Alpers' disease: Difference between revisions
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==Historical Perspective== | ==Historical Perspective== | ||
*Alpers disease was first described by a North-American neurologist named, Bernard Jacob Alpers in 1931.<ref name="Alpers1931">{{cite journal|last1=Alpers|first1=Bernard J.|title=DIFFUSE PROGRESSIVE DEGENERATION OF THE GRAY MATTER OF THE CEREBRUM|journal=Archives of Neurology And Psychiatry|volume=25|issue=3|year=1931|pages=469|issn=0096-6754|doi=10.1001/archneurpsyc.1931.02230030027002}}</ref> | *Alpers disease was first described by a North-American neurologist named, Bernard Jacob Alpers in 1931.<ref name="Alpers1931">{{cite journal|last1=Alpers|first1=Bernard J.|title=DIFFUSE PROGRESSIVE DEGENERATION OF THE GRAY MATTER OF THE CEREBRUM|journal=Archives of Neurology And Psychiatry|volume=25|issue=3|year=1931|pages=469|issn=0096-6754|doi=10.1001/archneurpsyc.1931.02230030027002}}</ref> | ||
*In 1970, Peter Richard Huttenlocher a [[pediatric neurologist]] and [[neuroscientist]] described more [[phenotypic]] features associated with the disease. <ref name="HuttenlocherSolitare1976">{{cite journal|last1=Huttenlocher|first1=P. R.|last2=Solitare|first2=G. B.|last3=Adams|first3=G.|title=Infantile Diffuse Cerebral Degeneration With Hepatic Cirrhosis|journal=Archives of Neurology|volume=33|issue=3|year=1976|pages=186–192|issn=0003-9942|doi=10.1001/archneur.1976.00500030042009}}</ref> | *In 1970, Peter Richard Huttenlocher a [[pediatric]] [[neurologist]] and [[neuroscientist]] described more [[phenotypic]] features associated with the disease. <ref name="HuttenlocherSolitare1976">{{cite journal|last1=Huttenlocher|first1=P. R.|last2=Solitare|first2=G. B.|last3=Adams|first3=G.|title=Infantile Diffuse Cerebral Degeneration With Hepatic Cirrhosis|journal=Archives of Neurology|volume=33|issue=3|year=1976|pages=186–192|issn=0003-9942|doi=10.1001/archneur.1976.00500030042009}}</ref> | ||
*Alpers disease is also refered as Alpers–Huttenlocher syndrome. | *Alpers disease is also refered as Alpers–Huttenlocher syndrome. | ||
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*Alpers disease is inherited in an [[autosomal recessive]] pattern. | *Alpers disease is inherited in an [[autosomal recessive]] pattern. | ||
*[[Mutation]] in [[POLG]]1 [[gene]] reduces [[polymerase gamma]] functionality resulting in defective [[mitochondrial DNA]] replication and causing depletion of [[mitochondrial DNA]]. <ref name="pmid22176657">{{cite journal| author=Copeland WC| title=Defects in mitochondrial DNA replication and human disease. | journal=Crit Rev Biochem Mol Biol | year= 2012 | volume= 47 | issue= 1 | pages= 64-74 | pmid=22176657 | doi=10.3109/10409238.2011.632763 | pmc=3244805 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22176657 }} </ref> | *[[Mutation]] in [[POLG]]1 [[gene]] reduces [[polymerase gamma]] functionality resulting in defective [[mitochondrial DNA]] replication and causing depletion of [[mitochondrial DNA]]. <ref name="pmid22176657">{{cite journal| author=Copeland WC| title=Defects in mitochondrial DNA replication and human disease. | journal=Crit Rev Biochem Mol Biol | year= 2012 | volume= 47 | issue= 1 | pages= 64-74 | pmid=22176657 | doi=10.3109/10409238.2011.632763 | pmc=3244805 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22176657 }} </ref> | ||
* | *[[Heterozygous]] [[mutation]] of POLG1 [[gene]] causes classic and severe presentation of the disease at an early age of onset. | ||
