CFC syndrome, especially caused by BRAF variant, should be included in the differential diagnosis of patients with developmental and epileptic encephalopathies and hyperekplexia.
This case shows that paroxysmal non-epileptic episodes of severe tremor and hyperekplexia-like startles and a striking vegetative component can be the first early symptoms of severe SCN8A developmental and epileptic encephalopathy.
Targeted gene panel next generation sequencing (NGS) and patient-parents trio analysis revealed a heterozygous de novo nonsense mutation in exon 3 of CTNNB1 identifying a novel association of β-catenin with hyperekplexia.
These observations establish the etiology of sustained myoclonus (sudden involuntary muscle movements) and early postnatal lethality characteristic of Slc7a10-null mice, and implicate SLC7A10 as a candidate gene and auto-antibody target in human hyperekplexia and stiff person syndrome, respectively.
Statistical coassembly of glycine receptor alpha1 wildtype and the hyperekplexia mutant alpha1(P250T) in HEK 293 cells: impaired channel function is not dominant in the recombinant system.
This family reveals that the phenotypic spectrum of ARHGEF9 is broader than commonly assumed and includes febrile seizures and focal epilepsy with intellectual disability in the absence of hyperekplexia or other clinically distinguishing features.
Three previously reported mutations of ARHGEF9 consisted of a missense mutation in a male patient with hyperekplexia and two chromosomal disruptions in two female patients.
Mice deficient in gephyrin develop a hereditary molybdenum cofactor deficiency and a neurological phenotype that mimics startle disease (hyperekplexia).
Together, our findings demonstrate that A384 is associated with the desensitization site of the α1 subunit and its proline mutation produced enhanced desensitization of GlyRs, which contributes to the pathogenesis of human hyperekplexia.<b>SIGNIFICANCE STATEMENT</b> Human startle disease is caused by impaired synaptic inhibition in the brainstem and spinal cord, which is due to either direct loss of GlyR channel function or reduced number of synaptic GlyRs.
Glycine receptor (GlyR) truncations in the intracellular TM3-4 loop, documented in patients suffering from hyperekplexia and in the mouse mutant oscillator, lead to non-functionality of GlyRs.
Thus, the hyperekplexia phenotype of Glra1(D80A) mice is due to the loss of Zn(2+) potentiation of alpha1 subunit containing GlyRs, indicating that synaptic Zn(2+) is essential for proper in vivo functioning of glycinergic neurotransmission.
GlyRs formed from alpha 1R271K subunits showed a reduction of beta-alanine and taurine affinities and maximal inducible currents; the mutants alpha 1R271Q and alpha 1R271L associated with human hyperekplexia gave no responses to these ligands.
Providing a better understanding of the molecular regulation of GlyT2 may help future investigations into the molecular basis of human disease states caused by dysfunctional glycinergic neurotransmission, such as hyperekplexia and chronic pain.
The postsynaptic α(1)-subunit (GLRA1) of the inhibitory glycine receptor (GlyR) and the cognate presynaptic glycine transporter (SLC6A5/GlyT2) are well-established genes of effect in hyperekplexia.
This study firmly establishes the combination of missense, nonsense, frameshift, and splice site mutations in the GlyT2 gene as the second major cause of startle disease.
However, new research suggests that mutations in the gene encoding the presynaptic glycine transporter GlyT2 are a second major cause of human hyperekplexia, as well as congenital muscular dystonia type 2 (CMD2) in cattle.
In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.