Publications by authors named "Anirban Majumdar"

19 Publications

  • Page 1 of 1

Syndromic disorders caused by gain-of-function variants in KCNH1, KCNK4, and KCNN3-a subgroup of K channelopathies.

Eur J Hum Genet 2021 Feb 16. Epub 2021 Feb 16.

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Decreased or increased activity of potassium channels caused by loss-of-function and gain-of-function (GOF) variants in the corresponding genes, respectively, underlies a broad spectrum of human disorders affecting the central nervous system, heart, kidney, and other organs. While the association of epilepsy and intellectual disability (ID) with variants affecting function in genes encoding potassium channels is well known, GOF missense variants in K channel encoding genes in individuals with syndromic developmental disorders have only recently been recognized. These syndromic phenotypes include Zimmermann-Laband and Temple-Baraitser syndromes, caused by dominant variants in KCNH1, FHEIG syndrome due to dominant variants in KCNK4, and the clinical picture associated with dominant variants in KCNN3. Here we review the presentation of these individuals, including five newly reported with variants in KCNH1 and three additional individuals with KCNN3 variants, all variants likely affecting function. There is notable overlap in the phenotypic findings of these syndromes associated with dominant KCNN3, KCNH1, and KCNK4 variants, sharing developmental delay and/or ID, coarse facial features, gingival enlargement, distal digital hypoplasia, and hypertrichosis. We suggest to combine the phenotypes and define a new subgroup of potassium channelopathies caused by increased K conductance, referred to as syndromic neurodevelopmental K channelopathies due to dominant variants in KCNH1, KCNK4, or KCNN3.
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http://dx.doi.org/10.1038/s41431-021-00818-9DOI Listing
February 2021

Mutations Expand the Phenotypic Spectrum of Alternating Hemiplegia of Childhood.

Neurology 2021 03 27;96(11):e1539-e1550. Epub 2021 Jan 27.

From the UCL Queen Square Institute of Neurology (S.Z., S.K., L.H.-H., H.M.C., S.M.S.), London; Chalfont Centre for Epilepsy (S.Z., S.K., H.M.C., S.M.S.), Buckinghamshire; Department of Neurology (D.S., A.V., J.H.C., M.A.K.), Great Ormond Street Hospital; Clinical Neurosciences (A.V., J.H.C.), and Neurogenetics Group (D.S., M.A.K.), Developmental Neurosciences NIHR BRC UCL Great Ormond Street Institute of Child Health, London; School of Life Sciences (S.K.), Faculty of Science and Engineering, Anglia Ruskin University, Cambridge, UK; Department of Neurology and Clinical Neurophysiology (K.M.G., M.D.K., B.J.L.), Children's Health Ireland at Temple Street, Dublin 1; School of Medicine and Medical Sciences (K.M.G., M.D.K.), University College Dublin, Dublin 4, Ireland; Danish Epilepsy Centre (R.S.M., T.B.H.), Dianalund; Department of Regional Health Research (R.S.M.), University of Southern Denmark, Odense; Department of Paediatric Neurology (R.S., A.A.M., A.M.), Bristol Royal Hospital for Children, UK; Pediatric Neurology (W.F.), Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne; Institute of Human Genetics (T.B.), University of Leipzig Medical Center, Germany; Departement de Neuropediatrie (D.D.), Centre de Référence Neurogénetique Mouvements Anormaux, Hôpital Armand Trousseau, and Department of Genetics (B.K., C.M.), La Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris; Centre de Référence Déficiences Intellectuelles de Causes Rares (C.M.); Departement de Pediatrie (N.B.), American Memorial Hospital, CHU Reims; CReSTIC (N.B.), University of Reims Champagne-Ardennes, France; University of Bristol (A.A.M.); Department of Haematology (A.S.-J.) and Cambridge Institute for Medical Research (F.L.R.), University of Cambridge; NIHR BioResource (A.S.-J., F.L.R.), Cambridge University Hospitals NHS Foundation Trust; Paediatric Neurology (A.B.), Great North Childrens Hospital, Newcastle upon Tyne; Population Health Sciences Institute (A.B.), Newcastle University, UK; Applied & Translational Genomics Group (H.S., S.W.), VIB-Center for Molecular Neurology, University of Antwerp; and Department of Neurology (H.S., S.W.), University Hospital Antwerp, Belgium.

