MitochondrialDz x.pdf

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The Physician's Guide to Laboratory Test Selection and Interpreta

ARUP LABORATORIES | 500 Chipeta Way | Salt Lake City, Utah 84108-1221 | (800) 522-2787 | www.arupconsult.com | www.aruplab.com 20062012 ARUP Laboratories. All Rights Reserved. Mitochondrial Diseases - p. 1 of

Mitochondrial DiseasesDiagnosis

Indications for Testing

Children with multiple complex neurologic symptoms or a single neurological symptom with other system

involvement Children presenting with lactic acidosis

Individuals with clinical symptoms characteristic of a specific mitochondrial disorder

Individuals with any progressive multisystem disorder of unknown etiology

Asymptomatic, at-risk family members

Family history assess inheritance pattern to help direct molecular testing

Laboratory Testing

Metabolic evaluation generally precedes molecular genetic testing unless a specific disorder is suspected

Serum

Chemistry panel

Liver function studies

Pyruvate concentration/lactate

Ammonia

Creatinine kinase (MM) rarely elevated

Plasma acylcarnitine

Ketone

Fasting glucose

Amino acids

Coenzyme Q deficient isolated myopathy, cerebellar ataxia, encephalomyopathy, Leigh

syndrome

Urine

Urinalysis

Organic acids

Amino acids

Cerebrospinal fluid

Routine studies

Lactate acid/pyruvate concentration

Amino acids

Molecular genetic testing

Molecular testing for mtDNA mutations may require testing be performed on DNA extracted from

skeletal muscle; nuclear gene mutations and some mtDNA mutations can be detected in DNA from

peripheral blood

Mitochondrial genome mutation scanning/sequencing Mitochondrial genome duplication/deletion testing

DNA testing for nuclear genes associated with mitochondrial disorders

Targeted testing for a family-specific mutation in at-risk or symptomatic family members

For classic syndrome presentation, genetic testing may be initial testing of choice

Imaging Studies

CT often normal

May demonstrate punctate calcifications

May see edema or atrophy (cerebral or cerebellar)


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ARUP LABORATORIES | 500 Chipeta Way | Salt Lake City, Utah 84108-1221 | (800) 522-2787 | www.arupconsult.com | www.aruplab.com

20062012 ARUP Laboratories. All Rights Reserved. Mitochondrial Diseases - p. 2 of

MRI

T2 signal that resembles stroke-like lesions

Abnormal myelination

Other Testing

Biochemistry Analysis of electron transport chain activity

ATP synthesis measures in fibroblasts

Coenzyme Q

Biochemical results may suggest genetic testing

Complex I deficiency analysis of mitochondrial DNA and nuclear encoded genes

Complex II deficiency analysis ofSDHA, SDHB, CDHC, SDHD

Complex III deficiency analysis ofMTCYB, 10 nuclear structural genes, BCS1L

Complex IV deficiency analysis of mitochondrial DNA cytochrome coxidase assembly factors

(SURF1, SCO1, SCO2, COX10, COX15)

Multiple complex deficiencies analysis of mitochondrial DNA and nuclear DNA mitochondrial

maintenance and translation genes Coenzyme Q deficiency analysis ofCABC1, COQ2, COQ9, PDSS1, PDSS2, ETFDH, APTX

Muscle biopsy

Light microscopy histochemistry

Detection of ragged red fibers (most common in mitochondrial mutations) by Gomori trichrome

stains

Subsarcolemmal accumulation of mitochondria on muscle pathology

Cytochrome coxidase-deficient fibers

Electron microscopy

Increase in mitochondrial number or size, increased lipid and glycogen droplets, increased

mitochondrial matrix

Can also perform liver, cardiac, or skin biopsy Neurophysiologic studies

Electroencephalography for individuals with suspected encephalopathy or seizures

Electromyography/nerve conduction velocity for individuals with limb weakness, sensory issues, or

areflexia

Electrocardiography/echocardiography

Evaluate cardiomyopathy or atrioventricular conduction defects

Auditory/ophthalmologic examinations to confirm defects

Differential Diagnosis

Neurological

Children/infants Metabolic diseases

Hypothyroidism

Muscular dystrophy

Developmental delay

Lysosomal storage diseases

Adults

Wilson disease

Multiple sclerosis
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Coenzyme Q disease

