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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 www.spiralnotebook.org.
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.
References:
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 at gdv@buffalo.edu
or 716-888-1379.
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