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COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature
Brain & Development xxx (2020) xxx–xxx www.elsevier.com/locate/braindev
Original article
COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature Prateek Kumar Panda 1, Indar Kumar Sharawat ⇑,1 Pediatric Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, Rishikesh, Uttarakhand 249203, India Received 31 October 2019; received in revised form 10 January 2020; accepted 11 January 2020
Abstract Background: Still, the genetic basis of a large number of cases of early-onset isolated dystonia continues to be a mystery. In recent years, many new candidate genes are being identified as putative pathogenic factors in children with isolated dystonia due to the easy availability of whole-exome sequencing. Recently biallelic mutations in the COL6A3 gene were identified as a cause of rare dystonia (DYT)-27 syndrome. Till date, only six cases of DYT27 have been reported in the literature. Methods: We report a new case of COL6A3 mutation associated early-onset isolated dystonia-DYT27. We did a review of the previously published cases of DYT27. Citations were identified through PubMed, Embase, Web of Science and Google scholar searches using the search terms (including variations), ‘‘Dystonia-27 or DYT27” or/and ‘‘COL6A3 mutation associated earlyonset isolated dystonia”, combined with study filters for original research, case reports and case series. Results: Next-generation sequencing in the index patient revealed two pathogenic compound heterozygous loss of function mutations in exon 10 and exon 12 of the COL6A3 gene coding for the alpha(a)3(VI) chain of type VI collagen. Together with the presented case, seven cases (five males) were available for analysis. The median age at onset was 22 years (range: 6–61). Dystonic symptoms were started from hands in five and from the neck in the remaining two patients. Five patients had favorable outcomes with trihexyphenidyl and botulinum toxin while tetrabenazine and levodopa were ineffective. Conclusions: Although it is a new entity that is only recently discovered, in future years many more new cases suffering from this particular entity are likely to be reported and the already heterogeneous clinical spectrum is likely to be further widespread in years to come. Ó 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Primary dystonia; DYT27; Oromandibular dystonia; COL6A3 gene; Early-onset primary dystonia
1. Introduction Early-onset primary dystonia usually starts in the first or second decade of life, starting from one extremity, initially only during performing some action such as walking or writing. Later it slowly progresses to involve ⇑ Corresponding author.
E-mail address: [email protected] (I.K. Sharawat). Both the authors contributed equally and share joint first authorship. 1
other parts of the body and tends to persist even at rest, without involving cognition, seizures or other neurological symptoms [1]. Idiopathic torsion dystonia (DYT1 caused by a mutation in TOR1A and rarely GNAL gene), dopa-responsive dystonia (DYT5 caused by a mutation in GCH gene), rapid-onset dystoniaparkinsonism (ATP1A3 gene) and myoclonus dystonia (SGCE gene coding for e-sarcoglycan) are some of the commonly reported primary dystonia syndromes with autosomal dominant inheritance [2–5]. Still, the genetic
https://doi.org/10.1016/j.braindev.2020.01.004 0387-7604/Ó 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Panda PK, Sharawat IK. COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature. Brain Dev (2020), https://doi.org/10.1016/j.braindev.2020.01.004
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P.K. Panda, I.K. Sharawat / Brain & Development xxx (2020) xxx–xxx
basis of a large number of cases of childhood and adolescent-onset segmental or generalized dystonia continues to be a mystery [4]. In recent years, many new candidate genes are being identified as putative pathogenic factors in children with isolated dystonia due to the easy availability of whole-exome sequencing [5]. Here, we report a case of isolated dystonia with onset from childhood and predominantly involving upper limb and cervical region unlike commonly identified lower limb or truncal predominant involvement in majority cases of primary dystonia. The novelty of the report lies in the fact that a pathogenic compound heterozygous mutation was identified in this child in the COL6A3 gene responsible for a recently identified rare dystonia (DYT)-27 syndrome, previously reported only in six cases. The study was approved from the institutional review board and informed consent was taken from the parents of the patients. 2. Case presentation An eight and half-year-old developmentally normal boy presented with involuntary twisted posturing of the right hand for the past two years. The symptoms were initially intermittent, appearing while performing actions like writing and approaching to grasp any object. It was also associated with intermittent action tremors of the right hand. The handwriting of the child worsened as the disease progressed and became illegible later onwards, forcing the child to use his left hand for these activities. After about six months of onset, the dystonic posturing of hand became constant throughout the day, with the increase in severity of dystonic tremor to an extent that the child was unable to perform any day to day activity requiring fine dexterity with the right hand. One year into the illness, there was involvement of the proximal part of the right upper limb and the child had started having cervical dystonia with extensor posturing of the neck in resting state. There was associated intermittent oromandibular dystonia while chewing and speaking and drooling. There was no history suggestive of diurnal fluctuations in the symptoms. There was no history of seizures, cognitive decline, behavioral changes, focal deficit, jaundice, and rashes. He was born to a non-consanguineous couple with a normal perinatal period. His family history for similar illness or any other neurological illness was unremarkable. On examination, he had normal mentation, normal head circumference, intermittent cervical and oromandibular dystonia, drooling, dysarthria, and intermittent dystonic posturing of the right upper limb along with tremors. His Burke-Fahn-Marsden dystonia rating scale (BFMDRS) [6] score was 23. His ophthalmic examination was normal. A clinical possibility of primary dystonia, Wilson disease, and mitochondrial disorders was considered.
Investigation showed normal serum ceruloplasmin, urinary copper, and arterial lactate levels. Blood, and urine amino acids and acylcarnitines levels by tandem mass spectrometry/gas chromatography-mass spectrometry were also normal. Magnetic resonance imaging (MRI) of the brain was normal (Fig. 1). Subsequently, with a clinical diagnosis of isolated dystonia syndrome, next-generation sequencing was performed to identify any pathogenic mutation. Selective capture and sequencing of the protein-coding regions of the whole genome were performed. DNA extracted from blood was used to perform targeted gene capture using a custom capture kit. The libraries were sequenced to mean >80–100X coverage on the Illumina sequencing platform. The sequences obtained are aligned to the human reference genome (GRCh37/hg19) using the BWA program and analyzed using Picard and GATK version 3.6 to identify variants relevant to the clinical indication. GATK’s best practices framework was followed for the identification of variants in the sample. Gene annotation of the variants is performed using the VEP program against the Ensembl release 87 human gene model. Clinically relevant mutations were annotated using published variants in literature and a set of diseases databases (ClinVar, OMIM, GWAS, HGMD,
Fig. 1. Magnetic resonance imaging of the brain. Axial [T1 (a), T2weighted (b) and fluid-attenuated inversion recovery (c)] and sagittal (d) T2-weighted sequences did not reveal any abnormality.
