What is Leigh syndrome?

Leigh syndrome (or Leigh’s disease) is a mitochondrial disorder, sometimes called subacute necrotizing encephalomyelopathy (SNE). Although rare, experts regard it as one of the most common clinical presentations of a mitochondrial disorder[1]. Leigh syndrome affects an estimated 1 in 40,000 individuals. In the Faroe Islands, the incidence is higher (1 in 1,700 individuals)[2].

Patients with Leigh syndrome typically have initial symptoms in infancy or childhood, usually within the first 2 years of life. In some cases, symptoms may start in adolescence or adulthood[3]. The disease may also cause heart, kidney, vision, and breathing complications in addition to the primary neurological manifestations. Many patients with Leigh syndrome may die due to respiratory failure in childhood, but those with less severe disease and a later onset may live into their mid-teens or early 20s[4].

Unfortunately, there is no cure for Leigh syndrome. However, supportive treatments may make a difference in an affected individuals’ quality of life.

What causes Leigh syndrome?

Leigh syndrome is caused by an inherited mutation in mitochondrial DNA or nuclear DNA. Most individuals with the disorder have a mutation in nuclear DNA; only 10-20% have a mutation in mitochondrial DNA.

More than 75 disease genes have been associated with Leigh syndrome. Most of these genes encode components critical to the metabolic processes responsible for energy generation in the cell. The list includes[5]:

  • Pyruvate dehydrogenase genes – PDHA1, PDHB, PDHX, DLAT, DLD, LIPT1, LIAS, TPK1, SLC19A3, SLC25A19
  • Complex I genes – MTND1, MTND2, MTND3, MTND4, MTND5, MTND6, NDUFV1, NDUFV2, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFA1, NDUFA2, NDUFA9, NDUFA10, NDUFA12, NDUFAF2, NDUFAF5, NDUFAF6, FOXRED1
  • Complex II genes – SDHA, SDHAF1
  • CoEnzyme Q10 genes – PDSS2
  • Complex III genes – UQCRQ, BCS1L, TTC19
  • Complex IV genes – MTCO3, NDUFA4, SURF1, COX10, COX15, SCO2, PET100, LRPPRC, TACO1, ETHE1
  • Complex V genes – MTATP6
  • Mitochondrial DNA maintenance genes – FBXL4, POLG, SUCLA2, SUCLG1
  • Mitochondrial translation genes- MTTI, MTTK, MTTL1, MTTV, MTTW, MTFMT, GTPBP3, TRMU, EARS2, FARS2, IARS2, NARS2, GFM1, GFM2, TSFM, C12orf65, PNPT1
  • Other genes – HIBCH, ECHS1, SERAC1, AIFM1, BTD

Because many individuals with Leigh syndrome remain without a genetic diagnosis, experts believe that this list is not yet complete. In some cases, acquired conditions can result in similar findings to Leigh syndrome, but the accepted definition of Leigh syndrome requires clear evidence of a primary mitochondrial disease as the cause of the symptoms.

What are the symptoms of Leigh syndrome?

The most common symptoms of Leigh syndrome are[3]:

  • developmental delay or regression
  • muscle weakness
  • lack of muscle control (ataxia)
  • diminished muscle tone (hypotonia)
  • tremors

Many individuals with Leigh syndrome also have other symptoms of nervous system abnormalities, including[6]:

  • seizures
  • involuntary eye movement (nystagmus)
  • drooping eyelids (ptosis)
  • weakness in the eye muscle
  • eye disease (optic atrophy and retinitis pigmentosa)
  • difficulty swallowing (dysphagia)
  • poor feeding
  • deafness

Some individuals with Leigh syndrome also experience heart, endocrine or GI problems[7]..

How do I know if my loved one has Leigh syndrome?

To determine if your loved one has Leigh syndrome, his or her health care provider will evaluate their symptoms and may perform some of the following tests[8]:

  • genetic testing for a Leigh syndrome-associated mutation
  • measurements of the level of lactic acid in the blood or cerebrospinal fluid (CSF)
  • blood tests for metabolic enzyme activity
  • a muscle sample (biopsy)
  • brain-imaging, such as a computed tomography (CT) scan or magnetic resonance imaging (MRI)

What are the treatments for Leigh syndrome?

Unfortunately, there is no cure or specific treatment for most causes of Leigh syndrome. However, available treatments can help manage symptoms and improve life for individuals and their families. These treatments include:[8]:

  • vitamins such as thiamine (Vitamin B1), coenzyme Q10, L-carnitine, and/or a vitamin cocktail that may benefit some individuals.
  • dietary interventions for individuals experiencing malnutrition or failure to thrive
  • a high fat, low carbohydrate (ketogenic) diet for individuals with Leigh syndrome who have a deficiency of the pyruvate dehydrogenase enzyme complex
  • ophthalmological services for symptoms of the eye
  • breathing support for some patients
  • antiepileptic drugs for those with seizures
  • medications and devices to address spasticity and dystonia (involuntary movements)

Since Leigh syndrome may be an inherited disorder and its inheritance pattern varies depending on whether the causative mutation is in nuclear DNA or mitochondrial DNA, genetic counseling for the family may also be recommended.

