Glycine encephalopathy

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Genes: GLDC (HGNC:4313) AMT (HGNC:473)
• Mode(s) of Inheritance: Autosomal Recessive
• Literature Search: 11/18/2024
• Curation Status: Released (1.0.0)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
GLDC	glycine encephalopathy (0011612)	605899	Limited Actionability
AMT	glycine encephalopathy (0011612)	620398	Limited Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric assessing for the attenuated form of the disease only. While individual scores may be different for the severe form, it is expected to have no actionability as a secondary finding.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality due to glycine encephalopathy / Referral to specialist to guide management.	1	3N	1C	2	7NC

Severity of Outcome

Prevalence of the Genetic Condition

The birth incidence of glycine encephalopathy (GCE) has been estimated between 1:55,000 to 1:76,000. An increased incidence has been reported in populations with founder variants.

Clinical Features (Signs / symptoms)

GCE is categorized into severe and attenuated form. Infants with the severe form make no developmental progress and have intractable epilepsy.

Attenuated GCE is characterized by variable developmental progress, and treatable or no epilepsy. Hyperactivity is common, often severe, and poorly responsive to interventions. Many have choreic movements. Individuals can have intermittent episodes of severe lethargy, often triggered by fever and infection.

Other symptoms of GCE can include delayed gastric emptying and poor gastrointestinal mobility. A few individuals (<1%) had sudden severe electrolyte imbalances including profound hypokalemia causing sudden cardiac arrest. A few individuals have reported dysuria with difficulty emptying the bladder. Children can have recurrent and long episodes of unexplained severe crying. Optic atrophy has been reported.

Natural History (Important subgroups & survival / recovery)

The natural history is dependent on the subtype. The majority of children with GCE present in the neonatal period or in early infancy. Most individuals have the severe form which usually has a neonatal presentation but universally presents before three months of age. Individuals with the attenuated form usually also present before three months of age. Presentation after three months of age is rare and always associated with the attenuated form. Only the mildest patients present in late infancy, childhood, or adulthood.Attenuated is further-still broken down into three outcomes: poor, intermediate, and good. Attenuated poor outcome is characterized by a developmental quotient (DQ) of <20. Individuals can grasp, sit, and develop some sign language. Spasticity is noticeably present. Epilepsy is usually controllable. Attenuated intermediate is characterized by DQ of 20 to 50. Individuals can walk, communicate with some speech but mostly sign language, eat independently, attend special education classes. They have choreatic movements and pronounced hyperactivity. Attenuated good is characterized by DQ > 50. Individuals make substantial developmental progress and do not have epilepsy. They sometimes can attend normal class in school and typically have ADHD.

Likelihood of Outcome

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

>1-2 in 100

In one European population, the estimated carrier rate was 1 in 125.

Tier 4

>1-2 in 100

The proportion of GCE attributed to pathogenic variants in AMT is 20% and in GLDC is 80%. More than 420 unique pathogenic variants were deposited in the Leiden Open Variant Database (LOVD) .

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

< 1 %

There are no clinical differences between individuals with pathogenic variants in GLDC and those with pathogenic variants in AMT.

Tier 4

>= 40 %

One reported cohort of 12 children (ages 6 to 21 years) with intermediate to good subtypes of attenuated GCE were recruited from North America and Europe. Those with IQ scores available had mild to moderate intellectual disability. Half of children had epilepsy. Maladaptive behaviors with ADHD-like characteristics were present in more than two thirds of children.

Tier 5

>= 40 %

A review of atypical GCE identified 50 individuals in the literature and classified them as neonatal (<1 month, n=8), infantile (2 months-2 years, n=28), or late onset (>2 years, n=11). The late onset patients were diagnosed based on mild elevation of CSF/plasma glycine ratio and all lacked enzymatic or genetic confirmation. Reported clinical features were:

Infantile Late-onset

Epilepsy 39% 9%

Hypotonia 69% 0

Choreoathetosis 14% 18%

Optic atrophy 0 18%

Peripheral neuropathy 0 27%

Behavioral problems 57% 50%

Mild cognitive impairment 32% 55%

Moderate-severe ID 51% 0

Tier 5

Relative Risk (Includes any high-risk racial or ethnic subgroups)

Unknown

No information on relative risk was found.

Expressivity

Although individuals usually have either an attenuated or severe course, there is a continuous clinical spectrum. The phenotype of severe versus attenuated is consistent within families, but the subcategory of attenuated and degree of developmental process can vary.

