Matter Over Mind: The Realities of a Common Muscle Disease

Georgirene D. Vladutiu, PhD

The adult form of carnitine palmitoyltransferase (CPT) II deficiency has been labeled as the most common lipid myopathy in humans even though its prevalence has not as yet been determined in the general population. This autosomal recessively inherited disease has earned this distinction in part, because the other lipid disorders with muscle symptoms, such as very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency or long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency are very rare. CPT II deficiency may be even more prevalent than generally believed due to under-recognition of the disorder. Before discussing the characteristics of the disease and which individuals may be at risk for having it, it is important to understand what role CPT II and closely related enzymes normally play in lipid metabolism.

CPT exists as two genetically and functionally distinct mitochondrial enzymes (CPT I and CPT II). CPT I is embedded in the outer mitochondrial membrane and CPT II is associated with the inner mitochondrial membrane. They work together with carnitine-acylcarnitine translocase, an inner mitochondrial membrane enzyme, to facilitate the transport of lipids (fatty acids) across these membranes and into the mitochondrial matrix where they ultimately are converted to energy in the form of ATP. There is a liver form and a muscle form of CPT I that are encoded by genes on different chromosomes. There is only one ubiquitous form of CPT II in the body.

Several disorders of varying severity and age of onset have been reported due to defects in either the CPT I or CPT II enzymes. Liver CPT I deficiency is a rare infantile disorder with the hallmark of potentially fatal hypoglycemia and the inability to produce ketone bodies. To date, no cases of muscle CPT I deficiency have been reported and a deficiency of this enzyme may be lethal given the importance of the enzyme for heart function. CPT II deficiency has three distinct clinical forms: the common adult myopathic form, the lethal neonatal form affecting many body systems, and the severe infantile form which has liver, heart and skeletal muscle involvement.

The adult-onset disease is the common lipid myopathy referred to above and is characterized by muscle pain and stiffness and, in severe cases, myoglobinuria (the presence of dark-colored urine caused by the release of myoglobin from damaged muscle tissue) occurring primarily in young adults who are exposed to certain triggers. Individuals with this disorder may be symptom-free until they are exposed to prolonged exercise, fasting, extremes in temperature, viral infection, sleep deprivation or general anesthesia during surgery. Even though the disorder is called an “adult-onset” disease, it has been reported in people of all ages including young children.

Not only does the age of onset vary in CPT II deficiency but also there has been a wide range of symptoms reported among affected individuals. Because some individuals remain asymptomatic until triggered, there are likely to be many people with the disorder who are completely unaware of its existence. The disorder has even been called “benign” in some scientific reports which could not be farther from the truth among individuals who have experienced life-threatening kidney failure following a severe episode of rhabdomyolysis (trigger-induced muscle breakdown). At the other end of the spectrum there are people with mild episodic symptoms who have never have had a major attack and wonder if they have a disease at all or if their symptoms are “all in their mind.” They may never have gone to a physician for evaluation or if they did, their doctor may not have known enough about the disease to recognize it or how to treat it. Many people have been initially misdiagnosed as having other disorders, such as fibromyalgia or chronic fatigue syndrome, before arriving at the correct diagnosis of CPT II deficiency. For additional reading about the features of this disease, patient surveys on the struggles of obtaining a diagnosis, common triggers, and effective treatment are regularly presented in a newsletter about CPT II deficiency, entitled The Spiral Notebook (Managing Editor, Barbara Seaman). This semi-annual publication also contains feature articles about the experiences of individual patients, scientific updates, nutritional tips, and important website resources. The newsletter may be found on the web at

More than 20 different mutations and 3 polymorphisms (so-called harmless changes in the gene’s DNA) have been identified in the CPT2 gene among patients with CPT II deficiency and many other mutations are yet to be identified. One mutation, known as Ser113Leu, accounts for 60% of the mutant alleles (different forms of the gene) responsible for the common adult form of the disease. Different mutations in the CPT2 gene are believed to account for the varying severities of CPT II deficiency. However, other genetic or environmental factors may also be involved in modifying the expression of the disease because unusual patient situations have been observed. For example, individuals in the same family with the same mutations causing their disease have been known to have varying symptoms (see the Spring 2000 issue of The Spiral Notebook for a personal account). Also, individuals known as “manifesting carriers” have been reported to have muscle symptoms although they have only 1 mutation in the CPT2 gene together with residual CPT II enzyme activity of about 50% of normal in their muscle biopsy. As carriers of a recessively inherited disorder, they should not be expected to have symptoms. In most cases, manifesting carriers either have a second metabolic muscle disease that compounds the CPT2 gene defect to produce symptoms or they are exposed to severe triggering such as combinations of triggers that may coexist during rigorous military training or during training for competitive sports.

