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Limb-girdle muscular dystrophy

Limb-girdle muscular dystrophy or Erb's muscular dystrophy is a type of muscular dystrophy that includes Duchenne muscular dystrophy, Becker's muscular dystrophy, and a large number of rarer disorders. more...

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The term "limb-girdle" is used to describe these disorders because the muscles most severely affected are generally those of the hips and shoulders -- the limb girdle muscles.

Common symptoms of limb-girdle muscular distrophy are muscle weakness, myoglobinuria, pain, myotonia, cardiomyopathy, elevated serum CK, and rippling muscles.

The muscle weakness is generally symmetric, proximal, and slowly progressive.

Generally pain is not present with LGMD, and mental function is not affected.

LGMD can begin in childhood, adolescence, young adulthood or even later. The age of onset is usually between 10 and 30. Both genders are affected equally. When limb-girdle muscular dystrophy begins in childhood the progression appears to be faster and the disease more disabling. When the disorder begins in adolescence or adulthood the disease is generally not as severe and progresses more slowly.

The distal muscles are affected late in LGMD, if at all. Over time (usually many years), the person with LGMD loses muscle bulk and strength. Eventually, he may need a power wheelchair or scooter, especially for long distances.

While LGMD isn't a fatal disease, it may eventually weaken the heart and lung muscles, leading to illness or death due to secondary disorders.

LGMD is typically an inherited disorder, though it may be inherited as a dominant, recessive, or X-linked genetic defect. The result of the defect is that the muscles cannot properly form the proteins needed for normal muscle function. Several different proteins can be affected, and the specific protein that is absent or defective identifies the specific type of muscular distrophy.

Treatment for LGMD is primarily supportive. Exercise and physical therapy are advised to maintain as much muscle strength and joint flexibility as possible. Assistive devices may be used to maintain mobility and quality of life. Careful attention to lung and heart health is also required.


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Oral creatine supplementation in Duchenne muscular dystrophy: A clinical and 31P magnetic resonance spectroscpy study
From Neurological Research, 3/1/00 by Felber, Stephan

The decrease in intracellular creative concentration in Duchenne muscular dystrophy may contribute to the deterioration of intracellular energy homeostasis and may thus be one of the factors aggravating muscle weakness and degeneration. Oral creative supplementation should have potential in alleviating the clinical symptoms. To test this hypothesis, creative was orally administered over a period of 155 days to a 9-yearold patient with Duchenne muscular dystrophy. In accordance with previous investigations on normal subjects and trained athletes, the patient experienced improved muscle performance during creative supplementation. Further evidence supporting this hypothesis derived from plasma creative kinase and lactate dehydrogenase activities and repeated 31 P magnetic resonance spectroscopy of the gastrocnemius muscle. These preliminary observations indicate a potential role for creative supplementation in the symptomatic therapy of patients with muscle disease. [Neurol Res 2000; 22: 145-150]

Keywords: Creatine; supplementation; Duchenne muscular dystrophy; muscle disease; 31P magnetic resonance spectroscopy


Creatine kinase (CK, EC, phosphorylcreatine (PCr) and creatine (Cr) are involved in the energy metabolism of cells with high and fluctuating energy demands1,2. CK isoenzymes catalyze the reversible transfer of the gamma-phosphate group of ATP to the guanidino group of Cr to yield PCr and ADP. In skeletal muscle, PCr and Cr serve as a 'reservoir' for 'high-energy phosphates' during short periods of intense work and as a 'transport device' providing a flux of high-energy phosphates within the cells during endurance exercise.

Several lines of experimental evidence indicate that disturbed function of the CK/PCr/Cr system, either on the enzyme or on the substrate level, lead to impaired muscle function 3,4. On the other hand, many (neuro-) muscular diseases are associated with disturbances in Cr metabolism, for example Duchenne (DMD) and Becker muscular dystrophy, facioscapulohumeral dystrophy, limb-girdle muscular dystrophy, myotonic dystrophy, spinal muscular atrophy, or amyotrophic lateral sclerosis. Common findings are increased serum CK activities, increased Cr concentrations in serum and urine, stimulation of creatinuria by oral supplementation with glycine or Cr, decreased urinary creatinine (Crn) excretion and, in particular, depressed muscle levels of Cr, PCr, Pi, glycogen and ATP.

Based on these findings, hypotheses have been raised as to how derangements in Cr metabolism may, directly or indirectly, contribute to the progression of muscle disease, and how oral Cr supplementation may alleviate at least some of the clinical symptoms3. Here, we report on our preliminary observations with oral Cr supplementation in a 9-year-old DMD patient. In addition to clinical measures, repeated 31 P magnetic resonance spectroscopy (MRS) of the gastrocnemius muscle was performed.