Please cite this article in press as: Panda PK, Sharawat IK. COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature. Brain Dev (2020), https://doi.org/10.1016/j.braindev.2020.01.004
P.K. Panda, I.K. Sharawat / Brain & Development xxx (2020) xxx–xxx
and SwissVar). Common variants were filtered based on allele frequency in 1000Genome Phase 3, ExAC, EVS, dbSNP147, 1000 Japanese genome and internal Indian population database of the laboratory. The nonsynonymous variant effect is calculated using multiple algorithms such as PolyPhen-2, SIFT, Mutation Taster2, Mutation Assessor, LRT, and other tools. Both non-synonymous and splice site variants were included in the analysis. Next-generation sequencing revealed two pathogenic compound heterozygous loss of function mutations in the COL6A3 gene coding for the alpha(a)3(VI) chain of type VI collagen. One heterozygous missense mutation was detected in exon 10 (chr2:238277557C>T; Depth:137x) that results in amino acid substitution of serine for glycine at codon 1517 (p.Gly1517Ser; ENST00000295550). Another heterozygous missense mutation was found in exon 12 of the COL6A3 gene (chr2: 238274498G>A; Depth: 126x) that results in amino acid substitution of leucine for proline at codon 1894 (p.Pro1894Leu; ENST00000295550) (Fig. 2). Recessive mutations in the COL6A3 gene have previously been reported in children with a particular variety of early-onset isolated dystonia syndrome called DYT27. Both the mutations were later confirmed by Sanger sequencing. Both the observed variations were found to lie in the von Willebrand factor type A domain of the COL6A3 protein. The parents were found to be heterozygous carriers of mutations in the COL6A3 gene. The Gly1517Ser and Pro1894Leu variants have previously not been reported in the 1000 genomes and ExAc (Exome Aggregation Consortium). The in silico predictions of both the variants were found to be possibly damaging by PolyPhen-2 (HumDiv) and deleterious by SIFT, LRT, Mutation Taster2 and Mutation Assessor. The final PROVEAN score of both the protein variants was also found to be deleterious. The evolutionary conservation of both the putative pathogenic mutations was also assessed by the HomoloGene tool. Both the reference codons corresponding to the putative pathogenic variants were found to be highly conserved across species. The results of bioinformatics analyses of both the mutations have been described in Table 1. Based on clinical presentation and investigations, a diagnosis of COL6A3 mutation associated early-onset isolated dystonia-DYT27 was concluded. He was started
3
on levodopa (maximum dose: 6 mg/kg/day) but he did not show any improvement in the symptoms. Subsequently, he was started on oral trihexyphenidyl and clonazepam. At three months follow up, although the child continued to have generalized dystonia, he showed partial improvement in the severity of dystonia, as his BFMDRS score had reduced to 14. 3. Search strategy and analysis of literature Citations were identified through PubMed, Embase, Web of Science and Google scholar searches using the search terms (including variations), ‘‘Dystonia-27 or DYT27” or/and ‘‘COL6A3 mutation associated earlyonset isolated dystonia”, combined with study filters for original research, case reports and case series. The identified reports were screened manually for patients fulfilling inclusion criteria (COL6A3 mutation associated DYT27). Additional articles were identified from the reference lists of identified papers. Only papers published in English were reviewed. Six previously published cases were identified in the literature [7–9]. 4. Results Together with the presented case, seven cases were thus available for analysis (Table 2). The median age at onset was 22 years (range: 6–61 years). All the cases had a slow progression of symptoms, with relatively preserved lower limb function. Out of seven patients, five were male. Dystonic symptoms started from hands in five cases and from the neck in the remaining two patients. Ultimately four patients had generalized and three had segmental dystonia. Five patients had favorable outcomes with trihexyphenidyl and botulinum toxin while tetrabenazine and levodopa were ineffective in two and one patient respectively. All patients had normal cognition, no neuropsychiatric features and no other upper motor neuron signs except tremors, which was attributed to dystonic tremors in most of the cases. 5. Discussion DYT27, caused by biallelic mutations in the COL6A3 gene, follows autosomal recessive inheritance, with inter individual heterogeneity of distribution and severity of
Fig. 2. COL6A3 mutations in the index child. Schematic representation of the COL6A3 gene (43 exons) showing biallelic mutations in the exon 10 and 12.
