Editor-In-Chief: C. Michael Gibson, M.S., M.D. ; Associate Editor(s)-in-Chief: Zehra Malik, M.B.B.S
Synonyms and keywords: Alpers-Huttenlocher Syndrome, Progressive Infantile Poliodystrophy, Mitochondrial Deoxyribonucleic acid (DNA) depletion syndrome-4A
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.
- Alpers disease was first described by a North-American neurologist named, Bernard Jacob Alpers in 1931.
- In 1970, Peter Richard Huttenlocher a pediatric neurologist and neuroscientist described more phenotypic features associated with the disease. 
- Alpers disease is also refered as Alpers–Huttenlocher syndrome.
- There is no established system for the classification of Alpers disease.
- 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. 
- 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.
- Brain, liver and skeletal muscles are most involved due to high number of mitochondria.
- Alpers disease is a mitochondrial disorder caused by a mutation in the POLG1 gene.
Differentiating Alpers disease from other Diseases
- Alpers disease must be differentiated from other mitochondrial diseases caused POLG gene mutation:
- Childhood Myocerbrohepatopathy Spectrum Disorder
- Myoclonus epilepsy myopathy sensory ataxia (MEMSA)
- Progressive external ophthalmoplegia
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. Although, it is seen in other ethnic groups as well.
- There are no established risk factors for Alpers disease.
- 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.
- The prognosis is generally poor, death usually occurs within ten years after diagnosis due to life threatening complications of the disease.
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.
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.
- 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.
- 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.
- There are no diagnostic laboratory findings associated with Alpers disease.
- However CSF lactate may be elevated in some cases due to respiratory chain disorder.
- There are no ECG findings associated with Alpers disease. However, cardiomyopathy may be one of the possible complications of Alpers disease.
- 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 may demonstrate areas of low density in occipital region and may show cerebral atrophy.
- MRI demonstrates gray matter involvement in regions with the highest metabolic activity.
- In most patients MRI demonstrated T2/FLAIR hyperintensities within the occipital region, basal ganglia, deep cerebellar nuclei, and thalamus.
Other Imaging Findings
- In areas of high diffusion signal, MR spectroscopy may show increased lactate signal intensity and decreased NAA signal intensity.
Other Diagnostic Studies
- Rhythmic high-amplitude delta with superimposed (poly)spikes(RHADS) on EEG are reported to be highly specific of Alpers disease.
- Other EEG finding includes abnormal, often assymetrical flash visual evoked potential (VEP).
- 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.
- 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.
- Surgical intervention is not recommended for the management of Alpers disease.
- There are no established measures for the primary prevention of Alpers disease.
- There are no established measures for the secondary prevention of Alpers disease.
- ↑ 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  23419467]] Check
- ↑ 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.
- ↑ Engelsen, B. A.; Tzoulis, C.; Karlsen, B.; Lillebo, A.; Laegreid, L. M.; Aasly, J.; Zeviani, M.; Bindoff, L. A. (2008). "POLG1 mutations cause a syndromic epilepsy with occipital lobe predilection". Brain. 131 (3): 818–828. doi:10.1093/brain/awn007. ISSN 0006-8950.
- ↑ 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.
- ↑ Flemming K, Ulmer S, Duisberg B, Hahn A, Jansen O (2002). "MR spectroscopic findings in a case of Alpers-Huttenlocher syndrome". AJNR Am J Neuroradiol. 23 (8): 1421–3. PMID 12223390.
- ↑ van Westrhenen, Anouk; Cats, Elisabeth A.; van den Munckhof, Bart; van der Salm, Sandra M.A.; Teunissen, Nico W.; Ferrier, Cyrille H.; Leijten, Frans S.S.; Geleijns, Karin P.W. (2018). "Specific EEG markers in POLG1 Alpers' syndrome". Clinical Neurophysiology. 129 (10): 2127–2131. doi:10.1016/j.clinph.2018.07.016. ISSN 1388-2457.
- ↑ 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.
- ↑ Giordano C, Sebastiani M, De Giorgio R, Travaglini C, Tancredi A, Valentino ML; et al. (2008). "Gastrointestinal dysmotility in mitochondrial neurogastrointestinal encephalomyopathy is caused by mitochondrial DNA depletion". Am J Pathol. 173 (4): 1120–8. doi:10.2353/ajpath.2008.080252. PMC 2543079. PMID 18787099.
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