Progressive Myopathy

Could It Be a Genetic Mitochondrial Disease?

Michio Hirano, MD
Lucy G. Moses Professor of Neurology
Chief, Neuromuscular Medicine Division
Director, H. Houston Merritt Neuromuscular Research Center
Columbia University Irving Medical Center
Vagelos College of Physicians and Surgeons

Marni J. Falk, MD
Professor, Division of Human Genetics, Department of Pediatrics
Executive Director, Mitochondrial Medicine Frontier Program
Children’s Hospital of Philadelphia
University of Pennsylvania Perelman School of Medicine

Colleen Clarke Muraresku, MS, LCGC

Senior Genetic Counselor and Program Director
Mitochondrial Medicine Frontier Program
The Children’s Hospital of Philadelphia
This activity is supported by an educational grant from Zogenix.
Faculty Disclosures

 Michio Hirano, MD
• Royalty: Modis Therapeutics
• Receipt of Intellectual Property Rights/Patent Holder: Modis Therapeutics
• Consulting Fees (e.g., advisory boards): Entrada Therapeutics, Modis Therapeutics
• Contracted Research: Entrada Therapeutics, Stealth BioTherapeutics
 Marni J. Falk, MD
• Royalty: Elsevier
• Receipt of Intellectual Property Rights/Patent Holder: Children’s Hospital of Philadelphia
• Consulting Fees (e.g., advisory boards): Astellas, Casma Therapeutics, Cyclerion
Therapeutics, Epirium Bio, IMEL Biotherapeutics, Khondrion, Larimar Therapeutics, Minovia
Therapeutics, NeuroVive, Stealth BioTherapeutics, Zogenix
• Contracted Research: Aadi Bioscience, Cardero Therapeutics, Cyclerion Therapeutics,
Epirium Bio, IMEL Biotherapeutics, Minovia Therapeutics, Mission Therapeutics, NeuroVive,
Raptor Pharmaceutical, Reata Pharmaceuticals, RiboNova, Standigm, Stealth
BioTherapeutics
• Ownership Interest less than 5% (stocks, stock options, or other ownership interest
excluding diversified mutual funds): MitoCureia; RiboNova
 Colleen Clarke Muraresku, MS, LCGC
• Has no financial relationships to report
2
Learning Objectives

 Demonstrate an enhanced index of suspicion for the

diagnosis of a genetic mitochondrial disease in infants,
children, and adults who present with progressive muscle
weakness
 Describe the diagnostic work-up for a patient with
mitochondrial disease and how to utilize genetic testing as
part of the diagnostic approach
 Describe key manifestations of thymidine kinase 2 (TK2)
deficiency across the spectrum of disease severity and age
as an example of mitochondrial DNA replication deficiency
syndrome (MDS)

3
Myopathy and
Progressive Muscle
Weakness
Common Manifestations of
Mitochondrial Disease
Audience Polling Question

When you see a patient with

progressive myopathy, do you
consider a mitochondrial
disorder…?
A. All the time
B. When neurological or muscular motor
symptoms are the only manifestations
C. What is a mitochondrial disorder?

5
What Are Mitochondria?

 Subcellular, cytoplasmic
organelles

 Arose from ancient symbiont

ancestor: purple sulfur bacteria
that could handle oxygen

 Regulate many cellular functions

1. ENERGY PRODUCTION
2. Calcium homeostasis
3. Apoptosis
4. Radical species generation
5. Radical species scavenging
6. Steroid biosynthesis
7. Orchestrate metabolism

Mccormick EM et al. Curr Genet Med Rep. 2018;6(2):52-61. 6

Clinical Features of Mitochondrial Disease

Gorman G et al. Nat Rev Dis Primers. 2016;2:16080.

Vafai SB, Mootha VK. Nature. 2012;491(7424):374-383. 7
Clinical Syndromes
mtDNA mtDNA mtDNA nDNA Gene-based
Point Mutations Single Large- Multiple Large- Clinical Syndromes
scale Deletions scale Deletions

Mitochondrial Pearson syndrome (PS) Progressive external Multi-system disorders

encephalomyoapthy and ophthalmoplegia
Stroke-like episodes (PEO or PEO+)
syndrome (MELAS)

Myoclonic epilepsy and Kearns-Sayre syndrome Mitochondrial Leigh syndrome

ragged red fibers (KSS) neurogastrointestinal
syndrome (MERRF) encephalomyopathy
(MNGIE)