Please cite this article in press as: Panda PK, Sharawat IK. COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature. Brain Dev (2020), https://doi.org/10.1016/j.braindev.2020.01.004
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Table 1 Results of bioinformatics analyses of both the mutations found in the index case. Variation nucleotide
chr2:238277557C>T
chr2: 238274498G>A
Variation amino acid Exon involved Type of mutation Frequency in ExAc genome Frequency in 1000 genome PolyPhen2 prediction SIFT MutationTaster2 Mutation Assessor PROVEAN Reference codon conserved across species
p.Gly1517Ser Exon 10 Missense Not found Not found Possibly damaging Damaging Deleterious Deleterious Deleterious Yes
p.Pro1894Leu Exon 12 Missense Not found Not found Possibly damaging Damaging Deleterious Deleterious Deleterious Yes
dystonia. COL6A3 gene mutations have been already implicated in Ulrich congenital muscular dystrophy and Bethlem myopathy [10,11]. Zech et al. described five cases of DYT27 in three German family kindreds [7]. Out of which three had generalized dystonia, predominantly affecting the cranio-cervical region, upper limbs, and trunk. In all five cases, initially, the neck or upper limb was involved, with onset in the first decade in one case, in the second decade in two cases and later onset in remaining of the two cases. Trihexyphenidyl, clonazepam, and botulinum toxin injection were tried in almost all cases with variable benefit [7]. Initially, Jochim et al. [8] identified these diseasecausing mutations by whole-exome sequencing in two siblings suffering from isolated dystonia, with probable autosomal recessive inheritance. Subsequently, they identified three cases from two additional recessive pedigrees by performing genetic screening of 367 patients with probable primary dystonia [7]. COL6A3 is a large gene with 43 exons. It encodes for a protein with more than 3000 amino acids. At least 1500 rare, potentially pathogenic variants have been detected to involve this gene [9]. The alpha-3 chain, of type VI collagen coded by this gene, is quite larger as compared to the other two chains (alpha-1 and alpha2), as it contains a number of extra subdomains in the amino-terminal [7,12]. One of them is the von Willebrand factor type-A subdomain located in the aminoterminal globular domain. It is involved in binding to extracellular matrix proteins, cell-to-cell interaction and other signaling pathways (integrin pathway). In the index case, both the mutations responsible for the disease are located within this subdomain, thereby explaining the neuropathogenicity. The pathogenicity was also predicted in various in silico analysis as the mutations in the index case were found to be possibly damaging by altering the functional structure of the protein. Most of the genes responsible for movement disorder either involve basal ganglia specific proteins or proteins involved in interneuronal interaction/neuronal circuit formation [13]. Mutation of several other genes also causes isolated dystonia in childhood and
adolescence. However, few of these already described dystonia predominant neurogenetic syndromes clinically somewhat resemble DYT27 caused by biallelic mutations in the COL6A3 gene. Clinical distinguishing features of these syndromes have been demonstrated in Table 3. At least one mutation in all five of the cases described by Zech et al. involved an exon-skipping mutation in exon 41 of the COL6A3 gene leading to in-frame deletion [7]. However, in the index case, pathogenic mutations involving exon 10 and 12 resulted in isolated dystonia. Thus, the postulate by Zech et al. regarding exon 41 of the COL6A3 gene being a hot spot for mutations causing isolated dystonia needs to be redefined with the discovery of these new novel pathogenic mutations. Moreover, Lohman et al. also found variable clinical expression in the pedigree described by him, who harbored mutations in exon 41 of the COL6A3 gene and mutations in other genes such as the PINK1 gene was found in the case with dystonia and parkinsonism. In their study, Lohmann et al. have screened 955 patients with combined or isolated dystonia to identify only one patient with a biallelic mutation in the COL6A3 gene [9]. The homozygous mutations in the PINK1 gene present in this person have already been found to be associated with early-onset parkinsonism. The mutual interaction between these two genes, even if any, is yet to be revealed [9]. However, this patient had both dystonia and parkinsonism unlike other family members, who only had parkinsonism and he was also of German ethnicity like the five cases described by Zech et al. [7]. Interestingly in this case also, the second mutation was a novel mutation in the amino-terminal of the COL6A3 gene like our case (exon 6). Zech et al. had reproduced the exon skipping mutation in exon 41 in Zebrafish embryos and the mouse brain resulted in the development of segmental dystonia, without any muscular disease [7]. Reduced axonal outgrowth, with abnormal neuronal circuitry formation, was demonstrated in all these animals, without any alteration in collagen deposition. The C4 domain of the collagen VI a3 (FN-III motif), exon 41 is in the orga-
Please cite this article in press as: Panda PK, Sharawat IK. COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature. Brain Dev (2020), https://doi.org/10.1016/j.braindev.2020.01.004
Clonazepam, Trihexiphenidyl
Generalized
Generalized
Segmental
Hand
Hand
Hand
c.7557C>T (p.Gly1517Ser) and c.4498G>A (p.Pro1894Leu)
Segmental Hand
c.8966-1G>C (p. Val2989_Lys3077delinsGlu) and c.7660G>A (p.Ala2554Thr) c.2195C>T (p.Thr732Met) and c.9245C>G (p.Pro3082Arg)
Generalized Segmental Neck Hand
c.8966-1G>C (p. Val2989_Lys3077delinsGlu) and c.7502G>A (p.Arg2501His)
Levodopa
Also had parkinsonism in the affected case and three female siblings, all harboring homozygous PINK1 mutations. But none of the other cases had dystonia – Information NA
Hypertension and cholecystectomy at 19 years –
–
Sibling of the first case Esophageal carcinoma at 62 years Genital tuberculosis at 23 years of age
Also had Crohn’s disease
Haloperidol, Tetrabenazine, Clozapine Tetrabenazine –
Clonazepam, Trihexyphenidyl, Botulinum toxin Botulinum toxin Clozapine Botulinum toxin Botulinum toxin Declined pharmacotherapy Clonazepam, Trihexiphenidyl, Botulinum toxin Information NA c.9128G>A (p.Arg3043His) and c.9245C>G (p.Pro3082Arg) Generalized Neck
Mutation Dystonia distribution Initial site of dystonia
Male Case 7, Index case
7
Male Case 6, Lohman et al.
61
Male Case 5, Zech et al.
6
Female Case 4, Zech et al.
24
Female Male Case 2, Zech et al. Case 3, Zech et al.
20 24
Male Case 1, Zech et al.
20
Sex
Age of onset (years)
5
nization of neuronal plasticity [8]. Similarly, the coding regions involving the mutations in exon 10 and 12 are also supposed to be involved in other functions in brain extracellular matrix such as neuronal organization, plasticity, and neuronal circuit formation. Mutations of the COL6A3 gene responsible for Ulrich muscular dystrophy are different from the mutations documented in all the six cases of DYT27 in the reported literature. COL6A3 gene is ubiquitously expressed in the brain. Hence, it is likely to have a significant role in neuronal proliferation and differentiation, apart from mere collagen deposition. As a result, the hypothesis given by Zech et al. regarding mutation in exon 41 is an essential prerequisite for producing dystonia that may need to be updated in the future with the discovery of other novel pathogenic mutations [7]. Exact neuronal functions of various subdomains of the COL6A3 gene are likely to be further elucidated when further cases of DYT27 with different mutations will be reported from various geographic regions of the world. Large distance geographic separation with ethnic diversity between Germany and India might be the responsible factor for the absence of exon 41 mutation in the Indian index case. Zech et al. [7] and Jochim et al. [8] had also studied the MRI of the brain of patients with DYT27 using special sequences like diffusion tensor imaging and demonstrated significantly reduced fractional anisotropy bilaterally in the pons, midbrain, cerebellar peduncles, thalamus, internal capsule, and frontal and parietal subcortical white matter, compared to healthy controls. Moreover, reduced fractional anisotropy between the bilateral dentate nucleus and thalamus was also found in tractography in their study [14]. This altered white matter structure involving various parts of the cerebello-thalamo-cortical network was proposed by the authors as the underlying causative neuropathogenetic factor for dystonia in patients with COL6A3 mutations. Perturbation of brain extracellular matrix and abnormal neural circuit formation have been proposed as the probable pathophysiological mechanism behind dystonia production due to few other genes responsible for causing isolated dystonia syndromes. 6. Conclusion
Case no, investigator
Table 2 Comparison of clinical characteristics of the patients with DYT27 caused by biallelic COL6A3 mutation.
