When to Consider Inborn Errors of Metabolism

These are considered rare, yet this reinforces the pattern of never looking for them, leading them to likely be massively under-diagnosed.

Disclaimer: I am not a medical doctor and this is not medical advice.

The following is a slightly modified excerpt from How to Interpret Ketone Ratios and Lactate/Pyruvate Ratios and deserves a place on its own.

By the way, don’t forget today is day 2 of the Mitochondrial Energy Summit. More on that below.

There are over 1400 inborn errors of metabolism. Many of them are as rare as one in 100,000 incidence, give or take. Yet, these add up. For example, if we just assume on some back-of-the-envelope math that all 1400 have 1 in 100,000 incidence, this would bring the total to 1.4% of the population. This is not an accurate number but is just a simple demonstration of how many rare things can be collectively common.

Heterozygosity is extremely common, and absolutely affects metabolism, even if it does not result in disease. I have argued in favor of its relevance in the full article, and will do so more comprehensively in the future. Here, I will comment only on when to look for diagnosable diseases, often but not always inherited in an autosomal recessive manner and thus requiring two copies of a defective gene.

These should not be conflated with diseases about which nothing can be done. Many are treatable, and some are curable when caught at the right time. Treatments can include megadoses of a vitamin cofactor or a shift of macronutrients, such as keto or low-fat, as examples.

The main reasons to suspect an inborn error of metabolism are that other more common explanations for constellations of health problems have been ruled out and systematic investigations of metabolism have revealed biochemical clues on such tests as amino acids, organic acids, acylcarnitines, acylglycines, and fuel molecules such as fatty acids, glucose, ketones, pyruvate, and lactate. These tests will cast a huge net that will provide clues toward the lion’s share of, though not all, inborn errors of metabolism.

Onsets can range anywhere from in utero to old age.

Proper diagnosis is hampered by two beliefs that are common but completely false: 1) inborn errors have onsets mainly in infancy, and never in adulthood; and 2) failure to capture the “pathognomonic” diagnostic patterns on the above-mentioned tests “rules out” a disorder. Thus, underdiagnosis, misdiagnosis, and failure to properly follow through on diagnostic testing is common, and, in my opinion, unfortunately the norm. For a full treatment, see the Saudubray textbook, Inborn Metabolic Diseases: Diagnosis and Treatment. What is contained herein is largely drawn from that textbook.

The patterns discussed below do not rule in or rule out such a disorder but they present patterns that can be used to increase the probability the solution lies in this direction.

Adult-onset inborn errors of metabolism often present with atypical psychosis, depression, unexplained coma, peripheral neuropathy, difficulty coordinating movements, intermittent paralysis of one half of the body, dementia, movement disorders, or epilepsy.

Onsets ranging from childhood to adulthood are often associated with intermittent illnesses that are repeating, unresponsive to treatment, or unexplained, often precipitated by immune events such as infection or vaccination, especially when accompanied by fever, or by prolonged or intense exercise or changes in dietary nutrients that stress the faulty system. For example, running marathons, eating keto, intermittent fasting, and MCT oil would put significant strain on fatty acid oxidation. Overdoing protein could stress the urea cycle or any one of the many different pathways of amino acid metabolism. Eating carbs would stress carbohydrate metabolism. Megadosing thiamin could stress the respiratory chain.

Coma, strokes, stroke-like episodes, vomiting, lethargy, seizures, improper muscle tone, or difficulty coordinating movements are often involved. Psychiatric symptoms include hallucinations, delirium, dizziness, aggressiveness, anxiety, agitation, and schizophrenic-like behavior.

Developmental delay that does not recover as expected with time or treatment, mental retardation, and autism are often caused in whole or in part by inborn errors of metabolism.

For infant-onset disorders, the signs are extremely non-specific, such as poor muscle tone, respiratory distress, poor sucking reflex, vomiting, diarrhea, dehydration, lethargy, and seizures. The signs are often confused with more common causes such as hypoxia or infection. Major red flags are a sibling having previously died in infancy or an infant relentlessly deteriorating despite treatment with no explanation, but these need not be present, and are often not present.