Neurogenic ataxia and Chronic progressive Aging mtDNA depletion

retinitis pigmentosa external ophthalmoplegia disorders
(NARP) (CPEO)

Leber’s hereditary optic Mitochondrial myopathy

neuropathy (LHON)

Leigh syndrome Mitochondrial

cardiomyopathy

8
mtDNA Depletion Syndromes

Suomolainen A, Isohanni P. Neuromuscul Disord. 2010;20(7):429-437. 9

Mitochondrial Disease Patient
Symptom Frequency
Top 5 symptoms Survey of
experienced 290
by mitochondrial
disease patients
Mitochondrial
Disease
Patients*

% of 290 patients who do or do not

experience each symptom:
*Zolkipli-Cunningham Z et al. PLoS One. 2018;13(5):e0197513. 10
 Mitochondrial Disease is Heterogeneous

“Any symptom, any organ, any age, any mode of inheritance”1

Paradigm Shift:
 No single biomarker for mitochondrial disease
Redefining Mitochondrial
 Many genetic causes across 2 genomes Disease 2,3

– Mitochondrial DNA: 37 genes

COMPUTATIONALLY SOPHISTICATED
– Nuclear DNA: >350 genes MOLECULAR DIAGNOSTIC AGE
FOR UNDERSTANDING
Collectively affect >1 inMITO DISEASE SUB-CLASSES :
4,300 people

PATHWAY-
ORGAN ENERGETIC
BASED
DISEASE DISEASE
DISEASE

Multi-organ OXPHOS Molecular

failure dysfunction etiology

1. Munnich A, Rustin P. Am J Med Genet. 2001;106(1):4-17.

2. McCormick EM et al. Neurotherapeutics. 2013;10(2):251-261.
IMPLICATIONS of PATHWAY-BASED MEDICINE:
3. McCormick EM et al. Curr Genet Med Rep. 2018;6(2):52-61. 11
Mitochondrial Disease Inheritance
Recurrence Risk to Recurrence Risk to
Inheritance Recurrence Risk to
Disease Example Offspring of Offspring of
Pattern Full Siblings
Affected Females Affected Males
1%-4% if no symptoms
in mother;
Up to 50% for both sons
Maternal mtDNA point mutation up to 50% if None
and daughters
symptomatic mother
(EMPIRIC RISK)
All children will be All children will be
Mutations in nDNA-encoded
carriers (likely carriers (likely
respiratory chain subunits or
Autosomal asymptomatic); asymptomatic);
assembly factors; 25%
recessive Affected status depends Affected status
mtDNA depletion (POLG1,
on population carrier depends on population
TK2, DGUOK, etc.)
frequency carrier frequency
<1% based on germline
Autosomal Progressive external 50% for both sons and 50% for both sons and
mosaicism if parent is
dominant ophthalmoplegia (POLG1) daughters daughters
asymptomatic
If mother is a carrier:
50% for brothers to be If symptomatic mother,
affected & 50% for 50% for sons to be None for sons;
Sideroblastic anemia (ABC7);
sisters to be carriers affected and 50% for
Barth syndrome (tafazzin); 50% for daughters to
X-linked (likely asymptomatic); daughters to be
Mohr-Tranebjaerg syndrome be carriers (likely
carriers/affected
(DDPI) If de novo, <1% for asymptomatic)
(depending on her x-
brothers to be affected or inactivation pattern)
sisters to be carriers
Muscle biopsy evidence of
Sporadic respiratory chain dysfunction Uncertain Uncertain Uncertain
without clear genetic etiology

Falk MJ. In: Mito 101. Parikh S, DiMauro S (eds.); United Mitochondrial Disease Foundation (UMDF). 12
Mitochondrial Disease Sequence Data Resource
https://mseqdr.org

Falk MJ et al. Mol Genet Metab. 2015;114(3):388-396. 13

Shen L et al. Hum Mutat. 2016;37(6):540-548.
Mitochondrial Disease
Molecular Pathways Effected by Genetic Disorders

