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Alpers-Huttenlocher syndrome

Reviewed June 2011

What is Alpers-Huttenlocher syndrome?

Alpers-Huttenlocher syndrome is one of the most severe of a group of conditions called the POLG-related disorders. The conditions in this group feature a range of similar signs and symptoms involving muscle-, nerve-, and brain-related functions. Alpers-Huttenlocher syndrome typically becomes apparent in children between ages 2 and 4. People with this condition usually have three characteristic features: recurrent seizures that do not improve with treatment (intractable epilepsy), loss of mental and movement abilities (psychomotor regression), and liver disease.

People with Alpers-Huttenlocher syndrome usually have additional signs and symptoms. Most have problems with coordination and balance (ataxia) and disturbances in nerve function (neuropathy). Neuropathy can lead to abnormal or absent reflexes (areflexia). In addition, affected individuals may develop weak muscle tone (hypotonia) that worsens until they lose the ability to control their muscles and movement. Some people with Alpers-Huttenlocher syndrome lose the ability to walk, sit, or feed themselves. Other movement-related symptoms in affected individuals can include involuntary muscle twitches (myoclonus), uncontrollable movements of the limbs (choreoathetosis), or a pattern of movement abnormalities known as parkinsonism.

Affected individuals may have other brain-related signs and symptoms. Migraine headaches, often with visual sensations or auras, are common. Additionally, people with this condition may have decreased brain function that is demonstrated as sleepiness, inability to concentrate, irritability, or loss of language skills or memory. Some people with the condition may lose their eyesight or hearing. People with Alpers-Huttenlocher syndrome can survive from a few months to more than 10 years after the condition first appears.

How common is Alpers-Huttenlocher syndrome?

The prevalence of Alpers-Huttenlocher syndrome is approximately 1 in 100,000 individuals.

What genes are related to Alpers-Huttenlocher syndrome?

Alpers-Huttenlocher syndrome is caused by mutations in the POLG gene. This gene provides instructions for making one part, the alpha subunit, of a protein called polymerase gamma (pol γ). Pol γ functions in mitochondria, which are structures within cells that use oxygen to convert the energy from food into a form cells can use. Mitochondria each contain a small amount of DNA, known as mitochondrial DNA (mtDNA), which is essential for the normal function of these structures. Pol γ "reads" sequences of mtDNA and uses them as templates to produce new copies of mtDNA in a process called DNA replication.

Most POLG gene mutations change single protein building blocks (amino acids) in the alpha subunit of pol γ. These changes result in a mutated pol γ that has a reduced ability to replicate DNA. Although the mechanism is unknown, mutations in the POLG gene often result in a reduced number of copies of mtDNA (mtDNA depletion), particularly in muscle, brain, and liver cells. MtDNA depletion causes a decrease in cellular energy, which could account for the signs and symptoms of Alpers-Huttenlocher syndrome.

A mutation in the POLG gene has not been identified in approximately 13 percent of people diagnosed with Alpers-Huttenlocher syndrome. Researchers are working to identify other genes that may be responsible for the condition.

Related Gene(s)

Changes in this gene are associated with Alpers-Huttenlocher syndrome.

  • POLG

How do people inherit Alpers-Huttenlocher syndrome?

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Where can I find information about diagnosis or management of Alpers-Huttenlocher syndrome?

These resources address the diagnosis or management of Alpers-Huttenlocher syndrome and may include treatment providers.

  • Gene Review: POLG-Related Disorders (http://www.ncbi.nlm.nih.gov/books/NBK26471/)
  • Genetic Testing Registry: Progressive sclerosing poliodystrophy (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0205710)
  • Mayo Clinic (http://www.mayoclinic.org/medical-edge-newspaper-2010/dec-24a.html)
  • United Mitochondrial Disease Foundation: Diagnosis of Mitochondrial Disease (http://www.umdf.org/site/c.otJVJ7MMIqE/b.5692885/k.E71C/Getting_a_Diagnosis.htm)

You might also find information on the diagnosis or management of Alpers-Huttenlocher syndrome in Educational resources (http://www.ghr.nlm.nih.gov/condition/alpers-huttenlocher-syndrome/show/Educational+resources) and Patient support (http://www.ghr.nlm.nih.gov/condition/alpers-huttenlocher-syndrome/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about Alpers-Huttenlocher syndrome?