Case report

Patient CID is the third child of healthy unrelated parents. Pregnancy, birth and development in the first years were reported normal. At the age of four years, the parents noticed hypertrophy of the calves and marked fatigue after moderate exercise. Clinical examination revealed diminished strength of the upper and lower extremities, pseudohypertrophy of the calves, gait with tiptoeing, and inability to lift the head when laying on the back. Gower sign was positive and tendon reflexes were normal. CK in the serum was elevated (10,000 UI^sup -1^; normal range 10-100UI^sup -1^). Muscle biopsy (M. vastus lateralis) was characteristic for muscular dystrophy. Further investigations with two anti-dystrophin antibodies, one against the 60kDa fragment and one against the C-terminus, revealed a large deletion in the dystrophin gene and the diagnosis of Duchenne progressive muscular dystrophy was established-5. Physiotherapeutic and orthopedic treatment were instituted.

At the beginning of the present study, at the age of nine years, CD was able to walk about 50 m but was unable to climb stairs. He had marked pseudohypertrophy of the calves and hyperlordosis of the lumbar spine. Weakness of the upper extremities was less severe. There were no joint contractures and there were no signs of cardiomyopathy. The patient attended regular ground school with good success and had no evidence of mental retardation. CK levels in the serum ranged between 2500 and 4000 U I^sup -1^. He had regular physiotherapy and he did not receive any oral or parenteral medications.

On days 1 and 2 of the study, while CD received placebo (6x3 g maltodextrin orally) base-line examinations were performed (ergometry, 31 P-MRS, and electrocardiography). On days 3-7, 31-35, 52-56, 73-77, 94-98 and 115-119, CD received 4x3gday^sup -1^ Cr. From day 121 on, Cr was given continuously at a dose of 2x 3g day^sup -1^ (at 9 am and 9 pm). Cr supplementation was separated from meals by at least 30-60 min.


Cr was generously supplied by Chemie Linz Ges.m.b.H (Linz, Austria). Cr was 99.8% pure and had a water content of 10.5% (w/w).

Metabolite and enzyme assays

Serum CK and lactate dehydrogenase (LDH) activities were determined at 30 deg C with commercial kits (No. 1.442.376 and 1.442.597, Boehringer, Mannheim, Germany). Serum, Cr and Cm concentrations were routinely measured with the 'Creatinine PAP' test kit (No. 839.434, Boehringer). Quantification of Cr is achieved by a coupled enzyme reaction that links the disappearance of Cr or Cm with the production of a quinone-imine dye, the absorption of which was measured at 510 nm.

Cr concentration was additionally measured at 37C in selected serum samples with the 'Creatinine-Duo UY test kit (Biomed, Oberschleissheim, Germany). In this assay, Cm is quantified by a coupled creatinine deiminase-glutamate dehydrogenase reaction which links the disappearance of Cm to a decrease in the absorbance of NADH at 340 nm. For measurements of Cr by this method, creatininase (Boehringer, No. 126.942) was added to the assay mixtures. The two methods yielded identical results, thus showing that potential interference by serum sarcosine in the 'Creatine PAP' method can be neglected.

31 P magnetic resonance spectroscopy

31 P-MRS was performed on a 1.5 T clinical scanner using a 5 cm-surface coil that can be tuned alternatively to the 1 H of 31 P nucleus resonance frequencies. The patient was positioned supine with the right calf in the center of the magnet. The coil was fixed to the gastrocnemius muscle with tape in order to preclude displacement during the dynamic part of the experiments. Prior to spectroscopy, gradient echo images (FLASH, TR = 60 msec, TE =10 msec, flip angle 15 deg, slice thickness 10 mm) were acquired to ensure comparable coil positions. The local magnetic field was optimized until a half-maximum line-width of the water resonance of 30 Hz (0.5 ppm) or better was achieved.

After switching the system to 27 MHz, the resonance frequency was centered between PCr and the gamma-phosphate group of adenosine triphosphate (gamma-ATP) signals. The excitation angle was optimized to the signal of PCr. During rest, a T1-relaxed spectrum with a repetition time (TR) of 12 sec was acquired.

The dynamic examinations were performed with a TR of 1 sec. Thirty-two transients were averaged for one spectrum, giving a time resolution of 1 min. The gastrocnemius muscle was loaded using a non-ferromagnetic expander. The tension of the expander allowed the patient to extend the foot in the ankle without support from muscles other than the gastrocnemius. The patient extended the foot at 2 sec intervals until he felt exhausted. Spectra were continuously recorded for up to 5 min after termination of work.

