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Nutritional Aspects of Neuromuscular Diseases
REHABILITATION OF NEUROMUSCULAR DISEASE
1047-9651198 $8.00
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NUTRITIONAL ASPECTS OF NEUROMUSCULAR DISEASES Megan A. McCrory, PhD, Nancy C. Wright, MA, and David D. Kilmer, MD
Both rapidly progressive Duchenne muscular dystrophy (DMD) and the slowly progressive neuromuscular diseases (SP-NMDs) are associated with loss of skeletal muscle, gain of excess body fat, and changes in energy metabolism and physical activity over time. This article reviews several nutritional techniques and their adequacy in monitoring changes in the nutritional status of these individuals as the diseases progress. In addition, nutritional interventions that aim to counteract the effects of the disease process and increase the quality of life in individuals with DMD are reviewed. Finally, new research on physical activity and body composition, and the potential for development of secondary chronic diseases in SP-NMD are discussed. DUCHENNEMUSCULARDYSTROPHY
There is a high prevalence of obesity in DMD. Excess body weight in DMD subjects burdens already weakened muscles and makes breathing and mobility difficult. Older DMD patients tend to lose weight as the disease progresses and there is an acceleration in the breakdown of This work was supported by Grant No. HI33830026 from the US Department of Education.
From the Energy Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts (MAM); the Department of Nutrition (MAM)and the Department of Physical Medicine and Rehabilitation (NCW), University of California, Davis, Davis; and the Department of Physical Medicine and Rehabilitation, University of Califomia, Davis Medical Center, Sacramento (DDK), Califomia
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skeletal muscle. The progressive loss of lean tissue in DMD can be monitored through nutritional techniques. Nutritional interventions including weight loss and dietary supplementation have been evaluated for their effectiveness in increasing quality of life in DMD patients and attenuating the disease process. The following section will review studies on nutritional assessment and management of DMD. Stature
Accurate measurement of stature of DMD patients is difficult because of the high incidence of spinal deformities and scoliosis in this population, particularly in the latter stages of the disease. Most crosssectional data38,47, 52 indicate that attained height in the first decade is similar to or slightly below the median height-for-age of the Xational Center for Health Statistics' but falls markedly below the fifth percentile during the second decade.3sMcDonald et a P found that this dramatic reduction in standing height relative to normal values occurred mainly in wheelchair users with contractures and scoliosis. These authors stated that although the incidence of scoliosis did not differ between boys in the lowest versus the highest quartile for stature, they could not rule out differences between quartiles in the severity of the scoliosis which potentially may have biased their results. However, longitudinal data from Eiholzer et all6 indicate slow linear growth in DMD patients beginning shortly after birth, before scoliosis occurs. Thus, the decreased linear growth seen in DMD subjects of all ages may not, in fact, be measurement artifact. McDonald and colleagues38point out that a lack of normal muscle tension or weight bearing on the skeleton may in theory contribute to decreased linear growth in this population, but this has not been evaluated by adequate techniques. The relatively short stature of individuals with DMD also may be due in part to undernourishment because they often do not consume enough protein and energy to meet their nutritional needs.38,44 The hypothesis that skeletal development is reduced in DMD subjects is supported by their lower bone mineral density compared with age-matched controls.46 Within the DMD group, there was a significant inverse relationship between bone mineral density and age; this relationship was not found for able-bodied controls. Weight and Body Composition
The appropriateness of body weight in DMD patients has traditionally been evaluated against national standards of weight-for-age. It should be kept in mind, however, that weight-for-height may be a better index than weight-for-age for evaluating current nutritional status because weight-for-age does not take into account differences in height.19 A subject's weight may be appropriate for his or her age, but since DMD
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subjects tend to be short for their age, using weight-for-age alone may underestimate the prevalence of overweight in this population. However, as stated in the previous section, accurate measurements of height often are difficult to obtain in individuals with DMD because of the presence of spinal abnormalities and contractures. Overweight vs Underweight
Compared to the United States reference population, the prevalence of underweight (defined as weight-for-age
Figure 1. Percentage of Duchenne muscular dystrophy (DMD) subjects classified as underweight (weight-for-age90th percentile) compared to the US reference population (Hamill et al) (A) and the DMD ideal weight chart (Griffiths and Edwards) (6).Dotted line = expected prevalence of overweight and underweight based on a normal distribution; Open bar = underweight; hatched bar = overweight. (Data from McDonald CM, Abresch RT, Carter GT, et al: Profiles of neuromuscular diseases: Duchenne Muscular Dystrophy. Am J Phys Med Rehabil74:S70-92, 1995.)
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of DMD subjects, between the ages of 9 and 16.9, about 40%0 were classified as overweight (defined as weight-for-age >90th percentile). These data indicate that in early adolescence there may be a divergence of weight in the DMD population such that many have either an extremely low or extremely high weight for their age, and that somewhere near late adolescence most individuals with DMD become underweight. Similar patterns of weight-for-age were reported by Willig et al,65who studied a sample of 252 DMD patients. They reported that 54% of their subjects were above the 90th percentile in weight-for-age by age 13, and 54% were below the 10th percentile by age 18. Scott et a152link the development of obesity in DMD with loss of independent ambulation. However, McDonald et aP8 found no relationship between the presence of a high weight-for-age and either the age of wheelchair dependence, loss of strength, timed motor performance, functional grade status, pulmonary function, likelihood of ECG abnormalities, or age at death. One limitation of simply using body weight as a standard is that the composition of the weight is unknown. Weight is made up of both fat and lean tissue, with skeletal muscle contained in the latter. Knowing the composition of the body allows us to gain insight into how much of the weight is excess body fat, or how much weight loss is due to loss in muscle mass from progression of the disease. Because the evolution of DMD is associated with progressive loss of skeletal muscle, at a given weight-for-age patients with DMD will have a lower lean mass than able-bodied subjects. Thus, an individual with DMD ideally should weigh less than an able-bodied individual for a given age, since loss of muscle mass over time is inevitable and excess body fat is undesirable. In 1988, Griffiths and Edwards24proposed an ideal weight chart for DMD patients, which was meant to serve as a guideline for weight management in this population. This theoretical chart was constructed from previous observations and assumes a 4% decline in muscle mass per year.14,Is, 57 The effect of this new chart on weight classification is that at a given age, DMD patients are classified at a higher percentile than they would be on the standard chart. For example, a 10-year-old DMD patient who weighs 25 kg appears to be in the 10th percentile of weight-for-age based on the normal chart, but is actually at the 50th percentile on the DMD chart. This was illustrated in the study by McDonald et a1,38 who found that a much higher percentage of their subjects were classified as overweight when using the Griffiths and chart than the standard weight chart (Fig. 1B). The Griffiths and Edwards2*chart was tested for validity in 1993 by another set of investigator^.^^ To evaluate the chart, Willig et a1" compiled data from previous studies and also used their own data to produce a final sample size of 252 DMD subjects. They compared their weight-for-age data with the reference chart for French patientss3 and also the new DMD ideal weight chart proposed by Griffiths and E d ~ a r d s These . ~ ~ authors concluded that while the chart is a valid tool for monitoring weight in DMD patients, it may slightly underestimate the effect of the disease.
