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 acyl-CoA; OMM, outer mitochondrial membrane; SCAD, short-chain acyl-CoA dehydrogenase; TCA, tricarboxylic acid cycle.

Question 5: which are the most useful Her serum-free carnitine concentration was mildly http://pn.bmj.com/ investigations to reach final diagnosis? reduced at 19 µmol/L (normal: 25–60) and total This patient has a lipid-storage myopathy with carnitine concentration was 23 µmol/L (normal: massive accumulation of lipids in muscle fibres, 5–29), which ruled out a primary carnitine defi- which can develop in primary carnitine deficiency, ciency. However, the acylcarnitine profile showed multiple acyl-CoA dehydrogenase deficiency high concentrations of short, medium and long acyl-

(MADD) or neutral lipid storage disease. These carnitines, and organic acids in urine showed eleva- on September 28, 2021 by guest. Protected copyright. diseases commonly manifest as progressive proximal tion of 2-hydroxyglutaric acid. This biochemical muscle weakness rather than as episodic exercise profile is characteristic of MADD. intolerance. Free and total carnitine concentrations in serum, acylcarnitines in serum (its diagnostic Question 6: how would you confirm yield increases following a 12-hour fasting period) diagnosis and treat this patient? and organic acids in urine will help to distinguish MADD is inherited in an autosomal recessive between these three conditions. In primary carnitine manner and most patients (93%) harbour mutations deficiency, serum free and total carnitine, and serum in ETFDH; this gene encodes an electron transfer acylcarnitines would be markedly reduced whereas flavoprotein–ubiquinone oxidoreductase (ETF-QO) urine organic acids would be normal. In MADD, in charge of transferring beta-oxidation-derived short (C4–C8), medium (C8–C12) and long (>C12) electrons to respiratory chain in mitochondria. Also, acylcarnitines would be all elevated in serum, free most patients respond to riboflavin supplementation. and total carnitine can be normal or secondarily Genetic testing of ETFDH identified two vari- reduced, and organic acids would be increased in ants in this patient: c.814G>A, p.Gly272Arg and urine. In neutral lipid storage disease, serum free and c.1204A>G, p.Thr402Ala. Her strength and func- total carnitine and acylcarnitines, and urine organic tion dramatically improved after 3 weeks of taking acids would be all normal because the accumulated riboflavin (400 mg/day). Thus, she did not need her lipids are triglycerides and not fatty acids. wheelchair anymore, she did not feel winded while

Gonzalez-Perez, MD, PhD P, et al. Pract Neurol 2019;19:321–325. doi:10.1136/practneurol-2019-002204 323 Test yourself Pract Neurol: first published as 10.1136/practneurol-2019-002204 on 4 April 2019. Downloaded from  … LPN1 Recurrent episodes of myoglobinuria in the setting of febrile illness in children.

Normal Normal  CPT2 Neonatal : encephalopathy, congenital malformations, hepatomegaly and cardiomegaly resulting in death. recurrent Infantile: attacks of acute liver hypoketotic failure, hypoglycaemia and seizures Juvenile/early adult episodes of muscle life: pain and myoglobinuria following intense and prolonged exertion, cold or infection, fasting.  xisome proliferator-activated xisome proliferator-activated riheptanoin Supplementation with medium-chain triglycerides in children (controversial adults) T Agonists of pero receptors (PPARs) ACADVL ► ► ► VLCAD/LCADD CPT2 deficiency† LIPIN1 deficiency Neonatal: hypertrophic Neonatal: cardiomyopathy and High liver failure. (50%– mortality rate 75%). hypoketotic Infantile: hypoglycaemia as the main feature. Juvenile/early adult life : episodes of myoglobinuria following intense and prolonged cold infection, exertion, or fasting (similar to the adult form of CPT2 deficiency). ► ► ►  , HADHB  …  Normal (or very mild lipidosis in muscle fibres) HADHA MTPD Infancy/early childhood : altered mental vomiting, hypoketotic status, hypoglycaemia, and hepatopathy, cardiomyopathy (mortality 50%). progressive Childhood: weakness and recurrent episodes of myoglobinuria following illness or exercise, fasting. cardiomyopathy Others: sensorimotor and polyneuropathy, pigmentary retinopathy.