Gorman G et al. Nat Rev Dis Primers. 2016;2:16080. 14

 Acknowledgements
CHOP MMFP LAB RESEARCH TEAM University of Pennsylvania
Active Past Joseph Baur, PhD
Eiko Nakamaru-Ogiso, PhD James Byrnes, PhD Christopher Fang-Yen, PhD
Xiaokang Bai, MS Stephen Dingley, BS, DO David L. Gasser, PhD
Chynna Broxton, PhD Sujay Guha, PhD Mark Allen, PhD
Yi Cheng, MD Jianping Kong, PhD
Smruthi Guha, MS Chigoziro Konkwo, BA
Suraiya Haroon, PhD Young-Joon (Fred) Kwon, BS
Prabhjot Kaur Richard Lightfoot, MS
FUNDING
R35-GM134864 (NIGMS, NIH)
Manuela Lavorato, PhD Julian Ostrovsky, MS
R01-GM120762 (NIGMS, NIH)
Neal Mathew, PhD Erzsebet Polyak, PhD
R01-GM115730 (NIGMS, NIH)
Min Peng, MD, PhD Judith Preston, MS R01-HD065858 (NICHD, NIH)
Heeyong Yoon, PhD Meera Rao, MS, PhD U24-HD086984 (NICHD, NIH)
Nina Shah, BA R03-DK082521 (NIDDK, NIH)
Mai Tsukikawa, MS, MD R01-DK055852 (NIDDK, NIH)
Holveck Lightening the Load Research Fund
Jaxson Flynt C12ORF65 Research Fund
CHOP MMFP CLINICAL RESEARCH TEAM Joshua Cohen DLD Research Fund
Sara Nguyen, MPH Juliet’s Cure Mitochondrial Disease FBXL4 Research
Cesar Alves, MD Fund
Michael Bennett, PhD Jamie Peterson, MS
Flynt-McCoy NUBPL Research Fund
Jean Flickinger, PT Mariya Redko
Will Woleben SURF1 Research Fund
Rebecca Ganetzky, MD Suraj Serai, PhD
Angelina Maio Research Fund
Ibrahim George-Sankoh Christoph Seiler, PhD
Kelsey Wright Foundation
Amy Goldstein, MD Edward Shadiack, DO Penn Orphan Disease Center
Kierstin Keller, MS Sonal Sharma, MD Center for Mitochondrial & Epigenomic Medicine &
Beth Heuer, NP Katelyn Stanley Mitochondrial Medicine Frontier Program, CHOP
Laura Macmullen Deanne Taylor, PhD Research Institute
Shana McCormack, MD Doug Wallace, PhD United Mitochondrial Disease Foundation (UMDF)
Elizabeth McCormick, MS Rui Xiao, PhD
Colleen Clarke Muraresku, MS Jim (Zhe) Zhang, PhD
Sergey Magnitsky, PhD Zarazuela Zolkipli-Cunningham, MBChB 15
Diagnosis Workup
and the Place of
Genetic Testing
Audience Polling Question

Can you diagnose mitochondrial

myopathy on physical exam alone?

A. Yes
B. No

17
Diagnostic Algorithm

Muraresku CC et al. Curr Genet Med Rep. 2018;6(2):62-72. 18

What to Order and Why?

Blood Other types of evaluation in myopathy

 Comprehensive chemistry panel patients
 Lactate and pyruvate  Physical therapy assessment
 Plasma amino-acid analysis  Electromyography (EMG) – can
 Carnitine analysis identify nerve dysfunction, muscle
dysfunction, or problems with nerve-
 Acylcarnitine analysis
to-muscle signal transmission
 CK
 Nerve conduction study (NCS) –
Urine can identify nerve damage
 Amino-acid analysis • Repetitive stimulation
 Organic-acid analysis consideration if myasthenia
 Urinalysis gravis is on the differential
CSF  Swallow assessment – can identify
 Lactate/pyruvate risk for aspiration
 Amino-acid analysis  Sleep study – can identify sleep
apnea
 Protein
 Brain MRI – can identify changes
and lesions in the brain
19
Audience Polling Question

All patients must have a muscle

biopsy to diagnosis mitochondrial
myopathy?

A. Yes
B. No

20
Tissue-based Analyses
Skeletal Muscle Biopsy
Location is critical: Vastus Lateralis,
needed for normative analyses for muscle
mitochondrial testing
Morphological Analysis
 Mitochondrial proliferation
• Ragged red fibers
• Subsarcolemmal accumulation of
mitochondria
 COX-deficient fibers
Electron Microscopy
 Increased number of mitochondria
 Structurally abnormal mitochondria
 Paracrystalline inclusions

Gamboa JL et al. Physiol Rep. 2016;4(9):e12780.