*[[Homozygous]] [[mutation]] results in the milder form with onset of symptoms in adolescence.<ref name="SanetoCohen2013">{{cite journal|last1=Saneto|first1=Russell P.|last2=Cohen|first2=Bruce H.|last3=Copeland|first3=William C.|last4=Naviaux|first4=Robert K.|title=Alpers-Huttenlocher Syndrome|journal=Pediatric Neurology|volume=48|issue=3|year=2013|pages=167–178|issn=08878994|doi=10.1016/j.pediatrneurol.2012.09.014}}</ref> | |||
*[[Brain]], [[liver]] and [[skeletal muscles]] are most involved due to high number of [[mitochondria]].<ref name="pmid23419467]">{{cite journal| author=Saneto RP, Cohen BH, Copeland WC, Naviaux RK| title=Alpers-Huttenlocher syndrome. | journal=Pediatr Neurol | year= 2013 | volume= 48 | issue= 3 | pages= 167-78 | pmid=23419467] | doi=10.1016/j.pediatrneurol.2012.09.014 | pmc=3578656 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23419467 }} </ref> | *[[Brain]], [[liver]] and [[skeletal muscles]] are most involved due to high number of [[mitochondria]].<ref name="pmid23419467]">{{cite journal| author=Saneto RP, Cohen BH, Copeland WC, Naviaux RK| title=Alpers-Huttenlocher syndrome. | journal=Pediatr Neurol | year= 2013 | volume= 48 | issue= 3 | pages= 167-78 | pmid=23419467] | doi=10.1016/j.pediatrneurol.2012.09.014 | pmc=3578656 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23419467 }} </ref> | ||
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*The [[prevalence]] of Alpers disease is approximately 1 per 100,000 individuals worldwide. | *The [[prevalence]] of Alpers disease is approximately 1 per 100,000 individuals worldwide. | ||
*Alpers disease affects men and women equally. | *Alpers disease affects men and women equally. | ||
*Higher [[carrier]] frequency is seen in the Northern European population.<ref name="pmid23419467]">{{cite journal| author=Saneto RP, Cohen BH, Copeland WC, Naviaux RK| title=Alpers-Huttenlocher syndrome. | journal=Pediatr Neurol | year= 2013 | volume= 48 | issue= 3 | pages= 167-78 | pmid=23419467] | doi=10.1016/j.pediatrneurol.2012.09.014 | pmc=3578656 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23419467 }} </ref> | *Higher [[carrier]] frequency is seen in the Northern European population.<ref name="pmid23419467]">{{cite journal| author=Saneto RP, Cohen BH, Copeland WC, Naviaux RK| title=Alpers-Huttenlocher syndrome. | journal=Pediatr Neurol | year= 2013 | volume= 48 | issue= 3 | pages= 167-78 | pmid=23419467] | doi=10.1016/j.pediatrneurol.2012.09.014 | pmc=3578656 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23419467 }} </ref> Although, it is seen in other ethnic groups as well. | ||
==Risk Factors== | ==Risk Factors== | ||
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==Natural History, Complications, and Prognosis== | ==Natural History, Complications, and Prognosis== | ||
*Common complications of Alpers disease include [[seizures]], [[liver failure]] poor growth, infection-associated [[encephalopathy]], increased muscle tone, [[gastrointesinal dysfunction]], [[dilated cardiomyopathy]], [[dementia]], [[cortical blindness]], [[spasticity]], [[jaundice]] and/or [[ascites]].<ref name="pmid27555780">{{cite journal| author=Saneto RP| title=Alpers-Huttenlocher syndrome: the role of a multidisciplinary health care team. | journal=J Multidiscip Healthc | year= 2016 | volume= 9 | issue= | pages= 323-33 | pmid=27555780 | doi=10.2147/JMDH.S84900 | pmc=4968991 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27555780 }} </ref> | *Common complications of Alpers disease include [[seizures]], [[liver failure]] poor growth, infection-associated [[encephalopathy]], increased muscle tone, [[gastrointesinal dysfunction]], [[dilated cardiomyopathy]], [[dementia]], [[cortical blindness]], [[spasticity]], [[jaundice]] and/or [[ascites]].