Alpers syndrome, also known as Alpers-Huttenlocher syndrome or progressive cerebral poliodystrophy, is a rare childhood neurodegenerative POLG-related disorder. Along with Leigh syndrome, it is one of the commonest childhood mitochondrial disorders 1.
Alpers syndrome is incredibly rare. The estimated prevalence is 1 per 100,000.
Alpers syndrome generally affects infants within the first year of life, but cases have been reported later in childhood through to early adulthood 2-4. Affected individuals often present with severe, refractory status epilepticus 2. Loss of motor coordination, decreased muscle tone, cognitive decline, optic nerve atrophy, and hepatic impairment are often reported in disease progression 1,5.
Autosomal recessive mutations in the DNA Polymerase Gamma, Catalytic Subunit (POLG) gene have been implicated in the majority of cases 5.
Neuroimaging findings are most frequently described.
Findings are often subtle and include low densities in the cortex and white matter, especially in the occipital lobes, and cerebral atrophy 7.
Features described include:
- regions of increased signal intensity on T2-weighted sequences and DWI, most often in the occipital lobes and thalami, involving both the cortex and deep gray matter 7-9
- these regions often correspond to areas of pathological electroencephalogram (EEG) activity and may even be absent if no recent seizure activity has occurred 7-9
- generalized cerebral atrophy, although may have an occipital preponderance 7-9
- prior to development of POLG-related neurological manifestations, features of chronic hepatic encephalopathy, such as increased signal intensity on T1-weighted sequences in the globi pallidi and subthalamic regions, or acute hepatic encephalopathy may be seen 10
- these features may be detected in prenatal MRI 8
MR spectroscopy may demonstrate an elevated lactate signal intensity and a reduced NAA signal intensity, in areas of high diffusion signal 10.
Treatment and prognosis
Treatment focuses on symptoms control. Sodium valproate as an agent for epilepsy control is generally avoided due to its hepatotoxicity which may result in rapid decline in liver function in patients with a predisposition to liver failure, such as those with Alpers syndrome 6.
Alpers syndrome often progresses rapidly, leading to death in childhood 5.
History and etymology
Alpers syndrome was first described by Bernard Alpers in 1931 11. In the late 1970s, Peter Huttenlocher associated further patient phenotypes with that of Alpers' patient and the eponymous name was coined 12.
- 1. Sofou K, Moslemi AR, Kollberg G, Bjarnadóttir I, Oldfors A, Nennesmo I, Holme E, Tulinius M, Darin N. Phenotypic and genotypic variability in Alpers syndrome. (2012) European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 16 (4): 379-89. doi:10.1016/j.ejpn.2011.12.006 - Pubmed
- 2. Hayhurst H, Anagnostou M-E, Bogle HJ, Grady JP, Taylor RW, Bindoff LA, McFarland R, Turnbull DM, Lax NZ. Dissecting the neuronal vulnerability underpinning Alpers’ syndrome: a clinical and neuropathological study. (2019) Brain Pathology. 29 (1): 97. doi:10.1111/bpa.12640 - Pubmed
- 3. Montine TJ, Powers JM, Vogel FS, Radtke RA. Alpers' syndrome presenting with seizures and multiple stroke-like episodes in a 17-year-old male. (1995) Clinical neuropathology. 14 (6): 322-6. Pubmed
- 4. Visser NA, Braun KP, van den Bergh WM, Leijten FS, Willems CR, Ramos L, van den Bosch BJ, Smeets HJ, Wokke JH. Juvenile-onset Alpers syndrome: interpreting MRI findings. (2010) Neurology. 74 (15): 1231-3. doi:10.1212/WNL.0b013e3181d90005 - Pubmed
- 5. Rahman S, Copeland WC. POLG -related disorders and their neurological manifestations. (2019) Nature Reviews Neurology. 15 (1): 40. doi:10.1038/s41582-018-0101-0
- 6. Gordon N. Alpers syndrome: progressive neuronal degeneration of children with liver disease. Developmental medicine and child neurology. 48 (12): 1001-3. doi:10.1017/S0012162206002209 - Pubmed
- 7. Engelsen, Bernt A., Tzoulis, Charalampos, Karlsen, Bjørn, Lillebø, Atle, Lægreid, Liv M., Aasly, Jan, Zeviani, Massimo, Bindoff, Laurence A.. POLG1 mutations cause a syndromic epilepsy with occipital lobe predilection. Brain. 131 (3): 818. doi:10.1093/brain/awn007
- 8. Wolf NI, Rahman S, Schmitt B, Taanman JW, Duncan AJ, Harting I, Wohlrab G, Ebinger F, Rating D, Bast T. Status epilepticus in children with Alpers' disease caused by POLG1 mutations: EEG and MRI features. Epilepsia. 50 (6): 1596-607. doi:10.1111/j.1528-1167.2008.01877.x - Pubmed
- 9. Saneto RP, Friedman SD, Shaw DW. Neuroimaging of mitochondrial disease. Mitochondrion. 8 (5-6): 396-413. doi:10.1016/j.mito.2008.05.003 - Pubmed
- 10. Flemming K, Ulmer S, Duisberg B, Hahn A, Jansen O. MR Spectroscopic Findings in a Case of Alpers-Huttenlocher Syndrome. American Journal of Neuroradiology. 23 (8): 1421. Pubmed
- 11. Alpers BJ. Diffuse progressive degeneration of gray matter of cerebrum. Arch. Neurol. Psychiat. 25: 469-505, 1931.
- 12. Huttenlocher PR, Solitare GB, Adams G. Infantile diffuse cerebral degeneration with hepatic cirrhosis. (1976) Archives of neurology. 33 (3): 186-92. Pubmed