Lorenzoni PJ et al. Arq Neuropsiquiatr. 2015;73(11):959-967. 21
Tissue-based Analyses
Skeletal Muscle Biopsy

Biochemical
 Electron transport chain (ETC) activity
• Reported relative to marker enzyme (citrate synthase)
• Isolated defects
• Multiple enzyme defects
 Coenzyme Q10 determination
• Primary CoQ10 deficiency is rare
• Secondary CoQ10 deficiency can be seen in those with
mitochondrial disease
– Can be used to adjust CoQ10 treatment
 mtDNA copy number analysis
• Assesses for mtDNA depletion
22
Genetics 101

Image courtesy of the Bioethics Advisory Committee. 23

Molecular Testing

 Mitogenome (mtDNA) sequencing/heteroplasmy analysis in

MULTIPLE tissues
 Nuclear gene sequencing
• Panels (obtains both sequencing and deletion/duplication of genes but is costly and typically leads to further testing)
• Exome sequencing (inclusive for all genetic causes and cost effective)
– Does NOT include all CNV changes and triplet repeats

• Genome sequencing (clinically, most insurances are not paying for this test yet, but research options are available)
 RNA sequencing (best in tissues)
• Clinically validated in fibroblasts, muscle, and blood
• Lead to diagnosis in 10% of unsolved cases and pointed to candidate
genes in remainder of cases*
• IMPORTANT: Tissue specificity – i.e., is gene expressed in tested tissue?

Kremer LS et al. Nat Commun. 2017;8:15824. 24

Tissue-based Analyses

mtDNA RNA mtDNA

Tissue Pathology ETC Other
sequencing sequencing content

Blood - + + - - -
80% correlation with
Buccal - + - - - skeletal muscle ETC*

Urine - + - - - -
Can be stored
Fibroblasts - + + + - indefinitely

Muscle + + + + + -

Liver + + - - + -

*Goldenthal MJ et al. Mol Genet Metab. 2012;105(3):457-462. 25

Audience Polling Question

All mitochondrial disease is inherited

from the mother?

A. Yes
B. No

26
Mitochondrial Disease Inheritance

 Mitochondrial DNA-related  Multiple copies of mtDNA are in

disease every cell/tissue/organ
• Inheritance: Maternal  Heteroplasmy vs homoplasmy
• Recurrence risk: challenging • Homoplasmic wild-type: only
(100%) wild-type mtDNA is
given heteroplasmy
present
– If not found in multiple tissues
and mother is asymptomatic,
• Homoplasmic mutant: only
this is considered to be low (100%) mutant mtDNA is present
(1%-4%) • Heteroplasmy: 2 different
– ALL maternal relatives should populations of mtDNA are present
be offered evaluation and in a given cell or tissue (e.g., wild-
testing type and mutant)
– SLSMDS are de novo (new)  Threshold Effect:
typically
• Specific heteroplasmy load for a
– Males will NOT pass this onto specific mtDNA mutation that any
their children given tissue tolerates before it
shows signs of pathology
27
mtDNA Inheritance

Mccormick EM et al. Curr Genet Med Rep. 2018;6(2):52-61. 28

Mitochondrial Disease Inheritance
 Nuclear-related Mitochondrial Disease
Recurrence Risk to Recurrence Risk to
Inheritance Recurrence Risk to
Disease Example Offspring of Offspring of
Pattern Full Siblings
Affected Females Affected Males
1%-4% if no symptoms
in mother;
Up to 50% for both sons
Maternal mtDNA point mutation up to 50% if None
and daughters
symptomatic mother
(EMPIRIC RISK)
All children will be All children will be
Mutations in nDNA-encoded
carriers (likely carriers (likely
respiratory chain subunits or
Autosomal asymptomatic); asymptomatic);
assembly factors; 25%
recessive Affected status depends Affected status
mtDNA depletion (POLG1,
on population carrier depends on population
TK2, DGUOK, etc.)
frequency carrier frequency
<1% based on germline
Autosomal Progressive external 50% for both sons and 50% for both sons and
mosaicism if parent is
dominant ophthalmoplegia (POLG1) daughters daughters
asymptomatic
If mother is a carrier:
50% for brothers to be If symptomatic mother,
affected & 50% for 50% for sons to be None for sons;
Sideroblastic anemia (ABC7);
sisters to be carriers affected and 50% for
Barth syndrome (tafazzin); 50% for daughters to
X-linked (likely asymptomatic); daughters to be
Mohr-Tranebjaerg syndrome be carriers (likely
carriers/affected
(DDPI) If de novo, <1% for asymptomatic)
(depending on her x-
brothers to be affected or inactivation pattern)
sisters to be carriers
Muscle biopsy evidence of
Sporadic respiratory chain dysfunction Uncertain Uncertain Uncertain
without clear genetic etiology
29
Falk MJ. In: Mito 101. Parikh S, DiMauro S (eds.); United Mitochondrial Disease Foundation (UMDF).
How to Read a Genetic Test Report

