Buys, CHCM

Cobben, JM

de Visser, M

Osinga, J

Scheffer, H

ten Kate, LP

van der Steege, G

van Ommen, GJ

English

University of Groningen

   University of GroningenConfirmation of Clinical Diagnosis in Requests for Prenatal Prediction of SMA Type ICobben, JM; de Visser, M; Scheffer, H; Osinga, J; van der Steege, G; Buys, CHCM; vanOmmen, GJ; ten Kate, LPPublished in:Journal of Neurology, Neurosurgery and PsychiatryIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1993Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Cobben, JM., de Visser, M., Scheffer, H., Osinga, J., van der Steege, G., Buys, CHCM., van Ommen, GJ.,& ten Kate, LP. (1993). Confirmation of Clinical Diagnosis in Requests for Prenatal Prediction of SMA TypeI. Journal of Neurology, Neurosurgery and Psychiatry, 56(3), 319-321.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 26-12-2020Journal of Neurology, Neurosurgery, and Psychiatry 1993;56:319-321LESSON OF THE MONTHConfirmation of clinical diagnosis in requests forprenatal prediction of SMA type IJ M Cobben, M de Visser, H Scheffer, J Osinga, G van der Steege, C H C M Buys,G J van Ommen, L P ten KateAbstractThe recent discovery of a major SMA-locus in the chromosomal region Sqmakes it possible to carry out prenatalDNA studies in families in which a childwith SMA type I has been born. Sincedirect mutation analysis is not yet possi-ble, the reliability of prenatal predictionof SMA type I usually depends on thecertainty of the clinical diagnosis in theindex patient. Sixteen requests werereceived for DNA studies in couples whohad had a previous child with SMA typeI. After re-evaluation, the performanceof prenatal diagnosis was rejected in fourcases. Among the other twelve familiesprenatal DNA analysis of chorion villusbiopsies has been carried out in threefamilies. In all three cases the fetus hadinherited the high-risk haplotypes fromboth parents, and the parents chose toterminate the pregnancy. An illustrationof the prenatal DNA studies in one familyis given. The importance of confirmationof the diagnosis SMA type I before per-forming DNA studies is emphasised.(3 Neurol Neurosurg Psychiatry 1993;56:319-32 1)Department ofMedical Genetics,University ofGroningenJ M CobbenH SchefferJ OsingaG van der SteegeC H C M BuysL P ten KateDepartent ofHuman Genetics,University of LeidenG J van OmmenDepartment ofNeurology, AcademicMedical Ventre ofAmsterdam, TheNetherlandsM de VisserCorrespondence to:Dr Cobben,Department of MedicalGenetics,Antonius Deusinglaan 4,9713 AW Groningen,The NetherlandsReceived 20 March 1990and in final revised form7 July 1992.Accepted 16 July 1992Proximal spinal muscular atrophies (SMA) ofchildhood can be classified into three types onthe basis of clinical criteria, SMA type I(Werdnig-Hoff:mann disease), SMA type II(intermediate SMA) and SMA type III(Kugelberg-Welander disease).' SMA type Iis a lethal, autosomal recessive disease witha gene frequency of approximately4-5/100,000.2 The clinical picture is charac-terised by onset of hypotonia, progressiveweakness, wasting of limb and trunk musclesand areflexia before six months of age.Children with classic SMA type I never gainthe ability to sit, and death usually occurswithin two years due to respiratory insuffi-ciency. The diagnosis is based on the charac-teristic clinical picture, on signs ofdenervation in EMG studies and on thehistopathological picture, that is, groups ofatrophic muscle fibres of either type in con-junction with hypertrophic, usually predomi-nantly type I, fibres. Inclusion and exclusioncriteria for the diagnosis of SMA type I haverecently been formulated.3 (Table)In 1990 a major gene for the autosomalrecessive types of SMA type I, II and III waslocalised in the chromosomal region 5ql2-ql3.49 The availability of several highly poly-morphic DNA-markers in this region permitsprenatal prediction of SMA type I by DNAstudies of chorionic villus or amniotic fluidcells in families with an affected child, makinguse of DNA from the affected child.'01'Caution is necessary, however, because of theprobable genetic heterogeneity of SMA.58 12We analysed the process of confirmation ofthe clinical diagnosis in requests for