(2012-2018) Julia Wang, BS (2018-present) Lee-Jun C Wong, PhD, FACMG (2012-present) Revision History 26 July 2018 (ma) Comprehensive update posted live 6 December 2012 (me) Review posted live 23 August 2012 (fs) Original submission References Literature [ncbi.nlm.nih.gov]

Malabsorption due to exocrine pancreatic insufficiency Characteristics: Presents at during infancy or early childhood. [cme.ucsd.edu]

There are two main clinical presentations : myopathic and hepatocerebral. In the first group children present with devasting myopathy and neurological abnormalities. [ashg.org]

Patients with this mutation in their mitochondrial DNA have the mutation present in heteroplasmic form. [mitochondrialdisease.nhs.uk]

• Fatigue

  Symptoms may include: nervous system impairment eye problems hearing issues cardiac irregularities skeletal muscle abnormalities gastrointestinal tract disorders muscle weakness and pain fatigue lack of endurance poor balance difficulty swallowing Treatment [muscle.ca]

  There are multiple clinical studies indicating that aerobic exercise programs are safe and beneficial for many aspects of PMM, including strength, fatigue, and quality of life. [rarediseases.org]

  Many patients have exercise intolerance and fatigue, which can make exercise particularly challenging, yet therapeutic. There is no specific recommended diet for mitochondrial disease. [childneurologyfoundation.org]

  You can improve muscle fatigue with regular gentle exercise. The condition can improve in a few patients with specific vitamins such as ubiquinone (coenzyme Q10) and riboflavin, but not in most. [musculardystrophyuk.org]

  Occasionally, patients may also have swallowing problems, palpitations and in common with other Mitochondrial Diseases, weakness and fatigue. [mitochondrialdisease.nhs.uk]

• Weight Loss

  acid reflux, All affected individuals develop weight loss and progressive gastrointestinal dysmotility manifesting as early satiety, nausea, diarrhea, vomiting, and stomach pain and swelling. [en.wikipedia.org]

  Gastrointestinal manifestations – colonic pseudo-obstruction, hepatopathy, and weight loss. [cme.ucsd.edu]

  Particularly in infancy, childhood, and adolescence; for adults, monitor for persistent weight loss, which may indicate inadequate nutrition. 2. In those with infantile-onset disease 3. For those who are able to cooperate 4. [ncbi.nlm.nih.gov]

• Anemia

  […] deficiency Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome Congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome Congenital disorder of glycosylation Congenital dyserythropoietic anemia [se-atlas.de]

  Neuropathy, ataxia, and retinitis pigmentosa (NARP): Occurs in early childhood or adulthood Causes uncoordinated muscle movement (ataxia) and degeneration of the retina in the eye, leading to loss of vision Pearson’s syndrome: Occurs in infancy Causes severe anemia [neurosciences.uvahealth.com]

  Renal manifestations – glomerulopathy (focul segmental glomerulosclerosis) and tubolopathy that resembles Fanconi syndrome Hematologic manifestations - Bone marrow dysfunction with prominent sideroblastic anemia. [cme.ucsd.edu]

  MITOCHONDRIAL DNA DEFECTS IN NUCLEAR DNA AFFECTING MITOCHONDRIAL DNA OR ENZYME COMPLEXES PEO/multisystem with PEO KSS Pearson syndrome/KSS MELAS MERRF MiMyCa NARP/MILS LHON Diabetes, optic atrophy, deafness Tubulopathy, diabetes, ataxia Sideroblastic anemia [slideshare.net]

  […] infantile-onset patients have had non-skeletal muscle manifestations including: dysphagia, multiple bone fractures, nephropathy, rigid spine, coma episodes, cardiomyopathy, biventricular hypertrophy, arrhythmia, esophageal atresia, severe peripartum asphyxia, anemia [ncbi.nlm.nih.gov]

• Wheelchair Bound

  The patient is now wheelchair-bound, has dysphagia, nasal dysarthria, and needs nocturnal noninvasive ventilator support. [ncbi.nlm.nih.gov]

  Childhood-onset TK2-related myopathy is usually rapidly progressive, and patients become wheelchair-bound within 10 years of disease onset. [frontiersin.org]

