Metabolic Dysfunction in Adult DiseasesIncluding Depression

Julian L. Ambrus Jr., MD

Professor of Medicine

Division of Allergy, Immunology and Rheumatology

SUNY at Buffalo School of Medicine

Disclosures

• Research in Sjogren’s Syndrome funded by Amgen

• Research in Sjogren’s Syndrome funded by Genentech

• Royalties received from Immco / Trinity for novel autoantibodies in Sjogren’s Syndrome

• Basic research funded by the National Institutes of Health

• Founding member Metabolic Disease Center of Western New York

Goals

• Review basic aspects of metabolism

• Review diagnosis of metabolic disorders in adults

• Review clinical manifestations of primary and secondary metabolic disorders in adults, including depression

• Review treatment of metabolic disorders in adults

Why Do We Care About Metabolism?

• Metabolism is defined as “all chemical reactions involved in maintaining the living state of the cells and the organism”

• No cell does anything without metabolism and all pathological states involve disruptions in metabolism

• Metabolism is critical to generate:– ATP that is used as the energy chip for many chemical reactions

• 95% comes from the mitochondria (aerobic metabolism) and 5% from anaerobic metabolism

– Building blocks that are critical for the synthesis of DNA, RNA, proteins, lipids

– Chemical messengers that are utilized for intracellular and intercellular communication

– Structural changes that are necessary for movement of molecules within cells and between cells as well as movement of cells themselves

– Generation of vesicles that are utilized in phagocytosis, degradation of abnormal particles, autophagy and mitophagy

– Differentiation of cells to perform particular functions

Interconnection of Metabolic Pathways

Common Presentations of Adult Onset Metabolic Dysfunction

• Fatigue and exercise intolerance– May be labeled as “chronic fatigue syndrome” or “fibromyalgia”

• Muscle cramping and pain, usually with disorders of anaerobic metabolism• Rhabdomyolysis – usually in the presence of some stressor• Recurrent infections• Accelerated osteoarthritis• Dyspnea• Bowel dysmotility – constipation, diarrhea, gastroparesis, nausea and

vomiting• Increased sensitivity to particular anesthetic agents• Statin reactions• Neurodegenerative diseases• Diabetes and reactions to Metformin• Migraine headaches and strokes• Depression and other neuro-cognitive problems

Aerobic Metabolism Occurs in the Mitochondria

• Mitochondrial are ancient bacterial symbionts that entered eukaryotic cells 2-3 billion years ago

– Each cell has hundreds of mitochondria and each mitochondrion has multiple copies of mitochondrial DNA

– Mitochondria are generally inherited from the mother, although one case has been described with paternal inheritance (New Eng.. Med. 347:576 -580,2002)

• Mitochondria are the primary source for ATP generation

– Oxidize hydrogen obtained from carbohydrates (tricarboxcylic acid cycle) and fats (-oxidation) use oxygen to generate heat and ATP

– They are responsible for generating the majority of reactive oxidative species (ROS) - heavy metals in various mitochondrial enzymes can be inactivated by ROS

• Mitochondrial play central roles in several other cellular functions including apoptosis, intracellular signaling and regulation of the cellular concentrations of several molecules including calcium

Mitochondria - 2

• Mitochondria contain their own DNA, RNA and protein synthesis system

– mtDNA lacks untranslated regions, introns and spacers

– mtDNA is symmetrically transcribed from 2 promoters - one on the H strand and one on the L strand

– mtDNA includes 37 genes that encode 13 proteins for oxidative phosphorylation, 22 tRNA and 12S and 16S rRNA

– mtDNA has a high mutation rate because of lack of histones, less developed DNA repair system and close proximity to ROS generation

• Nuclear DNA encodes over 1600 genes that are needed for mitochondrial function including all the respiratory chain complex II proteins, the mitochondrial DNA polymerase (POLG), the mitochondrial transcription factor (mtTFA), ribosomal proteins, mitochondrial elongation factor and all mitochondrial metabolic enzymes