Drug showing favorable clinical response
Drug showing no clinical response
Other remarks
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The clinical possibility of COL6A3 biallelic mutation associated DYT27 should be considered in children or adolescents with isolated dystonia starting from upper limb, cervical or oromandibular region. Although it is a new entity that is only recently discovered, in future years many more new cases suffering from this particular entity are likely to be reported. The already heterogeneous clinical spectrum is likely to be further widespread in years to come. For the time being trihexyphenidyl, clonazepam and if possible, botulinum toxin is the best
Please cite this article in press as: Panda PK, Sharawat IK. COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature. Brain Dev (2020), https://doi.org/10.1016/j.braindev.2020.01.004
GNAL Autosomal recessive Adults
Isolated focal or segmental dystonia involving cranio-cervical region including oromandibular/jaw, larynx, eyelids and often progresses to one arm Combined dystoniaparkinsonism syndrome. Dystonia is early-onset, progressively involving upper limb, laryngeal and oromandibular region, but incidence extremely rare Initially affects distal limbs and later involves the neck, orofacial, and cranio-cervical regions. It is slowly progressive and mild in severity Dystonia or dystonic tremor of a leg or arm is the most common presenting symptom. Initially, dystonia appears while performing specific actions such as writing or walking. Distinguishing clinical features
DYT25 DYT16
PRKR1A Autosomal recessive 1st or 2nd decade
THAP Autosomal dominant First and second decade Initially, isolated cranio-cervical dystonia causing dysphagia, dysarthria or blepharospasm and limbs are involved only in later stage
DYT6 DYT2
HPCA Autosomal recessive Childhood TOR1A Autosomal dominant Childhood or adolescence
DYT1
Causative gene Inheritance The usual age of onset
Table 3 Distinguishing features of other isolated neurogenetic dystonia syndromes, which sometimes may resemble DYT27 clinically [7,9,15–20].
COL6A3 Autosomal recessive Children and young adults Dystonia usually starts from the hands or cranio-cervical region causing writer’s cramp, postural dystonic tremors, and oromandibular dystonia. Trunk and laryngeal muscles can be involved in the later stage.
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DYT27
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possible treatment option for this rare neurogenetic syndrome in the absence of any genetically targeted treatment. Targeted therapies directed at the COL6A3 gene will be an attractive treatment option in years to come. 7. Funding/support None declared. 8. Disclaimers Nil. References [1] Weisheit CE, Pappas SS, Dauer WT. Inherited dystonias: clinical features and molecular pathways. Handb Clin Neurol 2018;147:241–54. [2] Lohmann K, Klein C. Update on the genetics of dystonia. Curr Neurol Neurosci Rep 2017;17:26. [3] Zech M, Boesch S, Sycha T, Mueller J, Poewe W, Winkelmann J. TOR1A, THAP1, and GNAL mutational screening in Austrian patients with primary isolated dystonia. Mov Disord 2015;30:1853–4. [4] LeDoux MS. The genetics of dystonias. Adv Genet 2012;79:35–85. [5] Charlesworth G, Bhatia KP, Wood NW. The genetics of dystonia: new twists in an old tale. Brain 2013;136:2017–37. [6] Kuiper MJ, Vrijenhoek L, Brandsma R, Lunsing RJ, Burger H, Eggink H, et al. The Burke-Fahn-Marsden dystonia rating scale is age-dependent in healthy children. Mov Disord Clin Pract 2016;3:580–6. [7] Zech M, Lam DD, Francescatto L, Schormair B, Salminen AV, Jochim A, et al. Recessive mutations in the a3 (VI) collagen gene COL6A3 cause early-onset isolated dystonia. Am J Hum Genet 2015;96:883–93. [8] Jochim A, Zech M, Gora-Stahlberg G, Winkelmann J, Haslinger B. The clinical phenotype of early-onset isolated dystonia caused by recessive COL6A3 mutations (DYT27). Mov Disord 2016;31:747–50. [9] Lohmann K, Schlicht F, Svetel M, Hinrichs F, Zittel S, Graf J, et al. The role of mutations in COL6A3 in isolated dystonia. J Neurol 2016;263:730–4. [10] Demir E, Sabatelli P, Allamand V, Ferreiro A, Moghadaszadeh B, Makrelouf M, et al. Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy. Am J Hum Genet 2002;70:1446–58. [11] Bo¨nnemann CG. The collagen VI-related myopathies: Ullrich congenital muscular dystrophy and Bethlem myopathy. Handb Clin Neurol 2011;101:81–96. [12] Marakhonov AV, Tabakov VY, Zernov NV, Dadali EL, Sharkova IV, Skoblov MY. Two novel COL6A3 mutations disrupt extracellular matrix formation and lead to myopathy from Ullrich congenital muscular dystrophy and Bethlem myopathy spectrum. Gene 2018;672:165–71. [13] Cordeiro D, Bullivant G, Siriwardena K, Evans A, Kobayashi J, Cohn RD, et al. Genetic landscape of pediatric movement disorders and management implications. Neurol Genet 2018;4 e265. [14] Balint B, Bhatia KP. Hot topic: recessive mutations in the a3(VI) collagen gene COL6A3 cause early-onset isolated dystonia. Mov Disord 2015;30:1622.
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P.K. Panda, I.K. Sharawat / Brain & Development xxx (2020) xxx–xxx [15] Domingo A, Erro R, Lohmann K. Novel dystonia genes: clues on disease mechanisms and the complexities of high-throughput sequencing. Mov Disord 2016;31:471–7. [16] Dauer W. Inherited isolated dystonia: clinical genetics and gene function. Neurother J Am Soc Exp Neurother 2014;11:807–16. [17] Bressman SB, Sabatti C, Raymond D, de Leon D, Klein C, Kramer PL, et al. The DYT1 phenotype and guidelines for diagnostic testing. Neurology 2000;54:1746–52. [18] Camargos S, Scholz S, Simo´n-Sa´nchez J, Paisa´n-Ruiz C, Lewis P, Hernandez D, et al. DYT16, a novel young-onset dystonia-
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parkinsonism disorder: identification of a segregating mutation in the stress-response protein PRKRA. Lancet Neurol 2008;7:207–15. [19] Khan NL, Wood NW, Bhatia KP. Autosomal recessive, DYT2like primary torsion dystonia: a new family. Neurology 2003;61:1801–3. [20] Stamelou M, Charlesworth G, Cordivari C, Schneider SA, Ka¨gi G, Sheerin U-M, et al. The phenotypic spectrum of DYT24 due to ANO3 mutations. Mov Disord 2014;29:928–34.
