A number sign (#) is used with this entry because of evidence that glycine encephalopathy with normal serum glycine is caused by homozygous mutation in the SLC6A9 gene (601019) on chromosome 11p15.

Glycine encephalopathy with normal serum glycine is a severe metabolic disorder characterized by arthrogryposis multiplex congenita, joint hyperlaxity, lack of neonatal respiratory effort, axial hypotonia, hypertonia with pronounced clonus, and delayed psychomotor development. Some patients may have dysmorphic facial features and/or brain imaging abnormalities. Laboratory studies show increased CSF glycine and normal or only mildly increased serum glycine. Most patients die in infancy. The disorder is similar to, but distinct from, glycine encephalopathy (GCE; 605899) due to mutations in genes encoding the glycine cleavage system (summary by Kurolap et al., 2016).

Alfadhel et al. (2016) reported a 15-month-old girl, born of consanguineous Saudi parents, with glycine encephalopathy. At birth she showed impaired respiratory function necessitating ventilation for 1 month. During the neonatal period, she had hyperekplexia with exaggerated startle reflexes that subsided by age 6 months. Additional features included axial hypotonia, weak cry, difficulty swallowing, failure to thrive, and microcephaly (-3.7 SD). Dysmorphic features included broad forehead, esotropia, low-set ears, retrognathia, deep prominent philtrum, and sparse eyebrows. She had significant global developmental delay, hyperreflexia, hip dysplasia, joint laxity around the elbows, and clubfeet. Plasma and urinary glycine were mildly increased, and CSF glycine was increased. Brain imaging showed subinsular T2-weighted hyperintensities and scattered subcortical and periventricular white matter changes.

Kurolap et al. (2016) reported 4 children from 2 unrelated consanguineous Arab-Muslim families with glycine encephalopathy with normal serum glycine. One family contained an affected living 2-year-old girl and a subsequent affected fetus that was terminated; the other family contained 3 affected sibs who died at ages 2 days, 18 days, and 7 months. Prenatal ultrasound in most patients showed features of arthrogryposis multiplex congenita, including clubfeet with overriding toes and clenched fists. Two fetuses showed nuchal translucency. Most of the patients were born prematurely due to fetal distress. At birth, the patients showed severe axial hypotonia with head lag, absent neonatal reflexes, and absence of respiratory drive necessitating mechanical ventilation. This progressed to hypertonia with startle-like clonus upon stimulation, which tended to resolve later. Skeletal anomalies included hyperextension of knees, hip dislocation, flexion contractures, overriding fingers, and foot deformities, presumably resulting from severe hypotonia in utero. Two patients were noted to have dysmorphic features including trigonocephaly, dolichocephaly, long myopathic facies with tent-shaped mouth, retrognathia, low-set ears, depressed nasal bridge with upturned nose, ptosis, long eyelashes, and pronounced eyebrows. At age 2 years, the only surviving patient had severely delayed psychomotor development: she could track objects and smile, but could not speak and had no spontaneous movements of the lower limbs. She continued to have recurrent episodes of respiratory failure. EEG in this patient showed mild generalized background slowing, but no evidence of epileptic discharge. Brain imaging of 2 patients showed variable abnormalities, including ventriculomegaly, thin corpus callosum, and optic atrophy. Laboratory studies showed mildly increased glycine in the CSF and increased urinary excretion of glycine, but normal serum glycine. CSF:plasma glycine levels were increased. These findings were not compatible with nonketotic hyperglycinemia caused by defects in the mitochondrial glycine cleavage system (605899). One patient developed hypertension associated with increased levels of urinary catecholamines.

The transmission pattern of glycine encephalopathy with normal serum glycine in the families reported by Kurolap et al. (2016) was consistent with autosomal recessive inheritance.

In a 15-month-old girl, born of consanguineous Saudi parents, with glycine encephalopathy with normal serum glycine, Alfadhel et al. (2016) identified a homozygous missense mutation in the SLC6A9 gene (S407G; 601019.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.

In affected children from 2 unrelated consanguineous Muslim-Arab families with glycine encephalopathy with normal serum glycine, Kurolap et al. (2016) identified 2 different homozygous truncating mutations in the SLC6A9 gene (601019.0002 and 601019.0003). The mutation in the first family was found by whole-exome sequencing and confirmed by Sanger sequencing; the mutation in the second family was found by direct sequencing of the SLC6A9 gene. Functional studies of the variants and studies of patient cells were not performed. However, mice treated with a Glyt1 inhibitor developed increased CSF glycine levels, hypoactivity, and hypertonic seizures, whereas total blood glycine was not elevated. These features were similar to those observed in the patients, suggesting that loss of SLC6A9 causing impaired glycine neurotransmission was responsible for the neurologic disorder.

SLCC6A9 maintains subsaturating concentrations of glycine at synaptic N-methyl-D-aspartate receptors (NMDAR; see 138249), which require the binding of both glycine and glutamate for activation. Tsai et al. (2004) disrupted the Glyt1 gene in mice. Homozygous mice died within 12 hours of birth. Heterozygous mice expressed 50% of the wildtype levels of Glyt1, and heterozygote forebrain homogenates showed a 50% reduction in Na(+)-dependent glycine transport. Reduced Glyt1 expression enhanced hippocampal NMDAR function and memory retention and protected against an amphetamine disruption of sensory gating.

Gomeza et al. (2003) created Glyt1-deficient mice. Homozygous null mice were born at expected mendelian ratios; however, they showed severe motor and respiration deficits and died during the first postnatal day. Histologic examination of several tissues and systematic analysis of the CNS revealed no obvious defect. Since Glyt1-null mice did not breathe properly, Gomeza et al. (2003) analyzed transverse slices from the caudal medulla for neuronal activity. In contrast to the regular rhythmic bursting observed in medulla slices from wildtype animals, Glyt1-null medulla slices showed prolonged periods of inactivity and variable interburst intervals. Respiratory activity was partly normalized by the glycine receptor agonist, strychnine. Conversely, glycine or a GLYT1 inhibitor suppressed respiratory activity in wildtype medulla slices. Gomeza et al. (2003) concluded that GLYT1 is essential for regulating glycine concentrations at inhibitory glycine receptors.