• Dysphagia

  Some individuals develop dysarthria, dysphagia, and/or hearing loss. Cognitive function is typically spared. [ncbi.nlm.nih.gov]

  Additional features: short stature, progressive ophthalmoplegia, cardiomyopathy, limb weakness, ataxia, retinitis pigmentosa, deafness, diabetes (hypoparathyroidism, growth hormone deficiency), endocrine dysfunction, dysphagia, and behavioral disorders [cme.ucsd.edu]

  Muscle weakness may also cause difficulty swallowing (dysphagia) and respiratory failure. Distal muscle weakness may be present but rarely seen early in the disease. [rarediseases.org]

  Notably, two siblings harboring DGUOK mutations displayed an atypical phenotype characterized by slowly progressive, predominantly distal, upper and lower limb muscle weakness, mild dysphonia and dysphagia, similarly to SMA-like presentations due to TK2 [mdpi.com]

• Failure to Thrive

  Physical examination at the time of admission revealed failure to thrive, microcephaly, hypotonia, typical rotary nystagmus, hepatosplenomegaly, jaundice, and ascites. [journals.lww.com]

  Infants with FBXL4 -related encephalomyopathic mtDNA depletion syndrome have weak muscle tone (hypotonia) and a failure to grow or gain weight at the expected rate (failure to thrive). [chiarigear.com]

  Symptoms: Encephalomyopathy and various manifestations, including failure to thrive, developmental delay, hyoptonia, lethargy, respiratory failure, ataxia, myoclonus. Lactic acidosis common. May cause Leigh Syndrome. [umdf.org]

  Other symptoms include problems with blood glucose levels, persistent vomiting and a failure to thrive when babies are in their first year of life. [thesun.co.uk]

• Thrombosis

  […] patients have had non-skeletal muscle manifestations including: dysphagia, multiple bone fractures, nephropathy, rigid spine, coma episodes, cardiomyopathy, biventricular hypertrophy, arrhythmia, esophageal atresia, severe peripartum asphyxia, anemia, thrombosis [ncbi.nlm.nih.gov]

• Liver Dysfunction

  Hepatocerebral MDS, caused by mutations in DGUOK, MPV17, POLG, or C10orf2, commonly have an early-onset liver dysfunction and neurological involvement. [ncbi.nlm.nih.gov]

  Additionally, although physical signs of chronic liver dysfunction may not be present, many people suffer liver impairment leading to liver failure. [8] [9] In MDDS associated with mutations in PEO1 / C10orf2 that primarily affect the brain and the liver [en.wikipedia.org]

  Urinary succinylacetone was not detected, and plasma amino acid analysis was remarkable for elevations of tyrosine suggestive of liver dysfunction. Transferrin isoelectric focusing was normal. [journals.lww.com]

  Symptoms: seizures, dementia, spasticity, blindness, liver dysfunction, and cerebral degeneration. Links: NIH Source: Dr. Rolf Luft; The development of mitochondrial medicine. [umdf.org]

  Certain forms of mitochondrial disease put individuals at risk of developing diabetes, kidney problems, liver dysfunction or other organ problems. Therefore, ongoing management and follow-up need to be tailored to individual patients. [musculardystrophyuk.org]

• Myopathy

  The MYH7-related myopathy is reported to be Laing distal myopathy, myosin-storage myopathy, and cardiomyopathy. [ncbi.nlm.nih.gov]

  Mitochondrial DNA depletion myopathy, TK2-related | definition of mitochondrial DNA depletion myopathy, TK2-related by Medical dictionary https://medical-dictionary.thefreedictionary.com/mitochondrial+DNA+depletion+myopathy%2c+TK2-related (redirected [medical-dictionary.thefreedictionary.com]

  Myopathy mtDNA depletion related TK2 (TK2-related mitochondrial DNA depletion syndrome, myopathic form) - Gen TK2. Myopathy mtDNA depletion related TK2 (TK2 - MDS) is an inherited disease, signs and symptoms usually begin in early childhood. [ivami.com]

  Homozygosity for R225W mutation manifested during the second year of life as a myopathy, and showed muscle-specific mtDNA depletion. [pubmed.ncbi.nlm.nih.gov]