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Whole-body Composition and Estimates of Skeletal Muscle Mass Whole-body composition, and thus lean tissue mass, in DMD has been estimated with highly specialized techniques such as magnetic resonance imaging?l computed t0mography,4~~ltrasonography,2~ potassium-40 counting? 33 and potassium-40 dilution.14In addition, estimates of muscle mass in DMD can be accomplished biochemically by 24-hour urinary creatinine, and skeletal muscle degradation can be estimated from 24-hour urinary 3-methylhistidine rnea~urements.~~-~~, 44 However, these methods are either tedious or not readily available, and are not well suited to routine clinical use. Two recent studies have used dual energy x-ray absorptiometry (DEXA) to assess whole-body composition in DMD.31,46 Using this technique, the body mass can be divided into regional and total body bone mineral, fat tissue, and soft lean tissue masses. The major portion of the latter is skeletal muscle; thus, determination of lean soft tissue mass by DEXA provides a proxy measurement of skeletal muscle mass. DMD patients have been shown to have a higher body fat mass and a lower lean soft tissue mass than controls.31,46 Palmieri et a146documented significant changes in body composition with increasing age in DMD. While the percentage of fat tissue mass increased with increasing age, the percentage of lean soft tissue mass decreased with increasing age. These relationships did not exist for control subjects. Further, these authors reported associations between the percentage of lean soft tissue mass and upper and lower extremity functional scores and manual muscle testing scores. Thus, DEXA may be useful for documenting changes in nutritional status with disease progression and responses to therapeutic interventions. Use of Anthropometry in DMD
Upper Arm Muscle Area. In the absence of highly technical equipment such as DEXA, simple anthropometric techniques can be used to determine the upper arm muscle cross-sectional area (UAMA) using the following formula by Frisancho et alls:
UAMA = [(C - (T X TSK))']/~T where C = mid-upper-arm circumference and TSK = triceps skinfold thickness. This equation has been found to overestimate mid-arm muscle area by 20% to 25%, and thus underestimates muscle atrophy.28However, expressing UAMA as a percentage of the median normal value negates this error, since the normal values also are overestimated by the same amount. In addition, the precision of estimates of UAMA by trained examiners is 7%; thus, it cannot be used to measure changes that are smaller than this. It must be emphasized that this equation only provides a rough estimate of UAMA. Caution also must be exercised when using this equation for individuals with DMD because of infiltra-
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tion of skeletal muscle with fatty and connective tissue in this disease. For example, progressive increases in absolute values of UAMA with increasing weight-for-age were noted in DMD patients.65However, when expressed in terms of Z-scores (number of standard deviations from the median normal value), DMD patients who were underweight had a higher UAMA Z-score than those who were overweight. Skinfold Thickness. Development of adiposity in DMD patients can be monitored by measuring the thickness of the subcutaneous fat layer at different sites and following the procedures recommended by Lohman et a1.34Willig et aP5compared skinfold measurements at biceps, triceps, subscapular, and suprailiac sites with weight-for-age classifications in 109 patients. They concluded that the subscapular and su.prailiac sites were the most useful for correctly classifying an individual as overweight (above the 90th percentile in weight-for-age), but none of the skinfold sites proved useful for classifying an individual as underweight. This result can be explained by the fact that underweight in DMD is associated with a lowered muscle mass, which is not measured by skinfold thickness. Using the sum of five skinfold sites (triceps, subscapular, abdominal, suprailiac and thigh), about half of the DMD subjects in McDonald et al's study were significantly fatter than control~.~~ Energy Metabolism
It is not understood why some individuals with DMD develop obesity and others do not. Excess energy stores (ES) can be attributed to an imbalance between energy intake (EI) and energy expenditure (EE), since over the long term ES = EI - EE. Thus, obesity in DMD may result from excessive EI, or from reduced EE. The components of EE can be expressed as follows: EE
=
REE
+ DIT + EEPA
where REE is the resting energy expenditure, defined as the energy cost of maintaining the metabolic processes of the body while at rest; DIT is dietary induced thermogenesis, defined as the energy cost of digestion, absorption, and assimilation of nutrients ingested; and EEPA is the energy expenditure in physical activity. A reduction in any one or more of these components can lead to a reduction in EE and thus lead to weight gain, all else being equal. Hankard et a1 examined this issue in five obese and eight nonobese ambulatory DMD patients, and nine controls.26All three groups were similar in age and height. Weight-for-age did not differ between the nonobese DMD subjects and controls, but was substantially higher in the obese DMD subjects. Fat-free mass (FFM) (determined by bioelectric impedance) did not differ between the obese and non-obese DMD subjects, but both had a significantly lower FFM than control subjects. Thus, the excess body weight in the obese DMD group could be attrib-
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uted entirely to an excess fat mass (FM). REE, which is proportional to FFM, was significantly lower in the nonobese DMD subjects than in control subjects, but not in the obese DMD subjects. When REE was expressed per kg FFM, both obese and nonobese DMD subjects had a higher REE/kg FFM, but the difference was significant only between controls and the obese DMD group. EI was significantly lower in the obese DMD patients compared to the nonobese DMD patients and the controls. This may seem contradictory; however, it is a common finding that individuals underreport their EI,2O, 41 and obese adolescents also have been found to underreport their EI.* Finally, postabsorptive fat utilization (as indicated by the respiratory quotient during the REE measurement) was found to be decreased in both DMD groups, but significantly decreased only in the nonobese DMD group. The lack of a significant difference between the two DMD groups may be related to the low statistical power in this data set, owing to the relatively small sample size. Neither EEPA nor DIT were measured in this study, so it is unknown if there were differences among the groups in these variables. More research is needed in this area to determine the potential role of fat utilization, physical activity, and DIT in the development of obesity in DMD. In addition, longitudinal studies are warranted because it is difficult to draw conclusions about cause and effect with crosssectional data. The rapid decline in body weight seen in the latter stages of DMD has been attributed to a hypermetabolic ~ t a t e Specifically, .~ increased rates of muscle protein turnover, including increases in both degradation and synthesis rates, have been reported.', 40, 48, 63 In a rigorous crosssectional analysis of over 300 Japanese DMD subjects aged from 11 to 29 years, Okada et a1 present evidence for hypermetabolism in this d i s e a ~ eAn . ~ increase in the basal metabolic rate (BMR), expressed as a percentage of the predicted BMR for a given age, increased progressively with age. Energy and protein intakes were high relative to normal adult requirements. Despite this, body weight expressed as a percentage of the median standard value decreased from 72% to 49% with increasing age. In addition, daily excretion of creatinine and 3-methylhistidine relative to control values suggested hypercatabolism of skeletal muscle in these subjects. Thus, protein in the diet was not being utilized effectively for body protein synthesis. The authors concluded that energy and protein requirements are substantially higher in DMD subjects than one would expect based on age and weight alone, and that relative energy and protein deficiencies may be contributing to the increased protein catabolism seen in these patients. In a second paper, Okada and colleagues45describe procedures for estimating the dietary energy and protein needs of DMD subjects using the easily measured parameters of body weight and 24-hour nitrogen excretion. First, BMR as a percentage of the standard BMR for a given age is predicted from body weight. This predicted BMR then can be used to estimate the energy allowance based on standard factorial proced u r e ~(Alternatively, .~~ measured BMR can be used if possible.) Nitrogen
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intake is then estimated from 24-hour nitrogen excretion, and converted to protein intake (nitrogen intake X 6.25). Energy intake can then be estimated, assuming a constant protein intake as a percentage of energy intake (an average of 14.6% in their study). The validity of these predictions of energy intake and allowance was verified by noting significant positive correlations between the adequacy of the energy intake (energy intake as a percentage of energy allowance) and concentrations of serum proteins, which turn over rapidly and are sensitive to energy deficiency. The authors are currently studying whether increasing the energy intake of DMD patients has any effect on physiologic and physical parameters in this p ~ p u l a t i o n . ~ ~ Nutritional Interventions Energy and Protein Supplementation
Studies carried out in the 1950s on energy and protein supplementation yielded mixed results.12,13, 60, 67 More recently, the effect of energy supplementation on muscle wasting and functional capacity was studied in six DMD patients aged 10 to 20 years for 3 months.21The supplement, containing 1000 kcal and 37.2 g protein, was administered each night by nasogastric tube feedings while the patients were hospitalized. The supplement was meant to provide extra nutrition in addition to their normal daily intake. At the end of the experimental period, daily energy intake had increased only by an average of 364 kcal, indicating that in part the supplement substituted for their normal daily caloric intake. Protein intake increased by 11.5 g/d, or 0.66 g/kg body weight/d, and body weight increased by 4.1 kg. The gain in body weight was comprised of both muscle and adipose tissue, as indicated by anthropometric measurements. In addition, nitrogen balance became more positive after the intervention, and no change occurred in urinary 3-methylhistidine excretion, possibly indicating improved muscle protein synthesis with no change in muscle protein degradation. There were no changes in hematologic and biochemical parameters, liver function tests, pulmonary function tests, muscular strength, or a general activity index. However, had a control group that received a placebo been included in this study, it might have provided valuable information because it is unknown whether these parameters would have worsened without supplementation. Regardless, the positive effects on muscle metabolism in this study warrant further investigation. Branched-chain Ketoacid Supplementation
Based on the observations that muscle protein degradation is accelerated in DMD,', 40, 63 and administration of branched-chain ketoacids reduces protein breakdown in fasting obese subjects,5O Stewart et a156 conducted a trial of branched-chain ketoacid supplementation. The ket447
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oacids of the branched-chain amino acids leucine, valine, and isoleucine were administered orally as ornithine salts at a dosage of 0.45 g/kg body weightld for 4 days in nine boys with DMD, aged 5 to 9 years, in a metabo1.i~ward. An equivalent amount of protein was removed from the diet during this time. Urinary creatinine and 3-methylhistidine excretions decreased, indicating a small but significant reduction in muscle protein degradation as a result of the treatment, and no negative effects were noted. However, as pointed out by Griggs et al,23 there may be problems with using 3-methylhistidine excretion to measure changes in muscle mass. Nevertheless, the results of this study are encouraging, and further research should be conducted to determine the effects of longer-term branched-chain ketoacid supplementation on muscle physiology and function in these patients. Weight Reduction
The advantages of reduction of excess adipose tissue in DMD include a lessening of the burden on already weakened muscles and potential improvement in mobility and ease of breathing. However, weight reduction in obese DMD patients has not been advocated because of the fear that a reduction in caloric intake will lead to acceleration of loss of muscle tissue. Contrary to this notion, Edwards et all5 demonstrated that weight reduction through a medically supervised decrease in energy intake could be achieved successfully in DMD without compromising skeletal muscle mass. They used nitrogen balance techniques for measuring whole-body protein stores to show that during the diet, two DMD patients (one nonambulatory) remained in positive nitrogen balance except for an initial transient nitrogen loss. The authors reported an improvement in walking performance in the ambulatory subject and an improvement in self-image and self-reliance in the nonambulatory subject. Both of these are extremely positive outcomes. It should be emphasized, however, that this study was done in only two patients and larger studies are needed to determine the safety, efficacy, and longterm outcome of weight reduction in individuals with DMD.
