DYT-TUBB4A: First Family from India with the Arg2Gly Mutation

Sir,

DYT-TUBB4A, formerly known as DYT-4, was first reported by Parker et al. in 1985,[1] and was termed ‘whispering dysphonia’ due to laryngeal dystonia. It occurs due to mutations in the TUBB4A gene. Only 35 cases of DYT-4 have been reported so far worldwide.[2] We now report two new cases, which are also the first cases of DYT-TUBB4A to be reported from India.

The proband, a 21-year-old male, presented with progressive pain in the right arm and difficulty in writing and gripping the bike handle with his right hand since the age of 18 years. He had also developed an abnormality of voice that started to sound strangled with frequent breaks. He had also noted spontaneous curling of the tip of the tongue for the past year, which contributed to his speech impairment. The patient reported some fluctuation, with the improvement of symptoms in the morning and worsening towards evening in the first year of the illness, but this phenomenon had not occurred for at least one year before presentation. He reported no response to a trial of levodopa. He had also developed generalized anxiety disorder for the past six months, for which he had been prescribed sertraline. On examination, he had dystonic posturing of the right upper limb with flexion of the wrist and fingers, which was aggravated by writing. He also had an associated dystonic tremor in the right upper limb. He also had tongue extrusion and curling dystonia and laryngeal adductor dystonia [Video 1]. He reported no geste antagoniste. The remaining neurological examination was normal. His mother, presently 42 years of age, had developed symptoms at the age of 37 years, with left upper limb posturing followed by severe jaw opening and lingual dystonia [Video 2]. She had also received a trial of levodopa therapy with no response. She had been receiving irregular botulinum injection therapy for oromandibular dystonia. She reported no geste antagoniste. Slit lamp examination for Kayser-Fleischer ring, 24-hour urine copper and serum ceruloplasmin, peripheral blood smear for acanthocytes, and MRI brain were normal in both the proband and the mother. The proband was managed with clonazepam (2 mg per day), trihexyphenidyl (6 mg per day), and baclofen (40 mg per day) with a mild response. He achieved good benefits with botulinum toxin for writer’s cramp and lingual dystonia and continues to be on follow-up. After several years of botulinum toxin therapy, his mother refused further botulinum injection therapy. She continues to be on clonazepam (2 mg per day) at present. None of the other members of the family reported any neurological complaints.

Clinical exome sequencing revealed a heterozygous missense variant (p.Arg2Gly) in exon 1 of the TUBB4A gene (chr19:g. 6502209G>C), which was confirmed on Sanger sequencing. The same mutation was confirmed to be present in the mother on Sanger sequencing. The p.Arg2Gly variant has not been reported in the 1000 genomes and gnomAD. The in-silico predictions of the variant are possibly damaged by Polyphen2 (HumDiv) and damaged by SIFT and MutationTaster2. Based on this, the variant was reported to be likely pathogenic. The original Australian family of DYT4 also carried the same heterozygous mutation in the TUBB4A gene (p.Arg2Gly).[3]

Thirty-five cases of DYT-TUBB4A have been reported in the literature so far, excluding the present cases. All cases reported so far hail from European ancestry, except the present two cases from India. It is an autosomal dominant condition. Laryngeal dystonia is a hallmark feature. Although ‘whispering dysphonia’ suggests a breathy quality due to abductor spasm, patients have adductor dysphonia.[4] Other regions of predilection for dystonia in DYT-TUBB4A include cervical and upper limbs, seen in around 60% of the cases, and generalized dystonia. Apart from “whispering dysphonia,” another typical feature observed in 25% of the cases is “hobby-horse” dystonic ataxic gait, which was not seen in our patients. This may respond to deep brain stimulation, propranolol, and tetrabenazine. Good response to deep brain stimulation of the globus pallidus interna (Gpi-DBS) has been reported in four patients regarding motor complaints[2,5] and to the ventral posterolateral nucleus of the thalamus in one patient. Laryngeal dystonia responds to a lesser extent. Stereotactic lesional surgery of the thalamus and globus pallidi have also been attempted without outstanding benefit. Some symptomatic improvement with alcohol ingestion is known.[6]

An unusual feature reported by our first patient was diurnal fluctuations in the early part of the illness with some sleep benefits. Based on this, levodopa therapy was attempted but without success. This feature has not been reported in relation to DYT-TUBB4A thus far.[2,4] He also reported generalized anxiety. Dementia and increased suicidal attempts have been reported in a few cases.[1] Additionally, the dystonia seen in both our patients continued to be segmental, particularly the mother with a disease duration of 5 years at the time of reporting.

TUBB4A mutations have also been associated with other phenotypes.[7] One of these is Hypomyelination with Atrophy of the Basal ganglia and cerebellum (H-ABC) or hypomyelination with nonspecific cerebellar atrophy.[8,9] In H-ABC, symptoms develop in infancy or childhood and comprise delayed development, dysarthria, spasticity, and hyperkinetic movement disorders, including chorea, dystonia, and seizures.[10] Unlike DYT-TUBB4A, wherein the neuroimaging is normal, hypomyelination is evident in patients with H-ABC, along with cerebellar atrophy and atrophy of the putamen.[10] Another phenotype associated with TUBB4A mutations is complicated spastic paraplegia.[11] H-ABC and DYT-TUBB4A share some phenotypic similarities, and it has been proposed that these disorders are part of a continuous spectrum.[12] An intermediate phenotype between H-ABC and DYT-TUBB4A has been previously reported from India.[13] TUBB4A encodes for beta-tubulin 4A protein, which is a contributor to microtubule polymerization and stability. Laryngeal involvement is seen in patients with generalized and segmental dystonia, including DYT1, DYT6, DYT25, and DYT28, although it is rarely a presenting feature in these patients, unlike DYT4. However, screening for TUBB4A variation in patients with isolated laryngeal dystonia has extremely poor yield.[14] Apart from the R2G missense variant identified in 2013 from members of the original family, the A271T missense variant in the TUBB4A gene was reported in a familial case of segmental dystonia with spasmodic dysphonia.[3] Other variants reported include D295N, R46M, Q424H, and R121W, with phenotypes similar to the original reports.[2]

We report the first family of DYT-TUBB4A from India. This disease should be suspected in young adults who present with segmental or generalized dystonia with predominant laryngeal involvement.

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Conflicts of Interest

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