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Proximal Muscle Weakness Pract Neurol: First Published As 10.1136/Practneurol-2019-002204 on 4 April 2019

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Proximal Muscle Weakness Pract Neurol: First Published As 10.1136/Practneurol-2019-002204 on 4 April 2019 TEST YOURSELF Proximal muscle weakness Pract Neurol: first published as 10.1136/practneurol-2019-002204 on 4 April 2019. Downloaded from Paloma Gonzalez-Perez, MD, PhD,1 Matthew Torre, MD,2 Jeffrey Helgager, MD, PhD,2 Anthony A. Amato, MD3 A 38-year-old woman gave a 1-year history of proximal weakness involving legs and of difficulties climbing stairs and walking arms. The differential diagnosis includes an long distances, needing a wheelchair at acquired (e.g., inflammatory or toxic myop- 1Department of Neurology, Harvard Medical School, times. More recently, she had also experi- athy) or genetic (e.g., muscular dystrophy, Massachusetts General Hospital, enced weakness of her arms with difficul- late-onset congenital myopathy or meta- Boston, Massachusetts, USA ties doing her hair or lifting light weights. bolic myopathy) myopathic disorder. A 2 Department of Pathology, She reported shortness of breath on mild neuromuscular junction disorder needs Harvard Medical School, Brigham Women’s Hospital, exertion and had lost 12 pounds in weight to be considered although the absence of Boston, Massachusetts, USA because of muscle loss. She had no muscle ocular symptoms (which occurs in 90% 3Department of Neurology, pain, episodes of dark urine, muscle of patients with myasthenia) and lack of Harvard Medical School, twitching, visual disturbances, hearing loss, fluctuating symptoms would be atypical Brigham Women's Hospital, Boston, Massachusetts, USA speech difficulties, dysphagia, numbness for myasthenia gravis, and the lack of auto- or tingling, bladder or bowel difficulties, nomic symptoms and intact patella reflexes Correspondence to fevers, rash or joint pain. She had met all would be atypical for Lambert-Eaton myas- Dr Paloma Gonzalez-Perez, MD, PhD, Department of Neurology, milestones at a normal age and had normal thenic syndrome. A motor neurone disease Harvard Medical School, development. such as spinal muscular atrophy type III is Massachusetts General Hospital, Her medical history was unremarkable. unlikely since muscle weakness typically Boston, MA 02114, USA; She had not taken any lipid-lowering agents progresses more slowly than in this case. pgonzalezperez@ partners. org and there was no illicit drug use or toxic Accepted 18 February 2019 exposure. There was no relevant family QUESTION 2: WHAT INVESTIGATIONS Published Online First history and no consanguinity. WOULD YOU LIKE TO PERFORM? 4 April 2019 On examination, she showed bilateral Serum creatine kinase concentrations were and symmetric scapular winging. There persistently elevated, ranging from 682 to was no percussion or action myotonia or 1464 U/L (reference range, 26–192). Full paramyotonia, and no fasciculations. Her blood count, serum electrolytes, anti-nu- http://pn.bmj.com/ muscle bulk and tone were normal. Cranial clear antibody, anti-neutrophil cytoplasmic nerves were all normal. Manual muscle antibodies, thyroid-stimulating hormone, strength testing showed the following erythrocyte sedimentation rate, C reactive Medical Research Council (MRC) grades protein, serum protein electrophoresis with (right/left where applicable): neck flexion immunofixation, hepatitis B and C serology, 4–, neck extension 5, shoulder abduction and myositis-specific antibody panel were on September 28, 2021 by guest. Protected copyright. 4/4, external rotation of elbow 4/4, elbow all normal or negative. She had already flexion 4/4, elbow extension 4+/4+, wrist undergone electromyography and a muscle flexion 5/5, wrist extension 5/5, finger biopsy of right gastrocnemius muscle before flexion 5/5, finger extension 5/5, hip flexion our initial evaluation. That electromyog- 4/4, hip extension 3/3, hip abduction 3/3, raphy had shown abnormal spontaneous knee extension 4+/4+, knee flexion 4/4, activity in the form of positive sharp waves ankle dorsiflexion 5/5 and ankle plantar and fibrillation potentials in right thoracic flexion 5/5. Deep tendon reflexes were 1+ paraspinal and right medial gastrocnemius at triceps, brachioradialis and ankles, and muscles, without any apparent abnormality © Author(s) (or their 2+ at biceps and knees bilaterally. She had in motor unit morphology or recruitment. employer(s)) 2019. Re-use permitted under CC BY-NC. No a waddling gait. Plantar responses were The muscle biopsy of right gastrocnemius commercial re-use. See rights flexor. Sensory and coordination exams muscle was normal. Also, a transthoracic and permissions. Published were normal. echocardiogram was normal. by BMJ. To cite: QUESTION 1: WHAT IS THE QUESTION 3: HOW WOULD YOU Gonzalez-Perez, MD, PhD P, Torre, MD M, Helgager, MD, PhD J, DIFFERENTIAL