Objective: To explore the phenotypic spectrum of -related disorders and specifically to determine whether patients fulfill criteria for alternating hemiplegia of childhood (AHC), we report the clinical features of 11 affected individuals.

Methods: Individuals with -related disorders were identified through a movement disorder clinic at a specialist pediatric center, with additional cases identified through collaboration with other centers internationally. Clinical data were acquired through retrospective case-note review.

Results: Eleven affected patients were identified. All had heterozygous missense variants involving exon 9 of , confirmed as de novo in 9 cases. All had a complex motor phenotype, including at least 2 different kinds of movement disorder, e.g., ataxia and dystonia. Many patients demonstrated several features fulfilling the criteria for AHC: 10 patients had a movement disorder including paroxysmal elements, and 8 experienced hemiplegic episodes. In contrast to classic AHC, commonly caused by mutations in , these events were reported later only in mutation-positive patients from 20 months of age. Seven patients had epilepsy, but of these, 4 patients achieved seizure freedom. All patients had intellectual disability, usually moderate to severe. Other features include episodes of marked skin color change and gastrointestinal symptoms, each in 4 patients.

Conclusion: Although heterozygous mutations were originally described in early infantile epileptic encephalopathy type 64, our study confirms that they account for a more expansive clinical phenotype, including a complex polymorphic movement disorder with paroxysmal elements resembling AHC. testing should therefore be considered in patients with an AHC-like phenotype, particularly those negative for mutations.
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http://dx.doi.org/10.1212/WNL.0000000000011543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032376PMC
March 2021

cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing.

Nat Genet 2020 12 23;52(12):1364-1372. Epub 2020 Nov 23.

Genomic and Post-Genomic Center, Istituto di Ricovero e Cura a Carattere Scientifico, Mondino Foundation, Pavia, Italy.

Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA.
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http://dx.doi.org/10.1038/s41588-020-00737-3DOI Listing
December 2020

Transgender Endocrinology.

Indian J Endocrinol Metab 2020 Mar-Apr;24(2):126-127. Epub 2020 Apr 30.

Department of Endocrinology, Bharti Hospital, Karnal, Haryana, India.

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http://dx.doi.org/10.4103/ijem.IJEM_177_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333745PMC
April 2020

Suboptimal glycemic control among subjects with diabetes mellitus in India: a subset analysis of cross-sectional wave-7 (2016) data from the International Diabetes Management Practices Study (IDMPS).

Ther Adv Endocrinol Metab 2020 27;11:2042018820937217. Epub 2020 Jun 27.

Clinical Study Unit, Sanofi Synthelabo India Limited, Mumbai, Maharashtra, India.

Objective: To assess the real-world management practices of subjects with type 2 diabetes mellitus (T2DM) and type 1 diabetes mellitus (T1DM) in India.

Methods: This cross-sectional study was conducted between 7 March 2016 and 15 May 2016 in India as part of the seventh wave (2016) of the International Diabetes Management Practices Study (IDMPS). Adult subjects with T1DM or T2DM visiting physicians during a 2-week recruitment period were included.

