GLYT1 Encephalopathy

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:

1. Developmental status

2. Respiratory function

3. Neurologic status

4. Musculoskeletal involvement

5. 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.