Deep Brain Stimulation as Management of Generalized Dystonia in the 18p Deletion Syndrome

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Chromosome 18p deletion (18p‐) syndrome was initially described in 1963 by de Grouchy and colleagues with characteristic features including developmental delay, dysmorphic facies, intellectual disability, and short stature.1 Subsequent reports have further characterized the clinical phenotype, which may include movement disorders. Dystonia has been reported in a small number of individuals with 18p‐, and no effective management has been reported to date. We present a case of an individual with 18p‐ syndrome who had gradually progressive, generalized dystonia successfully managed with DBS.

A 33‐year‐old female with intellectual and growth impairment, known to have 18p‐ syndrome with deletion of the entire short arm, was referred to adult neurology services with severe, progressive, adult‐onset dystonia. Before onset of her dystonia, she was able to walk independently and work in a supervised workplace. Other manifestations of her 18p‐ syndrome included pituitary abnormalities (present in ~15% of people with 18p‐2) with hyperprolactinemia and growth hormone deficiency. Her past medical history was also significant for autoimmune hepatitis and mediastinal masses (stable on monitoring, thought to reflect normal thymic tissue). She was the youngest of four children, having three older brothers. The common TOR1A mutation (DYT1) was not present. Her siblings and both parents had learning difficulties which had not been further characterized or investigated.

Her dystonic symptoms began at age 26 with involvement of her right hand and voice. Painful spasms and clumsiness of the right hand impaired her ability to work. The dystonia progressed over years to become generalized, with severe cervical and laryngeal involvement rendering her almost mute. She gained modest benefit from pharmacological treatment, including diazepam, clonazepam, gabapentin, and botulinum toxin. At age 33, she was admitted to our institution as she had become bedridden because of worsening dystonia.

Examination revealed short stature, dysmorphic facies consistent with 18p‐ syndrome, restricted vertical gaze, generalized dystonic posturing of all her limbs consistent with status dystonicus, and minimal fragmented speech, consistent with a complex laryngeal and oropharyngeal dystonia (see Video). MRI brain was normal with no features of holoprosencephaly.

Inpatient management included escalation of her antidystonic medications to clonazepam 4.5 mg/day, gabapentin 1.8 g/day, and benzhexol 9 mg/day alongside paracetamol and ibuprofen analgesia. These medications were of modest benefit, allowing a return home to her family, but she remained severely disabled and distressed by the dystonia, with minimal ability to speak or mobilize independently. Her family elected to proceed with DBS targeting the internal segment of the globus pallidus (GPi) bilaterally. She improved markedly within the first few weeks after surgery. Her DBS parameters were: amplitude 3.5 V (left GPi) and 3.2 V (right GPi), pulse width 90 ms, and frequency 130 per second bilaterally. She regained functional independence, being able to mobilize, feed herself, and communicate. Mild dystonia persisted, particularly involving the face and arms. Her clinical course was complicated by depression and hallucinations, which resolved by 6‐month follow‐up with weaning of her antidystonic medications and commencement of sertraline. She remained stable 12 months post‐DBS (see Video).

This is the fifteenth reported case of young‐adult‐onset dystonia and the 18p‐ syndrome, suggesting that this pattern of dystonia should be regarded as part of the chromosomal syndrome. The finding of vertical gaze restriction has been reported in one other person,3 raising the possibility that this may be another manifestation of 18p‐ syndrome. Three dystonia loci are present on the short arm of chromosome 18: DYT7, DYT15, and DYT25. DYT25 is an autosomal‐dominant adult‐onset dystonia typically involving neck, face, and larynx, with a mean age of onset of 28 years. DYT25 was mapped to the guanine nucleotide‐binding protein, alpha‐activating activity polypeptide, olfactory type [GNAL] gene on 18p11.21, and is termed DYT‐GNAL. The phenotype of our patient closely resembles that described with GNAL mutations.4 It should be noted that the pathogenesis of GNAL mutations is thought to be attributed to a dominant loss of function,5, 6 rather than the toxic gain of function of most dominant mutations, and therefore we postulate that the 18p‐ chromosomal deletion recapitulates the dominant loss of function mutations previously described in families with DYT25. Determining a genetic etiology may be important before embarking on DBS surgery, given that response to DBS may depend on underlying genetics.7 Of note, dystonia with GNAL mutations with successful treatment with DBS have been previously reported.8

In conclusion, 18p‐ syndrome may cause an adult‐onset dystonia that probably represents a form of DYT25 (i.e., loss‐of‐function mutation in GNAL) and can be difficult to treat with pharmacological therapy.3 To our knowledge, this is the first report of dystonia in 18p‐ syndrome successfully managed with GPi DBS, offering a useful therapeutic approach for a challenging genetic syndrome.

Author Roles

(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 the First Draft, B. Review and Critique.

S.D.: 1A, 1B, 1C, 3A

A.F.: 1A, 1B, 1C, 3B

H.M.B.: 1A, 1B, 1C, 3B

M.F.: 1B, 1C, 3B

J.C.: 1B, 1C, 3B

A.C.: 1B, 1C, 3B

J.M.: 1B, 1C; 3B

N.M.: 1A, 1B, 1C, 3B

Disclosures

Ethical Compliance Statement: The authors confirm that the approval of an institutional review board was not required for this work. 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. Signed authorization has been obtained from the patient to use the identifiable video content in both print and online publication formats.

Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.

Financial Disclosures for previous 12 months: SR Duma has received speaker honorarium from UCB. The authors declare that there are no disclosures to report.

Supporting information

Video S1. The video outlines the functional status of the patient's function pre‐DBS and post‐DBS. Segment 1 shows her during a hospital admission, during which she was unable to mobilize because of significant worsening of generalized dystonia. Segment 2 shows her just before DBS, following optimization of antidystonic medication, though still with significant generalized dystonia affecting her upper limbs and gait. Segment 3 shows significant improvement of upper limb function and gait following DBS.