321Gonzalez-Perez, MD, PhD P, et al. Pract Neurol 2019;19:321–325. doi:10.1136/practneurol-2019-002204

TesT yourself

1Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA2Department of Pathology, Harvard Medical School, Brigham Women’s Hospital, Boston, Massachusetts, USA3Department of Neurology, Harvard Medical School, Brigham Women's Hospital, Boston, Massachusetts, USA

Correspondence toDr Paloma Gonzalez-Perez, MD, PhD, Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA; pgonzalezperez@ partners. org

Accepted 18 February 2019Published Online First 4 April 2019

To cite: Gonzalez-Perez, MD, PhD P, Torre, MD M, Helgager, MD, PhD J, et al. Pract Neurol 2019;19:321–325.

Proximal muscle weakness

Paloma Gonzalez-Perez, MD, PhD,1 Matthew Torre, MD,2 Jeffrey Helgager, MD, PhD,2 Anthony A. Amato, MD3

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

A 38-year-old woman gave a 1-year history of difficulties climbing stairs and walking long distances, needing a wheelchair at times. More recently, she had also experi-enced weakness of her arms with difficul-ties doing her hair or lifting light weights. She reported shortness of breath on mild exertion and had lost 12 pounds in weight because of muscle loss. She had no muscle pain, episodes of dark urine, muscle twitching, visual disturbances, hearing loss, speech difficulties, dysphagia, numbness or tingling, bladder or bowel difficulties, fevers, rash or joint pain. She had met all milestones at a normal age and had normal development.

Her medical history was unremarkable. She had not taken any lipid-lowering agents and there was no illicit drug use or toxic exposure. There was no relevant family history and no consanguinity.

On examination, she showed bilateral and symmetric scapular winging. There was no percussion or action myotonia or paramyotonia, and no fasciculations. Her muscle bulk and tone were normal. Cranial nerves were all normal. Manual muscle strength testing showed the following Medical Research Council (MRC) grades (right/left where applicable): neck flexion 4–, neck extension 5, shoulder abduction 4/4, external rotation of elbow 4/4, elbow flexion 4/4, elbow extension 4+/4+, wrist flexion 5/5, wrist extension 5/5, finger flexion 5/5, finger extension 5/5, hip flexion 4/4, hip extension 3/3, hip abduction 3/3, knee extension 4+/4+, knee flexion 4/4, ankle dorsiflexion 5/5 and ankle plantar flexion 5/5. Deep tendon reflexes were 1+ at triceps, brachioradialis and ankles, and 2+ at biceps and knees bilaterally. She had a waddling gait. Plantar responses were flexor. Sensory and coordination exams were normal.

Question 1: what is the differential diagnosis?This 38-year-old woman likely has a myopathy given the symmetrical pattern

of proximal weakness involving legs and arms. The differential diagnosis includes an acquired (e.g., inflammatory or toxic myop-athy) or genetic (e.g., muscular dystrophy, late-onset congenital myopathy or meta-bolic myopathy) myopathic disorder. A neuromuscular junction disorder needs to be considered although the absence of ocular symptoms (which occurs in 90% of patients with myasthenia) and lack of fluctuating symptoms would be atypical for myasthenia gravis, and the lack of auto-nomic symptoms and intact patella reflexes would be atypical for Lambert-Eaton myas-thenic syndrome. A motor neurone disease such as spinal muscular atrophy type III is unlikely since muscle weakness typically progresses more slowly than in this case.

Question 2: what investigations would you like to perform?Serum creatine kinase concentrations were persistently elevated, ranging from 682 to 1464 U/L (reference range, 26–192). Full blood count, serum electrolytes, anti-nu-clear antibody, anti-neutrophil cytoplasmic antibodies, thyroid-stimulating hormone, erythrocyte sedimentation rate, C reactive protein, serum protein electrophoresis with immunofixation, hepatitis B and C serology, and myositis-specific antibody panel were all normal or negative. She had already undergone electromyography and a muscle biopsy of right gastrocnemius muscle before our initial evaluation. That electromyog-raphy had shown abnormal spontaneous activity in the form of positive sharp waves and fibrillation potentials in right thoracic paraspinal and right medial gastrocnemius muscles, without any apparent abnormality in motor unit morphology or recruitment. The muscle biopsy of right gastrocnemius muscle was normal. Also, a transthoracic echocardiogram was normal.

