diagnosis for which the natural history has been described (Hoover-Fong et al 2005). In cases of severe disease any treatment may prolong death and give false hope. Anti-epileptics have a variety of specific possible adverse effects. Valproic acid should be specifically avoided as it exacerbates symptoms. Dextromethorphan is associated with stroke. Hypocalcemia is a significant side effect of sodium benzoate administration.

What are the possible outcomes of Non-Ketotic Hyperglycinemia?

In meeting with a family to discuss NKH it is important to be explicit regarding the natural history of the disease. If a child survives the initial presentation their quality of life will be poor, children are unlikely ever to become mobile, severe seizures are common and extreme behavior problems are present. In addition; scoliosis, feeding problems and mental retardation and severe spasticity are likely.

Children with the severe form of the disease, which represents the majority of cases, have a developmental quotient <20. In cases of milder disease the developmental quotient is maybe greater.

Twenty percent of infants presenting as a neonate or during infancy have a milder outcome.

Patients with the classical neonatal presentation manifest symptoms within the first hours to days of life with progressive lethargy, hypotonia, apnea and death in the absence of aggressive intervention.

Severe cases do not reach developmental milestones. Seizures are the rule and usually require polypharmacy to manage. Other common findings include scoliosis, feeding dysfunction and spasticity.

Patients with milder forms of disease in which some enzymatic activity is present may achieve a developmental quotient somewhere between 20-65. Patients may walk, have limited language and interact with caregivers. In a review of patients with NKH only 20% of children learned to walk and say or sign words. These patients also tended to be hyperactive. Interestingly, patients with choreic movements tended to fare better.

Atypical forms range from mild disease, with onset anytime from infancy to adulthood, to severe unrelenting disease with later onset.

Steiner in 1996 reported 4 children with mild intellectual disability and episodes of chorea, vertical gaze palsy and delirium presenting at the time of a febrile illness. One of these patients was being treated with valproic acid, which was thought to lead to the acute decompensation in the reported patient.

Late onset disease with debilitating sequelae has been described in several individuals. These individuals' manifestations ranged from optic atrophy without seizures or cognitive impairment to mild intellectual disability to severe intellectual disability and seizures.

What causes this disease and how frequent is it?

In consanguineous unions occurring in Arab villages in Israel, mutations in GLDC and AMT account for the high incidence of glycine encephalopathy.

How do these pathogens/genes/exposures cause the disease?

Mutations of genes making up the glycine cleavage complex - i.e. GLDC, AMT and GCSH - may have sequence variants or exonic and whole gene deletions.

What complications might you expect from the disease or treatment of the disease?

As stated previously outcome is poor for patients with classical NKH. Anti-epileptic drugs may exacerbate seizures.

Are additional laboratory studies available; even some that are not widely available?

Children suspected of having NKH should have a full metabolic screen inclusive of plama amino acids, ammonia, CSF amino acids, lactate level, electrolyte panel, urine analysis, an arterial blood gas, fresh urine for sulfites (assessing for molybdenum cofactor deficiency), urine orotic acids, urine amino acids and urine organic acids. Simultaneous (as close in time as possible) CSF amino acids and plasma amino acids are essential to making a diagnosis.

Sequence and deletion testing can be sent after biochemical testing reveals the diagnosis.

How can Non-Ketotic Hyperglycinemia be prevented?

NKH is inherited in an autosomal recessive manner. At conception, each full sibling 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 sibling is known to be unaffected, the chance of his/her being a carrier is 2/3. Most individuals with NKH do not reproduce. Carrier testing and prenatal testing are possible if the disease-causing mutations in the family are known. t2]

What is the evidence?

Applegarth, DA, Toone, JR. "Nonketotic hyperlycinemia (glycine encephalopathy): laboratory diagnosis". Mol Genet Metab. vol. 74. 2001. pp. 139-146.

Boneh, A, Degani Y Harari, M. "Prognostic clues and outcome of early treatment of nonketotic hyperglycinemia". Pediatr Neurol.. vol. 15. 1996. pp. 137-141.

Hamosh, A, Van Hove, J. "Concerns regarding transience and heterozygosity in neonatal hyperglycinemia". Ann Neurol. vol. 53. 2003. pp. 685.

Hennerman, JB. "Clinical variability in glycine encephalopathy". Fut Neurol. vol. 1. 2006. pp. 621-630.

Hoover-Fong, JE, Shah, S, Van Hove, JL, Applegarth, D, Tone, J, Hamosh, A. "Natural history of nonketotic hyperglycinemia in 6 patients". Neurology. vol. 63. 2004. pp. 1847-1853.

Sener, RN. "Nonketotic hyperglycinemia: diffusion magnetic resonance imaging findings". J Comput Assist Tomogr. vol. 27. 2003. pp. 538-540.

Ongoing controversies regarding etiology, diagnosis, treatment

There is debate over treatment and if it should be initiated at all given the poor outcome of patients with NKH.

Korman et al. have reported benefit in using aggressive NMDA receptor blockers and benzoate in the first 2 years of life for individuals with residual enzyme activity. Benefit is reported generally as improved neurodevelopmental outcome compared to late treated controls.

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