In the recent past, CPT II deficiency could only be diagnosed by biochemical analysis of a muscle biopsy. While this remains the best specimen for a definitive diagnosis, the enzyme’s activity can also be measured in white blood cells and mutation screening can be performed for the common mutations in white blood cells or buccal (cheek) cells, both relatively noninvasive specimens. The problem with mutation screening for virtually any genetic disorder is that one cannot be certain that all mutations have been identified. However, a screen for a panel of 6 known mutations in the CPT2 gene rules out over 90% of causative mutations.

The treatment of CPT II deficiency is variable and often patient-specific considering the wide variation in symptoms and lifestyles. There are certain things affected individuals can do to prevent symptoms. Most try to avoid the triggers such as prolonged vigorous exercise, fasting, and extremes in temperature. If they need to have surgery with general anesthesia, they alert their physician to the need for alternative anesthetics that do not trigger symptoms, plus most people with CPT II deficiency wear Medic Alert tags describing their condition and the associated risks. Individuals with CPT II deficiency try to keep their water intake high, especially if they are athletes, and keep sources of simple carbohydrates handy such as Gatorade and Powerade. However, there are specific treatment regimens for CPT II-deficient patients, including the administration of MCT Oil (medium-chain triglycerides) or carnitine that should be established on a case by case basis under the supervision of a metabolic physician and nutritionist. Patients should not try to treat themselves without the involvement of these professionals because they may have adverse or suboptimal effects from certain treatments.

In spite of the fact that there is no cure for CPT II deficiency, it is a manageable disease in most cases. It is important that primary care physicians are informed about this disorder and its manifestations so that they can recognize the symptoms, provide genetic testing for a diagnosis and ameliorative treatment. Frequently patients who remain undiagnosed wonder if their symptoms are imagined or exaggerated because of the chronic nature of the disease. We have documented numerous cases of individuals who finally received a confirmed diagnosis after years of searching, and sometimes after many fruitless muscle biopsies.

CPT II deficiency is not a matter of mind. It is a real disease with real symptoms. We received very positive feedback recently from the wife of a 42-year old patient who was diagnosed by enzyme and mutation analysis in blood. She claimed that her husband was a “whole new man” after finally having a name for his condition. For 25 years he had thought his pain, cramps, and stiffness with exercise, as well as chronic bouts of myoglobinuria, represented an undefined disorder that he longed to understand. At the age of 20, he underwent a muscle biopsy that was considered to be normal but it was never tested for CPT II deficiency. After many years, he noticed on his own that he could decrease the risk of cramping by eating prior to activity or shorten the time to recovery by drinking carbohydrate-containing beverages after physical activity. Once he had his diagnosis, he knew that his symptoms were characteristic of a specific disorder and a new life began where his condition would no longer be trivialized as a case of mind over matter. Now he and his physicians were able to take control over his symptoms, improve his quality of life and that of his family and, perhaps most importantly for his peace of mind, he had a diagnosis.


Bonnefont J-P, Demaugre F, Prip-Buus C, Saudubray J-M, Brivet M, Abadi N, Thuillier L. Carnitine palmitoyltransferase deficiencies. Molec Genet Metab 68:424-440, 1999

Smail D, Gambino L, Boles C, Vladutiu GD: Rapid, cost-effective gene mutation screening for carnitine palmitoyltransferase II deficiency using whole blood on filter paper, Clin Chem 1999; 45:2035-2038

Dr. Vladutiu is an Associate Professor of Pediatrics, Neurology, and Pathology at the State University at Buffalo School of Medicine and Biomedical Sciences and also is the Director of The Robert Guthrie Biochemical Genetics Laboratory at Children’s Hospital of Buffalo. The laboratory performs over 3,000 esoteric diagnostic tests annually for inborn errors of metabolism with a particular emphasis on the metabolic myopathies and mitochondrial disease. Dr. Vladutiu is the principal investigator of a research grant from the Muscular Dystrophy Association awarded to improve the diagnosis of carnitine palmitoyltransferase II deficiency disorders. While seeking to understand the genotype (gene mutations) and phenotype (clinical symptoms) correlations in this disease, her laboratory performs both biochemical and molecular diagnostic testing for this and other relatively common disorders of exercise intolerance. Contact Dr. Vladutiu’s office at 716-888-1379.