prenataldiagnosis ofSMA type I.MethodsWe restricted prenatal diagnosis to cases withan unequivocal diagnosis of SMA type Ibecause of the reported genetic heterogeneityof SMA types II and III.12 In all cases thediagnosis SMA type I was evaluated by care-ful analysis of clinical data 'and re-evaluationof all available muscle biopsies.When there was no doubt about the diag-nosis of SMA type I, DNA from the parentsand all healthy siblings was isolated by routineprocedures, and DNA analysis was carriedout with markers available for the chromoso-mal region 5ql 2-ql 3.'311'7When both parents were informative forTable Criteria for diagnosis ofSMA type I1 Clinical symptoms of anterior horn cell diseasea-/hyporeflexiamuscle atrophyfasciculations2 Early onset and progressive courseage at onset < 1/2 yearage at death < 4 yearnever able to sit unsupported3 Creatine kinase normalCK <1 Ox higher reference value)4 Electromyographic study showing signs of anterior horncell involvement5 Muscle biopsy compatible with anterior horn cell disease6 Exclusion criteria:no symptoms of other neurological systemsno sensory lossno central motor neuron symptomsno mental retardationno arthrogryposisno evident facial involvementno other major organ involvementIn an isolated case all criteria except number 4 are obligate. Ina familial case only criteria 1, 2, 3 and 6 are obligate, while atleast one affected family member (sibling) must meet the cri-teria for an isolated case.319 on May 28, 2020 at University of Groningen. Protected by copyright.http://jnnp.bmj.com/J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.3.319 on 1 March 1993. Downloaded from Cobben, de Visser, Scheffer, Osinga, van der Steege, Buys, et almarkers on both sides of the SMA-locus,located between D5S6 and D5S 112, thefamily was informed that prenatal diagnosiswas possible with a specified reliability,dependent on the recombination distances ofinformative probes, the number of investigat-ed affected and healthy siblings and the pres-ence or absence of consanguinity. Weincorporated in the calculations the currentbest estimate of 5% for the proportion ofSMA type I families, which may not be dueto an autosomal recessive gene on 5ql2-ql3.In a particular family this a priori estimatedfigure of 5% was further modified for addi-tional support for 5q-linkage, derived fromthe family itself. Finally, the chance of errorsresulting from single and double recombina-tions between the SMA-locus and the infor-mative DNA-markers was incorporated.ResultsSixteen requests for prenatal diagnosis ofSMA type I were received by our centre. In4/16 cases prenatal diagnosis was declinedbecause the diagnosis did not fit classicalSMA type I. We describe these 4 cases, indi-cating the differential diagnosis in the discus-sion.Case ICase 1 was a male infant born with congeni-tal contractures of all joints, telecanthus, gen-eralised hypotonia and signs of respiratoryinsufficiency. EMG-studies showed livelvspontaneous muscle activity. Muscle biopsvrevealed extensive endomysial fibrosis. Afterextensive clinical and biochemical studiesbacteriology and virology, chromosome stud-ies, radiological and ultrasound examinations,ECG and CT scanning of the cerebrum), nodiagnosis could be made and the child died atthe age of two months. Necropsy revealed anobvious decrease in the anterior horn cellswith calcium deposits in these cells and thediagnosis of Werdnig-Hoffmann disease wasmade.Case 2Case 2 was a female infant born with congen-ital contractures of arms and legs, hygromacolli, a large atrial septal defect and gener-alised hypotonia with fasciculation of thetongue. She died when she was seven daysold of respiratory insufficiency. Necropsyshowed clear signs of anterior horn cellinvolvement, and it was concluded that thechild had Werdnig-Hoffmann disease.Case 3This male child appeared normal at birth, butin the first year hypotonia became evident.The child could not sit unsupported. At oneyear EMG-studies were normal, but a musclebiopsy revealed groups of atrophic musclefibres, lying amidst groups of normal to largecalibre, predominantly type I, fibres. Thediagnosis of spinal muscular atrophy was thenmade. At the age of 5, the child survived, buthad respiratory insufficiency.D5S6SMAMAPIBD5S204Figure Prenatal diagnosis in family SMA54. 