Please cite this article in press as: Panda PK, Sharawat IK. COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature. Brain Dev (2020), https://doi.org/10.1016/j.braindev.2020.01.004
Original article
COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature Prateek Kumar Panda 1, Indar Kumar Sharawat ⇑,1 Pediatric Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, Rishikesh, Uttarakhand 249203, India Received 31 October 2019; received in revised form 10 January 2020; accepted 11 January 2020
Abstract Background: Still, the genetic basis of a large number of cases of early-onset isolated dystonia continues to be a mystery. In recent years, many new candidate genes are being identified as putative pathogenic factors in children with isolated dystonia due to the easy availability of whole-exome sequencing. Recently biallelic mutations in the COL6A3 gene were identified as a cause of rare dystonia (DYT)-27 syndrome. Till date, only six cases of DYT27 have been reported in the literature. Methods: We report a new case of COL6A3 mutation associated early-onset isolated dystonia-DYT27. We did a review of the previously published cases of DYT27. Citations were identified through PubMed, Embase, Web of Science and Google scholar searches using the search terms (including variations), ‘‘Dystonia-27 or DYT27” or/and ‘‘COL6A3 mutation associated earlyonset isolated dystonia”, combined with study filters for original research, case reports and case series. Results: Next-generation sequencing in the index patient revealed two pathogenic compound heterozygous loss of function mutations in exon 10 and exon 12 of the COL6A3 gene coding for the alpha(a)3(VI) chain of type VI collagen. Together with the presented case, seven cases (five males) were available for analysis. The median age at onset was 22 years (range: 6–61). Dystonic symptoms were started from hands in five and from the neck in the remaining two patients. Five patients had favorable outcomes with trihexyphenidyl and botulinum toxin while tetrabenazine and levodopa were ineffective. Conclusions: Although it is a new entity that is only recently discovered, in future years many more new cases suffering from this particular entity are likely to be reported and the already heterogeneous clinical spectrum is likely to be further widespread in years to come. Ó 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Primary dystonia; DYT27; Oromandibular dystonia; COL6A3 gene; Early-onset primary dystonia
1. Introduction Early-onset primary dystonia usually starts in the first or second decade of life, starting from one extremity, initially only during performing some action such as walking or writing. Later it slowly progresses to involve ⇑ Corresponding author.
E-mail address: [email protected] (I.K. Sharawat). Both the authors contributed equally and share joint first authorship. 1
other parts of the body and tends to persist even at rest, without involving cognition, seizures or other neurological symptoms [1]. Idiopathic torsion dystonia (DYT1 caused by a mutation in TOR1A and rarely GNAL gene), dopa-responsive dystonia (DYT5 caused by a mutation in GCH gene), rapid-onset dystoniaparkinsonism (ATP1A3 gene) and myoclonus dystonia (SGCE gene coding for e-sarcoglycan) are some of the commonly reported primary dystonia syndromes with autosomal dominant inheritance [2–5]. Still, the genetic
https://doi.org/10.1016/j.braindev.2020.01.004 0387-7604/Ó 2020 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Panda PK, Sharawat IK. COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature. Brain Dev (2020), https://doi.org/10.1016/j.braindev.2020.01.004
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basis of a large number of cases of childhood and adolescent-onset segmental or generalized dystonia continues to be a mystery [4]. In recent years, many new candidate genes are being identified as putative pathogenic factors in children with isolated dystonia due to the easy availability of whole-exome sequencing [5]. Here, we report a case of isolated dystonia with onset from childhood and predominantly involving upper limb and cervical region unlike commonly identified lower limb or truncal predominant involvement in majority cases of primary dystonia. The novelty of the report lies in the fact that a pathogenic compound heterozygous mutation was identified in this child in the COL6A3 gene responsible for a recently identified rare dystonia (DYT)-27 syndrome, previously reported only in six cases. The study was approved from the institutional review board and informed consent was taken from the parents of the patients. 2. Case presentation An eight and half-year-old developmentally normal boy presented with involuntary twisted posturing of the right hand for the past two years. The symptoms were initially intermittent, appearing while performing actions like writing and approaching to grasp any object. It was also associated with intermittent action tremors of the right hand. The handwriting of the child worsened as the disease progressed and became illegible later onwards, forcing the child to use his left hand for these activities. After about six months of onset, the dystonic posturing of hand became constant throughout the day, with the increase in severity of dystonic tremor to an extent that the child was unable to perform any day to day activity requiring fine dexterity with the right hand. One year into the illness, there was involvement of the proximal part of the right upper limb and the child had started having cervical dystonia with extensor posturing of the neck in resting state. There was associated intermittent oromandibular dystonia while chewing and speaking and drooling. There was no history suggestive of diurnal fluctuations in the symptoms. There was no history of seizures, cognitive decline, behavioral changes, focal deficit, jaundice, and rashes. He was born to a non-consanguineous couple with a normal perinatal period. His family history for similar illness or any other neurological illness was unremarkable. On examination, he had normal mentation, normal head circumference, intermittent cervical and oromandibular dystonia, drooling, dysarthria, and intermittent dystonic posturing of the right upper limb along with tremors. His Burke-Fahn-Marsden dystonia rating scale (BFMDRS) [6] score was 23. His ophthalmic examination was normal. A clinical possibility of primary dystonia, Wilson disease, and mitochondrial disorders was considered.