Results: A total of 55 physicians included 539 subjects who met eligibility criteria. Of 495 subjects with T2DM, 303 were treated with oral glucose lowering drugs (OGLDs) only, 158 were treated with OGLD + insulin, and 27 received insulin only. Among 44 subjects with T1DM receiving insulin, 13 (29.5%) were also treated with OGLD therapy. The most commonly used insulin regimens were basal alone (69/184; 37.5%) and premixed alone (63/184; 34.2%) in subjects with T2DM, and basal + prandial insulin (24/44; 54.5%) in subjects with T1DM. Proportions of subjects achieving glycemic targets were low [glycated haemoglobin (HbA1c) <7%: T1DM = 7.3% (3/44), T2DM = 25.2% (106/495); as targeted by the treating physician: T1DM = 31.8% (14/44), T2DM = 32.1% (59/185); global target: T1DM = 4.8% (2/42) and T2DM = 1.7% (8/482)]. In subjects with T2DM, HbA1c <7% was noted in 11/22 subjects receiving insulin only and 76/260 receiving only OGLDs. Lack of experience in self-managing insulin dosing, poor diabetes education and failure to titrate insulin dosages were the main reasons for non-achievement of glycemic targets.

Conclusion: Timely insulinization, education and empowerment of people with diabetes may help improve glycemic control in India.
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http://dx.doi.org/10.1177/2042018820937217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325532PMC
June 2020

A novel de novo ACTA1 variant in a patient with nemaline myopathy and mitochondrial Complex I deficiency.

Neuromuscul Disord 2020 02 1;30(2):159-164. Epub 2019 Dec 1.

Department of Paediatric Neurology, University Hospitals Bristol NHS Foundation Trust, 6th Floor Education Centre, Upper Maudlin St, Bristol BS2 8BJ, United Kingdom. Electronic address:

We describe the presentation and follow-up of a three-year-old girl with nemaline myopathy due to a de-novo variant in ACTA1 (encoding skeletal alpha actin) and moderately low enzyme level of Complex I of the mitochondrial respiratory chain. She presented in the neonatal period with hypotonia, followed by weakness in the facial, bulbar, respiratory and neck flexors muscles. A biopsy of her quadriceps muscle at the age of one year showed nemaline rods. Based on her clinical presentation of a congenital myopathy and histopathological features on a muscle biopsy, ACTA1 was sequenced, and this revealed a novel sequence variant, c.760 A>C p. (Asn254His). In addition, mitochondrial respiratory chain enzymatic activity of skeletal muscle biopsy showed a moderately low activity of complex I (nicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase). Disturbances of Complex I of the respiratory chain have been reported in patients with nemaline myopathy, although the mechanism remains unclear.
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http://dx.doi.org/10.1016/j.nmd.2019.11.014DOI Listing
February 2020

Clinical and Genetic Features in a Series of Eight Unrelated Patients with Neuropathy Due to Glycyl-tRNA Synthetase (GARS) Variants.

J Neuromuscul Dis 2020 ;7(2):137-143

University Hospitals Bristol NHS Foundation Trust, Bristol, UK.

Pathogenic variants in the Glycyl-tRNA synthetase gene cause the allelic disorders Charcot-Marie-Tooth disease type 2D and distal hereditary motor neuropathy type V. We describe clinical features in 8 unrelated patients found to have Glycyl-tRNA synthetase variants by Next Generation Sequencing. In addition to upper limb predominant symptoms, other presentations included failure to thrive, feeding difficulties and lower limb dominant symptoms. Variability in the age at testing ranged from 14 months to 59 years. The youngest being symptomatic from 3 months and ventilator-dependent. Sequence variants were reported as pathogenic, p.(Glu125Lys), p.(His472Arg); likely pathogenic, p.(His216Arg), p.(Gly327Arg), p.(Lys510Gln), p.(Met555Val); and of uncertain significance, p.(Arg27Pro). Our case series describes novel Glycyl-tRNA synthetase variants and demonstrates the clinical utility of Next Generation Sequencing testing for patients with hereditary neuropathy. Identification of novel variants by Next Generation Sequencing illustrates that there exists a wide spectrum of clinical features and supports the newer simplified classification of neuropathies.
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http://dx.doi.org/10.3233/JND-200472DOI Listing
November 2020

Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy.

Hum Mutat 2020 02 3;41(2):403-411. Epub 2019 Dec 3.

Paediatric Neurology, Bristol Royal Hospital For Children, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom.

