Adult onset metabolic/mitochondrial myopathies and dystrophies

Adult onset metabolic/mitochondrial myopathies 

and dystrophies: how these cases can be 

missed 

Mark Roberts 

Greater Manchester Neurosciences Centre, Salford, UK

Disclosures 

Honorarium, Travel 

Genzyme 

Shire 

Amicus 

Biomarin

Genetic Myopathies 

Congential Myopathies (nemaline, core, actin, myosin, Ulrich) 

Congenital Muscular Dystrophies (DM1) 

Limb Girdle Dystrophies (BMD/DMD, FSHD, LGMD 22) 

Dystrophic and Non-Dystrophic Myotonias (DM1/DM2,Becker myotonia) 

Distal Myopathies (incl MFM, Myoshi, Nonanka) 

Metabolic (GSD, Lipid myopathy, Mitochondrial)

Myositis & Genetic Myopathies: Shared Features 

Clinical 

Weakness 

Wasting 

Pain 

Stiffness 

? Pigmenturia 

?Dyspnoea 

Laboratory 

CPK 

EMG Myopathic 

MRI signal change 

Muscle biopsy (HLA, 

lymphocytes)

Myositis & Genetic Myopathies: 

Potential Consequences of Misdiagnosis 

• Immunosuppression 

• Missed opportunities 

‣ Patient counselling 

‣ Genetic counselling (prenatal, PGD) 

‣ Surveillance for / prevention of complications 

‣ Clinical Trials, molecular and other therapies

Genetic Myopathies: Diagnosis 

• History of weakness / wasting 

• Early life (FM, milestones, sport) 

• Later functional problems, use of aids 

• Whistling, dressing, back pain and lordosis 

• Pain 

• Persistent, exercise, myotonia 

• ROS 

• Cardiac (rhythm, c’myopathy) Respiratory 

• Other endocrine, bone, dementia, deafness 

• FH 

• Inheritance (AR, AD, X linked, Mt), penetrance 

• Consanguinity

Genetic Myopathies: Gait

Genetic Myopathies: Diagnosis 

• Cranial Nerves 

• Ptosis, Facial, neck, bulbar weakness (fundoscopy) 

• Torso 

• Scapular, pectoralis, paraspinal 

• Limbs 

• Contractures, pattern of weakness, pseudohypertrophy, 

myotonia, rippling 

• CR ECG, ECHO, PFTS

Genetic Myopathies: Laboratory 

• CPK 

• Neuro/myopathic range 

• Ethnic variation 

• Fluctuation of CPK 

• Mild My, drugs, or metabolic 

• Marked My, Trauma, Myotoinc, Metabolic (Rhabdomyolysis) 

• EMG 

• Chronic Myopathy, “Myositis”, Myotonia, electrical silence 

Brody syndrome, Rippling muscle

Myotonic dystrophy 

DM1 the most common inherited NMD in UK 

AD (penetrance, anticipation) 

Muscle 

‣ Facial (neck, bulbar) 

‣ Limb, distal 

Pain (DM2)

Myotonic dystrophy: Clinical Manifestations 

NMD 

Respiratory 

Cardiac 

Gastrointestinal 

Cognitive 

Endocrine and Bone 

Cataracts

Myotonic dystrophy: Genetics 

A CTG repeat expansion in DM 

.... CTG CTG CTG CTG CTG .... 

(CTG) 5

Myotonic dystrophy: Genetics 

.... CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG 

CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG 





A CTG repeat expansion in DM 

CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG 















CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG CTG .... 

(CTG) 1000 

• such large expansions are usually associated with 

onset of symptoms at birth (congenital DM)

Duchenne / Becker muscular dystrophy 

DMD/BMD the most common form of LGMD 

X-Linked, 1/3000 live male births 

Mutations in dystrophin gene 

1/3 sporadic 

Manifesting female carriers 

Muscle, brain, skin 

each male with limb girdle weakness should first be 

tested for a dystrophinopathy

Dystrophin-Glycoprotein Complex 

Laminin-2 

a-, b-Dystroglycan 

ECM 

Sarcoglycans 

Sarcospan 

Caveolin-3 

Dysferlin 

d 

a 

b 

g 

Sarcolemma 

Grb2 

Dystrobrevin 

NOS1 

Syntrophins 

Dystrophin 

DMD / BMD 

F-Actin 

Cytoskeleton

DMD/BMD: Clinical Spectrum

DMD/BMD: Biopsy

Fascioscapulohumeral muscular dystrophy 

FSHD AD 

Around 3000 cases in UK (MDC) 

1/3 sporadic 

Muscle (Descending involvement) 

PAIN, hearing, eyes 

Respiratory but not cardiac

Fascioscapulohumeral muscular dystrophy

4q35 region 

DUX4 

ce 

n. 