↑ (Intra-episode) ↑ Long-chain acylcarnitines (often intra-episode) Normal (or non-specific abnormalities)

  … multi-mini-core Moderate  Moderate lipidosis/ ACADS Neonatal: Dysmorphic Neonatal: failure to thrive, facies, metabolic acidosis, myopathy. seizures, Infantile/early adult life : exercise intolerance, or progressive myalgias weakness. proximal ptosis, Others: progressive external ophthalmoplegia, muscle respiratory and weakness, cardiomyopathy. SCADD

Normal ↑ Short-chain acylcarnitines ↑ Ethylmalonic acid

 http://pn.bmj.com/ Riboflavin (100–400 mg/day) for life CoQ10 supplementation is advised ► ► Neonatal: congenital Neonatal: multisystem anomalies, death within involvement, neonate period. hypoglycaemia, Childhood: myopathy, encephalopathy, cardiomyopathy. progressive proximal Adult: myopathy (or rarely and exercise intolerance myoglobinuria). cardiac, Others: gastrointestinal, respiratory hepatomegaly, dropped-head failure, bent-spine syndrome, and sensory syndrome, axonal polyneuropathy. MADD ► ► 1–20×ULN Normal or slightly reduced (secondary carnitine deficiency) Long-chain, medium- ↑ Long-chain, chain and short-chain acylcarnitines 2-Hydroxyglutaric acid ↑ 2-Hydroxyglutaric ETFDH , ETFB ETFA on September 28, 2021 by guest. Protected copyright. (NLSDM)  … NLSD-Myopathy (NLSDM): NLSD-Myopathy (NLSDM): slowly progressive proximal and and distal myopathy, dilated cardiomyopathy. NLSD-ichthyosis (NLSDI): non-bullous congenital ichthyosiform erythroderma, myopathy (60%) proximal and hepatomegaly.

Neutral lipid storage lipid storage Neutral disease* >5×ULN Normal Normal Normal PNPLA2 ABHD5 (NLSDI) -carnitine (100–300 l avenous carnitine mg/kg/day) for life 100–400 mg/kg/day during life-threatening events Intr PO  Massive accumulation of lipids in muscle fibres ► ► ► Primary carnitine deficiency attacks of Infantile: altered mental vomiting, hypoglycaemia, status, hepatomegaly (resembling syndrome). Reye’s Childhood/early adult (more frequent phenotype): myopathy and hypertrophic/ dilated cardiomyopathy. rhabdomyolysis and Others: muscle weakness respiratory can also occur. ↓↓↓ ↓↓↓ Normal

OCTN2 ► Differential diagnosis of lipid-storage myopathies Differential diagnosis of lipid-storage

 Muscle biopsy reatment Table 1 Table Of note, medium-chain acyl-CoA deficiency (MCAD) is the most common disease of the mitochondrial fatty acid oxidation; however, its myopathic form is extremely rare and therefore it has not been included in this table. its myopathic form is extremely however, oxidation; medium-chain acyl-CoA deficiency (MCAD) is the most common disease of mitochondrial fatty acid Of note, disease (NLSD). lipid storage anomaly) on blood smear is a pathognomonic finding of neutral in leucocytes (Jordan’s presence of lipid-containing vacuoles *The †CPT2 deficiency is the most common recognised cause of recurrent rhabdomyolysis in adults. myopathies shown have an autosomal recessive inheritance pattern. ‡All lipid-storage mitochondrial trifunctional protein MTPD, multiple acyl-CoA dehydrogenase deficiency; MADD, or phosphatidic acid phosphatase deficiency; LIPIN, long-chain acyl-CoA dehydrogenase deficiency; LCADD, II; carnitine palmitoyl transferase CPT2, very-long-chain acyl-CoA dehydrogenase deficiency. VLCAD, upper limit of normal; ULN, short-chain acyl-CoA dehydrogenase deficiency; SCADD, disease; lipid storage neutral NLSD, deficiency/long-chain HAD deficiency; Phenotype Creatine kinase 1–15×ULN Free carnitine Free AC Urine organic acids