11-I was a boy with SMA type I, who diedin 1987. DNA was extractedfrom a frozen muscle biopsy, which had been stored. Bothparents were informative for DSS6, the father informative for MAPIB and the motherforD5S204. The fetus I-2 inherited the same haplotype from the parents as the affected child.Assuming a genetic distance between DSS6 and MAPIB of2-4cM and between MAPIBand 6741 of 4-6cM, and taking into account a 5% proportion of a priori non-5q-linkedSMA I-families, the risk of the fetus being affected with SMA type I was calculated to be92-93%. The parents chose to terminate the pregnancy. * = male with SMA I.0= female, healthy. 0 = chorionic villus biopsy. + = SMA-allele. -=normal allele.Case 4Case 4 was a male infant, noted to be pro-gressively hypotonic at age one. There wasdecreased facial muscle activity and kneejerks were preserved. EMG studies revealedno abnormalities. A muscle biopsy was per-formed and a diagnosis of Werdnig-Hoffmann disease was made. Re-evaluationof the muscle biopsy, however, showed only aslight variation in the size of the individualmuscle fibres, without groups of atrophicfibres or other signs indicative of spinal mus-cular atrophy.In the remaining 12 families DNA-studieswere completed. In all families the parentswere informative for DNA-markers flankingthe SMA-gene. In 3 of the 12 families prena-tal diagnosis by DNA-analysis of chorionicvillus biopsy material was performed. In allthree cases the fetus was probably affectedwith SMA type I (with a risk of 90%,92-93% and 94% respectively). The couplesopted for selective abortion before the fif-teenth week of pregnancy. An example of onefamily in which prenatal diagnosis was actual-ly performed is represented in the figure.DiscussionIt is important to confirm the clinical diagno-sis of SMA type I by all available methods toSMA541 2I2 32 12 21 31 11 22212 12 12 12 1320 on May 28, 2020 at University of Groningen. Protected by copyright.http://jnnp.bmj.com/J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.3.319 on 1 March 1993. Downloaded from Confirmation of clinical diagnosis in requests for prenatal prediction ofSMA type Iavoid errors in prenatal diagnosis of this dis-ease. The SMA gene itself has not yet beenfound, so direct mutation DNA analysis isimpossible.The four cases in the families not offeredprenatal diagnosis were considered not tohave classic SMsA type I.Although contractures may develop duringthe course of SMA type I (case 1), the associ-ation of spinal muscular atrophy in childrenwith congenital arthrogryposis may representa separate disease entity.'8The congenital contractures, cardiacdefect, hygroma colli and facial dysmorphiain case 2 are all unusual signs in SMA type I.Case 2 possibly represents a unique syn-drome with signs of anterior horn disease,and resembles another case which has beendocumented.'9 Although the first pathologisthad diagnosed "Werdnig-Hoffnann disease"this term is, often used erroneously, as a syn-onym for anterior horn cell disease.20The clinical course in case 3 does not fit adiagnosis of SMA type I but could be consis-tent with SMA type II. Genetic heterogeneityfor SMA type II is described with a propor-tion of cases not autosomal recessive inherit-ed but either due to phenocopies or toautosomal dominant mutations.'2 Progressivehypotonia in infancy (case 4) has a wide dif-ferential diagnosis and the diagnosis in thischild is not yet clear.The importance of confirming the clinicaldiagnosis SMA before embarking on DNAstudies has recently been emphasised.320 It isdifficult to define rigid diagnostic criteria.There will always be cases on which everyexpert agrees that it must be SMA type I,even though not all criteria (table 1) are met.With the current availability of highlyinformative CA- or GT-repeat DNA-mark-ers, parental uniformativeness for all markersin the 5ql2-13 region will be rare, and didnot occur in our cases. The DNA-studies willtherefore reveal whether or not the fetus hasinherited the same relevant portion of theparental chromosomes 5 as the precedingchild