• Muscle Weakness

  In its mildest form, affected individuals may report myalgia and muscle weakness; in severe cases muscle weakness can progress to the point that ventilator assistance is required. [ncbi.nlm.nih.gov]

  Speech Therapy Muscle weakness in the throat may make talking or swallowing difficult. Speech therapy can help strengthen the muscles or work around the weakness. [neurosciences.uvahealth.com]

  weakness and depletion of mtDNA in skeletal muscle. [medical-dictionary.thefreedictionary.com]

  bulbar weakness), encephalomyopathic (i.e. hypotonia, muscle weakness, psychomotor delay) or neurogastrointestinal (i.e gastrointestinal dysmotility, peripheral neuropathy). [orpha.net]

• Proximal Muscle Weakness

  muscle weakness, facial and bulbar weakness and failure to thrive. [orpha.net]

  Thymidine kinase 2 (TK2) deficiency is an extremely rare disease with variable onset age and symptoms.1,2 Proximal muscle weakness, respiratory failure, facial weakness, and ptosis are the main symptoms. [ncbi.nlm.nih.gov]

  The most typical presentation is progressive muscle disease characterized by generalized hypotonia, proximal muscle weakness, loss of previously acquired motor skills, poor feeding, and respiratory difficulties. TK2-MDS usually affects the muscles. [cags.org.ae]

  Mutations in the same gene have been more recently observed in adult phenotypes with ptosis, external ophthalmoplegia, slowly-progressive proximal muscle weakness, muscular atrophy and dysarthria [ 84, 85 ]. [mdpi.com]

• Muscle Hypotonia

  The patients seemed normal at birth and had an uneventful early development, apart from a mild to moderate muscle hypotonia. [cags.org.ae]

  Primary symptoms of the disease are developmental delay, progressive intellectual disability, hypotonia (low muscle tone), spasticity (stiffness of the limbs) possibly leading to quadriplegia, and progressive dementia. [en.wikipedia.org]

• Fracture

  In some cases, CPEO+ respiratory phenotype •One-third of patients have extraskeletal muscle manifestations including: dysphagia, multiple bone fractures, nephropathy, rigid spine, coma episodes, and cardiomyopathy •30% of patients have CNS involvement [ncbi.nlm.nih.gov]

• Encephalopathy

  Ehlers-Danlos syndrome, musculocontractural type Encephalopathy due to GLUT1 deficiency Encephalopathy due to hydroxykynureninuria Encephalopathy due to prosaposin deficiency Encephalopathy due to sulfite oxidase deficiency Encephalopathy-hypertrophic [se-atlas.de]

  Background Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome is a multisystem and progressive neurodegenerative disorder. [emedicine.medscape.com]

  […] gene - Leigh syndrome. • SCO2 gene — a Mitochondrial copper chaperone- Hypertrophic cardiomyopathy and Encephalopathy • SCO1 gene — Familial hepatopathy and ketoacidotic coma. [slideshare.net]

  Format Definition An autosomal recessive mitochondrial disorder characterized by lethal infantile encephalopathy, hypertrophic cardiomyopathy and optic atrophy. Skeletal muscle biopsies show significant mtDNA depletion and abnormal mitochondria. [uniprot.org]

  These are severe disorders presenting in early infancy or childhood with profound weakness encephalopathy, seizures and liver failure. [newcastle-mitochondria.com]

• Seizure

  Symptoms: general: mental retardation, seizures, speech delay. [umdf.org]

  Mitochondrial Myopathy Symptoms Generally, mitochondrial myopathies cause: Muscle weakness or exercise intolerance Lack of balance or coordination Arryhthmias of the heart or heart failure Problems with eye movements Seizures Stroke-like episodes Vomiting [neurosciences.uvahealth.com]

  These are severe disorders presenting in early infancy or childhood with profound weakness encephalopathy, seizures and liver failure. [newcastle-mitochondria.com]

  In some patients there is also seizures and thus they have not only myoclonic epilepsy, but generalised tonic-clonic seizures. [mitochondrialdisease.nhs.uk]

  The 11-month-old cannot breathe on his own, has seizures, and is blind and deaf, the Times reported. [livescience.com]

• Limb Weakness

  […] movement (ataxia) Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Occurs before age 20 Causes eye movement problems (PEO), drooping eyelid, limb weakness, digestive problems and peripheral neuropathy Neuropathy, ataxia, and retinitis pigmentosa [neurosciences.uvahealth.com]