– Imported via complex import systems that recognize specific targeting peptides

• There are direct connections between the mitochondria and endoplasmic reticulum for exchange of proteins

Mitochondria - 3

• The electron transport chain (ETC) of the mitochondria uses the energy released by the flow of electrons to pump protons out of the mitochondrial inner membrane through complexes I, III and IV

• Complex V utilizes the electrochemical gradient to convert ADP to ATP

• The adenine nucleotide translocator (ANT) exchanges matrix ATP for cytosolic ADP

• When the ETC is efficient and complex V is efficient, the majority of calories are utilized to generate ATP

– If the coupling between the ETC and complex V is inefficient, more heat is generated and less ATP for the same number of calories

– When the ETC is inefficient and harbors more electrons, excess electrons are donated to oxygen generating superoxide which is converted to hydrogen peroxide by superoxide dismutase

• Hydrogen peroxide is converted to water by catalase or glutathione peroxidase

Structure / Function of Mitochondria

From: RAJ Smith et. Al. Trends in Pharm. Sci. 33: 341 – 352, 2012

Mitochondria - 4

• Apoptosis occurs when the mitochondrial permeability transition pore (mtPTP) opens because of increased calcium, oxidative stress or decrease in ADP or ATP

– Ions equilibrate leading to mitochondrial swelling and release of contents from the inter-membranous space into the cytosol

• Cytochrome C, pro-caspases 2,3,9, SMAD, endonuclease G and outer mitochondrial membrane serine protease 24

• Cytochrome C activates Apaf-1 (apoptosis protease activating factor - 1) which activates pro-caspase 9

• To compensate for low ATP, mitochondria replicate and there is increased synthesis of mitochondrial proteins by nuclear genes

• Defective mitochondria replicate more than normal mitochondria

– Chronic increased physical activity induces increased numbers of mitochondria

– Tissues with high energy requirements have increased mitochondria: brain, heart muscle, type I skeletal muscle fibers

Mitochondrial Mutations

in Normal Human Physiology

• The accumulation of mitochondrial mutations is part of the normal aging clock (DW Wallace Ann. Rev. Gen. 39: 359 - 407, 2005)

– D257A mutation in mtDNA polymerase , which reduces its proof reading ability, causes cardiomyopathy, weight loss and premature aging / decreased lifespan when knocked into mice (Trifunovic et. Al. Nature 429: 417-23, 2004)

• The adaption to cold resulted in the accumulation of mutations in various mitochondrial genes causing increased “uncoupling” and hence more heat generated per calories ingested

– Haplogroup C has conserved mutations in cytochrome b (IL53T) and ND4 (A404T) (DW Wallace Science 256: 628 -632, 1999)

Mitochondrial Haplogroups

From: DC Wallace Annual Rev. Genetics 39: 359 - 407, 2005

Carnitine

• Carnitine is involved with bringing fatty acids into the mitochondria for – oxidation to generate NADH that is utilized by the mitochondrial respiratory chain to generate ATP

• Carnitine is obtained from dietary sources (red meat, dairy and fruits), so deficiencies in carnitine may result from diet or from malabsorption (i.e. celiac sprue, inflammatory bowel diseases, etc.)

• Pediatric onset carnitine deficiency can result for a mutation in the carnitine transporter OCTN2

• Adult onset carnitine palmitoyl transferase deficiency results in the inability of long chain fatty acids to be transported into the mitochondria with carnitine– Pathological mutations may be in up to 5% of the population

– Patients will have fatigue, exercise intolerance, rhabdomyolysis with lipid loading, infections or statins; severe patients can have cardiomyopathy and neurological sequelae

Myoadenylate Deaminase Deficiency

• Defect in anaerobic metabolism that occurs in 1-2% of the population

• MAD converts adenosine monophosphate (AMP) into inosine monophosphate; failing to do this results in:– Loss of AMP causing secondary loss of ribose – muscle lose the ability to normally

repair themselves with exercise and patients experience muscle pain and cramps

– Loss of ammonia and secondary depletion fumarate (needed in citric acid cycle – there is a disconnect between the demands for energy and the ability of the mitochondria to generate ATP – patients experience muscle weakness and fatigue