For in utero-onset disorders, about 30-40% of inborn errors lead to craniofacial abnormalities at birth. Some associated with the production of toxic molecules from food and can make the mother sick from eating when she is pregnant, and a wide variety of highly non-specific abnormalities are often present in imaging.

Respiratory chain disorders are comprised of hundreds of specific defects with dozens of symptom clusters, and many patients have unique constellations that seem to copy and paste from the different clusters. This makes generalizations difficult.

However, the following is a highly abbreviated list of signs and symptoms that may occur, and having any random copy-and-paste selection of them could be a result of a respiratory chain disorder:

Peripheral neuropathy, stroke-like episodes, seizures, difficulty controlling movements, Parkinsonism, cognitive decline, drooping eyes, paralysis of the eye muscles, numerous types of problems with vision, hearing loss and auditory dysfunction, cardiomyopathy, Wolff-Parkinson-White Syndrome (a conduction defect causing a rapid heart rate), pulmonary hypertension, defects in kidney function, liver failure, problems with gut motility, deficiency of pancreatic enzymes, chronic diarrhea, diverse forms of endocrine dysfunction including diabetes and thyroid problems, low sex hormones, immune deficiency, various deficiencies of blood cells including anemia, neutropenia, and pancytopenia, exercise intolerance, rhabdomyolysis, excessive hair growth or baldness, fragile and twisted hair, bluish discoloration of the skin, loose skin, petechiae (pinpoint blood spots that reach the skin), and lipoma.

The mitochondrial respiratory chain constitutes about half of mitochondrial energy metabolism and in and of itself has 297 different known genetic defects. Many pharmaceutical drugs are respiratory chain poisons in vitro, and other such toxins can be found among food components, supplements, and environmental toxins. Among the many are the toxic alcohols (methanol, ethylene glycol, and diethylene glycol), the anesthetic propofol, reverse transcriptase inhibitors, cyanide, salicylates, metformin, and berberine. Ciprofloxacin appears to impair the respiratory chain by damaging mitochondrial DNA.

Since it is extremely rare to have a genetic disorder with 100% penetrance — meaning everyone with the genes gets the clinical presentation of the disease — and when we do have such estimates it is probably a result of sampling error, it is a complete fallacy to create a dichotomy between genetic disorders and environmental triggers. The stresses on the vulnerable system can be responsible for modifying the onset, including bringing it forward into a developmental stage that elicits a specific permanent phenotype, such as autism, and can be responsible for increasing the penetrance of the disorder when they are imposed on a population.

If you suspect you or a loved one have an inborn error of metabolism, you can seek out a local clinical geneticist. I would look for someone whose profile shows they are actively publishing in the field. Anecdotally, I believe it is extremely common for people with inborn errors of metabolism to be turned away with an “I can’t help you” when using this approach because they do not fit a cookie-cutter set of “pathognomonic” diagnostic criteria. It is probably best to find high-quality scientific papers about a suspected disorder, and find an author of one of those papers who operates a clinical practice in an accessible area, and try to get an appointment with them, but this might be a bit like trying to get an appointment with House and winding up seeing Foreman, Cameron, or Chase.

I am not an expert in this field and I am not a health care practitioner, so I cannot diagnose or treat any of these diseases. However, as a data analyst, I can help discern probabilities and provide educational help about action plans as they relate to nutrition in the context of a consultation.

The Mitochondrial Energy Summit is currently ongoing, and my friend and colleague Gabrielle Lyon is presenting today. Wendy Myers is tomorrow, Stephanie Seneff is Friday, Terry Wahls is Saturday, and Morley Robbins and I are on Sunday. I spend a portion of my talk covering this issue, though the bulk of my talk is about more common aspects of mitochondrial health.

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