When is CPT II deficiency really CPT+?

Back and Next

When is CPT II deficiency really CPT+ ?

--Georgirene D. Vladutiu, Ph.D.

Right puzzle person

The typical symptoms of adult-onset CPT II deficiency include pain, cramps and stiffness following prolonged exercise. Other factors, or “triggers,” can also induce symptoms including fasting, sleep deprivation, extremes in temperature, viral infection or anesthesia. If symptoms become severe, they can lead to muscle damage (known as rhabdomyolysis) accompanied by dark, coca-cola colored urine due to the release of a substance called myoglobin from the muscles.

Usually individuals with this form of CPT II deficiency feel relatively normal between episodes and, with guidance from their physicians and a nutritionist, learn how to avoid triggering events.

Some cases, however, are not typical. At least 2 categories of atypical individuals exist:
those who may have symptoms of CPT II deficiency but on biochemical analysis of their muscle biopsy either do not have CPT deficiency and have a different metabolic muscle disease or only have a partial reduction in CPT enzyme activity (40-60% of normal) and are considered “manifesting carriers.” Carriers of just one mutation in the CPT2 gene derived from only one parent usually are not symptomatic. However, with a manifesting carrier, the mutation may be severe enough to cause symptoms when the individual is appropriately triggered or a co-existing disease may also be present that contributes to the disease process.

those who have a typical CPT II enzyme deficiency with reductions of at least 80% and have unusual symptoms such as continuous (rather than episodic) pain and stiffness regardless of exposure to triggers, a progressive course, weakness and perhaps an earlier age of onset of symptoms. These individuals may also have a co-existing disorder or a combination of 2 particularly severe mutations in the CPT2 gene or both.

The diagnosis of these complex disorders is not always straightforward. Certain relatively non-invasive tests can be performed before considering muscle biopsy. One test known as the ischemic forearm exercise test measures the production of both lactic acid and ammonia in the blood during exertion. This test helps to rule out triggerable muscle diseases caused by defects in glycogen metabolism, such as McArdle’s disease (a deficiency in phosphorylase enzyme activity), and the most common metabolic muscle disease, myoadenylate deaminase deficiency, also known as MADD.

MADD occurs in every 1 in 50 individuals in the general population and every 1 in 5 individuals is a carrier for one mutation in the MAD gene. The symptoms of MADD are similar to those of McArdle’s disease and CPT II deficiency, however, not everyone with MADD is symptomatic making it one of the most puzzling disorders of exercise intolerance.

While it may be very unusual for individuals to have co-existing metabolic disorders with each caused by 2 mutations, carrier status for more than one disorder is predicted to be more common. Eventually it will become routine to screen a blood sample from individuals with exercise intolerance for mutations causing the common triggerable muscle diseases. These studies are performed now on a research basis and it is possible to detect from 85 to 95% of the disease-causing mutations depending on the disorder.

However, the problem with mutation screening is that if the patient has none of the mutations it does not absolutely rule out any of the disorders in the screening. Muscle biopsy provides the most thorough diagnostic evaluation with microscopic inspection as well as biochemical analysis for specific enzyme deficiencies.

If an individual with a partial or more severe CPT II deficiency has features that are atypical of the usual symptoms of CPT deficiency, then it may be advisable to look for a second co-existing disorder causing the patient to have what may be called “CPT+.”

CPT + McArdle's--A case history

A number of patients with exercise intolerance disorders have been reported to have co-existing disorders. These individuals are either double carriers for 2 or more diseases that contribute additively to create their symptoms or they actually have 2 complete disorders.

As an example, 10 years ago we diagnosed McArdle’s disease in a 25-year old woman who had exercise intolerance. She had a complete absence of phosphorylase enzyme activity in her muscle biopsy. Seven years later on follow up, she was found to be severely disabled and unable to walk or write. She also had painful swelling in her arms and thighs. Recently we screened DNA isolated from her muscle biopsy for the most common mutations causing CPT II deficiency, McArdle’s disease and MADD and found that she was a double carrier for mutations in the phosphorylase gene and for the common S113L mutation in the CPT2 gene. She is likely to have a second yet to be identified mutation in the phosphorylase gene because of the complete absence of that enzyme in her muscle biopsy. (There was no tissue remaining to measure residual CPT activity.)

Although we cannot say with absolute certainty that this patient’s extraordinary symptoms are due to her co-existing muscle diseases, reports of other combinations among the triggerable myopathies have also been associated with increased severity of symptoms.
--Georgirene D. Vladutiu, Ph.D.

Dr. Vladutiu is Associate Professor of Pediatrics, Neurology and Pathology at the State University of New York at Buffalo School of Medicine. The recipient of an MDA research grant, her recent work has focused on molecular genetic studies of carnitine palmitoyltransferase deficiencies.

More cases of CPT+

Partial CPT deficiency plus partial Complex I deficiency in an adult male

CPT deficiency plus myoadenylate deficiency in two children, a brother and sister

Partial CPT deficiency plus a second fatty acid oxidation defect in an adult male

CPT deficiency plus a global mitochondrial defect in an adult female

References:
Vladutiu GD. Muscle Nerve 2000; 23:1157-59
Vladutiu GD at al. Mol Genet Metab 2000;70:134-141
Vockley J et al. Mol Genet Metab 2000;71:10-18

Related links:
Myoadenylate deaminase deficiency

Biochemical and clinical presentation, diagnosis, treatment and inheritance.

Genotype/phenotype correlation in carnitine

palmitoyltransferase II deficiency: lessons from a compound heterozygous patient

Running on Empty
December 1999 article from Quest on CPT II deficiency and other metabolic myopathies.

For more about the differences between McArdle's Disease and CPT deficiency, visit Split the difference.

For more about metabolic myopathies, visit In the long run and Battery not included.

The majority of patients with myoadenylate deaminase deficiency have presented with muscle cramps or myalgias following exercise and 67% of them had their first symptoms in childhood or adolescence. Muscle weakness has been found in 27% of patients, but muscle wasting has not been reported. Some studies have failed to find an association between the enzyme deficiency and exertional myalgia or cramps. Such discrepancies may relate to the fact that the defect may be primary (inherited) or secondary to an associated muscular disorder.
--ESSPPMM

© 1999-2000 The Spiral Notebook All Rights Reserved