Dementia

Migraine disorder

Parkinson disease

Sarcoidosis

Vasculidities

Connective tissue diseases

Infectious fungal, viral

Chronic demyelinating disease

Paraneoplastic syndrome

Stroke

Seizure disorder

Endocrinological

Diabetes mellitus

Thyroid disease (hypo/hyper)

Autoimmune adrenal disease

Hepatic disease

Reye syndrome

Wilson disease

Acute hepatitis B orC

Myopathy

Dermatomyositis

Chronic demyelinating inflammatory polyneuropathy

Paraneoplastic syndrome

Guillain-Barr syndrome

Lactic acidosis

Sepsis

Polymyositis

Inborn errors of metabolism

Clinical BackgroundMitochondrial diseases are a group of disorders originating from mutations in nuclear DNA or mitochondrial

DNA (mtDNA) and resulting in a wide spectrum of pathological conditions, often with significant neurologic

and myelopathic symptoms. Many commonly seen conditions can be classified as discrete clinical

syndromes; however, the presentation and severity of the conditions may vary, creating challenges in

diagnosis and treatment.

Epidemiology

Prevalence approximately 1/8,500

Age all ages

Sex M:F, equal

Inheritance

Mitochondrial disorders may be caused by mutations in nuclear DNA or mtDNA

Nuclear gene defects may be inherited in an autosomal recessive or autosomal dominant manner

mtDNA defects are maternally transmitted

mtDNA deletions generally occur de novo

mtDNA point mutations and duplications are maternally inherited
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Affected individuals with mtDNA mutations often have a mixture of mutated and normal mtDNA within

each cell (heteroplasmy)

Disease severity and the age of onset are affected by the amount of heteroplasmy and the number

and type of cells containing the mtDNA mutation

Females with heteroplasmy but no clinical symptoms may have affected offspring

Poor genotype/phenotype correlation exists; the same mutation may cause different clinical syndromes

Pathophysiology

Mitochondria are ubiquitous, complex, intracellular organelles containing non-nuclear DNA

Each cell may contain hundreds to thousands of copies of mtDNA

Mitochondria are essential in many cell processes, including the generation of adenosine triphosphate

during oxidative metabolism

Mutations in the mitochondrial genome or in nuclear DNA involved in the respiratory chain principally

affect tissues that are heavily dependent on oxidative metabolism (eg, central nervous system,

cardiovascular, musculoskeletal)

Clinical Presentation

Many mitochondrial diseases can be classified as a discrete clinical syndrome based on characteristic

clinical features; however, clinical overlap occurs

Some mitochondrial disorders only affect a single organ, such as in Leber hereditary optic neuropathy

(LHON) and nonsyndromic sensorineural deafness

Mitochondrial disorders may present at any age

Presentation of nuclear DNA mutations typically occurs in childhood; mtDNA abnormalities are more

likely to present in late childhood or adulthood

Clinical presentation is highly variable

Features of mitochondrial DNA-associated diseases

Features of Mitochondrial DNA-Associated Diseases

Children Cardiac biventricular hypertrophic cardiomyopathy, rhythm abnormalities, cardiac murmur, sudden death

Dermatological erythema, lipomatosis, reticular pigmentation, hypertrichosis, vitiligo, alopecia

Endocrine diabetes mellitus, adrenal failure, growth failure, hypothyroidism, hypogonadism,

hypoparathyroidism

Gastrointestinal vomiting, failure to thrive, dysphagia, GI motility problems, vomiting, pseudoobstruction

Hematological anemia, pancytopenia

Hepatic hepatic failure (very sensitive to valproate)

Musculoskeletal weakness, myopathy

Neurological myopathy (proximal > distal, upper extremities > lower), developmental delay, ataxia,

spasticity, dystonia, hypotonia, bulbar signs, chorea, seizures, myoclonus, stroke

Ophthalmological optic atrophy, retinitis pigmentosa, ptosis, diplopia, cataract

Otological sensorineural deafness Renal renal tubular defects (proximal defect renal tubular acidosis most common), nephrotic syndrome,

tubulointerstitial nephritis

Respiratory central hypoventilation, apnea

Adults

Cardiac heart failure, conduction block, cardiomyopathy, sudden death

Endocrine diabetes, thyroid disease, parathyroid disease

Gastrointestinal constipation, irritable bowel syndrome, dysphagia, anorexia, abdominal pain, diarrhea

