Clinical characteristics.

GLYT1 encephalopathy is characterized in neonates by severe hypotonia, respiratory failure requiring mechanical ventilation, and absent neonatal reflexes; encephalopathy, including impaired consciousness and unresponsiveness, may be present. Arthrogryposis or joint laxity can be observed. Generalized hypotonia develops later into axial hypotonia with limb hypertonicity and a startle-like response to vocal and visual stimuli which should not be confused with seizures. To date, three of the six affected children reported from three families died between ages two days and seven months; the oldest reported living child is severely globally impaired at age three years. Because of the limited number of affected individuals reported to date, the phenotype has not yet been completely described.

Diagnosis/testing.

The diagnosis of GLYT1 encephalopathy is established in a proband with mildly elevated cerebrospinal fluid glycine levels, normal or slightly elevated serum or plasma glycine levels, and biallelic pathogenic variants in SLC6A9 on molecular genetic testing.

Management.

Treatment of manifestations: To date, no treatment has been effective in mitigating the manifestations of GLYT1 encephalopathy. A multidisciplinary team is recommended to manage global developmental delay, respiratory failure, and feeding difficulties and to maintain range of motion and prevent contractures.

Surveillance: The following should be routinely monitored:

• Developmental status
• Respiratory function
• Neurologic status
• Musculoskeletal involvement
• Nutritional status and feeding

Monitor as needed: blood pressure, renal function, vision, hearing.

Agents/circumstances to avoid: None known; however, valproate – which is contraindicated in glycine encephalopathy – should be avoided as it increases the concentration of blood and CSF glycine.

Genetic counseling.

GLYT1 encephalopathy is inherited in an autosomal recessive manner. 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 the SLC6A9 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

GLYT1 encephalopathy should be suspected in individuals with the following clinical and laboratory findings [Alfadhel et al 2016, Kurolap et al 2016].

Clinical findings

• Early respiratory insufficiency
• Hypotonia later transitioning to hypertonicity of the extremities
• Startle response provoked by sudden loud sounds and tactile stimulation (which may be confused with myoclonic seizures)
• Encephalopathy (present in some)
• Arthrogryposis multiplex congenita or joint laxity
• Dysmorphic features that may include trigonocephaly or dolichocephaly, low-set ears, long myopathic face, broad forehead, broad or sparse eyebrows, long eyelashes, esotropia, ptosis, depressed nasal bridge, short nose, upturned nasal tip, prominent philtrum, tented vermilion of the upper lip, and retrognathia (Figure 1)
• Microcephaly and failure to thrive

Figure 1.

A girl age six months with GLYT1 encephalopathy. Note facial dysmorphism including trigonocephaly, long myopathic facies, broad forehead, broad eyebrows, long eyelashes, esotropia, ptosis, depressed nasal bridge, short nose, upturned nasal tip, prominent (more...)

Laboratory findings

• Cerebrospinal fluid (CSF) glycine levels*: mildly elevated (21-33 µmol/L) (normal 3.8-8 µmol/L) [Kurolap et al 2016]. Note: Normal values vary by laboratory.
• Blood (serum or plasma) glycine levels*: normal. Note: Normal values vary by age.
• Glycine CSF-to-plasma ratio: abnormal (>0.04)

* Amino acid concentrations should be measured simultaneously in CSF and blood.

Establishing the Diagnosis

The diagnosis of GLYT1 encephalopathy is established in a proband by identification of biallelic pathogenic variants in SLC6A9 by molecular genetic testing [Alfadhel et al 2016, Kurolap et al 2016] (see Table 1).

Molecular genetic testing approaches to be considered include single-gene testing and use of a multigene panel:

• Single-gene testing. Sequence analysis of SLC6A9 is performed first. Gene-targeted deletion/duplication analysis may be performed if only one or no pathogenic variant is found; however, to date no deletions/duplications have been described.
• A multigene panel that includes SLC6A9 and the two genes causing classic nonketotic hyperglycinemia (GLDC and AMT) (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

GLYT1 encephalopathy is characterized in neonates by severe hypotonia, respiratory failure requiring mechanical ventilation, and absent neonatal reflexes; encephalopathy, including impaired consciousness and unresponsiveness, may be present. Arthrogryposis or joint laxity may be observed. Generalized hypotonia later develops into axial hypotonia with limb hypertonicity and a startle-like response provoked by vocal and visual stimuli as well as sudden loud sounds and tactile stimulation and not to be confused with seizures. To date, six affected individuals from three families have been reported [Alfadhel et al 2016, Kurolap et al 2016]. Because of the limited number of affected individuals reported to date, the phenotype has not yet been completely described.

Prenatal. Findings on prenatal ultrasound examination can include increased nuchal translucency, hydrops fetalis, polyhydramnios, arthrogryposis, and\or absent or limited fetal movements.