You may find the following resources about Alpers-Huttenlocher syndrome helpful. These materials are written for the general public.

  • MedlinePlus - Health information

    • Health Topic: Balance Problems (http://www.nlm.nih.gov/medlineplus/balanceproblems.html)
    • Health Topic: Degenerative Nerve Diseases (http://www.nlm.nih.gov/medlineplus/degenerativenervediseases.html)
    • Health Topic: Genetic Brain Disorders (http://www.nlm.nih.gov/medlineplus/geneticbraindisorders.html)
    • Health Topic: Liver Diseases (http://www.nlm.nih.gov/medlineplus/liverdiseases.html)
    • Health Topic: Movement Disorders (http://www.nlm.nih.gov/medlineplus/movementdisorders.html)
    • Health Topic: Seizures (http://www.nlm.nih.gov/medlineplus/seizures.html)
  • Genetic and Rare Diseases Information Center - Information about genetic conditions and rare diseases (http://rarediseases.info.nih.gov/gard/5783/resources/resources/1)

  • Additional NIH Resources - National Institutes of Health

    • National Institute of Neurological Disorders and Stroke: Alpers Disease (http://www.ninds.nih.gov/disorders/alpersdisease/alpersdisease.htm)
    • National Institute of Neurological Disorders and Stroke: Myoclonus (http://www.ninds.nih.gov/disorders/myoclonus/myoclonus.htm)
    • National Institutes of Health Rare Diseases Clinical Research Network: North American Mitochondrial Disease Consortium (http://rarediseasesnetwork.epi.usf.edu/NAMDC/index.htm)

  • Educational resources - Information pages

    • Cleveland Clinic: Mitochondrial Diseases (http://my.clevelandclinic.org/disorders/mitochondrial_disease/hic_myths_and_facts_about_mitochondrial_diseases.aspx)
    • Cleveland Clinic Online Health Chats: Understanding Mitochondrial Disorders (http://my.clevelandclinic.org/multimedia/transcripts/parikh_understanding_mitochondrial_disorders.aspx)
    • Madisons Foundation: Alpers Disease (http://www.madisonsfoundation.org/index.php?option=com_mpower&task=disease&diseaseID=347)
    • Mayo Clinic (http://www.mayoclinic.org/medical-edge-newspaper-2010/dec-24a.html)
    • Mayo Clinic: Mitochondrial Disease Biobank (http://www.mayo.edu/research/centers-programs/mitochondrial-disease-biobank/overview)
    • MitoAction (http://www.mitoaction.org/)
    • Orphanet (http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=726)

  • Patient support - For patients and families

    • American Liver Foundation: The Progression of Liver Disease (http://www.liverfoundation.org/abouttheliver/info/progression/)
    • Epilepsy Foundation (http://www.epilepsyfoundation.org/)
    • Family Village: Mitochondrial Disorders (http://www.familyvillage.wisc.edu/lib_mito.htm)
    • Muscular Dystrophy Association: Facts About Mitochondrial Myopathies (http://mda.org/sites/default/files/publications/Facts_MITO_P-216.pdf)
    • National Organization for Rare Disorders: Alpers Disease (http://www.rarediseases.org/rare-disease-information/rare-diseases/byID/610/viewAbstract)
    • United Mitochondrial Disease Foundation: Mitochondrial Disease (http://www.umdf.org/site/c.otJVJ7MMIqE/b.5692879/k.3851/What_is_Mitochondrial_Disease.htm)

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

  • Gene Reviews - Clinical summary (http://www.ncbi.nlm.nih.gov/books/NBK26471/)