Musculoskeletal rhabdomyolysis, muscle weakness, exercise intolerance
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Neurological migraine, stroke, seizures, dementia, myopathy, peripheral neuropathy, ataxia, speech

disturbances, bulbar signs, myoclonus, tremor

Ophthalmological optic atrophy, cataracts, progressive external ophthalmoplegia, ptosis, pigmentary

retinopathy, vision loss, diplopia

Otological sensorineural deafness

Reproductive pregnancy loss in mid to late gestation, hypogonadism Respiratory respiratory failure, nocturnal hypoventilation, recurrent aspiration, pneumonia

Examples of inherited mitochondrial disorders caused by nuclear DNA mutations

Autosomal recessive external ophthalmoplegia

Hypertrophic cardiomyopathy

Myoneurogastrointestinal encephalomyopathy

Leigh syndrome

Mitochondrial depletion syndrome

Dominant optic atrophy

Examples of inherited disorders caused by mtDNA mutations

Mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) Myoclonic epilepsy associated with ragged red fibers (MERRF)

Neuropathy, ataxia, retinitis pigmentosa/maternally inherited Leigh syndrome

Leber hereditary optic neuropathy (LHON)

Chronic progressive external ophthalmoplegia

Maternally inherited diabetes and deafness

Non-syndromic maternally inherited deafness

Examples of typically sporadic disorders caused by mtDNA deletions (can be maternally transmitted)

Kearns-Sayre syndrome (KSS)

Pearson syndrome

Presence of substantial intellectual disability or significant dysmorphic features should steer testing

toward other disorders

Lab TestsIndications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations. For test-specific information, refer to the

test number in the ARUP Laboratory Test Directory on the ARUP Web site at www.aruplab.com.

Test Name and Number Recommended Use Limitations Follow Up

Mitochondrial Disorders

Panel (mtDNA and

108 Nuclear Genes)

Sequencing and

Deletion/Duplication2006054

Method:

Massive Parallel

Sequencing

Diagnose mitochondrial disorders

caused by mutations within the

mitochondrial genome and nuclear

genes

Diagnosis of

mitochondrial disorders

may be tissue specific

Nuclear DNAmutations and large

deletions/duplications

within the mitochondrial

genome will not be

detected

Heteroplasmy levels

of


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Mitochondrial Disorders

(mtDNA) Sequencing

2006065

Method:

Massive Parallel

Sequencing

Diagnose mtDNA disorders

caused by mutations within the

mitochondrial genome

Large

deletions/duplications

within the mitochondrial

genome and nuclear

genes will not be

detected

Heteroplasmy levels

of


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Carnitine Panel

0081110

Method:

Tandem Mass

Spectrometry

Rule out other metabolic disorders

Organic Acids, Urine0098389

Method:

Gas

Chromatography/Mass

Spectrometry


Amino Acids Quantitative,

Plasma

0080710

Method:

Ion Exchange

Chromatography


Amino Acids Quantitative,

Urine

0080044

Method:

Ion Exchange

Chromatography


Acylcarnitine Quantitative

Profile, Plasma

0040033

Method:

Tandem Mass

Spectrometry


Glucose, Plasma or Serum

0020024

Method:

Quantitative Enzymatic


Additional Tests Available

Test Name and Number Comments

Urinalysis, Complete

0020350

Method:Reflectance Spectrophotometry/Microscopy

Mitochondrial Disorders (108 Nuclear Genes) Sequencing and

Deletion/Duplication

2006878

Method:

Massive Parallel Sequencing/Exonic Oligonucleotide-based

CGH Microarray
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Mitochondrial Disorders (mtDNA) Sequencing and

Deletion/Duplication

2006872

Method:

Massive Parallel Sequencing/Exonic Oligonucleotide-based

CGH Microarray

Guidelines

Finsterer J, Harbo HF, Baets J, Van Broeckhoven C, Di Donato S, Fontaine B, De Jonghe P, Lossos A, Lynch T,

Mariotti C, Schols L, Spinazzola A, Szolnoki Z, Tabrizi SJ, Tallaksen CM, Zeviani M, Burgunder JM, Gasser T. EFNS

guidelines on the molecular diagnosis of mitochondrial disorders.Eur J Neurol. 2009; 16 (12) :1255-1264.

