Bansagi, Boglarka

Chinnery, Patrick F

Duff, Jennifer

Griffin, Helen

Horvath, Rita

Pyle, Angela

Ramesh, Venkateswaran

English

PubMed

Apollo (Cambridge)

LETTER TOTHE EDITORThe p.Ser107Leu in BICD2 is a mutation ‘hot spot’ causing distal spinal muscularatrophyBoglarka Bansagi,1,2,* Helen Griffin,1,2,* Venkateswaran Ramesh,3,* Jennifer Duff,2Angela Pyle,2 Patrick F. Chinnery2 and Rita Horvath1,2*These authors contributed equally to this work.1 The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine,Newcastle University, Newcastle upon Tyne, UK2 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK3 Department of Paediatric Neurology, Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust,Newcastle upon Tyne, UKCorrespondence to: Dr Rita Horvath,Institute of Genetic Medicine,Newcastle University,Newcastle upon Tyne,NE1 3BZ,UKE-mail: Rita.Horvath@ncl.ac.ukSir,We read with great interest the recent paper by Rossor et al.(2015), reporting two new patients and summarizing obser-vations on 30 previously published patients worldwide withBICD2-related spinal muscular atrophy. The work providesa timely overview of the main clinical characteristicsobserved in patients carrying the six currently known dom-inant BICD2 mutations. The paper also highlights the cur-rent knowledge of the structural and interaction specificitiesof BICD2 protein affected by the described missense muta-tions and supports dynein-dynactin trafficking impairment asa common pathomechanism (Oates et al., 2013).The most common BICD2 mutation reported in four ofthe nine families was c.320C4T, p.Ser107Leu. The muta-tion in two large pedigrees originating from Australia andAustria fell on a shared eight single nucleotide polymorph-ism (SNP) haplotype, spanning a 0.1Mb region and with abackground frequency of 2% in the European population,suggesting a recent founder mutation between the twofamilies. The same haplotype background was predictedin another affected family from the USA with Europeanancestors. A four-generation Bulgarian family withTurkish ethnic origin, originally reported by Peeters et al.(2013), was the fourth family carrying the same mutationwithin a 12.7Mb region of linkage. In this family the dis-ease arose as a consequence of a de novo mutation in theproband. In addition a three-generation Dutch family pub-lished by Neveling et al. (2013), had a similar phenotypeand carried the same c.320C4T, p.Ser107Leu missensemutation within a 10Mb region of linkage.Here, we would like to expand the clinical presentationand haplotype background of the p.Ser107Leu BICD2 mu-tation with five additional patients from two North UKfamilies (Fig. 1). A 41-year-old mother presented with herthree children affected by the same disorder (Family 1). Shehad a longstanding history of muscle weakness that hasremained stable throughout her life. She was born withtoe deformities and had mildly delayed motor development.She always had difficulties rising from the floor and withphysical exercise. She developed a locked jaw in her uni-versity years and she was provided with a night splint toprevent its recurrence. On neurology examination she hadmild weakness both proximally and distally in her lowerlimbs. She had a positive Gower’s manoeuvre and shedoi:10.1093/brain/awv159 BRAIN 2015: 138; 1–4 | e391Advance Access publication June 10, 2015 The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse,distribution, and reproduction in any medium, provided the original work is properly cited.could not perform heel walking. Muscle strength in herupper limbs was entirely preserved but there was a mildscapular winging on the left side. Her deep tendon reflexeswere brisk and asymmetric in her upper limbs. No cranialnerve involvement and sensory impairment were found.Except for a mildly elevated creatine kinase (292U/l,normal 5200), all other laboratory parameters werenormal. Sensorimotor nerve conduction velocities andaction potentials were within the normal ranges. On elec-tromyography she had evidence of severe chronic neuro-genic changes in both her upper and lower limbs. Thefindings were compatible with segmental motor neurono-pathy. Her muscle MRI showed symmetrical prominentfatty replacement of gluteus medius, vastus lateralis,rectus femoris, semi-membranosus, lateral and medialgastrocnemius.Her pregnancies and deliveries were uncomplicated. Herfirst born, currently 6-year-old daughter was noted to havea minor foot abnormality at birth. She did not walk until20 months of age, and started walking on the medial aspectof her feet. The 5-year-old twin brothers had a very similarclinical course. Both had mild motor delay, and currentlyhave mild weakness in both proximal and distal muscles oftheir lower limbs associated with disproportionate atrophyof the distal muscles (Fig. 1). Their upper body and armsare particularly strong with good manual dexterity but theyshow mild scapular winging. All three children have diffi-culties with rising from the floor, climbing stairs, runningand they cannot perform heel walking. All receive physio-therapy and orthotic support. All four family membershave normal cognition.Another North British individual patient had no familyhistory of neuromuscular disease (Family 2). His parentswere non-consanguineous and healthy, and his olderbrother is asymptomatic. The proband was born from anunremarkable pregnancy and delivery, but at birth he wasnoted with congenital bilateral talipes. After trials ofphysiotherapy and serial castings of his foot, the deformitywas surgically corrected at age 1 year. His motor develop-ment was subsequently delayed, and he started walkingonly around the age of 3 years. He remained ambulantwith a waddling gait, but he requires wheelchair supportfor longer distances. His cognition is normal.On examination he had mild weakness, predominantly inthe proximal muscles of his lower limbs