We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1:c.39974-11T>G), inherited in trans with a second pathogenic TTN variant. Muscle-derived RNA studies of three individuals confirmed mis-splicing induced by the c.39974-11T>G variant; in-frame exon 214 skipping or use of a cryptic 3' splice-site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213-217 within the described skeletal muscle TTN N2A isoform. However, RNA-sequencing from 365 adult human gastrocnemius samples revealed that 56% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate ≥66%). Further, RNA-sequencing of five fetal muscle samples confirmed that 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57%). Contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript-only exons.
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http://dx.doi.org/10.1002/humu.23938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306402PMC
February 2020

Clinical presentation and proteomic signature of patients with TANGO2 mutations.

J Inherit Metab Dis 2020 03 13;43(2):297-308. Epub 2019 Aug 13.

Secció d'Errors Congènits del Metabolisme - IBC, Servei de Bioquímica I Genètìca Molecular, Hospital Clínìc, IDIBAPS, CIBERER, Barcelona, Spain.

Transport And Golgi Organization protein 2 (TANGO2) deficiency has recently been identified as a rare metabolic disorder with a distinct clinical and biochemical phenotype of recurrent metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias, and encephalopathy with cognitive decline. We report nine subjects from seven independent families, and we studied muscle histology, respiratory chain enzyme activities in skeletal muscle and proteomic signature of fibroblasts. All nine subjects carried autosomal recessive TANGO2 mutations. Two carried the reported deletion of exons 3 to 9, one homozygous, one heterozygous with a 22q11.21 microdeletion inherited in trans. The other subjects carried three novel homozygous (c.262C>T/p.Arg88*; c.220A>C/p.Thr74Pro; c.380+1G>A), and two further novel heterozygous (c.6_9del/p.Phe6del); c.11-13delTCT/p.Phe5del mutations. Immunoblot analysis detected a significant decrease of TANGO2 protein. Muscle histology showed mild variation of fiber diameter, no ragged-red/cytochrome c oxidase-negative fibers and a defect of multiple respiratory chain enzymes and coenzyme Q (CoQ ) in two cases, suggesting a possible secondary defect of oxidative phosphorylation. Proteomic analysis in fibroblasts revealed significant changes in components of the mitochondrial fatty acid oxidation, plasma membrane, endoplasmic reticulum-Golgi network and secretory pathways. Clinical presentation of TANGO2 mutations is homogeneous and clinically recognizable. The hemizygous mutations in two patients suggest that some mutations leading to allele loss are difficult to detect. A combined defect of the respiratory chain enzymes and CoQ with altered levels of several membrane proteins provides molecular insights into the underlying pathophysiology and may guide rational new therapeutic interventions.
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http://dx.doi.org/10.1002/jimd.12156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078914PMC
March 2020

Static and Dynamic Synthesis of Bengali and Devanagari Signatures.

IEEE Trans Cybern 2018 Oct 27;48(10):2896-2907. Epub 2017 Sep 27.

Developing an automatic signature verification system is challenging and demands a large number of training samples. This is why synthetic handwriting generation is an emerging topic in document image analysis. Some handwriting synthesizers use the motor equivalence model, the well-established hypothesis from neuroscience, which analyses how a human being accomplishes movement. Specifically, a motor equivalence model divides human actions into two steps: 1) the effector independent step at cognitive level and 2) the effector dependent step at motor level. In fact, recent work reports the successful application to Western scripts of a handwriting synthesizer, based on this theory. This paper aims to adapt this scheme for the generation of synthetic signatures in two Indic scripts, Bengali (Bangla), and Devanagari (Hindi). For this purpose, we use two different online and offline databases for both Bengali and Devanagari signatures. This paper reports an effective synthesizer for static and dynamic signatures written in Devanagari or Bengali scripts. We obtain promising results with artificially generated signatures in terms of appearance and performance when we compare the results with those for real signatures.
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http://dx.doi.org/10.1109/TCYB.2017.2751740DOI Listing
October 2018

A study to evaluate the prevalence of hypogonadism in Indian males with Type-2 diabetes mellitus.