DIAGNOSIS? INTERPRET THESE TEST RESULTS? et al. Pract Neurol This 38-year-old woman likely has a Fibrillation potentials and positive sharp 2019;19:321–325. myopathy given the symmetrical pattern waves are not specific since they can Gonzalez-Perez, MD, PhD P, et al. Pract Neurol 2019;19:321–325. doi:10.1136/practneurol-2019-002204 321 TEST YOURSELF develop in either a neuropathic or a myopathic process enzyme replacement therapy. Finally, lipid storage myop- Pract Neurol: first published as 10.1136/practneurol-2019-002204 on 4 April 2019. Downloaded from with muscle membrane irritability (inflammatory, toxic/ athies, which are rarer, can present in a similar fashion. necrotic, dystrophic, and selected congenital and meta- Whereas a dynamic form of lipid storage myopathy bolic myopathies). Morphology of motor unit potentials (such as mitochondrial trifunctional protein deficiency, (high amplitude and long duration in neurogenic disor- very-long-chain acyl-CoA dehydrogenase deficiency and ders and low amplitude and short duration in myopa- carnitine palmitoyl transferase II deficiency) is unlikely, thies) and recruitment (reduced in neurogenic and early static and progressive forms within this group need to in myopathic disorders) would help to distinguish a be considered. myopathic from a neuropathic process, but there were none of these abnormalities on this electromyography study. The right gastrocnemius muscle had full strength QUESTION 4: HOW WOULD YOU PROCEED on examination, which significantly reduces the diag- NOW? nostic yield of a biopsy; an optimal muscle to biopsy We tested for serum acid α-glucosidase activity to should be clinically weak but not end stage. Thus, we screen for Pompe’s disease and performed genetic continue to favour a myopathy in her case based on testing for the most common forms of limb-girdle history, examination and high serum creatine kinase. muscular dystrophy (ANO5, CAPN3, CAV3, DMD, The most likely diagnosis is an adult-onset limb-girdle DES, DNAJB6, DYSF, FKRP, FKTN, GAA, GMPPB, muscular dystrophy, given scapular winging—which is LMNA, MYOT, POMGNT1, POMT1, POMT2, not typical of acquired myopathies—and her pattern of SGCA, SGCB, SGCD, SGCG, TCAP, TNPO3, weakness. Less commonly, some congenital myopathies TRIM32 and TTN), which were all normal. We (e.g., central core) can present like this in adulthood. then performed an electromyography that showed Finally, metabolic myopathies need to be considered. increased insertional activity and abnormal sponta- She had no exercise intolerance with myoglobinuria to suggest a dynamic form of glycogen storage disease neous activity in the form of positive sharp waves such as McArdle's disease. However, others such as an and fibrillation potentials in left deltoid and biceps adult-onset Pompe’s disease (glycogenosis type II) may muscles, with early recruitment of short-duration, manifest with progressive proximal weakness, together low-amplitude and polyphasic motor unit poten- with mild-to-moderately elevated serum creatine kinase, tials. On the same day, we performed a muscle and myopathic features on electromyography involving biopsy of right deltoid to avoid potential needle thoracic paraspinal muscles. It is important to consider insertion–related inflammatory changes present on Pompe’s disease as there is now treatment in the form of the left (figure 1). http://pn.bmj.com/ on September 28, 2021 by guest. Protected copyright. Figure 1 Muscle biopsy of the right deltoid. The right deltoid muscle biopsy shows (A) numerous vacuolated myofibres (black arrows) (frozen section H&E, ×400); (B) the cytoplasmic vacuoles contain lipid (arrows) (oil red O stain, ×400) but (C) not glycogen (arrows) (PAS stain, 400x); (D) electron microscopy images show myofibres with abundant intracellular myocyte lipid vacuoles. 322 Gonzalez-Perez, MD, PhD P, et al. Pract Neurol 2019;19:321–325. doi:10.1136/practneurol-2019-002204 TEST YOURSELF Pract Neurol: first published as 10.1136/practneurol-2019-002204 on 4 April 2019. Downloaded from Figure 2 Fatty acid transport and β-oxidation in the mitochondria. The transport of long-chain fatty acids into the mitochondria is CPT complex dependent unlike short-chain fatty acids. LCAD, MCAD and SCAD are enzymes in charge of the β-oxidation of acyl- CoA which releases electrons that are transferred to ETF (encoded by ETFA and ETFB), then ETF-QO (encoded by ETFDH), and lastly to mitochondrial respiratory chain. FAD is a cofactor of both ETF and ETF-QO. Riboflavin is a precursor of FAD and the mainstay treatment of MADD due to ETFDH and ETFA/B mutations. CPT I and II, carnitine palmitoyl transferase I and II; ETF, electron transfer flavoprotein; ETF-QO, electron transfer flavoprotein–ubiquinone oxidoreductase; FA, fatty acid; FAD, flavin adenine dinucleotide; IMM, inner mitochondrial membrane; LCAD, long-chain acyl-CoA dehydrogenase; MCAD, medium-chain
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