Category: Rare Genetic and Metabolic Diseases
Objective: To describe two patients with CTNNB1 mutation with a startle reflex, an underrecognised clinical sign.
Background: CTNNB1 mutations is an increasingly recognised cause of syndromic neurodevelopmental delay and cerebral palsy 1 2. Dopa-responsive dystonia has been reported. A startle reflex is unusual for genetic dopa-responsive dystonia. This sign can be a helpful diagnostic clue in patients with dystonia combined with developmental delay3.
Method: We report two patients with exaggerated startle reflex.
Results: A 22-year-old female of non-consanguineous parents and a product of a normal pregnancy and delivery had delayed milestones with hypotonia in infancy and was non-verbal. She had abnormal posturing in the lower limbs on walking. At 5 years low dose levodopa/benserazide was trialled for a year without improvement. Her mobility worsened gradually, necessitating a walker with diurnal variations. At 20 years, she was commenced on levodopa/benserazide 200mg TDS with some improvement. Examination showed mild dysmorphic features and microcephaly with generalised dystonia in the neck, upper and lower limbs. She had a dystonic gait with foot inversion, improved with wearing shoes. A non-habituating exaggerated startle and head retraction reflex were present. MRI Brain was normal. CSF showed elevated protein (0.84g/L) and low HIAA (0.11mmol/L) levels. A movement disorder panel on a Whole Exome backbone showed a likely de novo pathogenic variant in the CTNNB1 gene.
A 14-year-old male of non-consanguineous parents and of normal pregnancy and delivery. He had global developmental delay; unable to sit unsupported at 21 months and remained non-verbal. There was heterochromia and persistent hyperplastic primary vitreous. He had one seizure at 5 months without recurrence. His examination showed no dysmorphic features, hypotonia with intermittent dystonic posturing of upper and lower limbs. There was a non-habituating startle reflex to auditory stimulation but no head retraction reflex. MRI brain showed mild prominence of the ventricles and extra axial CSF spaces. CSF showed normal protein and amino acid profile. He was commenced on levodopa with mild improvement in dystonia at age 13. Whole exome sequencing revealed de novo heterozygous frame shift variant in the CTNNB1 gene (c.2261del).
Conclusion: Startle and head retraction reflex in the context of neurodevelopmental delay with or without dopa-responsive dystonia can point to a CTNNB1 mutation.
References: 1. Kayumi S, Pérez-Jurado LA, Palomares M, et al. Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants. Genetics in Medicine 2022;24(11):2351-66. doi: https://doi.org/10.1016/j.gim.2022.08.006
2. Pipo-Deveza J, Fehlings D, Chitayat D, et al. Rationale for dopa-responsive CTNNB1/ß-catenin deficient dystonia. Movement Disorders 2018;33(4):656-57. doi: https://doi.org/10.1002/mds.27320
3. Bulot V, Ramond F, Mauguière F, et al. Startle Disease. Neurology Genetics 2022;8(6):e200039. doi: 10.1212/NXG.0000000000200039
To cite this abstract in AMA style:
S. Nagaratnam, D. Wilson, M. Garcia, J. Qiu, D. Hadi, S. Mohammad, H. Morales Briceno. Startle Reflex in CTNNB1 Mutations: A diagnostic Clue [abstract]. Mov Disord. 2024; 39 (suppl 1). https://www.mdsabstracts.org/abstract/startle-reflex-in-ctnnb1-mutations-a-diagnostic-clue/. Accessed October 4, 2024.« Back to 2024 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/startle-reflex-in-ctnnb1-mutations-a-diagnostic-clue/