Investigation showed normal serum ceruloplasmin, urinary copper, and arterial lactate levels. Blood, and urine amino acids and acylcarnitines levels by tandem mass spectrometry/gas chromatography-mass spectrometry were also normal. Magnetic resonance imaging (MRI) of the brain was normal (Fig. 1). Subsequently, with a clinical diagnosis of isolated dystonia syndrome, next-generation sequencing was performed to identify any pathogenic mutation. Selective capture and sequencing of the protein-coding regions of the whole genome were performed. DNA extracted from blood was used to perform targeted gene capture using a custom capture kit. The libraries were sequenced to mean >80–100X coverage on the Illumina sequencing platform. The sequences obtained are aligned to the human reference genome (GRCh37/hg19) using the BWA program and analyzed using Picard and GATK version 3.6 to identify variants relevant to the clinical indication. GATK’s best practices framework was followed for the identification of variants in the sample. Gene annotation of the variants is performed using the VEP program against the Ensembl release 87 human gene model. Clinically relevant mutations were annotated using published variants in literature and a set of diseases databases (ClinVar, OMIM, GWAS, HGMD,
Fig. 1. Magnetic resonance imaging of the brain. Axial [T1 (a), T2weighted (b) and fluid-attenuated inversion recovery (c)] and sagittal (d) T2-weighted sequences did not reveal any abnormality.
Please cite this article in press as: Panda PK, Sharawat IK. COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature. Brain Dev (2020), https://doi.org/10.1016/j.braindev.2020.01.004
P.K. Panda, I.K. Sharawat / Brain & Development xxx (2020) xxx–xxx
and SwissVar). Common variants were filtered based on allele frequency in 1000Genome Phase 3, ExAC, EVS, dbSNP147, 1000 Japanese genome and internal Indian population database of the laboratory. The nonsynonymous variant effect is calculated using multiple algorithms such as PolyPhen-2, SIFT, Mutation Taster2, Mutation Assessor, LRT, and other tools. Both non-synonymous and splice site variants were included in the analysis. Next-generation sequencing revealed two pathogenic compound heterozygous loss of function mutations in the COL6A3 gene coding for the alpha(a)3(VI) chain of type VI collagen. One heterozygous missense mutation was detected in exon 10 (chr2:238277557C>T; Depth:137x) that results in amino acid substitution of serine for glycine at codon 1517 (p.Gly1517Ser; ENST00000295550). Another heterozygous missense mutation was found in exon 12 of the COL6A3 gene (chr2: 238274498G>A; Depth: 126x) that results in amino acid substitution of leucine for proline at codon 1894 (p.Pro1894Leu; ENST00000295550) (Fig. 2). Recessive mutations in the COL6A3 gene have previously been reported in children with a particular variety of early-onset isolated dystonia syndrome called DYT27. Both the mutations were later confirmed by Sanger sequencing. Both the observed variations were found to lie in the von Willebrand factor type A domain of the COL6A3 protein. The parents were found to be heterozygous carriers of mutations in the COL6A3 gene. The Gly1517Ser and Pro1894Leu variants have previously not been reported in the 1000 genomes and ExAc (Exome Aggregation Consortium). The in silico predictions of both the variants were found to be possibly damaging by PolyPhen-2 (HumDiv) and deleterious by SIFT, LRT, Mutation Taster2 and Mutation Assessor. The final PROVEAN score of both the protein variants was also found to be deleterious. The evolutionary conservation of both the putative pathogenic mutations was also assessed by the HomoloGene tool. Both the reference codons corresponding to the putative pathogenic variants were found to be highly conserved across species. The results of bioinformatics analyses of both the mutations have been described in Table 1. Based on clinical presentation and investigations, a diagnosis of COL6A3 mutation associated early-onset isolated dystonia-DYT27 was concluded. He was started
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on levodopa (maximum dose: 6 mg/kg/day) but he did not show any improvement in the symptoms. Subsequently, he was started on oral trihexyphenidyl and clonazepam. At three months follow up, although the child continued to have generalized dystonia, he showed partial improvement in the severity of dystonia, as his BFMDRS score had reduced to 14. 3. Search strategy and analysis of literature Citations were identified through PubMed, Embase, Web of Science and Google scholar searches using the search terms (including variations), ‘‘Dystonia-27 or DYT27” or/and ‘‘COL6A3 mutation associated earlyonset isolated dystonia”, combined with study filters for original research, case reports and case series. The identified reports were screened manually for patients fulfilling inclusion criteria (COL6A3 mutation associated DYT27). Additional articles were identified from the reference lists of identified papers. Only papers published in English were reviewed. Six previously published cases were identified in the literature [7–9]. 4. Results Together with the presented case, seven cases were thus available for analysis (Table 2). The median age at onset was 22 years (range: 6–61 years). All the cases had a slow progression of symptoms, with relatively preserved lower limb function. Out of seven patients, five were male. Dystonic symptoms started from hands in five cases and from the neck in the remaining two patients. Ultimately four patients had generalized and three had segmental dystonia. Five patients had favorable outcomes with trihexyphenidyl and botulinum toxin while tetrabenazine and levodopa were ineffective in two and one patient respectively. All patients had normal cognition, no neuropsychiatric features and no other upper motor neuron signs except tremors, which was attributed to dystonic tremors in most of the cases. 5. Discussion DYT27, caused by biallelic mutations in the COL6A3 gene, follows autosomal recessive inheritance, with inter individual heterogeneity of distribution and severity of
Fig. 2. COL6A3 mutations in the index child. Schematic representation of the COL6A3 gene (43 exons) showing biallelic mutations in the exon 10 and 12.
