Anaplerotic Therapy in Propionic Acidemia

Nicola Longo

Status and phase: Completed; Phase 1

Conditions: Propionic Acidemia

Treatments: Drug: disodium citrate; Drug: glutamine; Drug: ornithine alpha ketoglutarate

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00645879

24806

ANA-PA-001 (Other Identifier)

1R21DK077415-01A1 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

The objective of this project is to define whether nutritional supplements (ornithine alpha-ketoglutarate, glutamine, or citrate) capable of filling-up the citric acid cycle (anaplerotic therapy) can improve hyperammonemia, glutamine levels, and outcome in patients with propionic acidemia. Ornithine alpha-ketoglutarate, glutamine, and citrate are commonly used as nutritional supplements specially by athletes to increase muscle strength. They can be mixed with formula or other foods.

Full description

Propionic acidemia is caused by deficiency of propionyl CoA carboxylase that impairs the supply of succinyl CoA to the citric acid (Krebs) cycle. The Krebs cycle is responsible for obtaining energy from food in the form of ATP. ATP is essential for muscle contraction and correct functioning of all organs including the hearth, the kidney, and the pancreas.

Patients with propionic acidemia develop hyperammonemia at birth that recurs during episodes of metabolic decompensation. We found that plasma levels of the amino acids glutamine/glutamate are reduced in patients with propionic acidemia and decrease, rather than increase (like in urea cycle defects or other types of hyperammonemia) with hyperammonemia. Since alpha-ketoglutarate is the main source of endogenous glutamate/glutamine synthesis, our hypothesis is that chronic hyperammonemia and progressive dysfunction of multiple organs in patients with propionic acidemia is due to a functional insufficiency of the citric acid (Krebs) cycle with defective production of alpha-ketoglutarate. The basic deficiency of intermediates of the Krebs cycle can decrease production of ATP and explain the low muscle tone, progressive organ dysfunction, and poor long-term outcome of patients with propionic acidemia.

To test this hypothesis, we will test whether dietary supplementation with alpha ketoglutarate precursors (in the form of ornithine alpha ketoglutarate, glutamine or citrate) can improve plasma ammonia and overall outcome in patients with propionic acidemia. In this study, a limited number of patients (3) with propionic acidemia will be given the 3 different nutritional supplements and studied at regular intervals to see whether their glutamine/glutamate levels improve and if they have fewer episodes of hyperammonemia or acute decompensation. The supplement that produces the best increase in plasma glutamine levels will be tested for an additional 30 weeks. Children's development and motor skills will be tested before and after therapy to see if there is any improvement. The study will be conducted on outpatients at the University of Utah Clinical Research Center. If the initial trial is successful, we will try to launch a national trial involving multiple centers in the US and abroad to involve the largest number of patients possible.

The current therapy of propionic acidemia is based on restriction of precursors of propionic acid (methionine, valine, isoleucine, threonine, odd chain fatty acids, cholesterol) and administration of carnitine to help remove toxic organic acids. This therapy is not effective in preventing the long-term complications of the disease, even in children identified at birth by newborn screening. This research will test a completely new way of treating patients with severe and disabling metabolic disorders using replacement of downstream products involved in the generation of energy (ATP). This approach, if effective, could be extended to a number of other diseases, including other organic acidemias and mitochondrial disorders.

Enrollment: 3 patients

Sex: All

Ages: 5 to 12 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Confirmed diagnosis of propionic acidemia (propionyl CoA carboxylase deficiency)

Exclusion criteria

• Severe illness with cardiac or hepatic compromise that could affect study results
• Use of other investigative therapies
• Inability to comply with study directions

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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3 participants in 1 patient group

OKG, Glutamine, and Disodium Citrate

Experimental group

Description:

Ornithine Alpha Ketoglutarate for 4 weeks, followed by 2 week washout period. 4 weeks Glutamine, followed by 2 week washout period. 4 weeks Disodium Citrate, followed by 2 to 12 week washout period. Then continue an additional 30 weeks on Disodium Citrate (drug producing the best increment in plasma glutamine levels).

Treatment:

Drug: ornithine alpha ketoglutarate

Drug: glutamine

Drug: disodium citrate