<ref name="pmid27555780">{{cite journal| author=Saneto RP| title=Alpers-Huttenlocher syndrome: the role of a multidisciplinary health care team. | journal=J Multidiscip Healthc | year= 2016 | volume= 9 | issue= | pages= 323-33 | pmid=27555780 | doi=10.2147/JMDH.S84900 | pmc=4968991 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27555780 }} </ref> | ||
*The [[prognosis]] is | *The [[prognosis]] is generally poor, death usually occurs within ten years after diagnosis due to life threatening complications of the disease. | ||
==Diagnosis== | ==Diagnosis== | ||
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'''Laboratory Findings''' | '''Laboratory Findings''' | ||
*There are no diagnostic laboratory findings associated with Alpers disease. | *There are no diagnostic laboratory findings associated with Alpers disease. | ||
*However CSF lactate may be elevated in some cases due to respiratory chain disorder.<ref name="WolfRahman2009">{{cite journal|last1=Wolf|first1=Nicole I.|last2=Rahman|first2=Shamima|last3=Schmitt|first3=Bernhard|last4=Taanman|first4=Jan-Willem|last5=Duncan|first5=Andrew J.|last6=Harting|first6=Inga|last7=Wohlrab|first7=Gabriele|last8=Ebinger|first8=Friedrich|last9=Rating|first9=Dietz|last10=Bast|first10=Thomas|title=Status epilepticus in children with Alpers’ disease caused byPOLG1mutations: EEG and MRI features|journal=Epilepsia|volume=50|issue=6|year=2009|pages=1596–1607|issn=00139580|doi=10.1111/j.1528-1167.2008.01877.x}}</ref> | *However [[CSF]] [[lactate]] may be elevated in some cases due to respiratory chain disorder.<ref name="WolfRahman2009">{{cite journal|last1=Wolf|first1=Nicole I.|last2=Rahman|first2=Shamima|last3=Schmitt|first3=Bernhard|last4=Taanman|first4=Jan-Willem|last5=Duncan|first5=Andrew J.|last6=Harting|first6=Inga|last7=Wohlrab|first7=Gabriele|last8=Ebinger|first8=Friedrich|last9=Rating|first9=Dietz|last10=Bast|first10=Thomas|title=Status epilepticus in children with Alpers’ disease caused byPOLG1mutations: EEG and MRI features|journal=Epilepsia|volume=50|issue=6|year=2009|pages=1596–1607|issn=00139580|doi=10.1111/j.1528-1167.2008.01877.x}}</ref> | ||
'''Electrocardiogram''' | '''Electrocardiogram''' | ||
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*[[CT]] may demonstrate areas of low density in occipital region and may show [[cerebral atrophy]].<ref name="EngelsenTzoulis2008">{{cite journal|last1=Engelsen|first1=B. A.|last2=Tzoulis|first2=C.|last3=Karlsen|first3=B.|last4=Lillebo|first4=A.|last5=Laegreid|first5=L. M.|last6=Aasly|first6=J.|last7=Zeviani|first7=M.|last8=Bindoff|first8=L. A.|title=POLG1 mutations cause a syndromic epilepsy with occipital lobe predilection|journal=Brain|volume=131|issue=3|year=2008|pages=818–828|issn=0006-8950|doi=10.1093/brain/awn007}}</ref> | *[[CT]] may demonstrate areas of low density in occipital region and may show [[cerebral atrophy]].<ref name="EngelsenTzoulis2008">{{cite journal|last1=Engelsen|first1=B. A.|last2=Tzoulis|first2=C.|last3=Karlsen|first3=B.|last4=Lillebo|first4=A.|last5=Laegreid|first5=L. M.|last6=Aasly|first6=J.|last7=Zeviani|first7=M.|last8=Bindoff|first8=L. A.|title=POLG1 mutations cause a syndromic epilepsy with occipital lobe predilection|journal=Brain|volume=131|issue=3|year=2008|pages=818–828|issn=0006-8950|doi=10.1093/brain/awn007}}</ref> | ||
