J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.5.633 on 1 May 2003. Downloaded from 633 PAPER Muscle fibrillin deficiency in Marfan’s syndrome myopathy W M H Behan, C Longman,RKHPetty, P Comeglio, A H Child, M Boxer, P Foskett, D G F Harriman ............................................................................................................................. J Neurol Neurosurg Psychiatry 2003;74:633–639 See end of article for authors’ affiliations Objective: To report a family with Marfan’s syndrome in whom a myopathy was associated with res- ....................... piratory failure; muscle biopsies from affected individuals were examined to determine whether there Correspondence to: were abnormalities in fibrillin. ProfessorWMHBehan, Methods: 21 family members underwent detailed clinical examination, including neurological and Department of Pathology, pulmonary assessment. Muscle biopsies in the most severely affected cases were immunostained using Western Infirmary, monoclonal antibodies to specific fibrillin components. Genomic DNA from all 21 members was ana- Glasgow G11 6NT, UK; lysed for mutations in the fibrillin gene, FBN1, on 15q21. [email protected] Results: 13 individuals had a C4621T base change in exon 37 of the FBN1 gene, which in four cases Received 29 August 2002 segregated with muscle weakness or evidence of respiratory muscle dysfunction or both. Their muscle In revised form biopsies revealed an abnormality in fibrillin immunoreactivity. 10 December 2002 Accepted Conclusions: Abnormalities in fibrillin can be detected in muscle biopsies from patients with Marfan’s 11 December 2002 syndrome who have myopathy. This pedigree, with a point mutation in FBN1, also draws attention to ....................... the potential for respiratory failure associated with myopathy. arfan’s syndrome is the commonest autosomal domi- and abnormal fibrillin immunoreactivity in the endomysium nant inherited disorder of connective tissue, with a and perimysium. Mprevalence of 1/5000 to 1/10 000 individuals.12There is complete penetrance but great variability in phenotype, the latter varying from florid abnormalities to just outside normal METHODS limits.34 Needle muscle biopsy specimens were obtained from the vas- The diagnostic criteria have been established in two tus lateralis muscle of three cases (11:7, 11:4, 111:3) using a workshops as major features in the ocular, cardiovascular, and modified Arthrodax needle (Oxylitre, Edinburgh, Scotland) as skeletal systems associated with involvement of the lungs and described.18 Frozen sections of 5 µm thickness were examined integument.56Dural ectasia may be the most sensitive clinical using the following stains in the order given: haematoxylin diagnostic marker but its specificity remains to be and eosin, modified Gomori trichrome, adenosine triphos- http://jnnp.bmj.com/ established.7 If a mutation in the FBN1 fibrillin gene is phatase at pH 9.4 and 4.3, NADH-tetrazolium reductase, suc- detected, then a major criterion in an organ system and the cinate dehydrogenase, cytochrome oxidase, oil red O, PAS, PAS involvement of another is diagnostic; for relatives, a positive with diastase, and acid phosphatase. Stains for myophospho- family history, one major criterion, and involvement of a sec- rylase (MP), phosphofructokinase (PFK), and myoadenylate ond organ system meet the criteria.5 The skeletal anomalies deaminase (AMP) were included.18 Appropriate controls were which raise the possibility of Marfan’s syndrome are quite used in sequence. Antibodies to dystrophins (C terminal, N common in the general population and have necessitated the terminal, and rod domains), α, β, γ, and δ sarcoglycans, establishment of rigid guidelines. emerin, and merosin were used in a standard immunohisto- on September 27, 2021 by guest. Protected copyright. Poor muscle development was commented on by Marfan in chemical protocol.19 For electron microscopic examination, the his original description of an affected five year old child.8 specimens were left at 4°C overnight, processed, and examined Although then considered part of the symptom complex,9–11 it in a Philips CM10 electron microscope.18 was poorly characterised and myopathy is not mentioned in the most widely quoted review article3 or in the two Fibrillin studies international workshops.56 The following commercially available mouse monoclonal anti- Fibrillin-1, the 350 kDa glycoprotein involved in Marfan’s bodies to human fibrillin (Chemicon International, Harrow, syndrome, is present in the endomysium and perimysium of Middlesex, UK) were used: MAB 1919 to fibrillin, MAB 2499 skeletal muscles.12–14 It is widely distributed in the body, where to fibrillin-1, C terminal, and MAB 2502 to fibrillin-1, N it forms a major