ANT1 FRG1 FRG2 p13E11 pLAM Telomere 

DUX4c SSLP D4Z4 array β-sat A 

161 

FSHD 

< 10copies 

4q 

A

LGMD 

dominant 

LGMD1A 5q31 Myotilin 

LGMD1B 1q21 Lamin A/C 

LGMD1C 3p25 Caveolin-3 

LGMD1D 6q23 DNAJB6 

LGMD1E 7q ? 

LGMD1F 7q32 ? 

LGMD1G 4q21 ? 

‣ 90% autosomal recessive 

(CK- ) 

‣ 10% autosomal dominant 

(CK n- ) 

LGMD2A 

LGMD2B 

LGMD2C 

LGMD2D 

LGMD2E 

LGMD2F 

LGMD2G 

LGMD2H 

LGMD2I 

LGMD2J 

LGMD2K 

LGMD2L 

LGMD2M 

LGMD2N 

LGMD2O 

recessive 

15q15 

2p13 

13q12 

17q12 

4q12 

5q33 

17q11 

9q31 

19q13 

2q 

9q34 

11p13 

9q3 

14q24 

1p3 

Calpain-3 

Dysferlin 

g-Sarcoglycan 

a-Sarcoglycan 

b-Sarcoglycan 

d-Sarcoglycan 

Telethonin 

TRIM32 

FKRP 

Titin 

POMT1 

Anoctamin 5 

Fukutin 

POMT2 

POMGnT1

pathogenetic aspects of LGMDs 

LGMD1A 

LGMD2A 

LGMD2J 

LGMD1B 

LGMD2I 

LGMD2K 

LGMD2M-O 

LGMD1C 

LGMD2B 

LGMD2C-F 

LGMD2L 

Sarcomer Nuclear Lamina Golgi Apparatus Sarcolemma 

‣ cytoskeletal integrity 

‣ membrane damage 

‣ membrane repair 

‣ glycosylation

LGMD

clinical history 

diagnostic procedures 

clinical examination 

blood tests 

cardiac function 

lung function 

imaging 

muscle biopsy 

Disease Respirat. muscles Cardiac muscle 

LGMD1B Yes yes (A, CM) 

LGMD1C No No 

LGMD2A No No 

LGMD2B No No 

LGMD2C-F Yes yes (CM) 

LGMD2I/2K-N Yes yes (CM) 

genetic analysis

LGMD 2I – MRI findings 

A B C 

Fischer et al., J. Neurol, 2005

Metabolic Myopathies: 

Glycogen storage disease (McArdles GSD V, Pompe GSDII) 

Glycolytic defects 

Fatty acid oxidation defects 

Respiratory Chain defects and other Mitochondrial Defects 

Synergistic heterozygosity (partial defects) 

After Simon Olpin 2011

McArdles Myopathy (GSD5): 

Features N=59 % 

Exercise Related Pain/ Fatigue 59 100 

Second wind 51 86 

Myoglobinuria 36 61 

Renal Failure 6 10 

Hyperuricaemia 8 13 

Muscle Hypertrophy 24 41 

Muscle wasting 

Paraspinal, shoulder, 

Peri-scapular 

Muscle weakness MRC 4 

Shoulder girdle 

Axial 

16 27 

12 20

GSD V Diagnosis 

Basal CPK (>90%) 

Post Exercise (NI) CPK 

Forearm Ischaemic Lactate Test (but 

contractures, difficult, ammonia) NI 

Treadmill and cycle ergometer tests 

(including v02 max)

GSDV

Mutations of the PYGM gene 

From: From Rubio Rubio JC et al al 2007. Human Mutation Mutat. 28(2): 28: 203-204 203-4.