Tier 4

Intervention Effectiveness

Patient Management

To establish extent of disease and needs in an individual, the following evaluations are recommended:

• EEG

• Developmental assessment throughout the first years of life

• Neurologic assessment in the first year

• Ophthalmology assessment

• GI evaluation

• Consultation with medical geneticist and/or genetic counselor

Tier 4

For attenuated GCE treatment consists of reduction of plasma concentration of glycine by administration of sodium benzoate and blockade of NMDA receptors. Sodium benzoate can reduce the plasma glycine concentration into the normal range. It is known that treatment with sodium benzoate does not normalize CSF glycine concentration

Tier 4

Clinically used partial inhibitors of the NMDA receptor include dextromethorphan, ketamine, or felbamate. Dextromethorphan used in combination with sodium benzoate has improved neurocognitive outcome and decreased seizure propensity. Improved attention, school performance, and behavior, as well as decreased chorea, have been observed in several individuals with attenuated GCE. Improvement in outcome has also been documented for oral ketamine treatment.

Tier 4

Combination treatment with benzoate and dextromethorphan results in improvement of EEG background and reduced seizures. Many individuals with attenuated GCE do not experience seizures on this treatment.

Tier 4

Two independent studies have shown that early, aggressive treatment of children with pathogenic variants associated with residual glycine cleavage enzyme system (GCS) activity who are likely to develop attenuated GCE resulted in improved neurodevelopmental outcome and reduced propensity for epilepsy

• In four sibling pairs with attenuated GCE, one sibling was diagnosed and treated after 2-6 months, and the other sibling was treated with benzoate and dextromethorphan from the first week of life. In each sibling set, the second sibling treated from the neonatal period achieved earlier and more developmental milestones and had a higher developmental quotient. In 3 of 4 sibling pairs, the younger sibling had no seizures whereas the first child had a seizure disorder.

• Four children from two families presented with neonatal GCE. Three of four children were treated with sodium benzoate with or without ketamine and has symptom resolution with normal developmental outcomes.

Tier 3

In individuals with attenuated GCE, sodium benzoate improves alertness, reduces or eliminates episodic lethargy, and may also improve behavior

Tier 4

Ketogenic diet has been used in some individuals with variable success. Ketogenic diet always lowers the amount of glycine substantially and has resulted in improved seizure control, but did not change hypsarrhythmic background

Tier 3

Surveillance

In the first years of life, children should receive routine developmental assessments. Pulmonary function should be assessed, particularly in children who develop recurrent respiratory infections.

Tier 4

Circumstances to Avoid

Valproate is contraindicated in GCE as an anti-seizure medication. 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 individuals. An adult experienced acute decompensation while on valproate.

Tier 3

Vigabatrin has resulted in rapid loss of function when used to treat West syndrome in GCE .

Tier 3

Nature of Intervention

Nature of Intervention

Dosing of sodium benzoate should be divided into no less than three doses per day; doses are more frequent in infancy (neonates typically receive six doses daily). During treatment, plasma glycine concentration is measured regularly: every two weeks for infants, every month for young children, and every three months for older children. \n\nHigh dose sodium benzoate is frequently associated with gastritis, which may require oral administration of antacids, H2 antagonists, or proton pump inhibitors. High-dose sodium benzoate in young infants can be associated with excessive loss of carnitine. Excess sodium benzoate is dangerous: benzoate toxicity has high morbidity and mortality. Benzoate is unpalatable. \n\nOverdose of dextromethorphan can cause increases in sleepiness and movement.

Context: Adult Pediatric

Chance to Escape Clinical Detection

GCE may be underdiagnosed for several reasons. Attenuated GCE is clinically underappreciated and can present as autism and seizures. Attenuated GCE is phenotypically heterogeneous and nonspecific, making the diagnosis difficult.

Context: Adult Pediatric

Tier 3

Analysis of CSF amino acids to detect elevated CSF glycine in infants with neonatal/infantile epilepsy, a primary trigger for suspicion of GCE, is not consistently obtained. Furthermore, in GCE plasma glycine levels can be normal, and elevated levels are not specific for GCE. Multigene panels for neonatal/infantile epilepsy often do not include GLDC and AMT unless specifically requested.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			GLDC			605899	0011612
AMT			620398	0011612

References List

Atypical glycine encephalopathy. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=289863

Dinopoulos A, Matsubara Y, Kure S. (2005) Atypical variants of nonketotic hyperglycinemia. Molecular genetics and metabolism. 86(1096-7192):61-9.

GLYCINE ENCEPHALOPATHY 2; GCE2. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 620398, (2024) World Wide Web URL: http://omim.org/

GLYCINE ENCEPHALOPATHY; GCE. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 605899, (2018) World Wide Web URL: http://omim.org/

Glycine encephalopathy. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=407

Infantile glycine encephalopathy. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=289860

J. Van Hove, C. Coghlin, M. Swanson and J. Hennerman. Nonketotic Hyperglycinemia (GR). (2019) URL: https://www.ncbi.nlm.nih.gov/books/NBK1357/#top

Van Hirtum LDFM, Van Damme T, Van Hove JLK, Steyaert JG. (2024) The behavioral phenotype of children and adolescents with attenuated non-ketotic hyperglycinemia, intermediate to good subtype. Orphanet journal of rare diseases. 19(1750-1172):150.