– Loss of ammonia results in reduced production of nitric oxide – because nitric oxide is an important vasodilator patients may experience vasoconstriction ; nitric oxide also plays roles in various intracellular signaling pathways

– Loss of inosine monophosphate – the clinical significance of this is unknown

• Patients may present with fatigue, exercise intolerance, muscle pain, muscle weakness, Rhabdomyolysis and/or neuropathy

• Patients will often get muscle pain and fatigue when given statins

Late Onset Glycogen Storage Diseases

• Group of disorders in which enzyme deficiencies prevent the normal synthesis or breakdown of glycogen

• Adult onset forms are most commonly:– Pompe’s Disease (GSD Type II) = isomaltase deficiency – presents are respiratory

failure after infections and/or carbohydrate loading, dyspnea on exertion, limb girdle weakness

– McArdle’s Disease (GSD Type V) = myophosphorylase deficiency – presents with fatigue, exercise intolerance, muscle cramps, Rhabdomyolysis, statin reactions

– Tarui’s Disease (GSD Type VII) = muscle phosphofructokinase deficiency – presents fatigue, exercise induced muscle cramps and weakness, hemolytic anemia

– Lactate dehydrogenase deficiency (GSD Type IX) - presents as fatigue, exercise induced muscle weakness and cramps, rhabdomyolysis

• Other glycogen storage diseases (von Gierke’s disease, Forbes disease, Andersen Disease, Hers’ disease, Fanconi-Bickel syndrome) more likely to onset in young children

Diagnostic Evaluation – 1Laboratory Studies

• Start with a consistent history, with or without a consistent family history

• Laboratory Studies– Carnitine

– TSH and Free T4 – thyroid hormone regulates the synthesis of the complex II proteins of the mitochondrial respiratory chain

– Aldolase, LDH

– 6 minute walk study : cpk, lactic acid and ammonia pre – and post – 6 minute walk –this is a period of time in which one should stay in aerobic metabolism

– Ischemic forearm test – resting lactic acid and ammonia then a tourniquet is placed and the arm is pumped for 1-2 minutes; then lactic acid and ammonia are checked every 5 minutes – this is a test for anaerobic metabolism

– Plasma amino acids

– Urinary Orotic acid

– Other studies may be used to evaluate other disorders that may involve chronic inflammation or malabsorption such as celiac sprue, inflammatory bowel disease, etc.

Diagnostic Evaluation – 2Muscle Biopsy

• The purpose of the muscle biopsy is to look at the histology of the muscle as well as to do biochemical studies on the muscle tissue– Muscle has high energy demands so abnormal mitochondrial are more likely to be found in

muscle than in tissues requiring less energy, such as skin and blood

– Inflammatory muscle disease often occurs together with metabolic muscle disease and can only be evaluated with a muscle biopsy

– Muscle biopsy can suggest other forms of muscle disease such as muscular dystrophies, myofibrillar myopathies, toxic myopathies, neurological problems, etc.

• Most commonly the initial histological studies in patients with metabolic muscle disease will show only fiber atrophy, without any pathognomotic features

• With mitochondrial diseases one may see– Ragged red fibers – due to increased numbers of mitochondria

– Decreased activity of particular mitochondrial respiratory chain enzymes, such as cytochrome C oxidase (COX)

– Electron micrographs demonstrate increased numbers of mitochondria and may demonstrate para crystalline inclusions within mitochondria

Findings on Muscle Biopsy

in Mitochondrial Myopathies

Ragged Red Fibers Decreased COX Activity:

Blue Fibers COX Deficient

Findings on Muscle Biopsy

in Mitochondrial Myopathies - 2

Increased Numbers Mitochondria Para crystalline Inclusions

Diagnostic Evaluation – 3Muscle Biopsy

• Glycogen storage diseases may see:

– Fiber atrophy

– Subsarcolemmal vacuoles

– Necrosis and regeneration

– Increase in muscle glycogen

– Rimmed vacuoles

• Myoadenylate Deaminase deficiency– Generally see only fiber atrophy unless special staining is done for

myoadenylate deaminase

– May see fiber necrosis and regeneration

– May see features of secondary mitochondrial dysfunction

Glycogen Storage DiseaseMuscle biopsy

Vacuoles Glycogen Deposition

Muscle BiopsyMyoadenylate Deaminase Deficiency

Muscle BiopsyBiochemical Studies

• Biochemical studies are done to evaluate the activity of particular enzymes in the muscle:

– Mitochondrial respiratory chain – NADH dehydrogenase, NADH cytochrome C reductase, succinate dehydrogenase, succinate cytochrome C reductase, cytochrome C oxidase; citrate synthase, a citric acid cycle enzyme is used as a control

– Carnitine palmitoyl transferase

– CoQ10

– Myoadenylate deaminase

– Glycogen storage enzymes – phosphorylase, phosphorylase b kinase, phosphofructokinase, phosphoglycerate mutase, acid and neutral maltase, lactate dehydrogenase

Mitochondrial Respiratory Chain Evaluation

Genetic Studies for Metabolic Work Up

• Genetic studies are done under particular circumstances:– Laboratory and biochemical studies are equivocal

– Presence of a familial problem is being evaluated

– Specific treatment is envisioned that requires precise definition of gene mutations

– Confirmation of disease is required for Insurance purposes

• Genetic studies currently available:– Sequencing the mitochondrial DNA

– Evaluation of chromosomal genes known to affect mitochondrial function

– Whole exome sequencing

• Genetic Studies not yet available:– Analysis of small and regulatory RNA

• Interpretation of genetic studies is often difficult– Phenotype may require polymorphisms in multiple genes

– Some genes have common polymorphisms that may or may not be pathological in different settings

– Understanding of the systems biology is very primitive

Common Clinical Situations in which Secondary Metabolic Dysfunction Occurs

• Sepsis (Journal of Infectious Diseases 2012;205(3):392-400; Immunity 2014;40(4):464-76)– Various organisms produce toxins that damage the mitochondrial leading to:

• Increased production of free oxygen radicals and NO

• Increased activity of uncoupling protein

• Inappropriate opening of the permeability transition pore

• Increased autophagy and mitophagy

• Decreased production of mitochondria

– Hypoxemia causes further damage to the mitochondria

– Clinically this results in:• Cardiomyopathy (Heart 2014;100(8):611-8.; International Journal of Molecular

Sciences 2015;16(8):17763-78)

• Respiratory muscle dysfunction (Journal of Clinical Investigation 2016;126(3):809-20; Journal of Innate Immunity 2016;8(2):121-8.)

• Dysfunction of the Immune System (Journal of Immunology Research 2014; Nature Reviews Molecular Cell Biology 2015;15(1):18-29.).

Common Clinical Situations in which Secondary Metabolic Dysfunction Occurs - 2

• Hypoxemia:

– May occur as a result of asthma, COPD, sleep apnea,, pulmonary hypertension, atherosclerotic vascular disease, thrombotic diseases, etc.

– Since the mitochondria are the only organelle that utilize oxygen, low level of oxygen cause damage to the mitochondria• Increased production of free oxygen radicals that damage mitochondrial DNA and

oxidize heavy metals which are essential components of various enzymes

• Decreased production of ATP

– Secondarily this leads to:• Induction of HIF (hypoxia inducible factors) that cause smooth muscle proliferation and

vascular and bronchial remodeling

• Reduced respiratory muscle function

• Reduced cardiac function

– Journal of Biological Chemistry 2008;283(16):10892-903.Annu. Rev. Physiol. 75: 95-126, 2013; Nutr Metab Cardiovasc Dis 2015;25(2):131-9.