Respiratory. Shortly after birth infants develop respiratory failure requiring mechanical ventilation. Although with time they may be weaned off ventilatory support, they remain dependent on supplemental oxygen.

Musculoskeletal. Severe hypotonia present at birth may progress to limb hypertonicity.

Arthrogryposis multiplex congenita with club feet, hyperextension of knees, bilateral hip dislocation, contractures of the elbows, wrists, and hips, and overriding toes and fingers was described in children from two of the three families reported.

Absent patellae were observed in one child.

Joint laxity with bilateral club feet was documented in the third family.

Neurologic. Encephalopathy, including impaired consciousness and unresponsiveness, was observed in two of the three families.

All affected children showed startle-like clonus with a normal electroencephalogram (EEG). The startle-like response may resolve over time.

All had severe global developmental delay. Developmental information, available for one child at age three years, revealed that the child had not reached any motor or speech milestones.

Disease complications include feeding difficulties requiring insertion of a gastrostomy tube.

Brain imaging (CT or MRI) findings may include ventriculomegaly, optic nerve atrophy, thin or normal corpus callosum, atrophy in the caudate nucleus, and white matter abnormalities. In addition, MRI in a child age two years (proband of Family 1 [Kurolap et al 2016]) showed a focal area of diffusion restriction in one cerebellar hemisphere.

Abnormal visual evoked potentials and brain stem evoked response audiometry as well as motor and sensory polyneuropathy were reported in one child [Kurolap et al 2016].

Additional features

• Hypertension with elevated urinary catecholamines was described in one child.
• Children from two families had hydronephrosis.
• One child had atrial septal defect, cryptorchidism, and inguinal hernia.

Life expectancy. Three affected sibs died from respiratory complications between ages two days and seven months. One child from a different family is currently three years old; long-term follow up is required to determine life expectancy.

Genotype-Phenotype Correlations

Given the small number of individuals reported to date, no genotype-phenotype correlations can be drawn.

Nomenclature

Collectively, neurologic disorders caused by disturbance of glycine metabolism and transport are termed glycine encephalopathy.

• Disorders of glycine metabolism that are caused by deficient activity of the glycine cleavage enzyme system (GCS) are called nonketotic hyperglycinemia (NKH).
  • Classic NKH is caused by biallelic pathogenic variants in one of the two genes encoding components of the GCS (GLDC and AMT).
  • Variant nonketotic hyperglycinemia (NKH) refers to a glycine encephalopathy phenotype with elevated glycine levels and deficient GCS enzyme activity, but no pathogenic variants observed in GLDC or AMT. Some individuals with variant NKH have impaired lipoylation or deficient lipoate, a cofactor of the GCS enzymes, caused by biallelic pathogenic variants in BOLA3, GLRX5, IBA57, LIAS, or NFU1 [Baker et al 2014].
• Disorders of glycine transport include GLYT1 encephalopathy, the subject of this GeneReview.

Prevalence

GLYT1 encephalopathy is rare; to date, only three families have been described, all of Muslim Arab origin. Two families reside in Israel; one family resides in Saudi Arabia [Alfadhel et al 2016, Kurolap et al 2016].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GLYT1 encephalopathy, the following evaluations are recommended if they have not already been completed:

• Metabolic evaluation including blood and CSF amino acid profile
• Neurologic assessment including EEG to distinguish seizures from a startle response. Brain imaging and physiologic tests, such as visual evoked potentials, brain stem evoked response audiometry, and evaluation of motor and sensory nerves, may be performed to better understand the extent of the clinical involvement.
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

To date, no treatment has been effective in mitigating the manifestations of GLYT1 encephalopathy.

The core management of GLYT1 encephalopathy is supportive care provided by a multidisciplinary team including specialists from clinical genetics, pediatric neurology and child development, pulmonology, orthopedics, physiotherapy, nutrition, and others depending on clinical findings (e.g., pediatric nephrology if hypertension is observed).

The management of GLYT1 encephalopathy includes the following:

• Address global developmental delay.
• While benzodiazepines or antiepileptic drugs are used to control the startle response in hyperekplexia [Bakker et al 2006], it is unknown whether these could also be helpful in GLYT1 encephalopathy.
• Mechanical ventilation is indicated when first signs of respiratory failure appear. If successful weaning off ventilation is achieved, supplemental oxygen may be required.
• Gastrostomy should be considered to assure adequate nutrition and to prevent microaspiration.
• Physiotherapy should be considered to preserve range of motion and prevent contractures.
• If hypertension is present, refer to pediatric nephrologist for appropriate treatment.

Note: Treatment with sodium benzoate and an NMDA receptor antagonist (e.g., ketamine or dextromethorphan), as customary in classic NKH, was unsuccessful in one child with GLYT1 encephalopathy [Kurolap et al 2016].

