Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 604159 (gene) , 614618 (trait)

Links to relevant human diseases in MONDO:

• MONDO:0013827: hyperekplexia 3

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2011

Cross-species summary: Renamed from 'Hyperekplexia (Startle disease)' to 'Hyperekplexia (Startle disease), SLC6A5-related' [12/06/2024]
See also entries for 'OMIA:000689 : Hyperekplexia, GLRA1-related'

Inheritance: Gill et al. (2019): "a rapid genotyping test that revealed heterozygosity for the deletion in the dam and sire and three other siblings, confirming recessive inheritance." Murphy et al. (2019): "Family members were genotyped for the deletion, and findings were consistent with an autosomal recessive inheritance pattern."

Molecular basis: Gill et al. (2011): "analysis of SLC6A5 revealed a homozygous 4.2 kb microdeletion encompassing exons 2 and 3 in both affected [Irish Wolfhound] animals.' Murphy et al. (2019): "Whole genome resequencing of an affected [Spanish greyhound] dog revealed a homozygous two base pair deletion in the ninth exon of SLC6A5, encoding the presynaptic glycine transporter. The deletion is predicted to cause a frameshift, p.S460FfsX47, leading to a premature stop codon that truncates over a third of the protein."

Clinical features: Clinical signs begin at birth. Puppies display an involuntary ‘startle response’ characterised by generalised or intermittent extensor rigidity induced by unexpected handling or noise (Gill et al., 2011). Neonatal Irish wolfhounds have been reported to develop cyanosis and pneumonia when feeding due to extended periods of rigidity causing apnoea (Gill et al., 2011). Neonatal Spanish greyhounds were unable to properly walk or stand due to episodes of extensor rigidity. When owners attempted to assists the puppies with walking, their touch induced further extensor rigidity (Murphy et al. ̧ 2019). Neonatal death in hyperekplexic puppies is not uncommon due to the complications of feeding and breathing during hypertonic episodes/startle responses. IT thanks DVM student Emily Ketchum, who provided the basis of this contribution in May 2023.

Pathology: Post-mortem examination of Irish Wolfhound puppies with hyperekplexia have revealed no obvious muscular or neurological lesions resulting from the generic variants (Gill et al., 2011). IT thanks DVM student Emily Ketchum, who provided the basis of this contribution in May 2023.

Prevalence: Murphy et al. (2019): "The [Spanish Greyhound] pathogenic variant was absent from 34 unrelated greyhounds, 659 domestic dogs of pure and mixed breeds, and 54 wild canids, suggesting it occurred recently and may be private to the family."

Breeds: Irish Wolfhound (Dog) (VBO_0200706), Spanish Greyhound (Dog) (VBO_0201274).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: