Baker-Gordon Syndrome

A number sign (#) is used with this entry because of evidence that Baker-Gordon syndrome (BAGOS) is caused by heterozygous mutation in the SYT1 gene (185605) on chromosome 12q21.

Description

Baker-Gordon syndrome (BAGOS) is a neurodevelopmental disorder characterized by infantile hypotonia, ophthalmic abnormalities, moderate to profound global developmental delay, poor or absent speech, behavioral abnormalities, hyperkinetic movements, and EEG abnormalities in the absence of overt seizures (summary by Baker et al., 2018).

Clinical Features

Baker et al. (2018) reported 11 unrelated patients with a similar neurodevelopmental disorder. One of the patients had previously been reported by Baker et al. (2015) and another by Cafiero et al. (2015). The patients, who ranged from 3 to 21 years of age, had global developmental delay from infancy, including hypotonia and delayed walking or inability to walk (7 patients), poor or absent speech, and moderate to profoundly impaired intellectual development. Most patients had abnormal involuntary movements, such as dystonia, ataxia, dyskinesias, choreoathetosis, and hyperkinetic or stereotypic movements. Other common features included feeding difficulties, including gastroesophageal reflux; behavioral abnormalities, including head-banging, hand chewing, stereotypic behaviors, and screaming outbursts; and ophthalmologic abnormalities, such as strabismus, esotropia, nystagmus, hypermetropia, poor visual attention, and central visual impairment. The patients had similar mild dysmorphic features, including prominent high forehead, horizontal low-set eyebrows, mild epicanthus, almond-shaped eyes, short nose with prominent nasal tip, smooth philtrum, and thin upper lip. Less common features included skeletal issues, such as joint laxity, foot deformities, and scoliosis, as well as central sleep apnea. Brain imaging was normal in most patients, although 1 had delayed myelination and 2 had nonspecific periventricular white matter abnormalities. Although none had overt seizures, most had abnormal EEG studies that showed absent background activity, symmetric bursts, multifocal discharges, and sharp and spike wave complexes. One patient was treated with a dopamine agonist (pramipexole), which lessened the severity of symptoms, particularly of the involuntary movements.

Molecular Genetics

In 11 unrelated patients with BAGOS, Baker et al. (2018) identified de novo heterozygous missense mutations in the SYT1 gene (see, e.g., 185605.0001-185605.0005). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in the gnomAD database. Five different amino acid substitutions were identified, and all occurred at highly conserved residues in the C2B calcium-binding domain. There were mutation-specific impacts on SYT1 function. Transfection of the mutations into rodent hippocampal neurons showed that all except 1 were expressed at normal levels and localized properly within the synapse. The M303K variant (185605.0004) was expressed at lower levels compared to wildtype and also failed to localize at nerve terminals. Functional studies showed that the other variants caused variable slowing of the endocytic or exocytic rate following action potential stimulation. Two variants, I368T (185605.0001) and N371K (185605.0003), were re-enriched at the nerve terminals during endocytosis comparable to wildtype, but 2 other variants affecting aspartic acid residues, D304G (185605.0005) and D366E (185605.0002), failed to relocalize to nerve terminals following stimulation, indicating impaired endocytic retrieval and trafficking of these mutant forms of SYT1. D304G showed a more severe defect. Further kinetic studies showed that all the variants slowed exocytosis compared to wildtype, but this could be altered by changing extracellular calcium concentrations. The findings indicated that mutations in the SYT1 gene cause a defect in presynaptic vesicle dynamics, resulting in a neurodevelopmental disorder.