Surveillance

The following should be routinely monitored:

• Developmental status
• Neurologic status
• Respiratory function
• Nutritional status and feeding
• Musculoskeletal involvement
• Sensory organ involvement (vision, hearing)

Monitor as needed:

• Blood pressure
• Renal function

Agents/Circumstances to Avoid

Although no specific agents/circumstances are known to exacerbate disease manifestations, valproate – which is contraindicated in classic NKH – should be avoided as it increases the concentration of blood and CSF glycine [Hall & Ringel 2004].

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

GLYT1 encephalopathy is inherited in an autosomal recessive manner.

Parents of a proband

• The parents of an affected child are obligate heterozygotes (i.e., carriers of one SLC6A9 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. Individuals with GLYT1 encephalopathy are not known to reproduce.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a SLC6A9 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SLC6A9 pathogenic variants in the family.

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/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the SLC6A9 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

GLYT1 encephalopathy is a glycinopathy caused by dysfunction of the sodium- and chloride-dependent glycine transporter 1 (also known as glial glycine transporter 1) (GLYT1) [Alfadhel et al 2016, Kurolap et al 2016]. GLYT1 is responsible for termination of glycinergic neurotransmission by removing glycine from the synapse; therefore, the clinical manifestations of the disorder are mostly attributed to excess glycinergic inhibitory neurotransmission [Eulenburg et al 2005, Harvey et al 2008].

Gene structure. The transcript variant NM_201649.3 (ENST00000360584) comprises 14 protein-coding exons. It represents the longest transcript and encodes the longest isoform NP_964012.2. SLC6A9 has multiple transcripts; for a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants

Normal gene product. GLYT1 (NP_964012.2) comprises 706 amino acids that form 12 transmembrane domains and intracellular N- and C-termini. The isoforms vary by splicing in the N- and C-termini [Eulenburg et al 2005]. GLYT1 is a transporter belonging to the Na+/Cl- dependent superfamily, similar to other monoamine transporters; it requires 2Na+/Cl-/glycine binding for activation and subsequent glycine uptake from the synapse [Eulenburg et al 2005].

Abnormal gene product. Both truncating variants known to date (Table 2) are predicted to cause premature termination and loss of protein expression [Kurolap et al 2016]. The missense variant p.Ser407Gly, which was observed in one affected individual, is predicted to affect the ion-binding site of the protein, thus disrupting the normal function of the transporter [Alfadhel et al 2016]. Abolished or decreased GLYT1 activity may result in glycine accumulation in the glycinergic synapses, causing over-inhibition, which leads to the clinical findings of hypotonia and respiratory failure.

Literature Cited

• Alfadhel M, Nashabat M, Al Qahtani H, Alfares A, Al Mutairi F, Al Shaalan H, 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. Hum Genet. 2016;135:1263–8. [PMC free article: PMC5052303] [PubMed: 27481395]
• Baker PR, 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, Spector E, Wempe MF, Van Hove JLK. Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. Brain. 2014;137:366–79. [PMC free article: PMC3914472] [PubMed: 24334290]
• Bakker MJ, van Dijk JG, van den Maagdenberg AM, Tijssen MA. Startle syndromes. Lancet Neurol. 2006;5:513–24. [PubMed: 16713923]
• Eulenburg V, Armsen W, Betz H, Gomeza J. Glycine transporters: essential regulators of neurotransmission. Trends Biochem Sci. 2005;30:325–33. [PubMed: 15950877]
• Hall DA, Ringel SP. Adult nonketotic hyperglycinemia (NKH) crisis presenting as severe chorea and encephalopathy. Mov Disord. 2004;19:485–6. [PubMed: 15077252]
• Harvey RJ, Carta E, Pearce BR, Chung SK, Supplisson S, Rees MI, Harvey K. A critical role for glycine transporters in hyperexcitability disorders. Front Mol Neurosci. 2008;1:1–6. [PMC free article: PMC2526004] [PubMed: 18946534]
• Kurolap A, Armbruster A, Hershkovitz T, Hauf K, Mory A, Paperna T, Hannappel E, Tal G, Nijem Y, Sella E, Mahajnah M, Ilivitzki A, Hershkovitz D, Ekhilevitch N, Mandel H, Eulenburg V, Baris HN. Loss of glycine transporter 1 causes a subtype of glycine encephalopathy with arthrogryposis and mildly elevated cerebrospinal fluid glycine. Am J Hum Genet. 2016;99:1172–80. [PMC free article: PMC5097939] [PubMed: 27773429]
• 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. Pediatr Neurol. 2017;71:65–9. [PubMed: 28363510]

Revision History

• 30 November 2017 (bp) Review posted live
• 15 June 2017 (hnb) Original submission