SLOWLY PROGRESSIVE NMD
In comparison to the rapidly progressive DMD, little nutritional research has been done in the SP-NMDs. In addition, most of the nutritional studies in the slowly progressive forms have been done in individuals with myotonic dystrophy. Because it is often difficult to get a sufficiently large sample size by studying just one disease, many studies evaluate several diagnoses together as one group. The following section will review studies on body composition and energy metabolism in SP-NMD, including our own recent work on physical activity and accretion of excess body fat in these subjects.
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Body Composition
Body composition measurements by skinfolds? 29, 32, 39 DEXA,3l total body potassium,lO,14, 30 and total body water14 indicate that SP-NMD subjects have a lower FFM and a higher FM than able-bodied controls. Recently, a new technology for determining body composition has emerged that is ideally suited for adult SP-NMD subjects because it requires very little effort for both the subject and technician and the measurement procedure is relatively brief.ll This method, air displacement plethysmography (BOD POD Body Composition System, Life Measurement Instruments, Concord CA), utilizes Boyle's law to determine body volume and the principles of den~itometry~~ to determine FM and FFM. Results from this method compare favorably with those from hydrostatic weighing in able-bodied subjects.35Using this new technology, we recently compared the body composition of a group of male and female SP-NMD subjects (including myotonic dystrophy, hereditary motor and sensory neuropathy, limb-girdle syndrome, and spinal muscular atrophy diagnoses) with able-bodied subjects who were similar in age and weight.37As shown in Figure 2A and B, body weight and body mass index (BMI) were not significantly different between SP-NMD and control subjects. However, SP-NMD subjects had a higher percentage of
$::Ini:in
A
$ 6
Women
Men
B
Women
D
Women
20 25
8 15
c
10 5 0
Women
Men
Men
fi Men
Figure 2. Body composition measured by air displacement plethysmography of slowly progressive neuromuscular disease (NMD) subjects and controls similar in age and weight. NMD subjects had a higher percentage of body fat and a lower fat-free mass (FFM) than controls (P<0.01). Solid bar = SP-NMD; open bar = control. (Data from McCrory MA, Kim HR, Wright NC, et al: Energy expenditure, physical activity and body composition of ambulatory adults with hereditary neuromuscular disease. Am J Clin Nutr, in press.)
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body fat and a lower FFM than able-bodied subjects (Fig. 2C and D). We are continuing to study this group of SF-NMD patients to determine longitudinal changes in body composition and associations among body composition, dietary intake, physical activity, energy expenditure, and blood lipid variables in this population. Kanda et a1 utilized DEXA to show that the body compositions of SP-NMDs of myogenic versus neurogenic origins differ.31Subjects with myogenic atrophy (limb-girdle syndrome, facioscapulohumeral dystrophy, myotonic dystrophy, and polymyositis) had significantly higher fat-to-lean soft tissue ratios than did subjects with neurogenic atrophy (amyotrophic lateral sclerosis and spinocerebellar degeneration), even though the BMIs were similar in all patients. The slope of the regression between the fat-to-lean soft tissue ratio and BMI was significantly higher in subjects with myogenic muscular atrophy compared with controls; this was not the case for subjects with neurogenic atrophy. The authors concluded that fat infiltration into the muscles of subjects with myogenic atrophy is reflected by their increased fat-to-lean soft tissue ratio. Energy Metabolism
Resting Energy Expenditure Most studies on resting energy expenditure (REE, or basal metabolic rate, BMR, used interchangeably for the purposes of this review) in SPNMD have been done in subjects with myotonic dystrophy. This research indicates that male subjects with myotonic dystrophy have a lower BMR than do able-bodied control^,^, 8, 30* 62 which is not related to In addition, Welle et aP4reported a relatively low thyroid dysf~nction.~ BMR for a mixed group of SP-NMD subjects (seven myotonic dystrophy, one limb-girdle syndrome, one facioscapulohumeral dystrophy). In contrast, male subjects with limb-girdle syndrome had a BMR very similar to the predicted control value.44However, several standard equations are available for predicting BMR, and the value of the predicted BMR differs widely, depending on which equation is used.17 Thus, the conclusions drawn from comparison of BMR in SP-NMD subjects to predicted values will depend on which prediction equation is used. Because BMR depends somewhat on the amount of FFM present, one might expect SP-NMD subjects to have a relatively low BMR. Thus, it often is conventional to normalize BMR for FFM or some index of FFM such as total body potassium. Josefowicz et a130 reported an elevated BMR/total body potassium ratio in men with myotonic dystrophy, suggesting hypermetabolism. However, the authors noted that this hypermetabolism may not be due to skeletal muscle itself, but to other tissues that may contribute to a higher proportion of overall metabolism. In fact, MTelle et al" argue that it is incorrect to express BMR relative to FFM, since the two are not directly proportional (i.e., they don't have a
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1:l relationship). Instead, BMR should be adjusted statistically for FFM (i.e., FFM should be included as a covariate in analysis of variance) when comparing the BMRs of two groups (in this case, SP-NMD to controls). Differences in methods for comparison of BMR in SP-NMD to control values may be, in part, responsible for the conflicting information in this area. Our group recently determined that the REE of SP-NMD subjects was not different from that of control subjects, regardless of whether REE was corrected statistically for FFM.37 24-h Energy Expenditure and Physical Activity
To our knowledge, there are no published reports of physical activity or 24-hour energy expenditure in SP-NMD. We recently used the heart-rate monitoring (HRM) rnethod3(j,55 to compare physical activity and 24-hour energy expenditure in SP-NMD subjects to that of ablebodied controls similar in age and weight.37The 24-hour energy expenditure in SP-NMD subjects was, on average, 20% to 25% lower than that of the controls. Because there was no significant difference in the REE between groups, this difference in 24-hour energy expenditure was due entirely to differences in physical activity. In fact, energy expenditure in physical activity was between 32% and 51% lower in NMD subjects than in controls. Figure 3 illustrates differences in activity levels between SPNMD and control subjects. There was no difference in the amount of time spent sleeping between SP-NMD and controls. However, SP-NMD subjects spent a significantly higher proportion of their waking hours being sedentary and a significantly lower proportion of their waking
Sleep 33%
Figure 3. Daily activity of slowly progressive NMD subjects (A) and controls (6) similar in age and weight. NMD subjects spent a significantly higher proportion of their waking hours being sedentary and a significantly lower proportion of their waking hours being active than did control subjects (P<0.001). (Data from McCrory MA, Kim HR, Wright NC, et al: Energy expenditure, physical activity and body composition of ambulatory adults with hereditary neuromuscular disease. Am J Clin Nutr, in press.)
