Dystonia Combined with Startle Is a Syndromic Clue for CTNNB1 ‐Associated Neurodevelopmental Disorder

Dominant CTNNB1 variants are associated with syndromic neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV, OMIM 615075). Dystonia has been reported in many large case series; however, startle has been observed in a few cases. Here we report two cases of CTNNB1 with dystonia combined with startle, with neurophysiological assessment in one. A 22-year-old female of non-consanguineous Chinese parents and a product of a normal pregnancy and delivery had delayed milestones with hypotonia, delayed language and intellectual disability in infancy. She had abnormal posturing in the lower limbs on walking from 12 months old and was diagnosed with dystonic cerebral palsy, although there were no risk factors. At 5 years, low-dose levodopa was trialed for a year without improvement. By her mother's description she was easily startled by touch. Her mobility worsened gradually, necessitating a walker and she gradually developed a generalized dystonia with spread to the upper body and neck. At 20 years, she was re-trialed on levodopa/benserazide 600 mg/day with some improvement in gait. At examination she could speak a few sentences, but with relatively preserved receptive language, microcephaly with generalized dystonia with trunk, neck, upper and lower limbs distribution. She had a dystonic gait with foot inversion and moderate plantar flexion, which improved with wearing shoes. She had bilateral ankle hypertonia, but no clonus or spasticity. There was mild bradykinesia on finger tapping, but no tremor. She had non-habituating generalized startle with nose tapping (Video 1). Neurophysiological assessment revealed caudal brainstem muscle recruitment, beginning in the sternocleidomastoid at 65 ms after median nerve stimulation (Fig. 1). Ophthalmological examination, and MRI brain were normal. CSF showed elevated protein (0.84 g/L) and low HIAA (0.11 mmol/L) levels, with normal neopterin and biopterin. Chromosomal microarray (CMA) was normal. WES showed a likely de novo pathogenic variant in CTNNB1 (NM_001904.4): c.[495 + 1G>C];[=] p.[(?)]:[=] (See supplementary Material in Data S1). A 14-year-old male of non-consanguineous parents and of normal pregnancy had mild respiratory distress during a vaginal delivery, but no significant resuscitation was needed. He was admitted to the special care nursery for a week prior to being discharged. There was heterochromia and persistent hyperplastic primary vitreous with an ovoid lens in the left eye. He had one seizure at 5 months in the context of a respiratory illness, without recurrence. He had global developmental delay and was unable to sit unsupported at 21 months and remained non-verbal. He had failure to thrive with feeding difficulties. His examination showed no dysmorphic features, limb hypotonia and dystonic posturing of the upper and lower limbs. He preferred knee crawl, sitting on his knees with legs flexed, but walked with dystonic foot inversion and flexion with a 4-wheel walker. Deep tendon reflexes were normal with equivocal plantar responses. There was a non-habituating startle to auditory stimulation, but no head retraction reflex; however, a neurophysiological assessment was not performed to substantiate whether the startle was objectively non-habituating (Video 2). He also had sleep and behavioral issues over time, characterized by extreme agitation and self-injurious behaviors. MRI brain showed mild prominence of the ventricles and extra-axial CSF spaces. CSF was normal, including monoamine profile. He was treated with botulinum toxin for lower limb dystonia with some benefit and commenced on levodopa with minimal response at age 13, but dose escalation was limited by nausea and vomiting and was ceased after a few months. CMA was normal. Whole exome sequencing revealed de novo, likely pathogenic, heterozygous frame shift variant in CTNNB1 (NM_001904.4):c.[2261del];[=]p.[(Pro754Glnfs*34)];[=] (See supplementary Material in Data S1)). We describe two cases with neurodevelopmental delay (NDD), generalized dystonia and startle due to CTNNB1 variants. CTNNB1 variants are recognized in syndromic NDD and cerebral palsy.1-3 Common features described included NDD (94%), microcephaly (74%), oculomotor abnormalities (53%), lower limb spasticity (81%) and visual defects due to exudative vitreoretinopathy (23%).4 Lower limb hypertonia, rather than spasticity, has been described in recent case series, which is similar to our patients.5 Neurobehavioral features of CTNNB1 include self-injurious behaviors, as seen in one of our patients. Dystonia is the most frequently reported movement disorder.4, 6 In our cases the dystonia was generalized, with partial responsiveness to levodopa in one, although not as robust as a classic dopa-responsive dystonia (DRD). Nevertheless a trial of levodopa is warranted, given the existence of cases with more clear response.7 A distinctive feature in both patients was a non-habituating generalized startle response. One was tactile stimulus sensitive, and the other was auditory. In one patient, the response was consistent with exaggerated startle, with a pattern suggesting a brainstem origin as seen in hyperekplexia.8 A limitation of our assessment is the absence of orbicularis oris recording to demonstrate a craniocaudal recruitment response. Startle has been previously reported in single cases of CTNNB1; however, it is possible that it is underrecognized, as shown by its high frequency as reported by patients’ family members.9 Furthermore, the combination of dystonia and startle is uncommon in NDD syndromes, including cerebral palsy; thus, it can be a helpful diagnostic clue.10 In conclusion, we strengthen the association between startle and CTNNB1 variants, suggesting this is a helpful diagnostic clue in patients with dystonia and developmental delay. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. SN: 1A, 1B, 1C, 3A, 3B. DH: 1A, 1B, 1C, 3A, 3B. JQ: 1A, 1B, 1C, 3B. SM: 1A, 1B, 1C, 3B. NM: 1A, 1B, 1C, 3B. HMB: 1A, 1B, 1C, 3B. We thank the patients and their families for their time and providing videos. Ethical Compliance Statement: This work did not require ethics committee approval. The patients provided written consent. Video consent for patient 2 was provided through SCHN/2019/ETH6134. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: The authors declare that there are no funding sources or conflicts of interest relevant to this work. Financial Disclosures for previous 12 months: SN, DH, JQ, SM, NM and HMB have no additional disclosures to report. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. Data S1. Supporting Information. 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