  Exercise intolerance, limb weakness, hearing loss, and diabetes may also precede the occurrence of the stroke-like episodes. [umdf.org]

  Juvenile/childhood onset with generalized proximal weakness and survival to at least 13 years Late-/adult-onset myopathy with facial and limb weakness and mtDNA deletions. [ncbi.nlm.nih.gov]

  Additional features: short stature, progressive ophthalmoplegia, cardiomyopathy, limb weakness, ataxia, retinitis pigmentosa, deafness, diabetes (hypoparathyroidism, growth hormone deficiency), endocrine dysfunction, dysphagia, and behavioral disorders [cme.ucsd.edu]

  PEO is often associated with other signs of skeletal muscle involvement, typically slow progressive axial and proximal limb weakness affecting predominantly the hip and shoulder girdle muscles often with muscle wasting. [rarediseases.org]

• Peripheral Neuropathy

  Finally, TYMP mutations have been associated with mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease that typically presents before the age of 20 years with progressive gastrointestinal dysmotility and peripheral neuropathy. [ncbi.nlm.nih.gov]

  Other associated complications: optic atrophy, peripheral neuropathy, diabetes, cardiomyopathy, kidney and endocrine abnormalities. [cme.ucsd.edu]

  neuropathy Neuropathy, ataxia, and retinitis pigmentosa (NARP): Occurs in early childhood or adulthood Causes uncoordinated muscle movement (ataxia) and degeneration of the retina in the eye, leading to loss of vision Pearson’s syndrome: Occurs in infancy [neurosciences.uvahealth.com]

• Chronic Progressive External Ophthalmoplegia

  progressive external ophthalmoplegia (CPEO) in which the predominant clinical problem relates to an eye movement disturbance and ptosis. [jmg.bmj.com]

  Some affected individuals develop respiratory insufficiency, chronic progressive external ophthalmoplegia, dysphagia, and dysarthria. Diagnosis/testing. [ncbi.nlm.nih.gov]

  progressive external ophthalmoplegia), KSS (Kearns-Sayre syndrome), Pearson marrow-pancreas syndrome and Leigh syndrome. [cme.ucsd.edu]

  Progressive External Ophthalmoplegia (CPEO) Danish patients between 18-80 years of age with verified single large-scale mtDNA deletions and chronic progressive external ophthalmoplegia. [mitoaction.org]

  Most often, patients with single deletions experience difficulty with eye movement (chronic progressive external ophthalmoplegia or CPEO) and develop droopy eyelids on one or both sides, beginning in early middle-age. [mitochondrialdisease.nhs.uk]

Both tests revealed no specific findings; therefore, she was hospitalized for extensive workup. [ncbi.nlm.nih.gov]

• Prolonged QT Interval

  Less than 20% of the patients showed non-skeletal muscle involvement including hearing loss, as well as 1 patient each with cognitive decline, encephalopathy, prolonged QT interval, arrhythmias, multiple bone fractures, renal tubulopathy, and gynecomastia [ncbi.nlm.nih.gov]

• Biventricular Hypertrophy

  Approximately one-third of the infantile-onset patients have had non-skeletal muscle manifestations including: dysphagia, multiple bone fractures, nephropathy, rigid spine, coma episodes, cardiomyopathy, biventricular hypertrophy, arrhythmia, esophageal [ncbi.nlm.nih.gov]

His parents want to take him to the United States for an experimental treatment, but his doctors have disagreed, saying that the treatment would not help and would only extend Charlie's suffering. [livescience.com]

Orphan designation of the medicine has been granted in the United States for treatment of thymidine kinase 2 deficiency. [ema.europa.eu]

Treatment Treatment Options: No treatment has been reported. [disorders.eyes.arizona.edu]

Listing these organizations is not a recommendation or referral in any regard for seeking treatment or consultation or support for treatment. [chiarigear.com]

treatment See Hereditary Hearing Loss and Deafness Overview. [ncbi.nlm.nih.gov]

Overall, MDS are severe disorders with poor prognosis in the majority of affected individuals. No efficacious therapy is available for any of these disorders. [ncbi.nlm.nih.gov]