with SMA did. A complicating factor isthat a recombinant between the flankingmarkers of one or both parents may bedetected in prenatal DNA-studies. A singlerecombination can greatly influence the riskof the fetus being affected. Before prenataldiagnosis, parents should be informed of thepossibility and probability of results likethese. The probabilities differ from family tofamily, depending on the precise family situa-tion and on which DNA-markers are infor-mative. In most families, however, as long asthe gene has not been found, the reliability ofprenatal testing for SMA type I is mainlydependent on the certainty of the clinicaldiagnosis in the index patient.This work was supported by the Prinses Beatrixfonds (grantnumber 89-2949) and the Preventiefonds (grant number28-1983).1 Dubowitz V.Muscle disorders in childhood. Philadelphia;Saunders 1978:146-78.2 Pearn J. The gene frequency of acute Werdnig-Hoffmandisease (SMA type I). A total population survey inNorth-East England. Jf Med Genet 1973;10:260-5.3 Munsat TL. Workshop report-International SMA col-laboration. Neuromusc Dis 1991;1:814 Brzustowicz LM, Lehner T, Castilla LH, et al. Geneticmapping of chronic childhood-onset spinal muscularatrophy to chromosome 5q1 12-13-3. Nature 1990;344:540-1.5 Gilliam TC, Brzustowicz LM, Castilla LH, et al. Genetichomogeneity between acute and chronic forms of spinalmuscular atrophy. Nature 1990;345:823-5.6 Melki J, Sheth P, Abdelhak S, Burlet P, et al. Mapping ofacute (type I) spinal muscular atrophy to chromosome5ql2-ql4. Lancet 1990;337:271-3.7 Melki J, Abdelhak S, Sheth P, et al. Gene for chronicproximal spinal muscular atrophies maps to chromo-some 5q. Nature 1990;344:767-8.8 Sheth P, Abdelhak S, Bachelot MF, et al. Linkage analysisin spinal muscular atrophy, by six closely flanking mark-ers on chromosome 5. AmJHum Genet 1991;48:764-8.9 Daniels RJ, Thomas NH, MacKinnon RN, et al. Linkageanalysis of spinal muscular atrophy. Genomics1992;12:335-9.10 Daniels RJ, Suthers GK, Morrison KE, Thomas NH,Francis MJ, Mathew CG, Loughlin S, Heiberg A,Wood D, Dubowitz V, Davies KE. Prenatal predictionof spinal muscular atrophy. J7 Med Genet 1992;29:165-170.11 Melki J, Abdelhak S, Burlet P, et al. Prenatal prediction ofWerdnig-Hoffmann disease using linked polymorphicDNA-probes. JfMed Genet 1992;29: 171-174.12 Zerres K, Rudnik-Schonebom S, Rietschel M.Heterogeneity in proximal spinal muscular atrophy.Lancet 1990;336:749-50.13 Kidd K, Bowcock AM, Schmidtke K, et al. Report of theDNA-committee and catalogues of cloned and mappedgenes and DNA polymorphisms, Human GeneMapping 10. Tenth Intemational Workshop on HumanGene Mapping. Cytogenet Cell Genet 1989;51:622-947.14 Lien LL, Boyce M, Kleyn P, et al. Mapping of humanmicrotubule-associated protein 1B in proximity to thespinal muscular atrophy locus at 5ql 3. Proc Natl AcadSci USA 199 1;88:7873-6.15 Williamson R, Bowcock AM, Kidd K, et al. Report of theDNA committee and catalogues of cloned and mappedgenes and DNA polymorphisms. Human GeneMapping 10-5 (1990). Update to the TenthIntemational Workshop on Human Gene Mapping.Cytogenet Cell Genet 1990;55:457-778.16 Morrison KE, Daniels RJ, Suthers GK, Flynn GA,Francis MJ, Buckle VJ, Davies KE. High resolutionmap around the spinal muscular atrophy locus on chro-mosome 5. Am 7Hum Genet 1992;50:520-7.17 Mankoo BS, Sherrington R, De La Concha A, et al. Twomicrosatellite polymorphisms at the D5S39 locus. NuclAcid Res 1990;19:1963.18 Greenberg F, Fenolio KR, Hejtmancik JF, et al. X-linkedinfantile spinal muscular atrophy. Am J Dis Child 1988;142:217-19.19 Mitsumoto H, Adelman LS, Liu H-S. A case of congeni-tal Werdnig-Hoffmann disease with glial bundles inspinal roots. Ann Neur 1982;11:214-16.20 Dubowitz V. Chaos in classification of spinal muscularatrophies. Neuromusc Dis 1991;1:47-53.321 on May 28, 2020 at University of Groningen. 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Confirmation of Clinical Diagnosis in Requests for Prenatal Prediction of SMA Type I

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Confirmation of Clinical Diagnosis in Requests for Prenatal Prediction of SMA Type I

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