  • Genetic Testing Registry - Repository of genetic test information

    • Genetic Testing Registry: Progressive sclerosing poliodystrophy (http://www.ncbi.nlm.nih.gov/gtr/conditions/C0205710)
  • ClinicalTrials.gov - Linking patients to medical research (http://clinicaltrials.gov/ct2/results?term=%22Alpers-Huttenlocher%20syndrome%22%20%5BDISEASE%5D%20OR%20%22Diffuse%20Cerebral%20Sclerosis%20of%20Schilder%22%20%5BDISEASE%5D%20OR%20NCT00831948%20%5BID-NUMBER%5D%20OR%20NCT01148550%20%5BID-NUMBER%5D%20OR%20NCT00457314%20%5BID-NUMBER%5D%20OR%20NCT01001585%20%5BID-NUMBER%5D)
  • PubMed - Recent literature (http://www.ncbi.nlm.nih.gov/pubmed?term=((Alpers-Huttenlocher%20syndrome%5BTIAB%5D)%20OR%20(Alpers%20syndrome))%20AND%20english%5Bla%5D%20AND%20human%5Bmh%5D%20AND%20%22last%203600%20days%22%5Bdp%5D)
  • OMIM - Genetic disorder catalog (http://omim.org/entry/203700)

What other names do people use for Alpers-Huttenlocher syndrome?

  • Alpers diffuse degeneration of cerebral gray matter with hepatic cirrhosis
  • Alpers disease
  • Alpers progressive infantile poliodystrophy
  • Alpers syndrome
  • diffuse cerebral sclerosis of Schilder
  • progressive sclerosing poliodystrophy

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about Alpers-Huttenlocher syndrome?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding Alpers-Huttenlocher syndrome?

acids ; ataxia ; autosomal ; autosomal recessive ; cell ; cerebral gray matter ; cirrhosis ; depletion ; DNA ; DNA replication ; gene ; hepatic ; hypotonia ; involuntary ; migraine ; mitochondria ; muscle tone ; mutation ; myoclonus ; neuropathy ; oxygen ; parkinsonism ; prevalence ; protein ; psychomotor ; recessive ; regression ; sclerosis ; subunit ; syndrome

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • Chan SS, Longley MJ, Copeland WC. The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. J Biol Chem. 2005 Sep 9;280(36):31341-6. Epub 2005 Jul 16. (http://www.ncbi.nlm.nih.gov/pubmed/16024923?dopt=Abstract)
  • Gene Review: POLG-Related Disorders (http://www.ncbi.nlm.nih.gov/books/NBK26471/)
  • Milone M, Massie R. Polymerase gamma 1 mutations: clinical correlations. Neurologist. 2010 Mar;16(2):84-91. doi: 10.1097/NRL.0b013e3181c78a89. Review. (http://www.ncbi.nlm.nih.gov/pubmed/20220442?dopt=Abstract)
  • Moraes CT, Shanske S, Tritschler HJ, Aprille JR, Andreetta F, Bonilla E, Schon EA, DiMauro S. mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases. Am J Hum Genet. 1991 Mar;48(3):492-501. (http://www.ncbi.nlm.nih.gov/pubmed/1998336?dopt=Abstract)
  • Nguyen KV, Sharief FS, Chan SS, Copeland WC, Naviaux RK. Molecular diagnosis of Alpers syndrome. J Hepatol. 2006 Jul;45(1):108-16. Epub 2006 Feb 20. (http://www.ncbi.nlm.nih.gov/pubmed/16545482?dopt=Abstract)
  • Rocher C, Taanman JW, Pierron D, Faustin B, Benard G, Rossignol R, Malgat M, Pedespan L, Letellier T. Influence of mitochondrial DNA level on cellular energy metabolism: implications for mitochondrial diseases. J Bioenerg Biomembr. 2008 Apr;40(2):59-67. doi: 10.1007/s10863-008-9130-5. Epub 2008 Apr 16. (http://www.ncbi.nlm.nih.gov/pubmed/18415670?dopt=Abstract)
  • Stumpf JD, Copeland WC. Mitochondrial DNA replication and disease: insights from DNA polymerase γ mutations. Cell Mol Life Sci. 2011 Jan;68(2):219-33. doi: 10.1007/s00018-010-0530-4. Epub 2010 Oct 8. Review. (http://www.ncbi.nlm.nih.gov/pubmed/20927567?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: June 2011
Published: June 17, 2013