'''MRI''' | '''MRI''' | ||
*[[MRI]] demonstrates [[gray matter]] involvement in regions with the highest metabolic activity.<ref name="HikmatEichele2017">{{cite journal|last1=Hikmat|first1=Omar|last2=Eichele|first2=Tom|last3=Tzoulis|first3=Charalampos|last4=Bindoff|first4=Laurence|title=Understanding the Epilepsy in POLG Related Disease|journal=International Journal of Molecular Sciences|volume=18|issue=9|year=2017|pages=1845|issn=1422-0067|doi=10.3390/ijms18091845}}</ref> | |||
*In most patients [[MRI]] demonstrated T2/FLAIR hyperintensities within the occipital region, [[basal ganglia]], deep [[cerebellar nuclei]], and [[thalamus]].<ref name="Tzoulis2006">{{cite journal|last1=Tzoulis|first1=C.|title=The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases|journal=Brain|volume=129|issue=7|year=2006|pages=1685–1692|issn=0006-8950|doi=10.1093/brain/awl097}}</ref> | *In most patients [[MRI]] demonstrated T2/FLAIR hyperintensities within the occipital region, [[basal ganglia]], deep [[cerebellar nuclei]], and [[thalamus]].<ref name="Tzoulis2006">{{cite journal|last1=Tzoulis|first1=C.|title=The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases|journal=Brain|volume=129|issue=7|year=2006|pages=1685–1692|issn=0006-8950|doi=10.1093/brain/awl097}}</ref> | ||
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'''Other Diagnostic Studies''' | '''Other Diagnostic Studies''' | ||
* | *Rhythmic high-amplitude delta with superimposed (poly)spikes(RHADS) on [[EEG]] are reported to be highly specific of Alpers disease.<ref name="van WestrhenenCats2018">{{cite journal|last1=van Westrhenen|first1=Anouk|last2=Cats|first2=Elisabeth A.|last3=van den Munckhof|first3=Bart|last4=van der Salm|first4=Sandra M.A.|last5=Teunissen|first5=Nico W.|last6=Ferrier|first6=Cyrille H.|last7=Leijten|first7=Frans S.S.|last8=Geleijns|first8=Karin P.W.|title=Specific EEG markers in POLG1 Alpers’ syndrome|journal=Clinical Neurophysiology|volume=129|issue=10|year=2018|pages=2127–2131|issn=13882457|doi=10.1016/j.clinph.2018.07.016}}</ref> | ||
*Other [[EEG]] finding includes abnormal, often assymetrical flash [[visual evoked potential]] (VEP). | |||
==Treatment== | ==Treatment== | ||
'''Medical Therapy''' | '''Medical Therapy''' | ||
*There is no treatment for Alpers disease and no way to slow its progression; the mainstay of therapy is supportive and [[palliative]] care. | *There is no treatment for Alpers disease and no way to slow its progression; the mainstay of therapy is supportive and [[palliative]] care, achieved by a multidisciplinary care team. | ||
*[[Seizure]] management should be achieved by with drugs with newer generation drugs(lamotrigine, primidone, topiramate, oxcarbazepine) with low hepatic impact. | *[[Seizure]] management should be achieved by with drugs with newer generation drugs(lamotrigine, primidone, topiramate, oxcarbazepine) with low hepatic impact. | ||
*[[Valproic acid]] should be avoided for [[seizure]] management as it can worsen liver disease.<ref name="pmid23419467">{{cite journal| author=Saneto RP, Cohen BH, Copeland WC, Naviaux RK| title=Alpers-Huttenlocher syndrome. | journal=Pediatr Neurol | year= 2013 | volume= 48 | issue= 3 | pages= 167-78 | pmid=23419467 | doi=10.1016/j.pediatrneurol.2012.09.014 | pmc=3578656 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23419467 }} </ref> | *[[Valproic acid]] should be avoided for [[seizure]] management as it can worsen liver disease.<ref name="pmid23419467">{{cite journal| author=Saneto RP, Cohen BH, Copeland WC, Naviaux RK| title=Alpers-Huttenlocher syndrome. | journal=Pediatr Neurol | year= 2013 | volume= 48 | issue= 3 | pages= 167-78 | pmid=23419467 | doi=10.1016/j.pediatrneurol.2012.09.014 | pmc=3578656 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23419467 }} </ref> | ||