Common Clinical Situations in which Secondary Metabolic Dysfunction Occurs - 3

• Chronic Inflammation can damage the mitochondria because of production of local toxins, as well as local hypoxemia– Damaged mitochondria occur only locally, i.e. in the gastrointestinal tract, lung,

etc. where the inflammation is present

– Mitochondria in other tissues may be completely normal

• At the same time, metabolic dysfunction of any kind leads to subtle immunodeficiency that leads to difficulty handling infections – this predisposes to chronic inflammation and autoimmune disease:– Inflammatory Bowel Disease - Molecular and Cellular Biochemistry 2010;342(1-

2):111-5.

– Celiac sprue and food hypersensitivities - Mitochondrion 4: 601 - 607, 2004

– Sjogren’s syndrome - Pathobiology 2006;73(5):252-60; Arthritis & Rheumatology 2014;66:S1113-S.

– Systemic Lupus Erythematosus - Autoimmunity 2014;47(4):256-64.

– Inflammatory muscle diseases - Neurology 2006;66:S49-S55.; Current Opinion in Rheumatology 2010;22(6):651-7.

Common Adult Diseases that Involve Metabolic Dysfunction

Diabetes

• Mitochondrial dysfunction has been implicated in both Type 1 and Type 2 Diabetes– Mitochondrial generated ATP is necessary for the synthesis and

release of insulin (Cell Calcium 2008;44(1):64-76.)– Various other intermediate products of the TCA cycle may contribute

to the second phase of insulin secretion (MJ MacDonald et. Al. Am.J.Physiol.Endocrinol.Metab. 288:E1-15, 2005)

– Mitochondria are necessary for the normal functioning of the insulin receptor –defects cause insulin resistance (Nature Reviews Endocrinology 2012;8(2):92-103.)

• Various complications of diabetes involve primary or secondary mitochondrial dysfunction– Cardiomyopathy (Journal of Biological Chemistry 2012;287(26):22174-82.)

– Neuropathy (Cell Calcium 2008;44(1):112-22.)

– Nephropathy (Diabetes 2015;64(3):663-72.)

– Deafness (Diabetes & Metabolism 2008;34(6):620-6.)

Common Adult Diseases Involving Metabolic Dysfunction

Neurodegenerative Diseases

• Parkinson’s Disease– The known genetic causes of Parkinson’s disease are all related to defects in

mitophagy (Movement Disorders 2011;26(5):784-91.; Embo Journal 2014;33(4):282-95.;Trends in Biochemical Sciences 2015;40(4):200-10.)

• Amyotrophic Lateral Sclerosis (ALS)– Certain forms os ALS involve defects in the mitochondrial superoxide dismutase (Proc

Nat Acad Sci Usa 2006;103(37):13860-5.; Journal of Bioenergetics and Biomembranes 2011;43(6):587-92.)

• Multiple Sclerosis– Mitochondrial dysfunction is described in various forms of MS, but it is unclear

whether this is a primary or secondary phenomenon (Neurology 2013;20(3):194-201.; Trends in Molecular Medicine 2014;20(3):179-87.)

• Peripheral Neuropathies– There may be mulifactorial reasons for the development of peripheral neuropathy, but

in some cases mitochondrial dysfunction is a prominent component (Antioxidants & Redox Signaling 2014;21(4):601-20.; Mitochondrion 2016;27:1-5.)

Psychiatric Disorders Reviewed in Allen et. Al. Frontiers Neuroscience 12: 386, 2018

• The brain utilizes more ATP (by 20X) than any other organ (Kety Trans. Stud. Coll Physicians 18: 103-8, 1950 ; Zhu et. Al Neuroimage 60: 2107-2117, 2012)

• ATP is needed for both neurotransmitter release and downstream signaling from receptors binding neurotransmitters (Devine and Kittler Nat. Rev. Neuroscience 19: 63-80, 2018; Moretti et. Al. Mol. Psychiatry 8: 773-785, 2003

• Depression Occurs in 54% of patients with mitochondrial disorders (Fattal et. Al. Psychosomatics 47: 1-7, 2006 )

• Mitochondrial mutations are common in patients diagnosed with depression (Munakata et. Al Biol. Psychiatry 57: 525-32, 2004; Ben-Schachar and Karry Plos One 3:e3676, 2008 Petschner et. Al. Neuroscience 370: 207-217, 2018