component of the microfibrillar system and terminal. The optimum dilutions for the antibodies were contributes to the mechanical properties of elastic fibres.12 13 15 established as 1:200 for MAB 1919 and MAB 2499, and 1:1500 Mutations in the FBN1 gene on chromosome 15q21 which for MAB 2502, with all incubations being for one hour at room encodes fibrillin-1 are associated with cases of Marfan’s temperature. Visualisation was obtained using avidin-biotin syndrome.16 Mutations in the FBN2 gene give rise to clinical complex in the Vector Elite kit.19 syndromes (fibrillinopathies) which show phenotypic overlap with Marfan’s syndrome,112while on the other hand one fam- ily with Marfan’s syndrome has been linked to a locus on CASE DESCRIPTIONS chromosome 3p.17 Thus the diagnosis of Marfan’s syndrome Diagnosis of Marfan’s syndrome in each case was based on the has remained a clinical one. strict clinical guidelines.56 Written informed consent to We report a family fulfilling the diagnostic criteria but also include their data was obtained from all family members having muscle weakness associated with respiratory failure except for II:8 and III:1, who declined assessment. www.jnnp.com 634 Behan, Longman, Petty, et al J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.5.633 on 1 May 2003. Downloaded from Table 1 Details of affected individuals Proband Feature II-1 II-2 II-4 II-5 II-6 II-7 III-3 III-6 III-7 III-8 III-9 III-10 III-11 Age (years) 48 42 46 45 40 38 20 13 21 26 20 17 14 FBN1mutation +++++++ + +++++ Span:height >1.05 + –––––– – ––––– Wrist/thumb sign – +++–++ + +– – + – Pectus carinatum – ++++++ + +++++ Pectus excavatum ––––––– – ––––– Scoliosis ––+––+––––––– Pesplanus ––––––– – ––––– Acetabular protrusion nt nt – nt nt – nt nt nt nt nt – nt Reduced elbow extension ––––––– – ––––– Marfanoid facies – ++++++ + +++++ Higharchedpalate –++++++ + +++++ Joint hypermobility ––––––+ + ––––– Mitral prolapse/regurgitation + nt – + – + + – – –––– Aortic dilatation + nt ––––– – –– – + – Recurrent pneumothorax – – + –––––––––– Skin striae ––––––+ – ++ + – + Recurrent hernias – + ––––+ – –– – + – Ectopialentis ntnt––––– – ––––– Myopia ––––––+ – –– – + – Dural extasia nt nt nt nt nt nt nt nt nt nt nt nt nt Limbweakness –––––++ – ––––– Respiratoryweakness–nt+––+–+––––– +, feature present; –, feature absent; nt, not tested. Case 1, proband II:7 activities. She has an asthenic build with poor muscle bulk but This woman underwent mitral valve replacement aged 18 no muscle weakness. She has minor pectus carinatum. years, subsequently developing left atrial enlargement and Pulmonary function tests revealed evidence of mild respira- atrial fibrillation with pulmonary hypertension. She was tory muscle weakness: FEV1 was 2.07 litres (71% of predicted), treated with digoxin and warfarin and remained well, and FVC, 2.14 litres (64% of predicted). Inspiratory mouth working as a full time secretary, until her emergency pressure was 62 cm H2O (normal > 70) and expiratory mouth admission at the age of 37 years with a deteriorating level of pressure 71 cm H2O (normal > 90). These measurements have consciousness following a two day history of fever and cough. remained stable for the past year. A muscle biopsy was done A diagnosis was made of type II respiratory failure secondary (see below). to bronchopneumonia and she was intubated and ventilated. She was slow to wean from the ventilator because of poor res- Case 3, proband III:3 piratory effort. This woman, aged 20 years, has had lifelong exertional Nerve conduction studies, late response tests, and needle dyspnoea on moderate exertion, for example when running, electromyography (EMG) were applied appropriately for the but is able to participate in kick boxing classes. On examina- http://jnnp.bmj.com/ clinical symptoms and signs. Repetitive stimulation studies of tion, she had mild lower limb weakness with some difficulty the right ulnar nerve were normal. Motor and sensory nerve rising on heels and toes and she was slow to rise from a squat. conduction studies were normal for velocity and latency, A muscle biopsy was done (see below). Pulmonary function although the computed motor action potential (CMAP) was tests were normal, including lying and standing FEV1 and FVC very small in each location. The F waves were absent. Needle and mouth pressures. EMG did not show any active membrane disturbance but the universal overall pattern was of very tiny, short duration, Case 4, proband III:6 on September 27, 2021 by guest. Protected copyright. triphasic motor unit potentials. The findings suggested an end This boy has mild pectus carinatum. He did not describe mus- stage congenital myopathy/dystrophy. Muscle biopsy was cle or respiratory symptoms, and had no muscle weakness on done (see