NUTRITIONAL ASPECTS OF NEUROMUSCULAR DISEASES
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'
I
Slowly Progressive NMD
&muscular
& FFM disuse atrophy
I
,
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strength and endurance
t &physical
of physical activity
A disuse 1I I1 1 1 -------,-J I I I I I I I atrophy
1 1
------------
intake relative
I I I I ---------------A
body fat
Figure 4. Model for the interrelationships among strength, body composition, energy intake, and physical activity in slowly progressive NMD. Dashed line = relationships that have not been determined.
hours being active than did control subjects. Furthermore, preliminary data indicate that SP-NMD subjects have a higher energy cost of physical activity than do control subjects. Whether this is due to the reduced muscle mass or increased adiposity of the SP-NMD subjects is not yet known. We also found that in both SP-NMD and control subjects the time spent being physically active was inversely correlated with adiposity, after accounting for differences in 24-hour energy expenditure and FFM between the two groups. However, the cross-sectional nature of this study limits the conclusions that can be drawn about cause and effect; that is, currently we are unable to determine whether their body composition determines their physical activity level or vice versa. In addition, our research has concentrated on ambulatory subjects, and these results may not be applicable to nonambulatory SP-NMD subjects. Based on our research thus far, we have developed a model that describes the development of excess body fat in SP-NMD, and relationships among body composition, physical activity, and energy intake in these subjects (Fig. 4). Future longitudinal studies will lend insight into the development of excess body fat and will help to identify appropriate target points for intervention in these subjects. Reduction of excess body fat (or prevention of fat gain) in slowly progressive SP-NMD may not only aid mobility, but potentially may also reduce risk for developing the secondary chronic diseases associated with obesity, such as adultonset diabetes, certain cancers, and coronary heart disease.58 The importance of physical activity lies in its ability to confer
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benefits of weight control, self-esteem, and reduced risk of several chronic diseases in the able-bodied p ~ p u l a t i o n .The ~ ~ role of physical activity in reducing the risk of secondary diseases and increasing the quality of life in SP-NMD subjects still remains to be determined. In fact, there is a paucity of information on physical activity in the disabled population as a whole.49Many SP-NMD subjects are afraid to exert themselves physically because of the belief that excessive physical activity will cause overwork weakness. However, in a short-term 12-week study of moderate aerobic walking in SP-NMD subjects, we found no adverse effects.66Further research is needed to determine optimal levels of physical activity for prevention of secondary diseases and promotion of physical and mental well-being in SP-NMD subjects.
SUMMARY Evidence suggests that individuals with DMD have reduced skeletal development, including decreased linear growth and bone mineral density, compared to normal subjects. Despite their reduced muscle mass, a high percentage of DMD patients are overweight. Body composition measurements can assist with monitoring changes in fat mass and skeletal muscle mass as the disease progresses. Weight management in overweight DMD patients is indicated because excess adiposity burdens mobility and breathing, but only one study in two DMD patients has documented that weight reduction can be done safely. In the latter stages of the disease most DMD subjects become underweight because of an acceleration in skeletal muscle protein degradation relative to its synthesis. Studies of energy, protein and branched chain amino acid supplementation in DMD have yielded promising but inconclusive results, and more well-designed studies are needed in this area. Although there is currently no cure for DMD, studies on the role of nutritional therapy in increasing the quality of life in these patients are urgently needed. Studies in adults with various SP-NMDs indicate a reduction in fatfree mass and an increase in fat mass relative to controls. The newly developed method of air displacement plethysmography for measuring body composition is ideally suited for SP-NMD subjects because it requires very little effort and the measurement procedure is relatively fast. Dual energy x-ray absorptiometry technology has been proposed for distinguishing myogenic from neurogenic SP-NMDs from calculation of the fat-to-lean soft tissue ratio, which is higher in patients with myogenic muscular atrophy. Studies on the energy metabolism of ambulatory SP-NMD subjects indicate that their basal metabolic rate is either similar to or slightly lower than controls, but 24-hour energy expenditure is about 25% lower than controls. This reduction in 24-hour energy expenditure is due to a reduction in physical activity in SP-NMD. Studies examining the roles of energy expenditure, physical activity, and
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diet in the development of adiposity and risk for secondary chronic diseases in SP-NMD subjects are currently underway. ACKNOWLEDGMENTS Our sincere appreciation to Christina Strongio for her assistance and to Susan Aitkens for her comments on this article.
References 1. Ballard FJ, Tomas FM, Stem LM: Increased turnover of muscle contractile proteins in Duchenne muscular dystrophy as assessed by 3-methylhistidine and creatinine excretion. Clin Sci 56:347, 1979 2. Bandini LG, Schoeller DA, Cyr HN, et al: Validity of reported energy intakes in obese and non obese adolescents. Am J Clin Nutr 52:421, 1990 3. Bjomtorp P, Schroder G, Omdahl G: Carbohydrate and lipid metabolism in relation to body composition in myotonic dystrophy. Diabetes 22:238, 1973 4. Borgstedt A, Forbes GB, Reina JC: Total body potassium and lean body mass in patients with Duchenne dystrophy and their female relatives. Neuropadiatrie 1:447, 1970 5. Braham J, Sarova-Pinhas I, Czerniak P: Radioisotope studies of thyroid function in progressive muscular dystrophy. Israel J Med Sci 5:1188, 1969 6. Carter GT, Abresch RT, Fowler WM Jr, et al: Profiles of neuromuscular diseases: Hereditary motor and sensory neuropathy, types I and 11. Am J Phys Med Rehabil 74:S140. 1995 7. caughLy JE, Brown J: Dystrophia myotonica: an endocrine study. Q J Med 19:303,1950 8. Caughey JE, Myrianthopoulos NC: Endocrine function. In Dystrophia Myotonica and Related Disorders. Springfield IL, Charles C Thomas, 1963 9. Danowski TS, Bastiani RM, McWilliams FD, et al: Muscular dystrophy. IV. Endocrine studies. Am J Dis Child 91:356, 1956 10. Delwaide PA, Delwaide PJ, Penders CA: Isotope studies of body composition in neuromuscular disease. J Neurol Sci 15339, 1972 11. Dempster P, Aitkens S: A new air displacement method for the determination of human body composition. Med Sci Sports Exerc 27:1692, 1995 12. Drew AL, Kruse F, Pelletier CJ: Failure of muscular dystrophy treatment with a protein hydrolysate. Neurology 4:789, 1954 13. ~ o n a l d s o nSJ, wratney MJ, Pascassio A, et al: Muscular dystrophy. Am J Dis Child 91:449, 1956 14. Edmonds CJ, Smith T, Griffiths RD, et al: Total body potassium and water, and exchangeable sodium, in muscular dystrophy. Clin Sci 68:379, 1985 15. Edwards RHT, Round JM, Jackson MJ, et al: Weight reduction in boys with muscular dystrophy. Dev Med Child Neurol 26:384, 1984 16. Eiholzer U, Boltshauser E, Frey D, et al: Short stature: a common feature in Duchenne muscular dystrophy. Eur J Pediatr 147:602, 1988 17. Elia M: Energy expenditure in the whole body. In Kinney JM, Tucker HN (eds): Energy Metabolism: Tissue Determinants and Cellular Corollaries. New York, Raven Press, 1992 18. Frisancho AR: New norms of upper limb fat muscle areas for assessment of nutritional status. Am J Clin Nutr 34:2540, 1981 19. Gibson RS: Anthropometric assessment of growth. In Principles of Nutritional Assessment. New York, Oxford University Press, 1990, p 173 20. Goldberg GR, Black AE, Jebb SA, et al: Critical evaluation of energy intake data using fundamental principles of energy physiology: 1. Derivation of cutoff limits to identify underrecording. Eur J Clin Nutr 45569, 1991 21. Goldstein M, Meyer S, Freund HR: Effects of overfeeding children with muscle dystrophies. Journal of Parenteral and Enteral Nutrition 13:603, 1989