Question 3: how would you interpret these test results?Fibrillation potentials and positive sharp waves are not specific since they can

on Decem

ber 24, 2019 by guest. Protected by copyright.

http://pn.bmj.com

/P

ract Neurol: first published as 10.1136/practneurol-2019-002204 on 4 A

pril 2019. Dow

nloaded from

322 Gonzalez-Perez, MD, PhD P, et al. Pract Neurol 2019;19:321–325. doi:10.1136/practneurol-2019-002204

TesT yourself

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.

develop in either a neuropathic or a myopathic process with muscle membrane irritability (inflammatory, toxic/necrotic, dystrophic, and selected congenital and meta-bolic myopathies). Morphology of motor unit potentials (high amplitude and long duration in neurogenic disor-ders and low amplitude and short duration in myopa-thies) and recruitment (reduced in neurogenic and early in myopathic disorders) would help to distinguish a myopathic from a neuropathic process, but there were none of these abnormalities on this electromyography study. The right gastrocnemius muscle had full strength on examination, which significantly reduces the diag-nostic yield of a biopsy; an optimal muscle to biopsy should be clinically weak but not end stage. Thus, we continue to favour a myopathy in her case based on history, examination and high serum creatine kinase. The most likely diagnosis is an adult-onset limb-girdle muscular dystrophy, given scapular winging—which is not typical of acquired myopathies—and her pattern of weakness. Less commonly, some congenital myopathies (e.g., central core) can present like this in adulthood. Finally, metabolic myopathies need to be considered. She had no exercise intolerance with myoglobinuria to suggest a dynamic form of glycogen storage disease such as McArdle's disease. However, others such as an adult-onset Pompe’s disease (glycogenosis type II) may manifest with progressive proximal weakness, together with mild-to-moderately elevated serum creatine kinase, and myopathic features on electromyography involving thoracic paraspinal muscles. It is important to consider Pompe’s disease as there is now treatment in the form of

enzyme replacement therapy. Finally, lipid storage myop-athies, which are rarer, can present in a similar fashion. Whereas a dynamic form of lipid storage myopathy (such as mitochondrial trifunctional protein deficiency, very-long-chain acyl-CoA dehydrogenase deficiency and carnitine palmitoyl transferase II deficiency) is unlikely, static and progressive forms within this group need to be considered.

Question 4: how would you proceed now?We tested for serum acid α-glucosidase activity to screen for Pompe’s disease and performed genetic testing for the most common forms of limb-girdle muscular dystrophy (ANO5, CAPN3, CAV3, DMD, DES, DNAJB6, DYSF, FKRP, FKTN, GAA, GMPPB, LMNA, MYOT, POMGNT1, POMT1, POMT2, SGCA, SGCB, SGCD, SGCG, TCAP, TNPO3, TRIM32 and TTN), which were all normal. We then performed an electromyography that showed increased insertional activity and abnormal sponta-neous activity in the form of positive sharp waves and fibrillation potentials in left deltoid and biceps muscles, with early recruitment of short-duration, low-amplitude and polyphasic motor unit poten-tials. On the same day, we performed a muscle biopsy of right deltoid to avoid potential needle insertion–related inflammatory changes present on the left (figure 1).

on Decem

ber 24, 2019 by guest. Protected by copyright.

http://pn.bmj.com

/P

ract Neurol: first published as 10.1136/practneurol-2019-002204 on 4 A

pril 2019. Dow

nloaded from

323Gonzalez-Perez, MD, PhD P, et al. Pract Neurol 2019;19:321–325. doi:10.1136/practneurol-2019-002204