Gene‡ T

324 Gonzalez-Perez, MD, PhD P, et al. Pract Neurol 2019;19:321–325. doi:10.1136/practneurol-2019-002204 Test yourself walking and she could stand up from a chair without fibres and confirmatory genetic testing. We would Pract Neurol: first published as 10.1136/practneurol-2019-002204 on 4 April 2019. Downloaded from using her arms. At 3-month follow-up, her examina- like this report to raise awareness of this myop- tion was improved in the following muscle groups athy, which in most cases responds spectacularly to (MRC grades, right/left where applicable): neck riboflavin supplementation, and also to review the flexion 4+, shoulder abduction 5/5, elbow external differential diagnosis of lipid-storage myopathies rotation 5/5, elbow flexion 5/5, elbow extension 5/5, (table 1).3 4 hip extension 4/4, hip abduction 4/4, knee extension 5/5, and knee flexion 5/5. Her serum creatine kinase Contributors PG-P drafted the initial manuscript, revised the final manuscript and was involved in the clinical care of the normalised to 89 U/L (reference range, 26–192) patient. MT and JH revised the final manuscript, performed and serum concentrations of acylcarnitines either pathological studies and provided figure. AAA drafted the normalised or decreased at 3 months post-treatment. manuscript, revised the manuscript until final version, and was We advised her to continue taking riboflavin 400 involved and supervised the clinical care of the patient. mg/day, which we suspect she will need for life. Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. Commentary Competing interests PG-P reports no disclosures. MT reports MADD (also called glutaric aciduria type II) is an no disclosures.JH reports no disclosures. AAmato served on autosomal recessive disease caused by mutations Scientific Advisory Boards or was a medical consultant for in ETFDH (93%) and ETFA/B (~7%) that halt the Novartis, Acceleron, Akashi, Idera and Alexion. He is also a medical consultant for Best US Doctors. He receives publishing transfer of electrons from the beta-oxidation of royalties for his book Neuromuscular Disease from McGraw- short-chain, medium-chain, and long-chain fatty Hill. He was a co-investigator on clinical trials sponsored acids to the respiratory chain in mitochondria. As by Novartis, Idera, Acceleron and Alexion. He receives an a result, all different length-chain fatty acids are honorarium from the American Academy of Neurology as Associate Editor of Neurology. increased in serum in the form of acylcarnitines, Patient consent for publication Obtained. and organic acids in urine are elevated, pointing to a failure of fatty acid oxidation.1 Provenance and peer review Not commissioned. Externally peer reviewed by Jon Walters, Swansea, UK. Riboflavin (or vitamin B ) is a precursor of flavin 2 Open access This is an open access article distributed in adenine dinucleotide, which is a required cofactor of accordance with the Creative Commons Attribution Non the flavoproteins encoded by E ETFDH (ETF-QO) Commercial (CC BY-NC 4.0) license, which permits others and ETFA/B (ETF) (figure 2). Riboflavin supple- to distribute, remix, adapt, build upon this work non- commercially, and license their derivative works on different mentation at a dose of 100–400 mg/day has been terms, provided the original work is properly cited, appropriate 1 reported in small series to be effective in MADD. credit is given, any changes made indicated, and the use is non-​ ​ The MADD phenotype varies greatly in different commercial.http://​ ​creativecommons.​org/​licenses/by​ -​nc/​4.​0/. age groups; the milder phenotype occurs in adult-

hood in the form of proximal myopathy, as in the References http://pn.bmj.com/ patient here presented. The neonatal form is often 1 Grünert SC. Clinical and genetical heterogeneity of late-onset fatal leading to multiorgan failure. Although rare in multiple acyl-coenzyme A dehydrogenase deficiency. Orphanet J Western countries, it is probably underdiagnosed. Rare Dis 2014;9. A normal serum creatine kinase, electromyography 2 Liu X-Y, Jin M, Wang Z-Q, et al. Skeletal muscle magnetic resonance imaging of the lower limbs in late-onset lipid storage study, serum acylcarnitine profile or urine organic myopathy with electron transfer flavoprotein dehydrogenase acids (which may occur under metabolically stable on September 28, 2021 by guest. Protected copyright. gene mutations. Chin Med J 2016;129:1425–31. conditions) do not rule out MADD. Although not 3 Amato AA, Russell JA. Neuromuscular disorders. 2nd Edn. specific, the MR scan may show fat infiltration and McGraw-Hill Education, 2016: 758–72. muscle atrophy in the posterior compartment of 4 Laforêt P, Vianey-Saban C, Vissing J. 162nd ENMC 2 thighs and gluteal muscles. However, diagnosis of international workshop: disorders of muscle lipid metabolism MADD mainly relies on muscle biopsy, which shows in adults 28–30 November 2008, Bussum, the Netherlands. massive accumulation of lipid droplets within muscle Neuromuscul Disord 2010;20:283–9.

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