POMPE (GSD2): 

PATHOGENESIS 

PATHOLOGY 

Raben N, et al. Curr Mol Med. 2002;2:145-166.

A rapid and near uniformly fatal 

disease course for untreated infants 

Infants presenting with signs within the first year of life typically have a poor prognosis, 

have a rapidly progressive disease course, and die early (m8.7) 

Survival in 163 untreated infants 

Proportion of patients surviving 

1.0 

0.9 

0.8 

0.7 

0.6 

0.5 

0.4 

0.3 

0.2 

0.1 

0 

Kaplan-Meier Survival Rate 

12 months 18 months 24 months 

25.7% 14.3% 9.0% 

0 3 6 9 12 15 18 21 24 27 30 

Age (months) 

Figure reprinted from Kishnani PS, et al. Infantile-Onset Pompe Disease Natural History Study Group. A retrospective, multinational, multicenter study 

on the natural history of infantile-onset Pompe disease. J Pediatr. 2006;148:671-676, with permission from Elsevier. 

33

LATE-ONSET POMPE DISEASE 

LatPompe Late presentation 

CLINICAL 

PRESENTATION 

Hirschhorn R, et al. In: The Metabolic and Molecular Bases of Inherited Disease. 2001:3389-3420.

Vacuolated Lymphocytes 

Haggemans et al. J Inherit Metab Dis. 2010 April; 33(2): 133–139.

DBS aids in early diagnosis 

The availability of a rapid and simple blood-based assay, DBS enables the early 

diagnosis of Pompe disease 

• Minimally invasive sample collection (Blood draw, heel prick, or finger stick) and 

convenience are compelling reasons for using DBS samples 

• Drying the sample on paper is the most cost efficient method for stabilizing enzymes 

for shipping 

• Clinical laboratory experience has shown 

that DBS is a reliable and robust method 

for screening a large number of patients, with results in days 

Winchester et al. Mol Genet Metab. 2008;93:275-281. 

Goldstein et al. Muscle Nerve. 2009;40(1):32-36. 

36

Dynamic organelles – ATP synthesis 

Chan, D.C. (2006) Cell:125;1241-1252

Cardiomyopathy 

Liver Failure 

Ophthalmoplegia / ptosis 

Encephalopathy 

Epilepsy / dementia 

Diabetes 

Gonadal failure 

Parkinsonism 

Dysphagia 

Dysmotility 

Ataxia 

Axonal 

sensori-motor 

neuropathy 

Myopathy 

Deafness

Mitochondrial DNA (mtDNA) 

• covalently-closed DNA 

molecule (16.6 kb) 

• located in mitochondrial 

matrix 

• high copy number 

• maternally-inherited 

• vulnerable to ROS-induced 

mutation 

• Replication, transcription 

and translation mediated by 

nuclear gene products 

• Unique genetics 

Tuppen et al. Biochim Biophys Acta 2010;1797;113-128

mtDNA mutations: phenotype-genotype correlation 

m.1624C>T – 

LS 

m.1555A>G – deafness 

O H 

m.14709T>C – myopathy, 

weakness, diabetes 

m.3243A>G - MELAS/MIDD/CPEO 

m.3271T>C – MELAS 

m.14484T>C – LHON 

m.14459G>A, m.14487T>C – LS 

m.3460G>A - LHON 

several mutations - MELAS 

m.13513G>A and other mutations 

MELAS, LS and overlap syndromes 

m.4300A>G 

cardiomyopathy 

m.5545C>T 

multisystemic disorder, 

RC deficiency 

4,977-bp deletion 

CPEO/KSS/PS 

m.11777C>A – LS 

m.11778G>A – LHON 

m.7445A>G, m.7472Cins 

deafness, myopathy 

m.10158T>C, m.10191T>C, m.10197G>A 

LS/Leigh-like syndrome 

m.8344A>G, m.8356T>C 

MERRF 

m.8993T>G/C, m.9176T>G/C 

NARP/MILS

Nuclear mitochondrial interactions 

Smits et al. J Biomed Biotechnol 2010:737385

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Adult onset metabolic/mitochondrial myopathies and dystrophies

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