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1 Enterprise Interest Nothing to declare

2 A rare cause of myopathy in adults Jorge Pinheiro MD, José Manuel Lopes MD, PhD Joint Slide Seminar Electron Microscopy and Trainees: Understanding diseases through the "big eye": an ultrastructural pathology seminar by pathologists in training

3 Clinical presentation 60 year-old woman Main complaints Progressive muscle weakness during one year, affecting predominantly proximal limb muscles and the neck, disclosing "drop head" Mild disphagia and horseness Muscle pain 10 kg weight loss Past & family history No relevant medical history Parents were consanguineous (cousins in 3rd degree) No relevant family history of neurological disease

4 Physical examination Myopatic gait and drop head Proximal predominant tetraparesia Muscle Group Superior limb Inferior limb Neck proximal distal proximal distal Mild facial muscle paresia Muscle atrophy No ptosis nor diplopia No sensorial alterations flexion / extensio n Grade G3 G4+ G4+ G5 G3

5 Ancilary studies Electromyography (EMG): myopathic tracings (as shown in B) in the proximal muscles of the inferior limbs and in the proximal and distal muscles of the upper limbs, with more severe alterations in the proximal muscles. A normal EMG B myopatic EMG ECG and cardiac ecography: normal Spirometry: normal

6 Ancilary studies Cell blood count: mild bicytopenia with leucopenia (2920/mm 3 ) and thrombocytopenia (133000/mm 3 ) albumin α 1 α 2 ß γ Protein electrophoresis: monoclonal gamopathy Immunofixation: Monoclonal gamopathy with lambda chains

7 Ancilary studies CK, aldolase and myoglobulin: normal TSH normal Immunological study was unremarkable ANA, anti-dsdna AMA anti-neuronal anti-ena panel HIV, HCV, HBV: negative

8 Muscle biopsy (deltoid muscle) H&E

9 ATPase ph 4.35 ATPase ph 9.4

10 Gomori

11 SDH COX

12 Tuloidine blue (x400)

13 Myotilin (IHC

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17 Diagnosis Adult-onset nemalinic myopathy (SLONM) assotiated with monoclonal gamopathy

18 Follow-up of the patient Muscle weakness Drop-head Muscle pain 10 kg weight loss Worsening of the muscle weakness in the acute phase Jan Jan Feb July 2017 Melphalan Autologous stem-cell transplantatio n Clinical stability of symptoms Persistence of monoclonal gamopathy Lenalidomide

19 Clinical classification of nemaline myopathy (by disease onset and severity of motor and respiratory involvement) Severe congenital (neonatal) (16%) Amish NM Intermediate congenital (20%) Typical congenital (46%) Childhood-onset (13%) SLONM (4%)* Ryan MM et al * The pathogenesis remains to be clarified

20 Frequency of genetic / phenotypic features and inheritance mode of nemaline myopathies Gene Frequency Inheritance Phenotype NEB Up to 50% AR Typical congenital (majority), and other ACTA % AD/AR Range from severe congenital to childhood onset Causes 50% of severe lethal NM TPM3 2%-3% AD/AR Severe (AR), intermediate and childhood (AD) TPM2 <1% AD Typical congenital TNNT1 Old Amish AR Amish NM CFL2 Rare AR Typical congenital KBTBD1 3 unknown AD Childhood onset, slowly progressive KLHL40 unknown AR Severe congenital lethal (fetal akhinesia) KLHL41 unknown AR Severe, intermediate and typical congenital LMOD3 unknown AR Severe and typical congenital Winter JM, Ottenheijm CAC (2017) other na AR na adapted from North KM & Ryan MM,

21 Definition: rare acquired, late-onset muscle disorder, with subacute progression, characterized by proximal muscle weakness and atrophy, and nemaline rods in myofibers. Mean age at onset: 52 years (range 25-78)

22 SLOMN 19.7% HIV related Early age at onset Disease progression similar to other nemaline myopathies No facial or respiratory muscle involvement Frequent myonecrosis and inflammatory infiltrates 35.5 % MGUS related Worse prognosis, with rapid progession in 50% of cases (as in the present case)

23 References Malfatti, E. & Romero, N. B. Nemaline myopathies: State of the art. Revue Neurologique 172, (2016). Milone, M. et al. Sporadic late onset nemaline myopathy responsive to IVIg and immunotherapy. Muscle and Nerve 41, (2010) North KN, Ryan MM. Nemaline Myopathy Jun 19 [Updated 2015 Jun 11]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; Romero, N. B., Sandaradura, S. a & Clarke, N. F. Recent advances in nemaline myopathy. Curr. Opin. Neurol. 26, (2013). Ryan, M. M. et al. Nemaline myopathy: A clinical study of 143 cases. Ann. Neurol. 50, (2001). Schnitzler, L. J. et al. Sporadic late-onset nemaline myopathy: clinicopathological characteristics and review of 76 cases. Orphanet J. Rare Dis. 12, 86 (2017). Voermans, N. C. et al. Sporadic late-onset nemaline myopathy with MGUS; Long-term follow-up after melphalan and SCT. Neurology 83, (2014)