TesT yourself

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 investigations to reach final diagnosis?This patient has a lipid-storage myopathy with massive accumulation of lipids in muscle fibres, which can develop in primary carnitine deficiency, multiple acyl-CoA dehydrogenase deficiency (MADD) or neutral lipid storage disease. These diseases commonly manifest as progressive proximal muscle weakness rather than as episodic exercise intolerance. Free and total carnitine concentrations in serum, acylcarnitines in serum (its diagnostic yield increases following a 12-hour fasting period) and organic acids in urine will help to distinguish between these three conditions. In primary carnitine deficiency, serum free and total carnitine, and serum acylcarnitines would be markedly reduced whereas urine organic acids would be normal. In MADD, short (C4–C8), medium (C8–C12) and long (>C12) acylcarnitines would be all elevated in serum, free and total carnitine can be normal or secondarily reduced, and organic acids would be increased in urine. In neutral lipid storage disease, serum free and total carnitine and acylcarnitines, and urine organic acids would be all normal because the accumulated lipids are triglycerides and not fatty acids.

Her serum-free carnitine concentration was mildly reduced at 19 µmol/L (normal: 25–60) and total carnitine concentration was 23 µmol/L (normal: 5–29), which ruled out a primary carnitine defi-ciency. However, the acylcarnitine profile showed high concentrations of short, medium and long acyl-carnitines, and organic acids in urine showed eleva-tion of 2-hydroxyglutaric acid. This biochemical profile is characteristic of MADD.

Question 6: how would you confirm diagnosis and treat this patient?MADD is inherited in an autosomal recessive manner and most patients (93%) harbour mutations in ETFDH; this gene encodes an electron transfer flavoprotein–ubiquinone oxidoreductase (ETF-QO) in charge of transferring beta-oxidation-derived electrons to respiratory chain in mitochondria. Also, most patients respond to riboflavin supplementation.

Genetic testing of ETFDH identified two vari-ants in this patient: c.814G>A, p.Gly272Arg and c.1204A>G, p.Thr402Ala. Her strength and func-tion dramatically improved after 3 weeks of taking riboflavin (400 mg/day). Thus, she did not need her wheelchair anymore, she did not feel winded while

on Decem

ber 24, 2019 by guest. Protected by copyright.

http://pn.bmj.com

/P

ract Neurol: first published as 10.1136/practneurol-2019-002204 on 4 A

pril 2019. Dow

nloaded from

324 Gonzalez-Perez, MD, PhD P, et al. Pract Neurol 2019;19:321–325. doi:10.1136/practneurol-2019-002204

TesT yourself

Tabl

e 1

Diffe

rent

ial d

iagn

osis

of li

pid-

stor

age

myo

path

ies

Prim

ary

carn

itin

e de

ficie

ncy

Neu

tral

lipi

d st

orag

e di

seas

e*M

AD

DSC

AD

DM

TPD

VLCA

D/L

CAD

DCP

T2 d

efici

ency

†LI

PIN

1 de

ficie

ncy

Phen

otyp

eIn

fant

ile: a

ttack

s of

vo

miti

ng, a

ltere

d m

enta

l st

atus

, hyp

oglyc

aem

ia,

hepa

tom

egal

y (re

sem

blin

g Re

ye’s

synd

rom

e).

Child

hood

/ear

ly ad

ult

(mor

e fre

quen

t phe

noty

pe):

myo

path

y an

d hy

pertr

ophi

c/di

late

d ca

rdio

myo

path

y.O

ther

s: rh

abdo

myo

lysis

and

resp

irato

ry m

uscle

wea

knes

s ca

n al

so o

ccur

.

NLS

D-M

yopa

thy

(NLS

DM):

slow

ly pr

ogre

ssiv

e pr

oxim

al

and

dist

al m

yopa

thy,

and

dila

ted

card

iom

yopa

thy.

NLS

D-ich

thyo

sis (N

LSDI

): no

n-bu

llous

con

geni

tal

ichth

yosif

orm

ery

thro

derm

a,

prox

imal

myo

path

y (6

0%)

and

hepa

tom

egal

y.

Neo

nata

l: co

ngen

ital

anom

alie

s, m

ultis

yste

m

invo

lvem

ent,

deat

h w

ithin

ne

onat

e pe

riod.