Psychiatric Disorders - 2

• Decreased activity of the ETC is seen in the muscle of patients with depression (Karabatsiakis et. Al. TranslPsychiatry 4:e397, 2014)

• Fluoxetine can increase ETC activity (Adzic et. Al Drug Dev Res 77: 400-406, 2013)

• The brains of depressed patients have less ATP (Souza et. Al

Biochem. Pharmacol. 48: 535-541, 2012 ) and reduced glucose metabolism (Baxter et. Al. Arch Gen Psychiatry 46: 243 – 250, 1989 ) that reverses with fluoxetine (Kennedy et. Al. Am. J. Psychiatry 158: 899-905,

2001) • Mitochondrial disorders have also been associated with both

bipolar disorders and schizophrenia (Cataldo et. Al. Am J Pathol177: 577-585, 2010 )

Common Adult Diseases Involving Metabolic Dysfunction

Osteoarthritis

• The underlying mechanism causing osteoarthritis in all cases is the fragmentation of cartilage that occurs because:

– Weakness of the cartilage (as in collagen type II mutations)

– Weakness of the ligaments supporting the joints ( as in Ehlers-Danlos syndrome)

– Weakness of the muscles supporting the joints (as in all metabolic diseases)

• Accelerated osteoarthritis is described in mitochondrial diseases (Nature Reviews Rheumatology 2011;7(3):161-9.)– The contribution of mitochondrial dysfunction is felt to be not only

secondary to muscle weakness but also secondary to poor cartilage repair (which requires ATP)

Common Adult Diseases that Involve Metabolic Dysfunction

Cancer

• The relationship between cancers and metabolism are as diverse as cancers themselves– Alterations in oncogenic proteins, such as p53, secondary to abnormal

metabolism can predispose to cancer (Nature Cell Biology 2011;13(10):1272-U234.)

– Chronic and recurrent infection and inflammation can predispose to cancer (Cancer Epidemiol Biomarkers Prev 2006;15(11):2069-77.)

– Some cancers utilize the mitochondria and the ATP they generate for cell growth (Molecular Cell 2016;61(5):667-76.)

– Some cancers block mitochondrial function to inhibit apoptosis and to decrease the requirement for metabolism dependent upon oxygen (Molecular Cell 2016;61(5):667-76.)

– Some of the most malignant cancers rely exclusively on anaerobic metabolism (Clinical Cancer Research 2016;22(3):540-5.)

– Cancers can alter existing metabolic pathways to devise novel pathways for energy and substrate generation (Cell 2015;162(6):1229-41.)

Treatment of Mitochondrial Dysfunction

• The goals of treatment of mitochondrial diseases is to improve mitochondrial function, increase production of ATP and decrease production / damage of ROS

– Ubiquinone (coenzyme Q10) is involved with the transport of electrons between complex I and III

• Oral replacement leads to enhanced function of the respiratory chain (Chen et. AL. Eur. Neurol. 37: 212 - 218, 1997, Bresolin et. AL. J. Neurol. Sci. 100: 70 - 78, 1990 and Glover et. Al. Muscle & Nerve 42: 739-748, 2010)

• Oral replacement leads to increased secretion of insulin in patients with mitochondrial diabetes (Liou et. AL. Eur. Neurol. 43: 54-5, 2000)

• May have anti-oxidant properties resulting in a decrease in mitochondrial mutations over time (Migliore et. Al. Mutagenesis 19: 43 -49, 2004)

• CoQ10 is not FDA regulated so there is a great deal of variability in the purity and activity of available preparations

• Analogues of CoQ10 are available such as idebenone and the recently FDA approved EPI - 743

Treatment of Mitochondrial Dysfunction - 2

• Creatine– Creatine kinase catalyzes the transfer of the phosphoryl group from Phosphocreatine (PCr) to

ADP to generate ATP -- creatine supplementation leads to enhanced formation of PCr