30
How to Read a Genetic Test Report

31
How to Read a Genetic Test Report

32
How to Read a Genetic Test Report

33
How to Read a Genetic Test Report

34
Family Planning with Mitochondrial Disease

 Prior to pregnancy
• Preimplantation Genetic Diagnosis: Harvest
embryos during an IVF protocol
– Test and implant embryos without pathogenic variants
– Test and implant embryos with low heteroplasmy

• Mitochondrial Replacement Therapy (MRT)

– Replacing the mutated maternal mitochondrial DNA in the
oocytes or zygotes
– Can potentially prevent transmission of mtDNA disease

35
Family Planning with Mitochondrial Disease

 During pregnancy
• Chorionic Villus Sample (CVS): Between 10-13
weeks, a sample of the chorionic villi is removed
from the placenta to test for genetic variants
• Amniocentesis: Between 15-20 weeks, a sample of
amniotic fluid is removed

 After pregnancy
• All full siblings can be tested and evaluated after
birth

36
Key Points

 Muscle biopsy should be considered in all cases

even with a negative genetic testing
 NOT all mitochondrial disease is inherited from the
mother
 Genetically confirming a mitochondrial myopathy aids in
access to clinical trials and targeted treatment, ends
diagnostic odyssey, and allows for recurrence risk and
family counseling
 If patient is undiagnosed, it is important to check back
with genetics every 1-2 years to assess for updating
diagnostic evaluations

37
Resources for Genetics and
Mitochondrial Disease
 Mitochondrial disease database
• www.mseqdr.org

 mtDNA resource
• www.mitomap.org
 Mitochondrial Disease Genes Compendium 1st
Edition: From Genes to Clinical Manifestations,
editor Marni Falk

38
Focus on TK2
Deficiency as an MDS
Case Presentation
Disorders of mtDNA Maintenance
Autosomal dominant and recessive mitochondrial
disorders with mtDNA depletion, multiple
deletions, or both in affected tissues

40
Mutations in 26 Nuclear Genes Cause mtDNA
Depletion, Multiple Deletions, or Both
mtDNA replication
• POLG1
• POLG2
• TWNK
• SSBP1
• MGME1
• DNA2
• RNaseHI
• TFAM
• TOP3A
Nucleoside/nucleotide metabolism
• TYMP
• ANT1
• TK2
• DGUOK
• GMPR
• SCL25A4
• RRM2B
• ABAT
• MPV17
• SUCLA2
• SUCLG1
Mitochondrial dynamics
• OPA1
• MFN2
• FBXL4
• SPG7
• AFG3L2
• GFER 41
TK2 Catalyzes the First Phosphorylation of
Pyrimidine Deoxynucleosides in Mitochondria

ATP ADP
TK2

dCtd dCMP dCDP dCTP

dThd dTMP dTDP dTTP
mdN H2O

Pi

42
TK2 Disease and Therapy Overview

Mutant mitochondrial thymidine kinase in

mitochondrial DNA depletion myopathy*
The activity of thymidine kinase 2 in
muscle mitochondria
Sample Substrate
[3H]dTHd [3H]dCyt
Patient 1 3.42±0.38 1.80±0.06
Patient 2 1.03±0.31 0.71±0.59
Patient 4 1.76±0.42 0.68±0.08
Controls 7.55±1.45 5.65±1.89
(5.40-10.51) (4.55-7.59)

 Early onset: from birth to 30 months

 Progressive weakness of skeletal and respiratory muscles
 Elevated CK and lactic acid
 Mean age of death: 2.6 years
*Saada A et al. Nat Genet. 2001;29(3):342-344. 43
TK2d Patient

 Normal early development: sitting at

6-7 months, cruising at 12 months
 At 12 months: trouble holding up
head
 At 15 months: unable to cruise or sit

 Admitted to a hospital for severe

weakness.
• CK 1,290-2,098 (NL 24-295)
• Venous lactate 3.9 mM (NL 0.5-2.2)
• Muscle biopsy: severe mtDNA
depletion (11% of normal)
• TK2 mutations: p. Lys50IlefsX99 and
p.Thr108Met

Image courtesy of Dr. Hirano. 44

TK2d Patient (cont.)