Child

hood

: hyp

oglyc

aem

ia,

ence

phal

opat

hy, m

yopa

thy,

card

iom

yopa

thy.

Adul

t: pr

ogre

ssiv

e pr

oxim

al

myo

path

y (o

r rar

ely

exer

cise

into

lera

nce

and

myo

glob

inur

ia).

Oth

ers:

card

iac,

gast

roin

test

inal,

he

pato

meg

aly,

resp

irato

ry

failu

re, d

ropp

ed-h

ead

synd

rom

e, b

ent-s

pine

sy

ndro

me,

and

sen

sory

ax

onal

pol

yneu

ropa

thy.

Neo

nata

l: Dy

smor

phic

facie

s, fa

ilure

to th

rive,

m

etab

olic

acid

osis,

se

izure

s, m

yopa

thy.

Infa

ntile

/ear

ly ad

ult l

ife:

exer

cise

into

lera

nce,

m

yalg

ias

or p

rogr

essiv

e pr

oxim

al w

eakn

ess.

Oth

ers:

ptos

is,

prog

ress

ive

exte

rnal

op

htha

lmop

legi

a,

resp

irato

ry m

uscle

w

eakn

ess,

and

card

iom

yopa

thy.

Infa

ncy/

early

chi

ldho

od:

vom

iting

, alte

red

men

tal

stat

us, h

ypok

etot

ic hy

pogl

ycae

mia

, he

pato

path

y, an

d ca

rdio

myo

path

y (m

orta

lity

50%

).Ch

ildho

od: p

rogr

essiv

e w

eakn

ess

and

recu

rrent

epi

sode

s of

m

yogl

obin

uria

follo

win

g ex

ercis

e, il

lnes

s or

fa

stin

g.O

ther

s: ca

rdio

myo

path

y se

nsor

imot

or

polyn

euro

path

y, an

d pi

gmen

tary

retin

opat

hy.

Neo

nata

l: hy

pertr

ophi

c ca

rdio

myo

path

y an

d liv

er fa

ilure

. Hig

h m

orta

lity

rate

(50%

–75

%).

Infa

ntile

: hyp

oket

otic

hypo

glyc

aem

ia a

s th

e m

ain

feat

ure.

Juve

nile

/ear

ly ad

ult

life:

epi

sode

s of

m

yogl

obin

uria

follo

win

g in

tens

e an

d pr

olon

ged

exer

tion,

infe

ctio

n, c

old

or fa

stin

g (s

imila

r to

the

adul

t for

m o

f CPT

2 de

ficie

ncy)

.

Neo

nata

l: en

ceph

alop

athy

, co

ngen

ital

mal

form

atio

ns,

hepa

tom

egal

y an

d ca

rdio

meg

aly

resu

lting

in

dea

th.

Infa

ntile

: rec

urre

nt

atta

cks

of a

cute

live

r fa

ilure

, hyp

oket

otic

hypo

glyc

aem

ia a

nd

seizu

res

Juve

nile

/ear

ly ad

ult

life:

epi

sode

s of

mus

cle

pain

and

myo

glob

inur

ia

follo

win

g in

tens

e an

d pr

olon

ged

exer

tion,

in

fect

ion,

col

d or

fa

stin

g.

Recu

rrent

epi

sode

s of

m

yogl

obin

uria

in th

e se

tting

of f

ebril

e ill

ness

in

chi

ldre

n.

Crea

tine

kina

se1–

15×

ULN

>5×

ULN

1–20

×UL

NN

orm

al↑

(Intra

-epi

sode

)

Free

car

nitin

e↓↓

↓N

orm

alN

orm

al o

r slig

htly

redu

ced

(sec

onda

ry c

arni

tine

defic

ienc

y)N

orm

al

AC↓↓

↓N

orm

al↑

Long

-cha

in, m

ediu

m-

chai

n an

d sh

ort-c

hain

ac

ylcar

nitin

es

↑ Sh

ort-c

hain

ac

ylcar

nitin

es↑

Long

-cha

in a

cylca

rniti

nes

(ofte

n in

tra-e

piso

de)