Indian J Endocrinol Metab 2017 Jan-Feb;21(1):64-70

Global Medical Affairs, MSD Pharmaceuticals Private Limited, 10th Floor, Platina Building, C-59, G-Block, Bandra Kurla Complex, Mumbai, Maharashtra, India.

Background: A high prevalence of hypogonadism in men with Type-2 diabetes mellitus (T2DM) has been reported worldwide.

Objectives: To evaluate the prevalence of hypogonadism in Indian males with T2DM and assess the primary and secondary hypogonadism along with androgen deficiency.

Materials And Methods: In this cross-sectional study, 900 men with T2DM were evaluated using androgen deficiency in aging male questionnaire. They were screened for demographic characteristics, gonadal hormone levels, lipid profile, and glycosylated hemoglobin.

Results: The prevalence of hypogonadism in T2DM patients was found to be 20.7% (186 out of 900). Hypogonadism was of testicular origin (primary) in 48/186 (25.8%) patients, of pituitary or hypothalamic origin (secondary) in 14/186 (7.53%), and remaining 124/186 (66.67%) patients were found to have low testosterone with the inappropriate normal level of luteinizing hormone and Follicle-stimulating hormone. 451/900 (50.1%) patients were only symptomatic but had normal testosterone levels. Further 263 patients out 900 were asymptomatic, of which 51/900 (5.7%) patients had low levels of testosterone and 212/900 (23.5%) patients had normal testosterone level without symptoms. There were no deaths or other serious adverse events except mild pyrexia which was not related to the study.

Conclusion: Hypogonadism diagnosis, at times, might not be validated with the help of androgen deficiency questionnaire or symptoms only. Given the large number of patients of T2DM in India, the incidence of hypogonadism is more in diabetic patients as compared to the general population. Hence, implementation of screening programs in diabetic patients is necessary to understand and detect individuals with low serum total testosterone at any early stage and to supplement testosterone accordingly.
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http://dx.doi.org/10.4103/2230-8210.196008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240083PMC
February 2017

Cochlear implantation for deafness and deep brain stimulation for movement disorders in children; lessons in shared learning.

Authors:
Anirban Majumdar

Eur J Paediatr Neurol 2017 01 8;21(1):9-10. Epub 2016 Dec 8.

Consultant Paediatric Neurology, Bristol, UK. Electronic address:

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http://dx.doi.org/10.1016/j.ejpn.2016.11.012DOI Listing
January 2017

Men with Duchenne muscular dystrophy and end of life planning.

Neuromuscul Disord 2017 Jan 28;27(1):38-44. Epub 2016 Sep 28.

University Hospitals Bristol NHS Foundation Trust, Bristol BS1 3NU, UK.

There is very limited evidence about the views of men with Duchenne muscular dystrophy (DMD) and end of life issues including death and dying. Studies have shown the physiological and psychological benefits of talking about and planning for end of life. Despite policy documents and guidance in the UK about end of life planning, there is consensus on the need for improvement. The study reported here is a qualitative one with 15 men with DMD (aged 20-45 years). Participants could not recall any significant conversations with clinicians about end of life and assumed that clinicians were reluctant to discuss the issue. The men in the study wanted to be given proactive cues that they could bring up topics such as death and dying and wanted to have these conversations with clinicians who combined expert knowledge about the condition as well as good listening skills. Topics of interest to participants included likely nature and place of death; practical planning for funerals and wills; and sources of information and support. Emotional or psychological support to think about end of life was not routinely offered and participants found it very difficult to discuss these issues with family members. The study suggests that more could be done to encourage clinicians, men with Duchenne, family members and the wider NMD community to pay attention to end of life planning issues and the associated need for emotional support and high quality interactions between patients and clinicians.
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http://dx.doi.org/10.1016/j.nmd.2016.09.022DOI Listing
January 2017

Low dose liraglutide in Indian patients with type 2 diabetes in the real world setting.