Please cite this article in press as: Panda PK, Sharawat IK. COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature. Brain Dev (2020), https://doi.org/10.1016/j.braindev.2020.01.004
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Table 1 Results of bioinformatics analyses of both the mutations found in the index case. Variation nucleotide
chr2:238277557C>T
chr2: 238274498G>A
Variation amino acid Exon involved Type of mutation Frequency in ExAc genome Frequency in 1000 genome PolyPhen2 prediction SIFT MutationTaster2 Mutation Assessor PROVEAN Reference codon conserved across species
p.Gly1517Ser Exon 10 Missense Not found Not found Possibly damaging Damaging Deleterious Deleterious Deleterious Yes
p.Pro1894Leu Exon 12 Missense Not found Not found Possibly damaging Damaging Deleterious Deleterious Deleterious Yes
dystonia. COL6A3 gene mutations have been already implicated in Ulrich congenital muscular dystrophy and Bethlem myopathy [10,11]. Zech et al. described five cases of DYT27 in three German family kindreds [7]. Out of which three had generalized dystonia, predominantly affecting the cranio-cervical region, upper limbs, and trunk. In all five cases, initially, the neck or upper limb was involved, with onset in the first decade in one case, in the second decade in two cases and later onset in remaining of the two cases. Trihexyphenidyl, clonazepam, and botulinum toxin injection were tried in almost all cases with variable benefit [7]. Initially, Jochim et al. [8] identified these diseasecausing mutations by whole-exome sequencing in two siblings suffering from isolated dystonia, with probable autosomal recessive inheritance. Subsequently, they identified three cases from two additional recessive pedigrees by performing genetic screening of 367 patients with probable primary dystonia [7]. COL6A3 is a large gene with 43 exons. It encodes for a protein with more than 3000 amino acids. At least 1500 rare, potentially pathogenic variants have been detected to involve this gene [9]. The alpha-3 chain, of type VI collagen coded by this gene, is quite larger as compared to the other two chains (alpha-1 and alpha2), as it contains a number of extra subdomains in the amino-terminal [7,12]. One of them is the von Willebrand factor type-A subdomain located in the aminoterminal globular domain. It is involved in binding to extracellular matrix proteins, cell-to-cell interaction and other signaling pathways (integrin pathway). In the index case, both the mutations responsible for the disease are located within this subdomain, thereby explaining the neuropathogenicity. The pathogenicity was also predicted in various in silico analysis as the mutations in the index case were found to be possibly damaging by altering the functional structure of the protein. Most of the genes responsible for movement disorder either involve basal ganglia specific proteins or proteins involved in interneuronal interaction/neuronal circuit formation [13]. Mutation of several other genes also causes isolated dystonia in childhood and
adolescence. However, few of these already described dystonia predominant neurogenetic syndromes clinically somewhat resemble DYT27 caused by biallelic mutations in the COL6A3 gene. Clinical distinguishing features of these syndromes have been demonstrated in Table 3. At least one mutation in all five of the cases described by Zech et al. involved an exon-skipping mutation in exon 41 of the COL6A3 gene leading to in-frame deletion [7]. However, in the index case, pathogenic mutations involving exon 10 and 12 resulted in isolated dystonia. Thus, the postulate by Zech et al. regarding exon 41 of the COL6A3 gene being a hot spot for mutations causing isolated dystonia needs to be redefined with the discovery of these new novel pathogenic mutations. Moreover, Lohman et al. also found variable clinical expression in the pedigree described by him, who harbored mutations in exon 41 of the COL6A3 gene and mutations in other genes such as the PINK1 gene was found in the case with dystonia and parkinsonism. In their study, Lohmann et al. have screened 955 patients with combined or isolated dystonia to identify only one patient with a biallelic mutation in the COL6A3 gene [9]. The homozygous mutations in the PINK1 gene present in this person have already been found to be associated with early-onset parkinsonism. The mutual interaction between these two genes, even if any, is yet to be revealed [9]. However, this patient had both dystonia and parkinsonism unlike other family members, who only had parkinsonism and he was also of German ethnicity like the five cases described by Zech et al. [7]. Interestingly in this case also, the second mutation was a novel mutation in the amino-terminal of the COL6A3 gene like our case (exon 6). Zech et al. had reproduced the exon skipping mutation in exon 41 in Zebrafish embryos and the mouse brain resulted in the development of segmental dystonia, without any muscular disease [7]. Reduced axonal outgrowth, with abnormal neuronal circuitry formation, was demonstrated in all these animals, without any alteration in collagen deposition. The C4 domain of the collagen VI a3 (FN-III motif), exon 41 is in the orga-
Please cite this article in press as: Panda PK, Sharawat IK. COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature. Brain Dev (2020), https://doi.org/10.1016/j.braindev.2020.01.004
Clonazepam, Trihexiphenidyl
Generalized
Generalized
Segmental
Hand
Hand
Hand
c.7557C>T (p.Gly1517Ser) and c.4498G>A (p.Pro1894Leu)
Segmental Hand
c.8966-1G>C (p. Val2989_Lys3077delinsGlu) and c.7660G>A (p.Ala2554Thr) c.2195C>T (p.Thr732Met) and c.9245C>G (p.Pro3082Arg)
Generalized Segmental Neck Hand
c.8966-1G>C (p. Val2989_Lys3077delinsGlu) and c.7502G>A (p.Arg2501His)
Levodopa
Also had parkinsonism in the affected case and three female siblings, all harboring homozygous PINK1 mutations. But none of the other cases had dystonia – Information NA
Hypertension and cholecystectomy at 19 years –
–
Sibling of the first case Esophageal carcinoma at 62 years Genital tuberculosis at 23 years of age
Also had Crohn’s disease
Haloperidol, Tetrabenazine, Clozapine Tetrabenazine –
Clonazepam, Trihexyphenidyl, Botulinum toxin Botulinum toxin Clozapine Botulinum toxin Botulinum toxin Declined pharmacotherapy Clonazepam, Trihexiphenidyl, Botulinum toxin Information NA c.9128G>A (p.Arg3043His) and c.9245C>G (p.Pro3082Arg) Generalized Neck
Mutation Dystonia distribution Initial site of dystonia
Male Case 7, Index case
7
Male Case 6, Lohman et al.
61
Male Case 5, Zech et al.
6
Female Case 4, Zech et al.
24
Female Male Case 2, Zech et al. Case 3, Zech et al.
20 24
Male Case 1, Zech et al.
20
Sex
Age of onset (years)
5
nization of neuronal plasticity [8]. Similarly, the coding regions involving the mutations in exon 10 and 12 are also supposed to be involved in other functions in brain extracellular matrix such as neuronal organization, plasticity, and neuronal circuit formation. Mutations of the COL6A3 gene responsible for Ulrich muscular dystrophy are different from the mutations documented in all the six cases of DYT27 in the reported literature. COL6A3 gene is ubiquitously expressed in the brain. Hence, it is likely to have a significant role in neuronal proliferation and differentiation, apart from mere collagen deposition. As a result, the hypothesis given by Zech et al. regarding mutation in exon 41 is an essential prerequisite for producing dystonia that may need to be updated in the future with the discovery of other novel pathogenic mutations [7]. Exact neuronal functions of various subdomains of the COL6A3 gene are likely to be further elucidated when further cases of DYT27 with different mutations will be reported from various geographic regions of the world. Large distance geographic separation with ethnic diversity between Germany and India might be the responsible factor for the absence of exon 41 mutation in the Indian index case. Zech et al. [7] and Jochim et al. [8] had also studied the MRI of the brain of patients with DYT27 using special sequences like diffusion tensor imaging and demonstrated significantly reduced fractional anisotropy bilaterally in the pons, midbrain, cerebellar peduncles, thalamus, internal capsule, and frontal and parietal subcortical white matter, compared to healthy controls. Moreover, reduced fractional anisotropy between the bilateral dentate nucleus and thalamus was also found in tractography in their study [14]. This altered white matter structure involving various parts of the cerebello-thalamo-cortical network was proposed by the authors as the underlying causative neuropathogenetic factor for dystonia in patients with COL6A3 mutations. Perturbation of brain extracellular matrix and abnormal neural circuit formation have been proposed as the probable pathophysiological mechanism behind dystonia production due to few other genes responsible for causing isolated dystonia syndromes. 6. Conclusion
Case no, investigator
Table 2 Comparison of clinical characteristics of the patients with DYT27 caused by biallelic COL6A3 mutation.