General References

Craigen WJ. Mitochondrial DNA mutations: an overview of clinical and molecular aspects.Methods Mol Biol. 2012; 837

:3-15.

Haas RH, Parikh S, Falk MJ, Saneto RP, Wolf NI, Darin N, Cohen BH. Mitochondrial disease: a practical approach for

primary care physicians.Pediatrics. 2007; 120 (6) :1326-1333.

Kisler JE, Whittaker RG, McFarland R. Mitochondrial diseases in childhood: a clinical approach to investigation and

management.Dev Med Child Neurol. 2010; 52 (5) :422-433.

Koenig MK. Presentation and diagnosis of mitochondrial disorders in children.Pediatr Neurol. 2008; 38 (5) :305-313.

Mancuso M, Orsucci D, Coppede F, Nesti C, Choub A, Siciliano G. Diagnostic approach to mitochondrial disorders:

the need for a reliable biomarker.Curr Mol Med. 2009; 9 (9) :1095-1107.

McFarland R, Taylor RW, Turnbull DM. A neurological perspective on mitochondrial disease.Lancet Neurol. 2010; 9 (8)

:829-840.

Rahman S, Hanna MG. Diagnosis and therapy in neuromuscular disorders: diagnosis and new treatments in

mitochondrial diseases.J Neurol Neurosurg Psychiatry. 2009; 80 (9) :943-953.

Scaglia F. Nuclear gene defects in mitochondrial disorders.Methods Mol Biol. 2012; 837 :17-34.

Siciliano G, Pasquali L, Mancuso M, Murri L. Molecular diagnostics and mitochondrial dysfunction: a future

perspective.Expert Rev Mol Diagn. 2008; 8 (4) :531-549.

Tuppen HA, Blakely EL, Turnbull DM, Taylor RW. Mitochondrial DNA mutations and human disease.Biochim Biophys

Acta. 2010; 1797 (2) :113-128.

References from the ARUP Institute for Clinical and Experimental Pathology

Dimmock DP, Zhang Q, onisi-Vici C, Carrozzo R, Shieh J, Tang LY, Truong C, Schmitt E, Sifry-Platt M, Lucioli

S, Santorelli FM, Ficicioglu CH, Rodriguez M, Wierenga K, Enns GM, Longo N, Lipson MH, Vallance H, CraigenWJ, Scaglia F, Wong LJ. Clinical and molecular features of mitochondrial DNA depletion due to mutations in

deoxyguanosine kinase.Hum Mutat. 2008; 29 (2) :330-331.

Dobrowolski SF, Hendrickx AT, van den Bosch BJ, Smeets HJ, Gray J, Miller T, Sears M. Identifying sequence variants

in the human mitochondrial genome using high-resolution melt (HRM) profiling.Hum Mutat. 2009; 30 (6) :891-898.

Longo N, Schrijver I, Vogel H, Pique LM, Cowan TM, Pasquali M, Steinberg GK, Hedlund GL, Ernst SL, Gallagher RC,

Enns GM. Progressive cerebral vascular degeneration with mitochondrial encephalopathy.Am J Med Genet A. 2008;

146 (3) :361-367.
http://www.aruplab.com/guides/ug/tests/2006872.jsp


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Reviewed by

Krautscheid, Patti, MS, LCGC. Genetic Counselor, Molecular Genetics and Special Genetics Laboratories at ARUP

Laboratories

Longo, Nicola, MD, PhD. Medical Co-Director, Biochemical Genetics at ARUP Laboratories; Professor, Pediatrics and

Pathology (Adjunct), University of Utah

Mao, Rong, MD. Medical Director, Molecular Genetics, Fragment Analysis and Sequencing at ARUP Laboratories;

Assistant Professor of Pathology (Clinical), University of Utah

Miller, Christine E., MS, LCGC. Genetic Counselor, Molecular Genetics Laboratory at ARUP Laboratories; Faculty,

Graduate Program in Genetic Counseling, University of Utah

Pasquali, Marzia, PhD. Medical Director, Newborn Screening Laboratory and Biochemical Genetics Laboratory at

ARUP Laboratories; Professor of Pathology (Clinical), University of Utah

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Last Update: August 2012

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