Indian J Endocrinol Metab 2013 Oct;17(Suppl 1):S301-3

Department of Endocrinology, KPC Medical College, Kolkata, West Bengal, India ; Department of Endocrinology, RTIICS, Kolkata, West Bengal, India.

Liraglutide, a human glucagon-like peptide-1 receptor agonist, decreases glycosylated hemoglobin and causes weight loss. However, the cost of therapy and gastrointestinal side- effects such as nausea and diarrhea are important impediments to adherence and long-term compliance. We assessed the efficacy, safety and tolerability of low dose (0.6 mg) liraglutide in obese uncontrolled longstanding type 2 diabetes in Indian patients. Low dose liraglutide improved glycemic control and decreased weight. However, there was a significant drop out because of gastrointestinal intolerance and financial constraints.
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http://dx.doi.org/10.4103/2230-8210.119629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3830340PMC
October 2013

Novel deletion of lysine 7 expands the clinical, histopathological and genetic spectrum of TPM2-related myopathies.

Brain 2013 Feb;136(Pt 2):508-21

Department of Paediatrics, University of Michigan Medical Centre, Ann Arbor, MI 48109-2200, USA.

The β-tropomyosin gene encodes a component of the sarcomeric thin filament. Rod-shaped dimers of tropomyosin regulate actin-myosin interactions and β-tropomyosin mutations have been associated with nemaline myopathy, cap myopathy, Escobar syndrome and distal arthrogryposis types 1A and 2B. In this study, we expand the allelic spectrum of β-tropomyosin-related myopathies through the identification of a novel β-tropomyosin mutation in two clinical contexts not previously associated with β-tropomyosin. The first clinical phenotype is core-rod myopathy, with a β-tropomyosin mutation uncovered by whole exome sequencing in a family with autosomal dominant distal myopathy and muscle biopsy features of both minicores and nemaline rods. The second phenotype, observed in four unrelated families, is autosomal dominant trismus-pseudocamptodactyly syndrome (distal arthrogryposis type 7; previously associated exclusively with myosin heavy chain 8 mutations). In all four families, the mutation identified was a novel 3-bp in-frame deletion (c.20_22del) that results in deletion of a conserved lysine at the seventh amino acid position (p.K7del). This is the first mutation identified in the extreme N-terminus of β-tropomyosin. To understand the potential pathogenic mechanism(s) underlying this mutation, we performed both computational analysis and in vivo modelling. Our theoretical model predicts that the mutation disrupts the N-terminus of the α-helices of dimeric β-tropomyosin, a change predicted to alter protein-protein binding between β-tropomyosin and other molecules and to disturb head-to-tail polymerization of β-tropomyosin dimers. To create an in vivo model, we expressed wild-type or p.K7del β-tropomyosin in the developing zebrafish. p.K7del β-tropomyosin fails to localize properly within the thin filament compartment and its expression alters sarcomere length, suggesting that the mutation interferes with head-to-tail β-tropomyosin polymerization and with overall sarcomeric structure. We describe a novel β-tropomyosin mutation, two clinical-histopathological phenotypes not previously associated with β-tropomyosin and pathogenic data from the first animal model of β-tropomyosin-related myopathies.
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http://dx.doi.org/10.1093/brain/aws344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3572924PMC
February 2013

COL4A1-related disease: raised creatine kinase and cerebral calcification as useful pointers.

Neuropediatrics 2012 Oct 29;43(5):283-8. Epub 2012 Aug 29.

Child Neurology and Psychiatry Unit, C. Mondino National Institute of Neurology Foundation, IRCCS, Pavia, Italy.

Background: Mutations in COL4A1 are responsible for a spectrum of clinical phenotypes characterized by neurological, ocular, and renal involvement. Neurological features are the most prominent but as such are rather nonspecific.

Case Presentation: Here, we report three new cases that, like five patients we previously described, show the novel common finding of raised creatine kinase (CK) concentration.