Are there any clinical trials for Leigh syndrome?

To see what trials you may qualify for, visit our Clinical Trials page – which also included a Clinical Trials Finder Tool. We also highly encourage you to join our patient registry, mitoSHARE, where we are actively recruiting families with Leigh syndrome.

How can my family cope with Leigh syndrome?

We are here to help. UMDF serves a number of families coping with Leigh syndrome. We suggest you reach out to our Support & Education Team – online, via email at support@umdf.org or phone at (888) 900-6486 – who can suggest a host of resources including doctors,  Leigh syndrome specific support meetings, and more. They’ll also connect you with a UMDF ambassador, likely a fellow Leigh syndrome patient or family member, who can help support and guide you through your questions.

 

What are the next steps if my loved one has Leigh syndrome?

  • Get Support
    Connect with our Support & Education Team online, via email at support@umdf.org or phone at (888) 900-6486.
  • Join our patient registry, mitoSHARE
    We are actively recruiting Leigh syndrome families to participate in our patient registry, mitoSHARE. Patient registries like mitoSHARE are an integral part in charting a course toward treatments and cures for Leigh syndrome and other mitochondrial diseases. There are currently over 30 active mitochondrial disease clinical trials. Next generation patient registries like mitoSHARE are an integral part of expanding that number.
  • Become an advocate
    Ask your representatives to prioritize mitochondrial disease research and support via the UMDF Advocacy Center. We’ll send regular action items so you – and your friends and family – can let Congress know where we need their support. Click here to sign up.

What is UMDF doing about Leigh syndrome?

UMDF is helping chart a path toward treatments and eventual cure of mitochondrial diseases like Leigh syndrome through:

  • Research & Funding: UMDF has provided more than $14 million in research funding to find treatments for diseases like Leigh syndrome. UMDF advocacy has helped secure an additional $55 million in federal funding via the Department of Defense and National Institutes of Health.  Additionally, along with five other organizations, UMDF is part of the Leigh Syndrome International Consortium, which collectively have pledged $1 million USD to fund research with a focus on improving diagnosis, therapeutic development and optimized patient care for Leigh syndrome patients. Click here to watch a video on the consortium.
  • Data: Over two decades ago, UMDF pioneered patient registries for the mitochondrial disease community. Today, our next generation patient registry, mitoSHARE, is helping chart a path toward the treatment and eventual cure of mitochondrial diseases.
  • Patient Support: Thousands of families just like you depend upon UMDF for support and education on diseases like Leigh syndrome. Attendance at our support meetings annually tops 7,000, including disease specific support meetings for families.
  • Clinician Support: To help educate clinicians on diseases like Leigh syndrome, we feature monthly Bench to Bedside clinician seminars, host the annual Mitochondrial Medicine Symposium, support the Mitochondrial Care Network, and educate clinicians on our Mito U platform.

Where can I find more information on Leigh syndrome?

I didn’t find what I’m looking for here. What should I do?

UMDF Is here to help. Contact the Support Line at (888) 900-6486 weekdays from 8:00am to 5:00pm EST to connect with our Patient Concierge. Or, via email contact support@umdf.org.

References

  1. Munaro M, Tiranti V, Sandonà D, et al. A single cell complementation class is common to several cases of cytochrome c oxidase-defective Leigh’s syndrome. Hum Mol Genet. 1997;6(2):221-228. doi:10.1093/hmg/6.2.221
  1. Rahman S, Blok RB, Dahl HH, et al. Leigh syndrome: clinical features and biochemical and DNA abnormalities. Ann Neurol. 1996;39(3):343-351. doi:10.1002/ana.410390311
  1. Hong CM, Na JH, Park S, Lee YM. Clinical Characteristics of Early-Onset and Late-Onset Leigh Syndrome. Front Neurol. 2020;11:267. Published 2020 Apr 15. doi:10.3389/fneur.2020.00267
  1. Sofou K, De Coo IF, Isohanni P, et al. A multicenter study on Leigh syndrome: disease course and predictors of survival. Orphanet J Rare Dis. 2014;9:52. Published 2014 Apr 15. doi:10.1186/1750-1172-9-52
  1. Lake NJ, Compton AG, Rahman S, Thorburn DR. Leigh syndrome: One disorder, more than 75 monogenic causes. Ann Neurol. 2016;79(2):190-203. doi:10.1002/ana.24551
  1. Chang X, Wu Y, Zhou J, Meng H, Zhang W, Guo J. A meta-analysis and systematic review of Leigh syndrome: clinical manifestations, respiratory chain enzyme complex deficiency, and gene mutations. Medicine (Baltimore). 2020;99(5):e18634. doi:10.1097/MD.0000000000018634
  1. Finsterer J. Leigh and Leigh-like syndrome in children and adults. Pediatr Neurol. 2008;39(4):223-235. doi:10.1016/j.pediatrneurol.2008.07.013
  1. Baertling F, Rodenburg RJ, Schaper J, et al. A guide to diagnosis and treatment of Leigh syndrome. J Neurol Neurosurg Psychiatry. 2014;85(3):257-265. doi:10.1136/jnnp-2012-304426