Nor

mal

Urin

e or

gani

c ac

ids

Nor

mal

Nor

mal

↑ 2-

Hydr

oxyg

luta

ric a

cid↑

Ethy

lmal

onic

acid

Nor

mal

(or n

on-s

pecifi

c ab

norm

aliti

es)

M

uscle

bio

psy

M

assiv

e ac

cum

ulat

ion

of li

pids

in m

uscle

fibr

es

Mod

erat

e lip

idos

is/m

ulti-

min

i-cor

e

Nor

mal

(or v

ery

mild

lipi

dosis

in m

uscle

fibr

es)

Gen

e‡O

CTN

2PN

PLA2

(NLS

DM)

ABHD

5 (N

LSDI

)ET

FDH

ETFA

, ETF

B

ACAD

S

HADH

A, H

ADHB

AC

ADVL

CP

T2

LPN

1

Trea

tmen

t

►PO

l-ca

rniti

ne (1

00–3

00

mg/

kg/d

ay) f

or li

fe

►In

tr ave

nous

car

nitin

e 10

0–40

0 m

g/kg

/day

du

ring

life-

thre

aten

ing

even

ts

…

►

Ribo

flavi

n (1

00–4

00

mg/

day)

for l

ife

►Co

Q10

sup

plem

enta

tion

is ad

vise

d

…

…

►

Supp

lem

enta

tion

with

med

ium

-cha

in

trigl

ycer

ides

in c

hild

ren

(con

trove

rsia

l in

adul

ts)

►

Trih

epta

noin

►

Agon

ists

of p

erox

isom

e pr

olife

rato

r-act

ivate

d re

cept

ors

(PPA

Rs)

…

Of n

ote,

med

ium

-cha

in a

cyl-C

oA d

eficie

ncy

(MCA

D) is

the

mos

t com

mon

dise

ase

of th

e m

itoch

ondr

ial f

atty

acid

oxi

datio

n; h

owev

er, i

ts m

yopa

thic

form

is e

xtre

mel

y ra

re a

nd th

eref

ore

it ha

s no

t bee

n in

clude

d in

this

tabl

e.*T

he p

rese

nce

of li

pid-

cont

aini

ng v

acuo

les

in le

ucoc

ytes

(Jor

dan’

s an

omal

y) o

n bl

ood

smea

r is

a pa

thog

nom

onic

findi

ng o

f neu

tral l

ipid

sto

rage

dise

ase

(NLS

D).

†CPT

2 de

ficie

ncy

is th

e m

ost c

omm

on re

cogn

ised

caus

e of

recu

rrent

rhab

dom

yolys

is in

adu

lts.

‡All

lipid

-sto

rage

myo

path

ies

show

n ha

ve a

n au

toso

mal

rece

ssiv

e in

herit

ance

pat

tern

.CP

T2, c

arni

tine

palm

itoyl

trans

fera

se II

; LCA

DD, l

ong-

chai

n ac

yl-Co

A de

hydr

ogen

ase

defic

ienc

y; LI

PIN,

or p

hosp

hatid

ic ac

id p

hosp

hata

se d

eficie

ncy;

MAD

D, m

ultip

le a

cyl-C

oA d

ehyd

roge

nase

defi

cienc

y; M

TPD,

mito

chon

dria

l trif

unct

iona

l pro

tein

de

ficie

ncy/

long

-cha

in H

AD d

eficie

ncy;

NLS

D, n

eutra

l lip

id s

tora

ge d

iseas

e; S

CADD

, sho

rt-ch

ain

acyl-

CoA

dehy

drog

enas

e de

ficie

ncy;

ULN,

upp

er li

mit

of n

orm

al; V

LCAD

, ver

y-lo

ng-c

hain

acy

l-CoA

deh

ydro

gena

se d

eficie

ncy.

on Decem

ber 24, 2019 by guest. Protected by copyright.

http://pn.bmj.com

/P

ract Neurol: first published as 10.1136/practneurol-2019-002204 on 4 A

pril 2019. Dow

nloaded from

325Gonzalez-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 using her arms. At 3-month follow-up, her examina-tion was improved in the following muscle groups (MRC grades, right/left where applicable): neck flexion 4+, shoulder abduction 5/5, elbow external rotation 5/5, elbow flexion 5/5, elbow extension 5/5, hip extension 4/4, hip abduction 4/4, knee extension 5/5, and knee flexion 5/5. Her serum creatine kinase normalised to 89 U/L (reference range, 26–192) and serum concentrations of acylcarnitines either normalised or decreased at 3 months post-treatment.