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*There are no established measures for the [[secondary prevention]] of Alpers disease. | *There are no established measures for the [[secondary prevention]] of Alpers disease. | ||
== | ==References== | ||
{{reflist|2}} | {{reflist|2}} | ||
{{Diseases of the nervous system}} | {{Diseases of the nervous system}} | ||
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[[fi:Alpersin tauti]] | [[fi:Alpersin tauti]] | ||
Latest revision as of 23:22, 10 September 2020
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Zehra Malik, M.B.B.S[3]
Synonyms and keywords: Alpers-Huttenlocher Syndrome, Progressive Infantile Poliodystrophy, Mitochondrial Deoxyribonucleic acid (DNA) depletion syndrome-4A
Overview
Alpers' disease is an autosomal recessive genetic syndrome characterized by seizures, hepatopathy, and progressive cognitive impairment. It is caused by mutation in the POLG gene resulting in mitochondrial DNA depletion.
Historical Perspective
- Alpers disease was first described by a North-American neurologist named, Bernard Jacob Alpers in 1931.[1]
- In 1970, Peter Richard Huttenlocher a pediatric neurologist and neuroscientist described more phenotypic features associated with the disease. [2]
- Alpers disease is also refered as Alpers–Huttenlocher syndrome.
Classification
- There is no established system for the classification of Alpers disease.
Pathophysiology
- Alpers disease is inherited in an autosomal recessive pattern.
- Mutation in POLG1 gene reduces polymerase gamma functionality resulting in defective mitochondrial DNA replication and causing depletion of mitochondrial DNA. [3]
- Heterozygous mutation of POLG1 gene causes classic and severe presentation of the disease at an early age of onset.
- Homozygous mutation results in the milder form with onset of symptoms in adolescence.[4]
- Brain, liver and skeletal muscles are most involved due to high number of mitochondria.[5]
Causes
- Alpers disease is a mitochondrial disorder caused by a mutation in the POLG1 gene.[6]
Differentiating Alpers disease from other Diseases
- Alpers disease must be differentiated from other mitochondrial diseases caused POLG gene mutation:
- Childhood Myocerbrohepatopathy Spectrum Disorder[7]
- Myoclonus epilepsy myopathy sensory ataxia (MEMSA)
- Progressive external ophthalmoplegia[8]
Epidemiology and Demographics
- The prevalence of Alpers disease is approximately 1 per 100,000 individuals worldwide.
- Alpers disease affects men and women equally.
- Higher carrier frequency is seen in the Northern European population.[5] Although, it is seen in other ethnic groups as well.
Risk Factors
- There are no established risk factors for Alpers disease.
Screening
- There is insufficient evidence to recommend routine screening for Alpers disease.
Natural History, Complications, and Prognosis
- Common complications of Alpers disease include seizures, liver failure poor growth, infection-associated encephalopathy, increased muscle tone, gastrointesinal dysfunction, dilated cardiomyopathy, dementia, cortical blindness, spasticity, jaundice and/or ascites.[9]
- The prognosis is generally poor, death usually occurs within ten years after diagnosis due to life threatening complications of the disease.
