Abstracts

Rationale:
Bassoon (BSN) gene is a novel protein component of the cytoskeleton at presynaptic neurotransmitter release sites (Winter et al., 1999).  Mutations of BSN may be expected to result in neurotransmitter dysfunction with impaired coding of neuronal networks and an increased likelihood for epileptic seizures (Altrock et al., 2003) but have not been previously implicated in any human disease.
Method:
A description of the clinical presentation and laboratory evaluation of a child with intractable epilepsy leading to a diagnosis of BSN related disorder.
Results:
A 17 year old male has had intractable epilepsy and global developmental delay since infancy.  At 3 months age he had onset of seizures with eye deviation and focal arm twitching, occurring up to 8-10x per hour. Video EEG confirmed focal seizures. Multiple antiseizure medications failed to control his intractable epilepsy. Seizures worsened with puberty and did not remit with a vagal nerve stimulator.   He sat independently at 3 years, learned to walk with assistance, though primarily uses a wheelchair. He holds and drinks from a sippy cup, eats by mouth, but cannot hold a spoon. The child is nonverbal and communicates by smiling when happy and moaning when upset. He developed choreiform arm movements, variable tone, and was diagnosed with athetoid cerebral palsy. He failed treatment with baclofen and botulinum toxin injections for rigidity.    A full metabolic workup was normal with the exception of CSF neurotransmitters. CSF abnormalities were significant for low MTHF, lactate, 5HIAA, HVA, and neopterin. Three separate acylcarnitine profiles reported possible glutaric acidemia type 1. Whole exome sequence analysis has revealed compound heterozygosity for p.S100F and p.N4941 variants in the BSN gene.    Carbidopa-levodopa enhanced his gross motor and fine motor function, as well as decreased full body jerking movements. Now he holds a ball in each hand and grasps a pencil.
Conclusion:
Dieck et al. (1998) found that BSN is widely distributed in synapses throughout the adult rat brain. Its location is concentrated at presynaptic terminals of hippocampal neurons, suggesting it serves specific functions at synaptic junctions. BSN is suspected to play a role in the structural and functional organization of the synaptic vesicle such as neurotransmitter release, endocytic vesicle retrieval, and neurotransmitter repletion (Dieck et al., 1998).  Mice lacking exons 4 and 5 of the BSN gene develop epileptic seizures (Altrock et al., 2003).   In the hippocampus, functional BSN deletion led to decreased excitability, reduced synaptic fatigue, and silencing of a significant portion of excitatory synapses (Altrock et al., 2003).      In addition to epilepsy, symptoms of neurotransmitter dysfunction may include developmental delay, pyramidal and extrapyramidal motor disorders, autonomic dysfunction and neuropsychiatric symptoms (Kurian et al., 2011).  Our patient with global delays, epilepsy and abnormal movements has documented low CSF neurotransmitters.  The finding of compound heterozygosity of the BSN gene is likely causative and the first reported case of human disease.   The BSN gene has a pivotal role in the assembly and functioning of CNS synapses (Altrock et al., 2003). The significance of BSN in relation to a neurotransmitter disorder is its presynaptic location as well as being highly enriched in synaptic protein preparations (Dieck et al., 1998). It is a strong candidate to be involved in cytomatrix organization at the site of neurotransmitter release (Dieck et al., 1998).
Funding:
:None.