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22. Griggs RC, Forbes GF, Moxley RT, et al: The assessment of muscle mass in progressive neuromuscular disease. Neurology 33:158,1983 23. Griggs RC, Rennie MJ: Muscle wasting in muscular dystrophy: Decreased protein synthesis or increased degradation? AM Neurol 13:125, 1983 24. Griffiths RD, Edwards RHT: A new chart for weight control in Ducheme muscular dystrophy. Arch Dis Child 63:1256, 1988 25. Hamill PVV, Drizd TA, Johnson CL, et al: Physical growth: National Center for Health Statistics percentiles. Am J Clin Nutr 32:607, 1979 26. Hankard R, Gottrand F, Turck D, et al: Resting energy expenditure and energy substrate utilization in children with Ducheme muscular dystrophy. Pediatr Res 40:29, 1996 27. Heckmatt JZ, Dubowitz V, Leeman S: Detection of pathological change in dystrophic muscle with B-scan ultrasound imaging. Lancet I:1289, 1980 28. Heymsfield SB, McManus CB, Smith J, et al: Anthropometric measurement of muscle mass: Revised equations for calculating bone-free arm muscle area. Am J Clin Nutr 36:680, 1982 29. Johnson ER, Abresch RT, Carter GT, et al: Profiles of neuromuscular diseases: Myotonic dystrophy. Am J Phys Med Rehabil74:S62,1995 30. Josefowicz RF, Welle SL, Nair, et al: Basal metabolic rate in myotonic dystrophy: evidence against hypometabolism. Neurology 37:1021, 1987 31. Kanda F, Fujii Y, Takahashi K, et al: Dual-energy x-ray absorptiometry in neuromuscular diseases. Muscle Nerve 17431,1994 32. Kilmer DD, Abresch RT, McCrory MA, et al: Profiles of neuromuscular diseases: Facioscapulohumeral muscular dystrophy. Am J Phys Med Rehabil74 Suppl:S131,1995 33. Kossman RJ, Peterson DC, Andrews HL: Studies in neuromuscular disease. I. Total body potassium in muscular dystrophy and related diseases. Neurology (Minneap) 15:855, 1965 34. Lohman TG, Roche AF, Martorell R: Anthropometric Standardization Reference Manual. Champaign, Human Kinetics, 1988 35. McCrory MA, Gomez TD, Bernauer EM, et al: Evaluation of a new air displacement plethysmograph for measuring human body composition. Med Sci Sports Exerc 27:1686, 1995 36. McCrory MA, MolC PA, Nommsen-Rivers LA, et al: Between-day and within-day variability in the relation between heart rate and oxygen consumption: Effect on the estimation of energy expenditure by heart-rate monitoring. Am J Clin Nutr 66:1, 1997 37. McCrory MA, Kim HR, Wright NC, et al: Energy expenditure, physical activity and body composition of ambulatory adults with hereditary neuromuscular disease. Am J Clin Nutr, in press 38. McDonald CM, Abresch RT, Carter GT, et al: Profiles of neuromuscular diseases: Duchenne Muscular Dystrophy. Am J Phys Med RehabiI74:570,1995 39. McDonald CM, Johnson ER, Abresch RT, et al: Profiles of neuromuscular diseases: Limb-girdle syndromes. Am J Phys Med Rehabil 74:S117, 1995 40. McKeran RO, Halliday D, Prukiss P: Increased myofibrillar protein catabolism in Duchenne muscular dystrophy measured by 3-methylhistidine excretion in the urine. J Neurol Neurosurg Psychiatry 40:979, 1977 41. Mertz W, Tsui JC, Judd JT, et al: What are people really eating? The relation between energy intake derived from estimated diet records and intake determined to maintain body weight. Am J Clin Nutr 54:291-295, 1991 42. National Research Council: Energy. In Recommended Dietary Allowances, ed 10, Washington, National Academy Press, 1989 43. O'Doherty DS, Schellinger D, Raptoponlos V: Computed tomographic patterns of pseudohypertrophic muscular dystrophy: preliminary results. J Comput Assist Tomogr 14:482, 1977 44. Okada K, Manabe S, Sakamoto S, et al: Protein and energy metabolism in patients with progressive muscular dystrophy. J Nutr Sci Vitaminol 38:141, 1992 45. Okada K, Manabe S, Sakamoto S, et al: Predictions of energy intake and energy allowance of patients with Duchenne muscular dystrophy and their validity. J Nutr Sci Vitaminol 38:155, 1992
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46. Palmieri GMA, Bertorini TE, Griffin JW, et al: Assessment of whole body composition with dual energy x-ray absorptiometry in Duchenne muscular dystrophy: correlation of lean body mass with muscle function. Muscle Nerve 19777, 1996 47. Rappaport D, Colleto GM, Vainzof M, et al: Short stature in Ducheme muscular dystrophy. Growth Regulation 1:11, 1991 48. Rennie MJ, Edwards RHT, Millward DJ, et al: Effects of Duchenne muscular dystrophy on muscle protein synthesis. Nature 296:165, 1982 49. Rimmer JH, Braddock D, Pitetti KH: Research on physical activity and disability: An emerging national priority. Med Sci Sports Exerc 28:1366, 1996 50. Sapir DG, Walser M: Nitrogen sparing induced early in starvation by infusion of branched-chain ketoacids. Metabolism 26:301, 1977 51. Schreiber A, Smith WL, Ionasescu V: Magnetic resonance imaging of children with Duchenne muscular dystrophy. Pediatr Radio1 17:495, 1987 52. Scott OM, Hyde SA, Goddard C, et al: Quantitation of muscle function in children: A prospective study in Duchenne muscular dystrophy. Muscle Nerve 5:291, 1982 53. Sempe M, PCdron G, Roy-Pernot MP: Auxologie: Methode et Sequences. Paris, Theraplix, 1979 54. Siri WE: Body composition from fluid spaces and density: Analysis of methods. In Brozek J, Henschel A (eds): Techniques for Measuring Body Composition. Washington, NAS/NRC, 1961 55. Spurr GB, Prentice AM, Murgatroyd PR, et al: Energy expenditure from minute-byminute heart-rate recording: Comparison with indirect calorimetry. Am J Clin Nutr 48:552, 1988 56. Stewart PM, Walser M, Drachman DB: Branched-chain ketoacids reduce muscle protein degradation in Duchenne muscular dystrophy. Muscle Nerve 5:197, 1982 57. Tanner JM, Whitehouse RH: Clinical longitudinal standards for height, weight, height velocity and weight velocity and stages of puberty. Arch Dis Child 51:170, 1976 58. U.S. Department of Health and Human Service, Public Health Service: The Surgeon General's Report on Nutrition and Health, Washington, PHs publication No. 8850210, 1988 59. U.S. Department of Health and Human Services, Public Health Service: Physical Activity and Health: A Report of the Surgeon General. Atlanta, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, 1996 60. Van Meter JR: Progressive muscular dystrophy: A preliminary report on treatment with amino acids, folic acid and vitamines. California Med 79:297, 1953 61. Wald SM, Lam RL: Treatment of muscular dystrophy with amino acids and vitamines. Neurology 52387, 1955 62. Waring JJ, Ravis A, Walker CE: Studies in dystrophia myotonica: Clinical features and treatment. Arch Intern Med 65:763, 1940 63. Wames DM, Thomas FM, Ballard FJ: Increased rates of myofibrillar protein breakdown in muscle wasting diseases. Muscle Nerve 4:62, 1981 64. Welle S, Jozefowicz R, Forbes G, et al: Effect of testosterone on metabolic rate and body composition in normal men and men with muscular dystrophy. J Clin Endocrinol Metab 74332, 1992 65. Willig TN, Carlier L, Legrand M, et al: Nutritional assessment in Duchenne muscular dystrophy. Dev Med Child Neurol 35:1074, 1993 66. Wright NC, Kilmer DD, McCrory MA, et al: Aerobic walking in slowly progressive neuromuscular disease: effect of a 12-week program. Arch Phys Med Rehabil 7754, 1996 67. Ziegler DK, VonStorch TJC: Evaluation of protein hydrolysate therapy in treatment of muscular dystrophy. JAMA 157:466, 1955
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NUTRITIONAL ASPECTS OF NEUROMUSCULAR DISEASES Megan A. McCrory, PhD, Nancy C. Wright, MA, and David D. Kilmer, MD
Both rapidly progressive Duchenne muscular dystrophy (DMD) and the slowly progressive neuromuscular diseases (SP-NMDs) are associated with loss of skeletal muscle, gain of excess body fat, and changes in energy metabolism and physical activity over time. This article reviews several nutritional techniques and their adequacy in monitoring changes in the nutritional status of these individuals as the diseases progress. In addition, nutritional interventions that aim to counteract the effects of the disease process and increase the quality of life in individuals with DMD are reviewed. Finally, new research on physical activity and body composition, and the potential for development of secondary chronic diseases in SP-NMD are discussed. DUCHENNEMUSCULARDYSTROPHY
There is a high prevalence of obesity in DMD. Excess body weight in DMD subjects burdens already weakened muscles and makes breathing and mobility difficult. Older DMD patients tend to lose weight as the disease progresses and there is an acceleration in the breakdown of This work was supported by Grant No. HI33830026 from the US Department of Education.
