PDC Deficiency (PDCD)

Mitochondrial Disease Types

What is PDCD?

Pyruvate dehydrogenase complex (PDC) deficiency (also known as PDC deficiency, or more commonly PDCD) is a rare mitochondrial disorder that causes impaired carbohydrate metabolism. This impairment results in neurological problems and the buildup of a chemical called lactic acid in the blood[1,2,3].

The age of onset and the severity of the symptoms of PDCD vary widely among affected individuals. The disorder can present[2]:

  • before birth, as brain abnormalities detected by routine ultrasound.
  • during infancy or early childhood, as developmental delay and chronic neurologic symptoms, including seizures.
  • in late childhood as a movement disorder such as ataxia (rarely).

In general, individuals with PDCD symptom onset before birth or in infancy die during childhood, sometimes from lactic acidosis. Those that present later may survive into adulthood[1,3].

Unfortunately, there is no cure for PDCD. Available treatments can address some of its symptoms and may increase lifespan in some cases[2,4]. Additionally, new potential therapies are being explored in clinical trials[5].

What causes PDCD?

PDCD is caused by mutations in the genes that make up or affect the activity of the PDC. The PDC is located in the mitochondria, the cell’s “powerhouse”, that makes almost all the energy (called ATP) we need to survive. The PDC is vital in converting the carbohydrates (sugars) we eat into ATP. Thus, when the PDC is defective, our cells suffer from a lack of ATP, and the signs and symptoms of PDCD reflect such energy failure[1,2].

An estimated 85% of cases of PDCD are caused by a mutation in the PDHA1 gene[6].

Other genes that have been linked to PDCD include[3]:

  • DLAT
  • DLD
  • PDHB
  • PDHX
  • PDP1

Although mutations that cause PDCD can be inherited, the majority appear by chance.

What are the symptoms of PDCD?

Almost all individuals with PDCD experience[1,2,3]:

  • developmental delay
  • poor muscle tone (hypotonia)
  • brain cell loss

Other common signs and symptoms of PDCD include:

  • seizures
  • incoordination (ataxia)
  • weakness, numbness, and/or pain in the hands and feet (peripheral neuropathy)
  • intellectual disability
  • respiratory distress
  • abnormal facial features
  • abnormally small head size
  • abnormal brain structures
  • lethargy
  • poor feeding
Rarely, PDCD has also been associated with eye symptoms, such as drooping eyelids (ptosis), eye misalignment (strabismus), involuntary eye movement (nystagmus), and worsening vision (optic atrophy)[1,2,3].

How do I know if my loved one has PDCD?

To determine if your loved one has PDCD, his or her health care provider will consider their medical history and family history. They will also perform the following[3]:

  • molecular genetic testing for a mutation that causes PDCD
  • physical examination
  • measurements of the level of lactate and pyruvate in the blood, urine, and/or cerebrospinal fluid (CSF)
  • testing of the activity of the PDC in patient cells collected via biopsy
  • magnetic resonance imaging (MRI) of the brain

*Note: Ohio residents may receive a newborn blood plasma amino acid test as part of a study aimed at developing a newborn screen for PDCD and other mitochondrial disorders[6].

What are the treatments for PDCD?

Unfortunately, there is no cure or specific treatment for PDCD that has been approved by the Food and Drug Administration.

However, available options for symptom management and general supportive care include[5]:

  • ketogenic diet for developmental delay, seizures, and incoordination[4]
  • physical and occupational therapy to help with muscle function
  • thiamine (may benefit rare individuals)[1]

Since PDCD can be caused by inherited mutations, genetic counseling for the family may also be recommended[3].

Are there any clinical trials for PDCD?

A phase 3 trial of oral dichloroacetate (DCA)[6] in the U.S. (NCT 02616484) will be completed in 2023. A phase 1 trial of oral phenylbutyrate (PB)[7] in Italy (NCT 03734263) has recently begun (as of April 2023).

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 PDCD families.

How can my family cope with PDCD?

We are here to help. UMDF serves a number of families coping with PDCD. 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, disease specific support meetings, and more. They’ll also connect you with a UMDF ambassador, likely a fellow PDCD patient or family member, who can help support and guide you through your questions.

What are the next steps if my loved one has PDCD?

  • 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 PDCD 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 PDCD and other mitochondrial diseases. There are currently over 30 active mitochondrial disease clinical studies. 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 where you – and your friends and family – can let Congress know we need their support. Click here to sign up.

What is UMDF doing about PDCD?

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

    • Research & Funding: UMDF has provided more than $15 million in research funding to find treatments for diseases like PDCD. UMDF advocacy has helped secure an additional $55 million in federal funding via the Department of Defense and National Institutes of Health.
    • 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. 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 PDCD, 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.
    • Regulatory Advocacy: The U.S. Food and Drug Administration (FDA) hosted a virtual FDA listening session, co-hosted by the United Mitochondrial Disease Foundation and MitoAction, focused on Pyruvate Dehydrogenase Complex Deficiency (PDCD). The session, The Voice of the Pyruvate Dehydrogenase Complex Deficiency (PDCD) Patient Community, was held virtually on Friday, September 8, 2023. Click here to download a full report of the session. Click here to view the PDCD Patient and Caregiver Survey Result.

Where can I find more information on PDCD?

For more information on PDCD, please visit:

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. DeBrosse SD, Okajima K, Zhang S, et al. Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype. Mol Genet Metab. 2012;107(3):394-402. doi:10.1016/j.ymgme.2012.09.001
  1. Patel KP, O’Brien TW, Subramony SH, Shuster J, Stacpoole PW. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol Genet Metab. 2012;106(3):385-394. doi:10.1016/j.ymgme.2012.03.017
  1. Ganetzky R, McCormick EM, Falk MJ. Primary Pyruvate Dehydrogenase Complex Deficiency Overview. 2021 Jun 17. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK571223/
  1. Sofou K, Dahlin M, Hallböök T, Lindefeldt M, Viggedal G, Darin N. Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes. J Inherit Metab Dis. 2017;40(2):237-245. doi:10.1007/s10545-016-0011-5
  1. Bedoyan JK, Hage R, Shin HK, et al. Utility of specific amino acid ratios in screening for pyruvate dehydrogenase complex deficiencies and other mitochondrial disorders associated with congenital lactic acidosis and newborn screening prospects. JIMD Rep. 2020;56(1):70-81. Published 2020 Aug 16. doi:10.1002/jmd2.12153
  1. Stacpoole PW, Shuster J, Thompson JLP, Prather RA, Lawson LA, Zou B, Buchsbaum R, Nixon SJ. Development of a novel observer reported outcome tool as the primary efficacy outcome measure for a rare disease randomized controlled trial. Mitochondrion 2018; 59-63 https://doi.org/10.1016/j.mito.2017.11.003
  1. Ferriero R, Manco G, Lamantea E, Nusco E., Ferrante MI, Sordino P, Stacpoole PW, Lee B, Zeviani M, and Brunetti-Pierri N. (2013). Phenylbutyrate therapy for pyruvate dehydrogenase complex deficiency and lactic acidosis. Sci. Transl. Med.5, 175ra31. https://doi.org/10.1126/scitranslmed.3004986