Myoclonus‐dystonia caused by GNB1 mutation responsive to deep brain stimulation

Abstract

Myoclonus-dystonia is commonly caused by mutations in SGCE, but other genotypes including ADCY5 and KCTD17 mutations have been recently described. We report the first patient with myoclonus-dystonia caused by a Guanine nucleotide-binding protein, beta-1 (GNB1) mutation who responded to bilateral globus pallidus interna (GPi) deep brain stimulation (DBS). The 16-year-old girl had a normal birth but was hypotonic in infancy and walked at age 3 years with an unsteady gait. At 4 years old she developed jerky movements of her neck, trunk, and proximal extremities that worsened with activity, illness, and fatigue. She had mild intellectual disability and obsessive-compulsive disorder that benefited from fluoxetine. For a decade, the jerks increased in amplitude and interfered with eating, writing, and daily functioning. They delayed her sleep onset by hours and caused accidental injury to herself and others. Examination at age 14 showed high-amplitude myoclonic jerks superimposed on generalized dystonia involving the neck, trunk, and upper limbs (Supporting Information Video). This may best be described as myoclonic-dystonia as recently proposed by Roze and colleagues. She had limited upward gaze and dysarthria. Cerebrospinal fluid monoamine metabolites were nondiagnostic, and brain MRI, electroencephalogram, metabolic screening, and microarray were normal (Supporting Information). The combination of hypotonia, myoclonus-dystonia, and upward-gaze palsy was suggestive of ADCY5; however, a de novo mutation in GNB1 NM_002074.4:c.352G>T, p.(Asp118Tyr) was identified on whole-genome massively parallel sequencing. In silico tools predicted the variant to be pathogenic and the Combined Annotation-Dependent Depletion score was 31 (Supporting Information). Clonazepam, clobazam, levodopa, haloperidol, sodium valproate, methylphenidate, and olanzapine exacerbated or failed to help her symptoms. Benzhexol reduced her myoclonus but caused agitation. Bilateral GPi DBS at age 15 immediately improved her myoclonus, and her dystonia responded over weeks (Supporting Information Video). Interleaving DBS settings of 3.5 and 1.0 V, 90 μs, and 125 Hz bilaterally have been optimal. After 12 months, her dystonia has progressed, but her myoclonus remains mild. She is independent with her daily functioning and her Canadian Occupational Performance Measures have significantly improved (Supporting Information). GNB1 is a recently described neurodevelopmental disorder with hypotonia and seizures being the most consistent features. Since the initial description, 46 cases of GNB1 have been published, and movement disorders have been documented in 18 cases. Dystonia is most common and has been associated with missense mutations causing p.Ile80 substitution, but myoclonus, chorea, athetosis, and/or tics are also noted. Only Steinrucke and colleagues have detailed the phenomenology of the movement disorder in a report of a 15-year-old girl with generalized dystonia and myoclonus and a missense mutation adjacent to our patient’s, c.353A>G, p.(Asp118Gly). GNB1 encodes guanine nucleotide-binding protein (G protein) subunit beta-1, a protein important in transducing signalling through G-protein coupled receptors expressed in cortical, striatal, and dopaminergic neurons. Our patient is the first described with GNB1 myoclonusdystonia undergoing DBS with remarkable initial benefit and sustained functional improvement albeit worsening dystonia at 1-year follow-up likely the result of the progressive nature of this disorder. GNB1 is a differential diagnosis of myoclonusdystonia, and DBS should be considered in these cases.