Drug showing favorable clinical response
Drug showing no clinical response
Other remarks
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The clinical possibility of COL6A3 biallelic mutation associated DYT27 should be considered in children or adolescents with isolated dystonia starting from upper limb, cervical or oromandibular region. Although it is a new entity that is only recently discovered, in future years many more new cases suffering from this particular entity are likely to be reported. The already heterogeneous clinical spectrum is likely to be further widespread in years to come. For the time being trihexyphenidyl, clonazepam and if possible, botulinum toxin is the best
Please cite this article in press as: Panda PK, Sharawat IK. COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature. Brain Dev (2020), https://doi.org/10.1016/j.braindev.2020.01.004
GNAL Autosomal recessive Adults
Isolated focal or segmental dystonia involving cranio-cervical region including oromandibular/jaw, larynx, eyelids and often progresses to one arm Combined dystoniaparkinsonism syndrome. Dystonia is early-onset, progressively involving upper limb, laryngeal and oromandibular region, but incidence extremely rare Initially affects distal limbs and later involves the neck, orofacial, and cranio-cervical regions. It is slowly progressive and mild in severity Dystonia or dystonic tremor of a leg or arm is the most common presenting symptom. Initially, dystonia appears while performing specific actions such as writing or walking. Distinguishing clinical features
DYT25 DYT16
PRKR1A Autosomal recessive 1st or 2nd decade
THAP Autosomal dominant First and second decade Initially, isolated cranio-cervical dystonia causing dysphagia, dysarthria or blepharospasm and limbs are involved only in later stage
DYT6 DYT2
HPCA Autosomal recessive Childhood TOR1A Autosomal dominant Childhood or adolescence
DYT1
Causative gene Inheritance The usual age of onset
Table 3 Distinguishing features of other isolated neurogenetic dystonia syndromes, which sometimes may resemble DYT27 clinically [7,9,15–20].
COL6A3 Autosomal recessive Children and young adults Dystonia usually starts from the hands or cranio-cervical region causing writer’s cramp, postural dystonic tremors, and oromandibular dystonia. Trunk and laryngeal muscles can be involved in the later stage.
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DYT27
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possible treatment option for this rare neurogenetic syndrome in the absence of any genetically targeted treatment. Targeted therapies directed at the COL6A3 gene will be an attractive treatment option in years to come. 7. Funding/support None declared. 8. Disclaimers Nil. References [1] Weisheit CE, Pappas SS, Dauer WT. Inherited dystonias: clinical features and molecular pathways. Handb Clin Neurol 2018;147:241–54. [2] Lohmann K, Klein C. Update on the genetics of dystonia. Curr Neurol Neurosci Rep 2017;17:26. [3] Zech M, Boesch S, Sycha T, Mueller J, Poewe W, Winkelmann J. TOR1A, THAP1, and GNAL mutational screening in Austrian patients with primary isolated dystonia. Mov Disord 2015;30:1853–4. [4] LeDoux MS. The genetics of dystonias. Adv Genet 2012;79:35–85. [5] Charlesworth G, Bhatia KP, Wood NW. The genetics of dystonia: new twists in an old tale. Brain 2013;136:2017–37. [6] Kuiper MJ, Vrijenhoek L, Brandsma R, Lunsing RJ, Burger H, Eggink H, et al. The Burke-Fahn-Marsden dystonia rating scale is age-dependent in healthy children. Mov Disord Clin Pract 2016;3:580–6. [7] Zech M, Lam DD, Francescatto L, Schormair B, Salminen AV, Jochim A, et al. Recessive mutations in the a3 (VI) collagen gene COL6A3 cause early-onset isolated dystonia. Am J Hum Genet 2015;96:883–93. [8] Jochim A, Zech M, Gora-Stahlberg G, Winkelmann J, Haslinger B. The clinical phenotype of early-onset isolated dystonia caused by recessive COL6A3 mutations (DYT27). Mov Disord 2016;31:747–50. [9] Lohmann K, Schlicht F, Svetel M, Hinrichs F, Zittel S, Graf J, et al. The role of mutations in COL6A3 in isolated dystonia. J Neurol 2016;263:730–4. [10] Demir E, Sabatelli P, Allamand V, Ferreiro A, Moghadaszadeh B, Makrelouf M, et al. Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy. Am J Hum Genet 2002;70:1446–58. [11] Bo¨nnemann CG. The collagen VI-related myopathies: Ullrich congenital muscular dystrophy and Bethlem myopathy. Handb Clin Neurol 2011;101:81–96. [12] Marakhonov AV, Tabakov VY, Zernov NV, Dadali EL, Sharkova IV, Skoblov MY. Two novel COL6A3 mutations disrupt extracellular matrix formation and lead to myopathy from Ullrich congenital muscular dystrophy and Bethlem myopathy spectrum. Gene 2018;672:165–71. [13] Cordeiro D, Bullivant G, Siriwardena K, Evans A, Kobayashi J, Cohn RD, et al. Genetic landscape of pediatric movement disorders and management implications. Neurol Genet 2018;4 e265. [14] Balint B, Bhatia KP. Hot topic: recessive mutations in the a3(VI) collagen gene COL6A3 cause early-onset isolated dystonia. Mov Disord 2015;30:1622.
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Please cite this article in press as: Panda PK, Sharawat IK. COL6A3 mutation associated early-onset isolated dystonia (DYT)-27: Report of a new case and review of published literature. Brain Dev (2020), https://doi.org/10.1016/j.braindev.2020.01.004