We advised her to continue taking riboflavin 400 mg/day, which we suspect she will need for life.

commentaryMADD (also called glutaric aciduria type II) is an autosomal recessive disease caused by mutations in ETFDH (93%) and ETFA/B (~7%) that halt the transfer of electrons from the beta-oxidation of short-chain, medium-chain, and long-chain fatty acids to the respiratory chain in mitochondria. As a result, all different length-chain fatty acids are increased in serum in the form of acylcarnitines, and organic acids in urine are elevated, pointing to a failure of fatty acid oxidation.1

Riboflavin (or vitamin B2) is a precursor of flavin adenine dinucleotide, which is a required cofactor of the flavoproteins encoded by E ETFDH (ETF-QO) and ETFA/B (ETF) (figure 2). Riboflavin supple-mentation at a dose of 100–400 mg/day has been reported in small series to be effective in MADD.1

The MADD phenotype varies greatly in different age groups; the milder phenotype occurs in adult-hood in the form of proximal myopathy, as in the patient here presented. The neonatal form is often fatal leading to multiorgan failure. Although rare in Western countries, it is probably underdiagnosed. A normal serum creatine kinase, electromyography study, serum acylcarnitine profile or urine organic acids (which may occur under metabolically stable conditions) do not rule out MADD. Although not specific, the MR scan may show fat infiltration and muscle atrophy in the posterior compartment of thighs and gluteal muscles.2 However, diagnosis of MADD mainly relies on muscle biopsy, which shows massive accumulation of lipid droplets within muscle

fibres and confirmatory genetic testing. We would like this report to raise awareness of this myop-athy, which in most cases responds spectacularly to riboflavin supplementation, and also to review the differential diagnosis of lipid-storage myopathies (table 1).3 4

Contributors PG-P drafted the initial manuscript, revised the final manuscript and was involved in the clinical care of the patient. MT and JH revised the final manuscript, performed pathological studies and provided figure. AAA drafted the manuscript, revised the manuscript until final version, and was involved and supervised the clinical care of the patient.

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.

Competing interests PG-P reports no disclosures. MT reports no disclosures.JH reports no disclosures. AAmato served on Scientific Advisory Boards or was a medical consultant for Novartis, Acceleron, Akashi, Idera and Alexion. He is also a medical consultant for Best US Doctors. He receives publishing royalties for his book Neuromuscular Disease from McGraw-Hill. He was a co-investigator on clinical trials sponsored by Novartis, Idera, Acceleron and Alexion. He receives an honorarium from the American Academy of Neurology as Associate Editor of Neurology.

Patient consent for publication Obtained.

Provenance and peer review Not commissioned. Externally peer reviewed by Jon Walters, Swansea, UK.

Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non- commercial. http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.

references 1 Grünert SC. Clinical and genetical heterogeneity of late-onset

multiple acyl-coenzyme A dehydrogenase deficiency. Orphanet J Rare Dis 2014;9.

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 myopathy with electron transfer flavoprotein dehydrogenase gene mutations. Chin Med J 2016;129:1425–31.

3 Amato AA, Russell JA. Neuromuscular disorders. 2nd Edn. McGraw-Hill Education, 2016: 758–72.

4 Laforêt P, Vianey-Saban C, Vissing J. 162nd ENMC international workshop: disorders of muscle lipid metabolism in adults 28–30 November 2008, Bussum, the Netherlands. Neuromuscul Disord 2010;20:283–9.

on Decem

ber 24, 2019 by guest. Protected by copyright.

http://pn.bmj.com

/P

ract Neurol: first published as 10.1136/practneurol-2019-002204 on 4 A

pril 2019. Dow

nloaded from