Primary generalized dystonia due to TOR1A ΔGAG mutation in an Indian family with intrafamilial clinical heterogeneity
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.263172
Source of Support: None, Conflict of Interest: None
Primary dystonia is a movement disorder characterized by sustained involuntary muscle contraction leading to abnormal postures and twisting movements. The prevalence of dystonia varies worldwide. In India, the prevalence rate is about 49.06 per 100,000 individuals with a higher prevalence of late-onset primary dystonia. There is strong evidence that genetic factors play a significant role in causing dystonia. So far, six genes (TOR1A, CIZ1, THAP1, GNAL, ANO3, and TUBB4) have been implicated for primary torsion dystonia (PTD); however, mutations in TOR1A and THAP1 have been found to be responsible for manifestations in a large number of patients with PTD irrespective of their ethnic background. A trinucleotide deletion (ΔGAG) in TOR1A gene has been reported to be the most common cause of PTD (DYT1) in various populations.,,, This mutation was found to be more common in Ashkenazi Jew patients though it was found in most of the world dystonia cohorts. DYT1 dystonia is an autosomal dominant primary dystonia with a reduced penetrance (30%–40%). Phenotypic characteristics of patients include early disease onset (<26 years) and the disease begins with the involvement of limbs which gradually progresses to other body parts except the craniocervical and oromandibular regions, leading to generalized dystonia. In this study, we report a family of four members from West Bengal, India, affected with DYT1 dystonia due to ΔGAG mutation in TOR1A gene with atypical phenotype and intrafamilial phenotypic variability.
The patients were diagnosed in the Movement Disorders Clinic at Bangur Institute of Neurosciences, Kolkata, India, and have negative history for developmental complications, malignancy, or any brain injury. Electroencephalogram, nerve conduction velocity (NCV) test with H-reflex, neuroimaging (computed tomography, magnetic resonance imaging, etc.) studies for any brain lesions, and measurement of biochemical parameters (e.g., serum ceruloplasmin, uric acid) were found to be normal. None of them had a Kayser–Fleischer (KF) ring, as verified by routine slit-lamp eye examination.
A 26-year old male patient [[Figure 1]a, proband, II: 1] was diagnosed as primary generalized dystonia with disease onset at 10 years. The proband was suffering from writing problem and holding objects in both the upper limbs. He felt an abnormal sensation with cramps in the right upper limb during writing and subsequently developed problem in holding objects. Gradually, the disease progressed to the lower limbs with abnormal posture during walking with a pattern of twisting gait. Later on, postural and action tremors developed in both the upper limbs along with a flexed posture in the right upper limb. The patient also developed truncal dystonia, an atypical feature for generalized dystonia with asymmetric distribution more towards the right side of the body (laterocorpus). The neck and shoulder position tilted slightly to the left side. At that time, the patient was treated with levodopa–carbidopa (55 mg TDS), clonazepam (0.5 mg BDS), tetrabenazine (25 mg BDS), and trihexyphenidyl (4 mg BDS).
The brother of proband [[Figure 1]a, II: 2], a 21-year old male, was also affected with primary generalized dystonia. He started having problem with dragging and lifting of toes during walking at 10 years of age. Gradually, the disease progressed to the upper body parts leading to generalized dystonia. He developed writer's cramp with overflow of muscle contraction and action tremor during writing with the right upper limb. Whole-body tremor, both postural and action, was also present. Asymmetric twisting posture with stiffness developed on the right side of the body. Twisting in the right toe was found during walking, though the tandem walking was normal. The tone and activation in both the upper limbs were normal. The patient was treated with the medicines including levodopa–carbidopa (110 mg TDS), clonazepam (0.5 mg BDS), trihexyphenidyl (2 mg TDS), and propranolol (40 mg OD). The personalized medications prescribed for both the patients were dependent on variable biological responses.
This study was approved by “Bioethical Committee for Animal and Human Research Studies, University of Calcutta” following the guidelines of Indian Council for Medical Research. For genetic study, blood samples were collected from the patients and their parents [Figure 1]. All exons, promoter and 3'UTR of TOR1A and THAP1 genes were screened by polymerase chain reaction and sequencing, as described elsewhere., A heterozygous trinucleotide deletion mutation (c.904-906/907-909ΔGAG; p.302/303ΔE) in TOR1A gene was detected in both the patients and their asymptomatic mother [[Figure 1], I: 2], but not in their father [[Figure 1], I: 1]. To understand the lack of penetrance in mother, we also analyzed the presence and orientation of c. 646C allele of rs1801968 (c.646G>C, p.D216E), as the presence of this allele in trans-orientation to the ΔGAG can greatly suppress the disease expression. However, none of the family members harbored the c. 646C allele in exon 4 of TOR1A gene. The clinical features of the individuals harboring ΔGAG mutations are presented in [Table 1]. Interestingly, while there are similarities in clinical features, several significantly different phenotypes were also observed among them.
Among the clinical features of primary dystonia, two phenotypes are relatively common: (1) early onset of symptoms and (2) onset of dystonia in a limb. However, the intrafamilial phenotypic variability of dystonia patients having ΔGAG deletion is relatively rare., The occurrence of ΔGAG mutation in Indian primary dystonia patients is rare. In this study, we are reporting two generalized dystonia patients having TOR1A ΔGAG mutation from a single family with atypical intrafamilial phenotypic variability. The anatomical sites for disease onset were different for the two patients; while the proband had upper limb onset, his brother had lower limb onset. The direction of disease progression to the generalized form was exactly opposite for both the patients. In addition, as the disease progressed, the proband developed truncal dystonia, whereas the sibling developed a tremor dominant generalized dystonia. So far, there are a few reports where generalized dystonia patients harboring TOR1A ΔGAG have truncal involvement.,,, Interestingly, the age of onset for both the patients was the same, that is, 10 years. This may be due to the age-related spatial expression of certain modifier genes in the cerebellum or could be triggered by environmental factors. Genetic analysis reveals that the mutant allele was inherited from their asymptomatic mother. Thus, in this family, the disease penetrance and phenotypic variation could be governed by some other genetic and/or environmental factors. This finding was previously presented in a conference as the first report of TOR1A ΔGAG mutation among Indian primary dystonia patients and published as a meeting proceeding.
The authors are thankful to the participating patients and their family members for their cooperation toward this study.
Financial support and sponsorship
This study was supported by a grant from the Department of Science and Technology [(DST-PURSE) and (DST-CSI to JR)], Govt. of India. SG was supported by DST, INSPIRE fellowship.
Conflicts of interest
There are no conflicts of interest.