From the Energy Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts (MAM); the Department of Nutrition (MAM)and the Department of Physical Medicine and Rehabilitation (NCW), University of California, Davis, Davis; and the Department of Physical Medicine and Rehabilitation, University of Califomia, Davis Medical Center, Sacramento (DDK), Califomia
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skeletal muscle. The progressive loss of lean tissue in DMD can be monitored through nutritional techniques. Nutritional interventions including weight loss and dietary supplementation have been evaluated for their effectiveness in increasing quality of life in DMD patients and attenuating the disease process. The following section will review studies on nutritional assessment and management of DMD. Stature
Accurate measurement of stature of DMD patients is difficult because of the high incidence of spinal deformities and scoliosis in this population, particularly in the latter stages of the disease. Most crosssectional data38,47, 52 indicate that attained height in the first decade is similar to or slightly below the median height-for-age of the Xational Center for Health Statistics' but falls markedly below the fifth percentile during the second decade.3sMcDonald et a P found that this dramatic reduction in standing height relative to normal values occurred mainly in wheelchair users with contractures and scoliosis. These authors stated that although the incidence of scoliosis did not differ between boys in the lowest versus the highest quartile for stature, they could not rule out differences between quartiles in the severity of the scoliosis which potentially may have biased their results. However, longitudinal data from Eiholzer et all6 indicate slow linear growth in DMD patients beginning shortly after birth, before scoliosis occurs. Thus, the decreased linear growth seen in DMD subjects of all ages may not, in fact, be measurement artifact. McDonald and colleagues38point out that a lack of normal muscle tension or weight bearing on the skeleton may in theory contribute to decreased linear growth in this population, but this has not been evaluated by adequate techniques. The relatively short stature of individuals with DMD also may be due in part to undernourishment because they often do not consume enough protein and energy to meet their nutritional needs.38,44 The hypothesis that skeletal development is reduced in DMD subjects is supported by their lower bone mineral density compared with age-matched controls.46 Within the DMD group, there was a significant inverse relationship between bone mineral density and age; this relationship was not found for able-bodied controls. Weight and Body Composition
The appropriateness of body weight in DMD patients has traditionally been evaluated against national standards of weight-for-age. It should be kept in mind, however, that weight-for-height may be a better index than weight-for-age for evaluating current nutritional status because weight-for-age does not take into account differences in height.19 A subject's weight may be appropriate for his or her age, but since DMD
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subjects tend to be short for their age, using weight-for-age alone may underestimate the prevalence of overweight in this population. However, as stated in the previous section, accurate measurements of height often are difficult to obtain in individuals with DMD because of the presence of spinal abnormalities and contractures. Overweight vs Underweight
Compared to the United States reference population, the prevalence of underweight (defined as weight-for-age
Figure 1. Percentage of Duchenne muscular dystrophy (DMD) subjects classified as underweight (weight-for-age
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of DMD subjects, between the ages of 9 and 16.9, about 40%0 were classified as overweight (defined as weight-for-age >90th percentile). These data indicate that in early adolescence there may be a divergence of weight in the DMD population such that many have either an extremely low or extremely high weight for their age, and that somewhere near late adolescence most individuals with DMD become underweight. Similar patterns of weight-for-age were reported by Willig et al,65who studied a sample of 252 DMD patients. They reported that 54% of their subjects were above the 90th percentile in weight-for-age by age 13, and 54% were below the 10th percentile by age 18. Scott et a152link the development of obesity in DMD with loss of independent ambulation. However, McDonald et aP8 found no relationship between the presence of a high weight-for-age and either the age of wheelchair dependence, loss of strength, timed motor performance, functional grade status, pulmonary function, likelihood of ECG abnormalities, or age at death. One limitation of simply using body weight as a standard is that the composition of the weight is unknown. Weight is made up of both fat and lean tissue, with skeletal muscle contained in the latter. Knowing the composition of the body allows us to gain insight into how much of the weight is excess body fat, or how much weight loss is due to loss in muscle mass from progression of the disease. Because the evolution of DMD is associated with progressive loss of skeletal muscle, at a given weight-for-age patients with DMD will have a lower lean mass than able-bodied subjects. Thus, an individual with DMD ideally should weigh less than an able-bodied individual for a given age, since loss of muscle mass over time is inevitable and excess body fat is undesirable. In 1988, Griffiths and Edwards24proposed an ideal weight chart for DMD patients, which was meant to serve as a guideline for weight management in this population. This theoretical chart was constructed from previous observations and assumes a 4% decline in muscle mass per year.14,Is, 57 The effect of this new chart on weight classification is that at a given age, DMD patients are classified at a higher percentile than they would be on the standard chart. For example, a 10-year-old DMD patient who weighs 25 kg appears to be in the 10th percentile of weight-for-age based on the normal chart, but is actually at the 50th percentile on the DMD chart. This was illustrated in the study by McDonald et a1,38 who found that a much higher percentage of their subjects were classified as overweight when using the Griffiths and chart than the standard weight chart (Fig. 1B). The Griffiths and Edwards2*chart was tested for validity in 1993 by another set of investigator^.^^ To evaluate the chart, Willig et a1" compiled data from previous studies and also used their own data to produce a final sample size of 252 DMD subjects. They compared their weight-for-age data with the reference chart for French patientss3 and also the new DMD ideal weight chart proposed by Griffiths and E d ~ a r d s These . ~ ~ authors concluded that while the chart is a valid tool for monitoring weight in DMD patients, it may slightly underestimate the effect of the disease.
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Whole-body Composition and Estimates of Skeletal Muscle Mass Whole-body composition, and thus lean tissue mass, in DMD has been estimated with highly specialized techniques such as magnetic resonance imaging?l computed t0mography,4~~ltrasonography,2~ potassium-40 counting? 33 and potassium-40 dilution.14In addition, estimates of muscle mass in DMD can be accomplished biochemically by 24-hour urinary creatinine, and skeletal muscle degradation can be estimated from 24-hour urinary 3-methylhistidine rnea~urements.~~-~~, 44 However, these methods are either tedious or not readily available, and are not well suited to routine clinical use. Two recent studies have used dual energy x-ray absorptiometry (DEXA) to assess whole-body composition in DMD.31,46 Using this technique, the body mass can be divided into regional and total body bone mineral, fat tissue, and soft lean tissue masses. The major portion of the latter is skeletal muscle; thus, determination of lean soft tissue mass by DEXA provides a proxy measurement of skeletal muscle mass. DMD patients have been shown to have a higher body fat mass and a lower lean soft tissue mass than controls.31,46 Palmieri et a146documented significant changes in body composition with increasing age in DMD. While the percentage of fat tissue mass increased with increasing age, the percentage of lean soft tissue mass decreased with increasing age. These relationships did not exist for control subjects. Further, these authors reported associations between the percentage of lean soft tissue mass and upper and lower extremity functional scores and manual muscle testing scores. Thus, DEXA may be useful for documenting changes in nutritional status with disease progression and responses to therapeutic interventions. Use of Anthropometry in DMD
Upper Arm Muscle Area. In the absence of highly technical equipment such as DEXA, simple anthropometric techniques can be used to determine the upper arm muscle cross-sectional area (UAMA) using the following formula by Frisancho et alls:
UAMA = [(C - (T X TSK))']/~T where C = mid-upper-arm circumference and TSK = triceps skinfold thickness. This equation has been found to overestimate mid-arm muscle area by 20% to 25%, and thus underestimates muscle atrophy.28However, expressing UAMA as a percentage of the median normal value negates this error, since the normal values also are overestimated by the same amount. In addition, the precision of estimates of UAMA by trained examiners is 7%; thus, it cannot be used to measure changes that are smaller than this. It must be emphasized that this equation only provides a rough estimate of UAMA. Caution also must be exercised when using this equation for individuals with DMD because of infiltra-
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tion of skeletal muscle with fatty and connective tissue in this disease. For example, progressive increases in absolute values of UAMA with increasing weight-for-age were noted in DMD patients.65However, when expressed in terms of Z-scores (number of standard deviations from the median normal value), DMD patients who were underweight had a higher UAMA Z-score than those who were overweight. Skinfold Thickness. Development of adiposity in DMD patients can be monitored by measuring the thickness of the subcutaneous fat layer at different sites and following the procedures recommended by Lohman et a1.34Willig et aP5compared skinfold measurements at biceps, triceps, subscapular, and suprailiac sites with weight-for-age classifications in 109 patients. They concluded that the subscapular and su.prailiac sites were the most useful for correctly classifying an individual as overweight (above the 90th percentile in weight-for-age), but none of the skinfold sites proved useful for classifying an individual as underweight. This result can be explained by the fact that underweight in DMD is associated with a lowered muscle mass, which is not measured by skinfold thickness. Using the sum of five skinfold sites (triceps, subscapular, abdominal, suprailiac and thigh), about half of the DMD subjects in McDonald et al's study were significantly fatter than control~.~~ Energy Metabolism
It is not understood why some individuals with DMD develop obesity and others do not. Excess energy stores (ES) can be attributed to an imbalance between energy intake (EI) and energy expenditure (EE), since over the long term ES = EI - EE. Thus, obesity in DMD may result from excessive EI, or from reduced EE. The components of EE can be expressed as follows: EE
=
REE
+ DIT + EEPA
