Dear Editor This 38-year-old male, born to nonconsanguineous parents, presented with slowness, stiffness, and tremors in both upper limbs (ULs), beginning on the left side 9 year ago progressing to the right UL after a year. He developed progressive gait difficulty over 7 years, characterized by a slow, short-stepped gait and dragging of the feet, with the left leg more affected than the right, along with frequent falls. In addition, upon lying down, he noted left foot inversion and knee flexion. There was no history of rapid eye movement sleep behavior disorder, bladder involvement, myoclonic jerks, sleep benefit, behavioral or cognitive symptoms, anosmia, seizures, cranial nerve deficits, or drug/toxin exposure. He did suffer from chronic constipation. His grandfather was diagnosed with parkinsonism at 65 years of age. clinical details unavailable; pedigree chart, Figure 1. Figure 1: Pedigree chart of the patient (III. 2- proband) showing I. 2- grandfather of the proband, diagnosed with PD at the age of 65 yearsExamination showed a positive Myerson’s sign, slow saccades, broken pursuits, left UL dystonia (flexion, pronation, and internal rotation at the shoulder with clenched fist), right UL rest tremors, and bilateral UL postural tremors. Bradykinesia and cogwheel rigidity were present in all four limbs Video 1. He scored 53 on the movement disorder society-sponsored revision of the unified Parkinson’s disease rating scale Part III. "href": "Single Video Player", "role": "media-player-id", "content-type": "play-in-place", "position": "float", "orientation": "portrait", "label": "Video 1", "caption": "", "object-id": {"pub-id-type": "doi", "id": "", "pub-id-type": "other", "content-type": "media-stream-id", "id": "1₉d5q1ese", "pub-id-type": "other", "content-type": "media-source", "id": "Kaltura"} Gait was slow and short stepped, with left foot drag. Arm swing was reduced bilaterally. The pull test was positive. There were no cerebellar or pyramidal signs. The Mini-Mental State Examination score was 30/30. With clinical suspicion of young-onset Parkinson’s disease (PD) versus combined parkinsonism-dystonia, he underwent a 99mTc-Technitium 99m TRODAT single photon emission computed tomography scan. It showed asymmetrically reduced uptake in the bilateral striatum (right > left) with a rostrocaudal gradient. non contrast computed tomography of the brain was normal. Magnetic resonance imaging of the brain revealed a small gliotic area in the left parasagittal region due to injury. His routine hematological and biochemical profile was normal. Thyroid, parathyroid, ceruloplasmin, and ferritin levels were also normal. Whole-exome sequencing revealed compound heterozygous variants of unknown significance (VUS) in COL6A3 (ENST00000295550. 9: exon 40, c. 8839G>A, p. Ala2947Thr and exon 40, c. 8726 C>T p. Ala2909Val). The two variants segregated in the mother and father, respectively. Variant p. Ala2947Thr had a minor allele frequency of 0. 002%, 0. 002%, and 0. 0003% in gnomAD (v3. 1), gnomAD (v2. 1), and TOPMed, respectively, whereas variant p. Ala2909Val was not reported in any of these databases. Both variants were conserved across species. He was diagnosed with combined parkinsonism and dystonia related to the COL6A3 gene; however, pathogenicity cannot be confirmed. Both variants were classified as VUS in accordance with American college of medical genetics and genomics guidelines, as the criteria for likely pathogenic (PM2 plus weakly PP4) and benign (BP4) were contradictory. Functional studies demonstrating a damaging effect on the gene product are needed to fulfill the PS1 criteria for pathogenicity. 1 A heterozygous variant in PDGFB (c. 424C>T, p. Arg142Cys) was also detected in him and his father. The absence of cognitive impairment and basal ganglia calcifications, combined with the reduced penetrance associated with this disorder, argued against this being the causal variant. 2 However, its influence on the phenotype cannot be ruled out. 2 He was treated with pramipexole (maximum dose 3 mg) and levodopa (maximum dose 400 mg) ; however, these caused backward and lateral bending of the trunk with no clinical improvement. Rasagiline, amantadine, and baclofen had minimal to no effect. Trihexphenidyl helped moderately with his tremors. Zech et al. identified a novel variant in COL6A3 in five cases with autosomal recessive isolated cervical or segmental dystonia, now known as DYT-COL6A3. Since then, four more cases of COL6A3 gene–related movement disorders have been reported (dystonia cases-8, PD- 1) Table 1. The majority presented with cervical dystonia (4/8), followed by focal hand dystonia (3/8). Age of onset ranged from 6 to 61 years. Table 1: Clinical details of all the COL6A3-associated movement disorder cases in the literatureEvidence suggests that the extracellular matrix plays an essential role in neural circuit formation, synaptogenesis, and synaptic stability. Zech et al. , 3 using Zebrafish models, demonstrated that COL6A3 variants impact axonal targeting mechanisms, interfering with early neural circuit development and neuroplasticity. They hypothesized that COL6A3 mutations may affect synaptic plasticity and brain maturation in the adult brain. Abnormal synaptic plasticity, one of the main causes of dystonia, may indicate a pathogenic role for COL6A3 mutations in dystonia. Jochim et al. 8 found reduced fractional anisotropy bilaterally in the midbrain, pons, cerebellar peduncles, cerebral peduncles, thalamus, internal capsule, and subcortical white mater in previously described cases, reemphasizing the role of COL6A3 in sensorimotor circuit development. Exon 41 and 42 were initially considered mutation hotspot for COL6A3-related dystonia until Panda et al. described a case of childhood-onset dystonia carrying variants in exon 10 and 12. 5 Another Chinese group detected disease-causing variants in exon 6 and 40. 7 The variants identified in the two reports, located in the von Willibrand factor domain, were also involved in neuronal plasticity and circuit formation. 7 A compound heterozygous mutation was reported in a case of PINK1-related PD with additional dystonia. This case also carried a variant in exon 6. 4 The variants detected in our case were also in exon 40. Our case presented with combined dystonia and parkinsonism. Jin et al. studied the association of COL6A3 with PD. They discovered two heterozygous variants in COL6A3 in a PD case, which led to further discovery of seven pathogenic variants in other PD cases. They demonstrated COL6A3 variants may increase the genetic burden in PD using SKAT- O analysis. 6 The variants detected in the index case can be best classified as VUS; however, based on previous literature and the clinical phenotype, further analysis with functional assays and Sanger sequencing is needed to confirm pathogenicity. Prominent truncal dystonia with dopamine treatment was an intriguing clinical feature in this case. Second, this case also expands the phenotypic spectrum of PARK/DYT-COL6A3. Many genes are known to cause dystonia-parkinsonism, such as GCH1, TH, PINK1, ATP7B, and PANK2; however, the interplay between PD and dystonia secondary to COL6A3 requires further exploration. Author contribution A. Research project: Conception: Vinay Goyal Organization: Tanushree Chawla, Vinay Goyal Execution: Tanushree Chawla, Chanchal Goyal, Vinay Goyal B. Statistical analysis: Design: Execution: Review and Critique C. Manuscript preparation: Writing of the first draft: Tanushree Chawla Review and Critique: Chanchal Goyal, Vinay Goyal Ethical compliance statement The authors confirm that approval from an institutional review board was not required for this work. The authors have obtained written documented informed consent from the patient. The patient has given consent for their images, videos, and other clinical information to be reported in the journal. The patients understands that their names and initials will not be published and that due efforts will be made to conceal their identity; however, anonymity cannot be guaranteed. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Chawla et al. (Thu,) studied this question.