 Age: 19 months
• Severe quadriparesis
(1-2/5 strength)
• Placed on mechanical
ventilation 24 h/day
• Gastrostomy

Video courtesy of Dr. Hirano. 45

Adult TK2d Patient

Video courtesy of Dr. Hirano. 46

Disease Spectrum of 92 TK2-deficient Patients
Infantile-onset Childhood-onset Late-onset
myopathy myopathy myopathy
39 (42.4%) 37 (40.2%) 16 (17.4%)
Onset ≤12 months >1-<12 years-old ≥12 years-old

Symptoms Diffuse muscle Proximal muscle Muscle

weakness, early weakness, areflexia weakness
respiratory failure

EMG Myogenic +/- Myogenic +/- Myogenic

neuropathic pattern neuopathic pattern pattern

CK ↑↑↑ ↑↑↑ normal-↑↑

mtDNA +++ +++ +/-

depletion
mtDNA _ _ +++
deletions
Other seizures 7, facial diplegia 11, ptosis 9, ptosis 9, PEO 8,
encephalopathy 5, PEO 3, hearing loss 2, dysphagia 6,
signs & cognitive dysfunction 3, cognitive decline 1, respiratory
symptoms ptosis 4, facial diplegia 3, encephalopathy 1, insufficiency 5,
dysphagia 3, multiple prolonged QT 1, dysarthria 3,
bone fractures 2, arrhythmia 1, multiple cardiomyopathy 2,
nephropathy 1, rigid spine bone fractures 1, renal gynecomastia 1,
1, coma episodes 1, tubulopathy 1, and Neuropathy 1,
cardiomyopathy 1, bi- gynecomastia 1 Hearing loss 1
ventricular hypertrophy 1,
arrhythmia 1 and
esophageal atresia 1

Garone C et al. J Med Genet. 2018;55(8):515-521. 47

 Manifestations Across TK2 deficiency Phenotypes
Early Onset (≤12 years-old) and Late Onset (>12 years-old)
Early Onset Late Onset
Symptom Early Onset Symptom Late Onset
Muscle weakness 61/63, 97% Muscle Weakness 8/8
Hypotonia 55/57, 96% Ptosis 7/7
Elevated serum CK 56/59, 95% Dysphagia 5/5
Respiratory difficulties 48/53, 91% Respiratory difficulties 2/4
Loss of previously acquired motor skills 43/49, 88%
mtDNA multiple deletions 4/4
mtDNA depletion 33/40, 83%
Elevated serum CK 2/2
Hyporeflexia 31/39, 79%
Dysphagia 7/18, 39%
Seizures 7/18, 39%
Motor development delay 18/49, 37%
Cognitive Impairment 4/43, 9%

Clear progressive decline 

No reports of remission / spontaneous improvement without treatment
Key differences: Rate of disease progression
Age at death
Wang J et al. J Mol Genet Metab. 2018;124(2):124-130.
Dominguez-Gonzalez C et al. Orphanet J Rare Dis. 2019;14(1):100.
48
Differential Diagnosis of TK2d

 Mitochondrial disorders including other

forms of MDS (mtDNA depletion syndrome),
reversible infantile respiratory chain
deficiency, CPEO
 Spinal muscular atrophy
 Acid maltase deficiency (Pompe disease)
 Congenital myopathies
 Muscular dystrophy

49
Clinical Clues to the Diagnosis of TK2d

 Typically normal at birth and in neonatal

period
 Subacute progressive weakness in proximal
muscles with early respiratory muscle
involvement
 Heart is typically spared (although sinus
tachycardia is common)
 Seizures and cognitive impairment are
occasionally present in early onset patients
50
Laboratory Clues to the Diagnosis of TK2d

 Elevated creatine kinase (CK) and aldolase

 Elevated resting venous lactate
 Elevated transaminases with normal
gamma-glutamyl transferase (GGT)

51
Diagnostic Testing for TK2d

 Genetic testing of blood, saliva, or buccal

swab for TK2 pathogenic variants
 If known variants are identified, muscle
biopsy is not required
 If TK2 variants of uncertain significance are
identified, then muscle biopsy can be useful
to confirm the diagnosis

52
How to Read a Genetic Test Report

53
Current Symptomatic Treatment
for TK2d
 Pulmonary care for restrictive lung disease with
non-invasive or invasive mechanical ventilation
and cough-assist
 Gastroenterology support includes
management of dysphagia
 Neurological treatment of seizures
 Neuromuscular physical and occupational
therapy
 Nutritional support

54
Q:
Audience Questions and Answers

55
Thank You

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