where REE is the resting energy expenditure, defined as the energy cost of maintaining the metabolic processes of the body while at rest; DIT is dietary induced thermogenesis, defined as the energy cost of digestion, absorption, and assimilation of nutrients ingested; and EEPA is the energy expenditure in physical activity. A reduction in any one or more of these components can lead to a reduction in EE and thus lead to weight gain, all else being equal. Hankard et a1 examined this issue in five obese and eight nonobese ambulatory DMD patients, and nine controls.26All three groups were similar in age and height. Weight-for-age did not differ between the nonobese DMD subjects and controls, but was substantially higher in the obese DMD subjects. Fat-free mass (FFM) (determined by bioelectric impedance) did not differ between the obese and non-obese DMD subjects, but both had a significantly lower FFM than control subjects. Thus, the excess body weight in the obese DMD group could be attrib-
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uted entirely to an excess fat mass (FM). REE, which is proportional to FFM, was significantly lower in the nonobese DMD subjects than in control subjects, but not in the obese DMD subjects. When REE was expressed per kg FFM, both obese and nonobese DMD subjects had a higher REE/kg FFM, but the difference was significant only between controls and the obese DMD group. EI was significantly lower in the obese DMD patients compared to the nonobese DMD patients and the controls. This may seem contradictory; however, it is a common finding that individuals underreport their EI,2O, 41 and obese adolescents also have been found to underreport their EI.* Finally, postabsorptive fat utilization (as indicated by the respiratory quotient during the REE measurement) was found to be decreased in both DMD groups, but significantly decreased only in the nonobese DMD group. The lack of a significant difference between the two DMD groups may be related to the low statistical power in this data set, owing to the relatively small sample size. Neither EEPA nor DIT were measured in this study, so it is unknown if there were differences among the groups in these variables. More research is needed in this area to determine the potential role of fat utilization, physical activity, and DIT in the development of obesity in DMD. In addition, longitudinal studies are warranted because it is difficult to draw conclusions about cause and effect with crosssectional data. The rapid decline in body weight seen in the latter stages of DMD has been attributed to a hypermetabolic ~ t a t e Specifically, .~ increased rates of muscle protein turnover, including increases in both degradation and synthesis rates, have been reported.', 40, 48, 63 In a rigorous crosssectional analysis of over 300 Japanese DMD subjects aged from 11 to 29 years, Okada et a1 present evidence for hypermetabolism in this d i s e a ~ eAn . ~ increase in the basal metabolic rate (BMR), expressed as a percentage of the predicted BMR for a given age, increased progressively with age. Energy and protein intakes were high relative to normal adult requirements. Despite this, body weight expressed as a percentage of the median standard value decreased from 72% to 49% with increasing age. In addition, daily excretion of creatinine and 3-methylhistidine relative to control values suggested hypercatabolism of skeletal muscle in these subjects. Thus, protein in the diet was not being utilized effectively for body protein synthesis. The authors concluded that energy and protein requirements are substantially higher in DMD subjects than one would expect based on age and weight alone, and that relative energy and protein deficiencies may be contributing to the increased protein catabolism seen in these patients. In a second paper, Okada and colleagues45describe procedures for estimating the dietary energy and protein needs of DMD subjects using the easily measured parameters of body weight and 24-hour nitrogen excretion. First, BMR as a percentage of the standard BMR for a given age is predicted from body weight. This predicted BMR then can be used to estimate the energy allowance based on standard factorial proced u r e ~(Alternatively, .~~ measured BMR can be used if possible.) Nitrogen
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intake is then estimated from 24-hour nitrogen excretion, and converted to protein intake (nitrogen intake X 6.25). Energy intake can then be estimated, assuming a constant protein intake as a percentage of energy intake (an average of 14.6% in their study). The validity of these predictions of energy intake and allowance was verified by noting significant positive correlations between the adequacy of the energy intake (energy intake as a percentage of energy allowance) and concentrations of serum proteins, which turn over rapidly and are sensitive to energy deficiency. The authors are currently studying whether increasing the energy intake of DMD patients has any effect on physiologic and physical parameters in this p ~ p u l a t i o n . ~ ~ Nutritional Interventions Energy and Protein Supplementation
Studies carried out in the 1950s on energy and protein supplementation yielded mixed results.12,13, 60, 67 More recently, the effect of energy supplementation on muscle wasting and functional capacity was studied in six DMD patients aged 10 to 20 years for 3 months.21The supplement, containing 1000 kcal and 37.2 g protein, was administered each night by nasogastric tube feedings while the patients were hospitalized. The supplement was meant to provide extra nutrition in addition to their normal daily intake. At the end of the experimental period, daily energy intake had increased only by an average of 364 kcal, indicating that in part the supplement substituted for their normal daily caloric intake. Protein intake increased by 11.5 g/d, or 0.66 g/kg body weight/d, and body weight increased by 4.1 kg. The gain in body weight was comprised of both muscle and adipose tissue, as indicated by anthropometric measurements. In addition, nitrogen balance became more positive after the intervention, and no change occurred in urinary 3-methylhistidine excretion, possibly indicating improved muscle protein synthesis with no change in muscle protein degradation. There were no changes in hematologic and biochemical parameters, liver function tests, pulmonary function tests, muscular strength, or a general activity index. However, had a control group that received a placebo been included in this study, it might have provided valuable information because it is unknown whether these parameters would have worsened without supplementation. Regardless, the positive effects on muscle metabolism in this study warrant further investigation. Branched-chain Ketoacid Supplementation
Based on the observations that muscle protein degradation is accelerated in DMD,', 40, 63 and administration of branched-chain ketoacids reduces protein breakdown in fasting obese subjects,5O Stewart et a156 conducted a trial of branched-chain ketoacid supplementation. The ket447
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oacids of the branched-chain amino acids leucine, valine, and isoleucine were administered orally as ornithine salts at a dosage of 0.45 g/kg body weightld for 4 days in nine boys with DMD, aged 5 to 9 years, in a metabo1.i~ward. An equivalent amount of protein was removed from the diet during this time. Urinary creatinine and 3-methylhistidine excretions decreased, indicating a small but significant reduction in muscle protein degradation as a result of the treatment, and no negative effects were noted. However, as pointed out by Griggs et al,23 there may be problems with using 3-methylhistidine excretion to measure changes in muscle mass. Nevertheless, the results of this study are encouraging, and further research should be conducted to determine the effects of longer-term branched-chain ketoacid supplementation on muscle physiology and function in these patients. Weight Reduction
The advantages of reduction of excess adipose tissue in DMD include a lessening of the burden on already weakened muscles and potential improvement in mobility and ease of breathing. However, weight reduction in obese DMD patients has not been advocated because of the fear that a reduction in caloric intake will lead to acceleration of loss of muscle tissue. Contrary to this notion, Edwards et all5 demonstrated that weight reduction through a medically supervised decrease in energy intake could be achieved successfully in DMD without compromising skeletal muscle mass. They used nitrogen balance techniques for measuring whole-body protein stores to show that during the diet, two DMD patients (one nonambulatory) remained in positive nitrogen balance except for an initial transient nitrogen loss. The authors reported an improvement in walking performance in the ambulatory subject and an improvement in self-image and self-reliance in the nonambulatory subject. Both of these are extremely positive outcomes. It should be emphasized, however, that this study was done in only two patients and larger studies are needed to determine the safety, efficacy, and longterm outcome of weight reduction in individuals with DMD.
SLOWLY PROGRESSIVE NMD
In comparison to the rapidly progressive DMD, little nutritional research has been done in the SP-NMDs. In addition, most of the nutritional studies in the slowly progressive forms have been done in individuals with myotonic dystrophy. Because it is often difficult to get a sufficiently large sample size by studying just one disease, many studies evaluate several diagnoses together as one group. The following section will review studies on body composition and energy metabolism in SP-NMD, including our own recent work on physical activity and accretion of excess body fat in these subjects.
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Body Composition
Body composition measurements by skinfolds? 29, 32, 39 DEXA,3l total body potassium,lO,14, 30 and total body water14 indicate that SP-NMD subjects have a lower FFM and a higher FM than able-bodied controls. Recently, a new technology for determining body composition has emerged that is ideally suited for adult SP-NMD subjects because it requires very little effort for both the subject and technician and the measurement procedure is relatively brief.ll This method, air displacement plethysmography (BOD POD Body Composition System, Life Measurement Instruments, Concord CA), utilizes Boyle's law to determine body volume and the principles of den~itometry~~ to determine FM and FFM. Results from this method compare favorably with those from hydrostatic weighing in able-bodied subjects.35Using this new technology, we recently compared the body composition of a group of male and female SP-NMD subjects (including myotonic dystrophy, hereditary motor and sensory neuropathy, limb-girdle syndrome, and spinal muscular atrophy diagnoses) with able-bodied subjects who were similar in age and weight.37As shown in Figure 2A and B, body weight and body mass index (BMI) were not significantly different between SP-NMD and control subjects. However, SP-NMD subjects had a higher percentage of
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Figure 2. Body composition measured by air displacement plethysmography of slowly progressive neuromuscular disease (NMD) subjects and controls similar in age and weight. NMD subjects had a higher percentage of body fat and a lower fat-free mass (FFM) than controls (P<0.01). Solid bar = SP-NMD; open bar = control. (Data from McCrory MA, Kim HR, Wright NC, et al: Energy expenditure, physical activity and body composition of ambulatory adults with hereditary neuromuscular disease. Am J Clin Nutr, in press.)