Diagnosis
Diagnostic Study of Choice
- There are no established criteria for the diagnosis of Alpers disease. However, it usually manifests with a triad consist of refractory seizures, hepatopathy, and psychomotor regression.
- The diagnosis is established by testing for the POLG gene.[4]
History and Symptoms
- Alpers disease has a bimodal age of onset. The majority cases present in first two years of life and the rest present between the ages of 2 and 25.[10]
- Alpers disease is characterized by presence of refractory seizures, psychomotor regression and liver failure.
- Other symptoms may include hypoglycemia secondary to underlying liver disease, vision changes, migraines, hallucinations, cognitive impairment, depression, anxiety and/or ataxia.[9]
Physical Examination
- Common physical examination findings of Alpers disease include spasticity, ataxia, altered muscle tone.
- Other physical findings include poor growth, developmental delay, failure to thrive, and/or vision changes.
Laboratory Findings
- There are no diagnostic laboratory findings associated with Alpers disease.
- However CSF lactate may be elevated in some cases due to respiratory chain disorder.[11]
Electrocardiogram
- There are no ECG findings associated with Alpers disease. However, cardiomyopathy may be one of the possible complications of Alpers disease.[12]
X-ray
- There are no x-ray findings associated with Alpers disease.
Echocardiography or Ultrasound
- There are no diagnostic echocardiography/ultrasound findings associated with Alpers disease.
CT scan
- CT may demonstrate areas of low density in occipital region and may show cerebral atrophy.[13]
MRI
- MRI demonstrates gray matter involvement in regions with the highest metabolic activity.[14]
- In most patients MRI demonstrated T2/FLAIR hyperintensities within the occipital region, basal ganglia, deep cerebellar nuclei, and thalamus.[15]
Other Imaging Findings
- In areas of high diffusion signal, MR spectroscopy may show increased lactate signal intensity and decreased NAA signal intensity.[16]
Other Diagnostic Studies
- Rhythmic high-amplitude delta with superimposed (poly)spikes(RHADS) on EEG are reported to be highly specific of Alpers disease.[17]
- Other EEG finding includes abnormal, often assymetrical flash visual evoked potential (VEP).
Treatment
Medical Therapy
- There is no treatment for Alpers disease and no way to slow its progression; the mainstay of therapy is supportive and palliative care, achieved by a multidisciplinary care team.
- Seizure management should be achieved by with drugs with newer generation drugs(lamotrigine, primidone, topiramate, oxcarbazepine) with low hepatic impact.
- Valproic acid should be avoided for seizure management as it can worsen liver disease.[18]
- Physical therapy may help relieve spasticity.
- Occupational/speech therapies may also help with neurological deficits.
- Tracheostomy, gastric feeding tube, and/or artificial ventilation may be helpful once the disease progresses.[19]
Surgery
- Surgical intervention is not recommended for the management of Alpers disease.
Primary Prevention
- There are no established measures for the primary prevention of Alpers disease.
Secondary Prevention
- There are no established measures for the secondary prevention of Alpers disease.
References
- ↑ Alpers, Bernard J. (1931). "DIFFUSE PROGRESSIVE DEGENERATION OF THE GRAY MATTER OF THE CEREBRUM". Archives of Neurology And Psychiatry. 25 (3): 469. doi:10.1001/archneurpsyc.1931.02230030027002. ISSN 0096-6754.
- ↑ Huttenlocher, P. R.; Solitare, G. B.; Adams, G. (1976). "Infantile Diffuse Cerebral Degeneration With Hepatic Cirrhosis". Archives of Neurology. 33 (3): 186–192. doi:10.1001/archneur.1976.00500030042009. ISSN 0003-9942.
- ↑ Copeland WC (2012). "Defects in mitochondrial DNA replication and human disease". Crit Rev Biochem Mol Biol. 47 (1): 64–74. doi:10.3109/10409238.2011.632763. PMC 3244805. PMID 22176657.