Conclusion: Raised CK concentration, in addition to intracranial calcification, is to be considered another useful pointer to a final diagnosis of COL4A1-related disease.
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http://dx.doi.org/10.1055/s-0032-1325116DOI Listing
October 2012

Genotype-phenotype correlation in a large population of muscular dystrophy patients with LAMA2 mutations.

Neuromuscul Disord 2010 Apr 6;20(4):241-50. Epub 2010 Mar 6.

Dubowitz Neuromuscular Centre, Institute of Child Health & Great Ormond Street Hospital, 30 Guilford Street, London WC1N 1EH, United Kingdom.

Merosin deficient congenital muscular dystrophy 1A (MDC1A) results from mutations in the LAMA2 gene. We report 51 patients with MDC1A and examine the relationship between degree of merosin expression, genotype and clinical features. Thirty-three patients had absence of merosin and 13 showed some residual merosin. Compared to the residual merosin group, patients with absent merosin had an earlier presentation (<7days) (P=0.0073), were more likely to lack independent ambulation (P=0.0215), or require enteral feeding (P=0.0099) and ventilatory support (P=0.0354). We identified 33 novel LAMA2 mutations; these were distributed throughout the gene in patients with absent merosin, with minor clusters in exon 27, 14, 25 and 26 (55% of mutations). Patients with residual merosin often carried at least one splice site mutation and less frequently frameshift mutations. This large study identified novel LAMA2 mutations and highlights the role of immunohistochemical studies for merosin status in predicting clinical severity of MDC1A.
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http://dx.doi.org/10.1016/j.nmd.2010.02.001DOI Listing
April 2010

Syndrome of fixed dystonia in adolescents--short term outcome in 4 cases.

Eur J Paediatr Neurol 2009 Sep 7;13(5):466-72. Epub 2008 Nov 7.

Department of Paediatric Neurology, Bristol Royal Hospital for Children, Level 6 UBHT Education Centre, Upper Maudlin Street, Bristol BS2 8AE, United Kingdom.

We describe the clinical features, investigations and outcome of 4 adolescents aged 13, 16, 17 and 19 years, with fixed dystonia. The diagnosis was made within 6 months of the onset of symptoms. One patient had an identifiable traumatic precipitant. All the affected extremities had pain, sudomotor and vascular changes which were consistent with complex regional pain syndrome. The extremities affected by dystonia were the foot and the hand. The dystonia spread to affect other extremities in one patient. One patient had hemifacial spasm. Examination of the central and peripheral nervous system and allied investigations failed to reveal an organic cause. Common genetic causes for dystonia were excluded. The response to physical treatments for the affected extremities, such as Botulinum Toxin and surgery was poor. In all our cases there were significant psychological and psychiatric factors. Three patients fully met the criteria for psychogenic dystonia and responded well to psychological intervention. Fixed dystonia in adolescents is an uncommon disorder of unknown aetiology, usually presenting in girls, which can be very disabling and difficult to treat. The affected parts of the body are usually painful and show vascular changes. The condition is allied to CRPS. Treatment with multidisciplinary approach including psychological measures and physiotherapy is more likely to be successful and may prevent unnecessary physical measures.
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http://dx.doi.org/10.1016/j.ejpn.2008.09.005DOI Listing
September 2009

Delayed and severe but transient Tourette syndrome after head injury.

Pediatr Neurol 2002 Oct;27(4):314-7

Roald Dahl EEG Unit, Alder Hey Children's Hospital, Liverpool, United Kingdom.

A previously well and intellectually normal 7(1/2)-year-old girl developed an acute and severe Tourette syndrome 15 months after sustaining a severe head injury. The patient displayed a dramatic response to haloperidol. Twelve months after the onset of Tourette syndrome the haloperidol was withdrawn, and there was no relapse of either her motor or phonic tics. Seven years after the head injury the patient remains tic free but demonstrates significant emotional and behavioral sequelae. The patient's brain magnetic resonance imaging findings were consistent with those reported previously in adults with Tourette syndrome.
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http://dx.doi.org/10.1016/s0887-8994(02)00446-0DOI Listing
October 2002