The phenotypic spectrum of GLYT1 encephalopathy has not yet been completely described. However, the common features of the disorder include:
• Neonatal onset.
• Severe hypotonia with progression to limb hypertonicity.
• Encephalopathy, including impaired consciousness and unresponsiveness, with absent neonatal reflexes.
• Respiratory failure requiring mechanical ventilation.
• Dysmorphic features. Myopathic face and retrognathia are usually observed, but other features have also been described: microcephaly, dolichocephaly, trigonocephaly, broad forehead, esotropia, sparse eyebrows, pronounced eyebrows, long eyelashes, ptosis, low set ears, small upturned nose, depressed nasal bridge, deep prominent philtrum, tent-shaped mouth, hypertrichosis, and increased skin on the back of the neck.
• Musculoskeletal abnormalities, including severe arthrogryposis multiplex congenita in all cases. Joint hyperlaxity has been observed in a single patient.
• Startle-like responses provoked by sudden loud sounds and tactile stimulation.
• Severe global developmental delay.
• Prenatal abnormal findings, being common polyhydramnios, fetal hydrops, increased nuchal translucency, arthrogryposis (i.e. bilateral clubfeet, overriding toes, clenched fists, or hyperextension of knees), and lack of fetal movements.
• Mildly elevated levels of glycine in cerebrospinal fluid, and normal or slightly elevated levels of glycine in serum.
• Abnormal brain magnetic resonance imaging is common, with a nonspecific pattern.
• Abnormal electroencephalogram has been described in two patients. In one a mild generalized slowing of background activity was observed, and the other one presented a burst-suppression pattern.
• Genitourinary malformations have been reported in two children, including hydronephrosis and cryptorchidism.
Additional characteristics have been described in single patients, including epilepsy with a burst suppression electroencephalographic pattern with transition to myoclonic jerks, hypertension with elevated urinary catecholamines, atrial septal defect, right inguinal hernia, motor and sensory polyneuropathy, abnormal visual evoked potentials, right mild conductive hearing loss, micropenis, and hydrocele. Of note, these anomalies should be considered with caution, as they may be the result of other concomitant defects.
Further studies reporting new patients will allow deciphering the full SLC6A9-related phenotype. These studies may also reveal if genotype/phenotype correlations can be performed for GLYT1 encephalopathy. These correlations cannot be established nowadays, as all cases described to date are severe.
SLC6A9