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body fat and a lower FFM than able-bodied subjects (Fig. 2C and D). We are continuing to study this group of SF-NMD patients to determine longitudinal changes in body composition and associations among body composition, dietary intake, physical activity, energy expenditure, and blood lipid variables in this population. Kanda et a1 utilized DEXA to show that the body compositions of SP-NMDs of myogenic versus neurogenic origins differ.31Subjects with myogenic atrophy (limb-girdle syndrome, facioscapulohumeral dystrophy, myotonic dystrophy, and polymyositis) had significantly higher fat-to-lean soft tissue ratios than did subjects with neurogenic atrophy (amyotrophic lateral sclerosis and spinocerebellar degeneration), even though the BMIs were similar in all patients. The slope of the regression between the fat-to-lean soft tissue ratio and BMI was significantly higher in subjects with myogenic muscular atrophy compared with controls; this was not the case for subjects with neurogenic atrophy. The authors concluded that fat infiltration into the muscles of subjects with myogenic atrophy is reflected by their increased fat-to-lean soft tissue ratio. Energy Metabolism
Resting Energy Expenditure Most studies on resting energy expenditure (REE, or basal metabolic rate, BMR, used interchangeably for the purposes of this review) in SPNMD have been done in subjects with myotonic dystrophy. This research indicates that male subjects with myotonic dystrophy have a lower BMR than do able-bodied control^,^, 8, 30* 62 which is not related to In addition, Welle et aP4reported a relatively low thyroid dysf~nction.~ BMR for a mixed group of SP-NMD subjects (seven myotonic dystrophy, one limb-girdle syndrome, one facioscapulohumeral dystrophy). In contrast, male subjects with limb-girdle syndrome had a BMR very similar to the predicted control value.44However, several standard equations are available for predicting BMR, and the value of the predicted BMR differs widely, depending on which equation is used.17 Thus, the conclusions drawn from comparison of BMR in SP-NMD subjects to predicted values will depend on which prediction equation is used. Because BMR depends somewhat on the amount of FFM present, one might expect SP-NMD subjects to have a relatively low BMR. Thus, it often is conventional to normalize BMR for FFM or some index of FFM such as total body potassium. Josefowicz et a130 reported an elevated BMR/total body potassium ratio in men with myotonic dystrophy, suggesting hypermetabolism. However, the authors noted that this hypermetabolism may not be due to skeletal muscle itself, but to other tissues that may contribute to a higher proportion of overall metabolism. In fact, MTelle et al" argue that it is incorrect to express BMR relative to FFM, since the two are not directly proportional (i.e., they don't have a
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1:l relationship). Instead, BMR should be adjusted statistically for FFM (i.e., FFM should be included as a covariate in analysis of variance) when comparing the BMRs of two groups (in this case, SP-NMD to controls). Differences in methods for comparison of BMR in SP-NMD to control values may be, in part, responsible for the conflicting information in this area. Our group recently determined that the REE of SP-NMD subjects was not different from that of control subjects, regardless of whether REE was corrected statistically for FFM.37 24-h Energy Expenditure and Physical Activity
To our knowledge, there are no published reports of physical activity or 24-hour energy expenditure in SP-NMD. We recently used the heart-rate monitoring (HRM) rnethod3(j,55 to compare physical activity and 24-hour energy expenditure in SP-NMD subjects to that of ablebodied controls similar in age and weight.37The 24-hour energy expenditure in SP-NMD subjects was, on average, 20% to 25% lower than that of the controls. Because there was no significant difference in the REE between groups, this difference in 24-hour energy expenditure was due entirely to differences in physical activity. In fact, energy expenditure in physical activity was between 32% and 51% lower in NMD subjects than in controls. Figure 3 illustrates differences in activity levels between SPNMD and control subjects. There was no difference in the amount of time spent sleeping between SP-NMD and controls. However, SP-NMD subjects spent a significantly higher proportion of their waking hours being sedentary and a significantly lower proportion of their waking
Sleep 33%
Figure 3. Daily activity of slowly progressive NMD subjects (A) and controls (6) similar in age and weight. NMD subjects spent a significantly higher proportion of their waking hours being sedentary and a significantly lower proportion of their waking hours being active than did control subjects (P<0.001). (Data from McCrory MA, Kim HR, Wright NC, et al: Energy expenditure, physical activity and body composition of ambulatory adults with hereditary neuromuscular disease. Am J Clin Nutr, in press.)
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'
I
Slowly Progressive NMD
&muscular
& FFM disuse atrophy
I
,
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strength and endurance
t &physical
of physical activity
A disuse 1I I1 1 1 -------,-J I I I I I I I atrophy
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intake relative
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Figure 4. Model for the interrelationships among strength, body composition, energy intake, and physical activity in slowly progressive NMD. Dashed line = relationships that have not been determined.
hours being active than did control subjects. Furthermore, preliminary data indicate that SP-NMD subjects have a higher energy cost of physical activity than do control subjects. Whether this is due to the reduced muscle mass or increased adiposity of the SP-NMD subjects is not yet known. We also found that in both SP-NMD and control subjects the time spent being physically active was inversely correlated with adiposity, after accounting for differences in 24-hour energy expenditure and FFM between the two groups. However, the cross-sectional nature of this study limits the conclusions that can be drawn about cause and effect; that is, currently we are unable to determine whether their body composition determines their physical activity level or vice versa. In addition, our research has concentrated on ambulatory subjects, and these results may not be applicable to nonambulatory SP-NMD subjects. Based on our research thus far, we have developed a model that describes the development of excess body fat in SP-NMD, and relationships among body composition, physical activity, and energy intake in these subjects (Fig. 4). Future longitudinal studies will lend insight into the development of excess body fat and will help to identify appropriate target points for intervention in these subjects. Reduction of excess body fat (or prevention of fat gain) in slowly progressive SP-NMD may not only aid mobility, but potentially may also reduce risk for developing the secondary chronic diseases associated with obesity, such as adultonset diabetes, certain cancers, and coronary heart disease.58 The importance of physical activity lies in its ability to confer
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benefits of weight control, self-esteem, and reduced risk of several chronic diseases in the able-bodied p ~ p u l a t i o n .The ~ ~ role of physical activity in reducing the risk of secondary diseases and increasing the quality of life in SP-NMD subjects still remains to be determined. In fact, there is a paucity of information on physical activity in the disabled population as a whole.49Many SP-NMD subjects are afraid to exert themselves physically because of the belief that excessive physical activity will cause overwork weakness. However, in a short-term 12-week study of moderate aerobic walking in SP-NMD subjects, we found no adverse effects.66Further research is needed to determine optimal levels of physical activity for prevention of secondary diseases and promotion of physical and mental well-being in SP-NMD subjects.
SUMMARY Evidence suggests that individuals with DMD have reduced skeletal development, including decreased linear growth and bone mineral density, compared to normal subjects. Despite their reduced muscle mass, a high percentage of DMD patients are overweight. Body composition measurements can assist with monitoring changes in fat mass and skeletal muscle mass as the disease progresses. Weight management in overweight DMD patients is indicated because excess adiposity burdens mobility and breathing, but only one study in two DMD patients has documented that weight reduction can be done safely. In the latter stages of the disease most DMD subjects become underweight because of an acceleration in skeletal muscle protein degradation relative to its synthesis. Studies of energy, protein and branched chain amino acid supplementation in DMD have yielded promising but inconclusive results, and more well-designed studies are needed in this area. Although there is currently no cure for DMD, studies on the role of nutritional therapy in increasing the quality of life in these patients are urgently needed. Studies in adults with various SP-NMDs indicate a reduction in fatfree mass and an increase in fat mass relative to controls. The newly developed method of air displacement plethysmography for measuring body composition is ideally suited for SP-NMD subjects because it requires very little effort and the measurement procedure is relatively fast. Dual energy x-ray absorptiometry technology has been proposed for distinguishing myogenic from neurogenic SP-NMDs from calculation of the fat-to-lean soft tissue ratio, which is higher in patients with myogenic muscular atrophy. Studies on the energy metabolism of ambulatory SP-NMD subjects indicate that their basal metabolic rate is either similar to or slightly lower than controls, but 24-hour energy expenditure is about 25% lower than controls. This reduction in 24-hour energy expenditure is due to a reduction in physical activity in SP-NMD. Studies examining the roles of energy expenditure, physical activity, and
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diet in the development of adiposity and risk for secondary chronic diseases in SP-NMD subjects are currently underway. ACKNOWLEDGMENTS Our sincere appreciation to Christina Strongio for her assistance and to Susan Aitkens for her comments on this article.
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Address reprint requests to Nancy C. Wright Dept. of Exercise Science University of California Davis, CA 95616-8669