• Increases ATP production (Wallimann et. Al. Biochem J 28: 21 - 40, 1992)

• Improves the function of the sarcoplasmic reticulum calcium ATPase and hence normal calcium homeostasis and improved muscle relaxation times (Steeghs et. Al. Cell 89: 93 -103, 1997)

• Stimulates mitochondrial respiration by increasing mitochondrial ADP levels in the vicinity of the adenine nucleotide translocator (Carnwath et. AL. J. Neurol. Sci. 80: 39 -54, 1987)

• Removes a stimulus for the replication of abnormal mitochondria

– Creatine supplementation in the mdx mouse (carries a point mutation in the dystrophin gene and has reduced mitochondrial respiratory chain function) results in reduced muscle necrosis and return of respiratory chain function to normal (Passaquin et. Al. Neuromusc. Disorders12: 174 - 182, 2002)

– Creatine improves muscle function in patients with mitochondrial myopathies (MA Tarnopolsky. Amino Acids 40: 1397-1407, 2011)

• Anti-oxidants to inhibit the effects of ROS

– Vitamin C, Vitamin E, a-lipoic acid

• Folic Acid or Folinic Acid

– Cofactor for various respiratory chain enzymes

Potential Future Treatments forMitochondrial Dysfunction / Disease

• Current research and clinical trials are exploring new avenues of treatment:– RTA 408 (Reata Pharmaceuticals) – an activator of Nrf2 to increase

mitochondrial biogenesis and respiratory function

– RP103 (Raptor Pharmaceuticals) – anti-oxidant that also increases production of glutathione

– Bendavia (Stealth Biotherapeutics) – a drug that stabilizes cardiolipin to enhance the efficiency of the mitochondrial respiratory chain

– Cyclosporine to treat LHON – inhibits the mitochondrial permeability transition pore

– Viral vector to treat G11778A mutation associated with LHON

– Replacement of mitochondria in defective ova

– Stem cell therapy for MINGE syndrome

Treatments for Carnitine Deficiency and Myoadenylate Deaminase Deficiency

• Carnitine deficiency and Carnitine Palmitoyl Transferase Deficiency– Replace carnitine

– Avoid long-chain fatty acids

– Treat secondary mitochondrial dysfunction

• Myoadenylate deaminase deficiency– Low protein (40 gram) diet

– Ribose 4-5 grams, 4-5 x day• Provides a simple sugar that can be easily metabolized and replaces ribose that is

not being adequately produced (Goebel HH, Bardosi A. Myoadenylate deaminase deficiency. Klin Wochenschr 1987;65(21):1023-33)

– Treat secondary mitochondrial dysfunction

Treatment for Adult OnsetGlycogen Storage Diseases

• Avoid complex carbohydrates – grains, potatoes, green vegetables

• Increase use of simple sugars – fruit drinks, sodas, candy, corn syrup, honey , table sugar– We often use ribose

– Zhang W, Bao CD, Gu YY, Ye S. Glycogen storage disease manifested as gout and myopathy: three case reports and literature review. Clinical rheumatology 2008;27(5):671-4.

• Treat secondary mitochondrial dysfunction

• Pompe’s disease – enzyme replacement therapy is available– Beek NA, Hagemans ML, Ploeg AT, et al. Pompe disease (glycogen

storage disease type II): clinical features and enzyme replacement therapy. Acta Neurol Belg. 2006;106:82–86.

Conclusions

• Metabolism is an essential function of life and therefore is a component of normal functioning as well as all disease states

• Defects in metabolism can be primary or secondary and may become clinically evident at any time of life

• Treatment of metabolic disorders contributes to improved patient outcomes• Metabolic disorders should be evaluated in the setting of:

– Fatigue– Depression– Exercise intolerance– Heat intolerance– Difficulty with anesthesia– Recurrent infection– Hypoxemia and Dyspnea– Accelerated osteoarthritis– Bowel dysmotility disorders– Cardiomyopathies– Diabetes– Neurodegenerative disorders

• This is a rapidly growing field for which only the surface has been scratched