- ↑ 4.0 4.1 Saneto, Russell P.; Cohen, Bruce H.; Copeland, William C.; Naviaux, Robert K. (2013). "Alpers-Huttenlocher Syndrome". Pediatric Neurology. 48 (3): 167–178. doi:10.1016/j.pediatrneurol.2012.09.014. ISSN 0887-8994.
- ↑ 5.0 5.1 Saneto RP, Cohen BH, Copeland WC, Naviaux RK (2013). "Alpers-Huttenlocher syndrome". Pediatr Neurol. 48 (3): 167–78. doi:10.1016/j.pediatrneurol.2012.09.014. PMC 3578656. PMID [1] 23419467]] Check
|pmid=value (help). - ↑ Qian Y, Ziehr JL, Johnson KA (2015). "Alpers disease mutations in human DNA polymerase gamma cause catalytic defects in mitochondrial DNA replication by distinct mechanisms". Front Genet. 6: 135. doi:10.3389/fgene.2015.00135. PMC 4391263. PMID 25914719.
- ↑ Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K; et al. (1993). "GeneReviews®". PMID 20301791.
- ↑ Wong LJ, Naviaux RK, Brunetti-Pierri N, Zhang Q, Schmitt ES, Truong C; et al. (2008). "Molecular and clinical genetics of mitochondrial diseases due to POLG mutations". Hum Mutat. 29 (9): E150–72. doi:10.1002/humu.20824. PMC 2891192. PMID 18546365.
- ↑ 9.0 9.1 Saneto RP (2016). "Alpers-Huttenlocher syndrome: the role of a multidisciplinary health care team". J Multidiscip Healthc. 9: 323–33. doi:10.2147/JMDH.S84900. PMC 4968991. PMID 27555780.
- ↑ Hayhurst, Hannah; Anagnostou, Maria‐Eleni; Bogle, Helen J.; Grady, John P.; Taylor, Robert W.; Bindoff, Laurence A.; McFarland, Robert; Turnbull, Doug M.; Lax, Nichola Z. (2018). "Dissecting the neuronal vulnerability underpinning Alpers' syndrome: a clinical and neuropathological study". Brain Pathology. 29 (1): 97–113. doi:10.1111/bpa.12640. ISSN 1015-6305.
- ↑ Wolf, Nicole I.; Rahman, Shamima; Schmitt, Bernhard; Taanman, Jan-Willem; Duncan, Andrew J.; Harting, Inga; Wohlrab, Gabriele; Ebinger, Friedrich; Rating, Dietz; Bast, Thomas (2009). "Status epilepticus in children with Alpers' disease caused byPOLG1mutations: EEG and MRI features". Epilepsia. 50 (6): 1596–1607. doi:10.1111/j.1528-1167.2008.01877.x. ISSN 0013-9580.
- ↑ Holmgren, D (2003). "Cardiomyopathy in children with mitochondrial disease Clinical course and cardiological findings". European Heart Journal. 24 (3): 280–288. doi:10.1016/S0195-668X(02)00387-1. ISSN 0195-668X.
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- ↑ Hikmat, Omar; Eichele, Tom; Tzoulis, Charalampos; Bindoff, Laurence (2017). "Understanding the Epilepsy in POLG Related Disease". International Journal of Molecular Sciences. 18 (9): 1845. doi:10.3390/ijms18091845. ISSN 1422-0067.
- ↑ Tzoulis, C. (2006). "The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases". Brain. 129 (7): 1685–1692. doi:10.1093/brain/awl097. ISSN 0006-8950.
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- ↑ Saneto RP, Cohen BH, Copeland WC, Naviaux RK (2013). "Alpers-Huttenlocher syndrome". Pediatr Neurol. 48 (3): 167–78. doi:10.1016/j.pediatrneurol.2012.09.014. PMC 3578656. PMID 23419467.
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