accompanied bymarked atrophy in the hip muscles. There was prominentmuscle amyotrophy of both anterior and posterior com-partments below the knee. He had full muscle power inFigure 1 Pedigrees and clinical presentations of 2 new families carrying the p.Ser107Leu mutation in BICD2. (A) Pedigrees of the NorthUK families. Probands of each family are indicated by an arrow. (B) Image of the proband and her three affected children from Family 1 presenting withlower limb wasting and feet deformities. (C) Images of proband from Family 2 demonstrating wasting of lower extremities and his postsurgical feet position.e391 | BRAIN 2015: 138; 1–4 Letter to the Editorthe shoulders and upper limbs but he showed scapularwinging bilaterally. Upper limb reflexes were easy to elicitwhile lower limb reflexes were reduced. He walked with ahigh-steppage gait and he could not achieve heel strike.Sensation was preserved. Nerve conduction studies werenormal. Electromyography revealed fibrillation potentialsand positive sharp waves and motor units were of mark-edly increased amplitude, polyphasic and unstable, suggest-ing chronic neurogenic process with spinal motor neuroninvolvement. Muscle biopsy showed neurogenic fibre atro-phy but no other specific changes.The clinical presentation of these five new patients is simi-lar to the patients reported by Rossor et al. (2015); however,we would emphasize that all our patients showed scapularwinging, which we believe is a common feature of BICD2deficiency. The heterozygous c.320C4T, p.Ser107Leu muta-tion is the cause of the disease in both families. It followedan autosomal dominant inheritance pattern in Family 1,however it is de novo in Family 2, as both parents weretested negative. It is indicating that the c.320C4T,p.Ser107Leu mutation arose independently in these twofamilies. This mutation is located in a methylated CpG di-nucleotide suggesting that recurrent mutations may occur atthis position due to methylation-mediated deamination.To determine whether the c.320C4T, p.Ser107Leu muta-tion in Family 1 is present on the same haplotype backgroundas three of the families reported by Rossor et al. (2015) orrather is a mutational hot spot, we performed haplotype ana-lysis. HapMap (data release 28) SNP genotype data from theCEU population, in a region surrounding BICD2 were usedto generate Haplotypes in Haploview (www.broadinstitute.org). There were 10 different haplotypes present in the CEUEuropean population in a single 0.1Mb block (Fig. 2).Genotypes from whole exome sequence data were presentfor the first five SNPs of the haplotypes and genotyping ofa further seven haplotype tagging SNPs allowed us to showthat the mutation was carried on a different haplotype back-ground each of our two families. Additionally, the mutation-carrying haplotype in Family 1 was present in 9.8% of theHapMap European population, which is presumably differentfrom the haplotype reported by Rossor et al. (2015), whichwas present in only 2% of Europeans. Our haplotype analysisexcludes the presence of a common founder mutation andfurther supports the theory that the c.320C4T position isas a mutational hot spot.The detection of more de novo cases suggests that thediagnosis of BICD2 mutations should be considered evenwith no positive family history, and particularly when thereis scapular winging associated with early onset distal lowerlimb motor neuropathy.FundingB.B. is supported by the MRC Centre for NeuromuscularDiseases. R.H. is supported by the Medical ResearchCouncil (UK) (G1000848) and the European ResearchCouncil (309548). P.F.C. is a Wellcome Trust Senior Fellowin Clinical Science and an NIHR Senior Investigator who alsoreceives funding from the Medical Research Council (UK), theUK Parkinson’s Disease Society, and the UK NIHRBiomedical Research Centre for Ageing and Age-related dis-ease award to the Newcastle upon Tyne FoundationHospitals NHS Trust.Figure 2 Ten European haplotype blocks in a 0.1Mb region surrounding BICD2 from Haplotype SNP IDs 01 (rs556) to 89(rs10117449). The BICD2 c.320C4T mutation is located between SNPs 19 and 20. Haplotype SNPs 01, 04, 05, 07 and 08 were genotyped fromwhole exome sequence; SNPs 15, 19, 52, 63, 73, 88 and 89 were genotyped from Sanger sequence (blue arrows). Affected members of Family 1shared haplotype block 3 (yellow box), present in the HapMap CEU population at a frequency of 0.098. The affected proband in Family 2 hadhaplotype blocks 2 and 4 (red and blue boxes) in the region surrounding the mutation; recombination not observed in the CEU populationoccurred between SNPs 63 and 73, so that this proband also had part of either blocks 7, 8 or 10.Letter to the Editor BRAIN 2015: 138; 1–4 | e391ReferencesNeveling K, Martinez-Carrera LA, Ho¨lker I, Heister A, Verrips A,Hosseini-Barkooie SM, et al. Mutations in BICD2, which encodesa golgin and important motor adaptor, cause congenital autosomal-dominant spinal muscular atrophy. Am J Hum Genet 2013; 92:946–54.Oates EC, Rossor AM, Hafezparast M, Gonzalez M, Speziani F,MacArthur DG, et al. Mutations in BICD2 cause dominantcongenital spinal muscular atrophy and hereditary spastic paraple-gia. Am J Hum Genet 2013; 92: 965–73.Peeters K, Litvinenko I, Asselbergh B, Almeida-Souza L, ChamovaT, Geuens T, et al. Molecular defects in the motor adaptorBICD2 cause proximal spinal muscular atrophy with auto-somal-dominant inheritance. Am J Hum Genet 2013; 92: 955–64.Rossor AM, Oates EC, Salter HK, Liu Y, Murphy SM, Schule R, et al.Phenotypic and molecular insights into spinal muscular atrophy dueto mutations in BICD2. Brain 2015; 138: 293–310.e391 | BRAIN 2015: 138; 1–4 Letter to the Editor

The p.Ser107Leu in BICD2 is a mutation 'hot spot' causing distal spinal muscular atrophy.

The p.Ser107Leu in BICD2 is a mutation 'hot spot' causing distal spinal muscular atrophy.

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