The prognosis for MELAS is poor. Typically, the age of death is between 10 to 35 years, although some patients may live longer. [umdf.org]

PROGNOSIS Prognosis depends upon which disorder, which symptoms and the severity of those symptoms. Some of the conditions we thought were uniformly progressive and fatal are not (Leigh syndrome, for example). [childneurologyfoundation.org]

Prognosis MELAS syndrome widely varies in presentation; however, patients in general tend to have a poor prognosis and outcome. The encephalomyopathy tends to be severe and progressive to dementia. [emedicine.medscape.com]

Conversely, the absence of eye abnormalities may portend a better prognosis and a possible beneficial effect of liver transplantation. [journals.lww.com]

Characteristic Features Linked by a common etiology or pathogenesis – abnormal function of the mitochondria or deficient mitochondrial energy metabolism. [cme.ucsd.edu]

Houston Recruiting NCT02023866 Open-Label, Dose-Escalating Study to Assess Safety, Tolerability, Efficacy, PK and PD of RP103 in Children With Inherited Mitochondrial Disease Genetically diagnosed mitochondrial disease Raptor Pharma Completed NCT02003170 Etiology [mitoaction.org]

Clinically-based whole exome sequencing revealed the underlying etiology in the proband and his similarly affected sister to be a previously reported pathogenic mutation in the DES gene. [frontiersin.org]

Her sister had had difficulties running, jumping and climbing stairs since childhood, but was never was evaluated by a neurologist or examined in an etiological study. [ncbi.nlm.nih.gov]

International The first assessment of the epidemiology of mitochondrial disorders found a prevalence of more than 10.2 per 100,000 for the m.3243A → G mutation in the adult Finnish population. [emedicine.medscape.com]

The epidemiology of pathogenic mitochondrial DNA mutations. Ann Neurol 2000 ; 48 : 188 –93. ↵ Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, Schon EA, Rowland LP. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. [jmg.bmj.com]

The Epidemiology of Pathogenic Mitochondrial DNA Mutations. Annals of Neurology. 48(2): 188-193. Chinnery, PF (2003). Mitochondrial Disorders Overview. GeneTests. Obtained online Nov. 22, 2005 at www.genetests.org. Chinnery, PF, et al (2004). [cme.ucsd.edu]

The incidence is unknown, although the epidemiological studies of the MELAS-3243 mtDNA mutation have estimated the prevalence to be 1-16/100,000 in the adult population. There is no cure or specific treatment for MELAS. [umdf.org]

Sectors of interest are epidemiological and clinical-molecular correlation studies in mitochondrial diseases, assessment of biological and genetic markers in amyotrophic lateral sclerosis, Alzheimer’s disease and other genetic neuromuscular and neurodegenerative [rarediseases.org]

Pathophysiology Strokelike episodes and mitochondrial myopathy characterize MELAS syndrome. [emedicine.medscape.com]

[…] article is freely available re-usable Review Genes and Pathways Involved in Adult Onset Disorders Featuring Muscle Mitochondrial DNA Instability Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Centre, Department of Pathophysiology [mdpi.com]

As strength this is the first study to our knowledge on adult post mortem tissues of a TK2-deficient patient, and our findings provide insight into the pathophysiological bases of the disease and the applicability of new treatments currently under clinical [ncbi.nlm.nih.gov]

Prevention of secondary complications: Chest physiotherapy can help reduce the risk of pulmonary infection; physical therapy can help prevent joint contractures. Surveillance: No clinical guidelines are available. [ncbi.nlm.nih.gov]

Mr Preston said he advised Ms Yates that if she and Mr Gard took on Great Ormond Street, the hospital would likely use the courts to prevent Charlie from leaving the ward. [northwichguardian.co.uk]

Can Alper's be prevented? If the genetic faults are present, then there is nothing that can be taken during pregnancy or given to the infant that will prevent Alper's occurring. [mitochondrialdisease.nhs.uk]

[…] accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 15 March 2017 recommending the granting of this designation. the seriousness of the condition; the existence of alternative methods of diagnosis, prevention [ema.europa.eu]

The mutation leads to a reduction in the amount of mitochondrial DNA, and prevents the mitochondria from working properly. [livescience.com]