Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology



Propionic acidemia (PA) is a rare genetic disorder that affects how the body breaks down certain amino acids and fatty acids. People with PA have high levels of toxic substances in their blood and urine, which can cause serious health problems. PA can also affect the brain and behavior, leading to intellectual disability and autism in some cases. But what are the biological mechanisms behind these outcomes? A new study published in Molecular Psychiatry sheds some light on this question.


The study


The researchers studied 33 people with PA who were enrolled in a natural history study at the National Institutes of Health. They collected detailed information on their medical history, genetic mutations, biochemical markers, and brain imaging. They also assessed their cognitive and adaptive abilities, and diagnosed them with intellectual disability (ID) or autism spectrum disorder (ASD) if they met the criteria.


The researchers then looked for associations between the neurodevelopmental outcomes and the biological parameters. They used artificial intelligence techniques to identify the most important factors that predicted ID or ASD in PA.


The results


The researchers found that 61% of the participants had ID and 39% had ASD.

They also found that ID and ASD were associated with different biological markers.

ID was associated with several indicators of disease severity and mitochondrial dysfunction, such as:

  • Higher levels of propionylcarnitine and 2-methylcitrate in the blood, which reflect the accumulation of toxic metabolites
  • Higher levels of erythropoietin in the blood, which reflects the stimulation of red blood cell production due to low oxygen levels
  • Higher levels of FGF21 and GDF15 in the blood, which reflect the stress response of mitochondria, the energy-producing organelles in the cells
  • Lower levels of glutamine in the blood and urine, which reflects the depletion of an important amino acid for brain function
  • Lower capacity to oxidize propionate, which reflects the impaired activity of the enzyme PCC


ASD, on the other hand, was only associated with two factors:

  • Higher levels of erythropoietin in the blood, which may indicate a link between low oxygen levels and ASD
  • Lower levels of glutamine in the blood, which may indicate a role of glutamine in ASD


Interestingly, the level of glycine, another amino acid that is affected by PA, was not associated with either ID or ASD.


The implications


The study suggests that ID and ASD in PA are influenced by different biological mechanisms. ID seems to be related to the overall severity of the disease and the damage to the mitochondria, while ASD seems to be related to specific factors that affect brain development and function.


The study also identifies potential biomarkers and surrogate endpoints for ID and ASD in PA, which could help monitor the disease progression and the response to treatments. For example, measuring the levels of FGF21 and GDF15 in the blood could indicate the degree of mitochondrial stress, and measuring the capacity to oxidize propionate could indicate the effectiveness of PCC enzyme replacement therapy.


The study also highlights the need for more research on the molecular and cellular pathways that link PA to ID and ASD, and the potential interventions that could prevent or reverse these outcomes.



How common is propionic acidemia?


Propionic acidemia is a rare disorder that affects about 1 in 100,000 to 1 in 250,000 people worldwide. The prevalence may vary depending on the ethnic background and the frequency of consanguineous marriages (marriages between relatives). For example, propionic acidemia is more common in Saudi Arabia, where it affects about 1 in 5,000 people.


What are the symptoms of propionic acidemia?


The symptoms of propionic acidemia can vary from person to person, depending on the type and severity of the mutations, the age of onset, the dietary intake, and the environmental factors. Some of the common symptoms include:

  • Poor feeding, vomiting, dehydration, and lethargy in newborns and infants
  • Failure to thrive, growth retardation, and developmental delay in children
  • Metabolic crises, which are episodes of severe illness triggered by infections, fasting, stress, or dietary changes, characterized by acidosis (excess acid in the blood), hyperammonemia (high ammonia levels in the blood), hypoglycemia (low blood sugar), and ketosis (high ketone levels in the blood)
  • Neurological symptoms, such as seizures, stroke, coma, intellectual disability, autism, movement disorders, and neuropathy
  • Cardiac symptoms, such as cardiomyopathy, arrhythmias, endocarditis, and pericarditis
  • Hepatic symptoms, such as liver failure, hepatomegaly, liver fibrosis, and liver cancer
  • Renal symptoms, such as renal tubular acidosis, chronic kidney disease, acute kidney injury, and nephrocalcinosis
  • Skeletal symptoms, such as rickets, osteoporosis, osteomalacia, and osteopenia
  • Hematological symptoms, such as anemia, leukopenia (low white blood cell count), thrombocytopenia (low platelet count), and pancytopenia (low blood cell count)
  • Immunological symptoms, such as immunodeficiency, autoimmunity, and inflammation

What are the treatments for propionic acidemia?


There is no cure for propionic acidemia, but the symptoms and complications can be managed with various treatments. The main treatments include:

  • A low-protein diet that restricts the intake of the propiogenic amino acids (isoleucine, valine, methionine, and threonine) and provides adequate calories, vitamins, and minerals.
  • Supplements of carnitine, biotin, and other cofactors that help the body use propionate and other organic acids.
  • Medications that lower the levels of ammonia and acid in the blood, such as sodium benzoate, sodium phenylacetate, sodium bicarbonate, and citrate.
  • Dialysis or hemofiltration to remove excess toxins from the blood during acute metabolic crises or when the medications are not effective.
  • Liver transplantation or combined liver-kidney transplantation to replace the defective enzyme and improve the metabolic function. However, these procedures are risky and may not prevent the neurological damage or the mitochondrial dysfunction caused by propionic acidemia.



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