The acquired spectra were Gauss filtered, corrected for linear phase shifts and plotted with the PCr peak at 0 ppm. For quantitative analysis, the peak integrals of inorganic phosphate (P^sub i^), phosphodiesters (PDE), PCr and alpha-ATP were calculated. Metabolite concentrations were expressed as ratios of P^sub i^/PCr, PDE/PCr, and alpha-ATP/ PCr. The relative chemical shift between P^sub i^ and PCr was used to calculate intracellular pH values6.


Cr uptake into the blood

In order to monitor Cr uptake in the intestinal tract and blood, the plasma concentration of Cr was measured before, during and after individual Cr supplementation periods. On a vegetarian diet, the baseline plasma [Cr] was 90.6 +/- 5.6 (mu)M (mean +/- SD; n = 7) as compared to 25.1 +/- 99.1 (mu)M in normal male vegetarians and 40.8 +/- 19.0 (mu)M in normal males of a reference population. At the onset of Cr supplementation, plasma [Cr] increased sharply. The highest values were observed at 4 pm and 8.30 pm (1080 +/- 120 (mu)M; n=4), while the lowest values were measured at 7.45 am (366 +/- 50 (mu)M; n=5). During the whole Cr suppmementation period, plasma [Cr] was increased at leat 4-fold. After the last Cr dose of an individual supplementaiton period, plasma [Cr] rapidly returned to pre-supplementation levels (within 36 h to 114 (mu)M and within 60h to 87.2 (mu)M).

In healthy subjects > 90% of the total Cr pool is found in muscle tissue, and since Cr and PCr are converted at an almost constant rate into Cm, the plasma and urine concentrations of Crn represent rough measures of the total muscle mass. In our patient, plasma [Crn] was 18.4 +/- 14.4 (mu)M (n=3) before Cr supplementation, compared to ~70 (mu)M in normal males7.

Effect of Cr supplementation plasma CK and LDH levels

Due to the increased leakiness of the membranes in DMD, the activities of CK and LDH are markedly increased in plasma. Plasma CK and LDH activities were considered to reflect the potential of Cr supplementation to protect the muscle cells from further membrane damage. During the five-day Cr supplementation periods, the plasma CK activity was significantly lower than before and in between these periods (4100 +/- 1020 UI^sup -1^ [n=13] vs. 5740 +/- 1770 UI^sup -1^ [n=16]; p

Effect of oral Cr supplementation on intracellular phosphorus metabolites

The gastrocnemius muscle of our patient showed advanced fatty degeneration (pseudohypertrophy) on MR-images and the CH^sub 2^ resonance constituted 70% of the total proton signal. As a result of muscle fiber loss, there is an overall reduction in 31P signal in MRS examinations8. Therefore, longer examination times for 31 P MRS (5 min for a T1 relaxed spectrum and 1 min for a dynamic spectrum) were necessary to achieve sufficient signal-to-noise ratios (Figure 1). The (alpha)ATP peak was chosen for quantification because the (Beta)ATP peak was not always free from secondary phase effects. The results of the T1 -relaxed 31 P spectra acquired at rest are summarized in Figure 2A. Resting pH values (7.047.19) were within normal limits throughout the observation period of 155 days.

In agreement with previous investigations9,10, the resting spectra before Cr supplementation showed abnormally elevated P^sub i^/PCr, ATP/PCr and PDE/PCr ratios, thus pointing to an abnormally low intracellular PCr concentration. Immediately after the onset of Cr supplementation, all of the aforementioned metabolite ratios decreased considerably, but the effect was transient. During continuous Cr supplementation, the resting P^sub i^/PCr and ATP/PCr ratios showed a trend to decrease again (Figure 2A).

Effect of oral Cr supplementation on exercise performance

At the beginning of this study, CD was able to walk 50 m, after which he was exhausted and complained about muscle cramps and he was unable to climb stairs. With Cr supplementation, muscle performance parameters improved. The parents reported an increase in general strength and a decrease in the frequency of accidental falling from the third day of Cr supplementation onwards up to five days after the end of an individual Cr supplementation period. Thereafter, the condition progressively worsened until the onset of the next Cr supplementation period. No such worsening was observed during continuous Cr supplementation. CD regained the ability to climb stairs, (47-95 sec for seven steps), and regularly walked 450m on a slightly ascending road, in times of 9min to 12 min. No difference in this latter parameter was seen between intermittent supplementation (days 47-91) and continuous supplementation with Cr (days 117-153).

Figure 2B shows the time needed to climb a 9 m-long 250 slope. Performance in this test steadily improved during the first 40 days, but then apparently reached a plateau. From days 99 to 114, CD received no Cr and discontinued regular exercise which is reflected in the poor performance data just afterwards. However, upon resumption of Cr supplementation and exercise, values returned to the pre-break level. Again, no significant difference was observed between intermittent and continuous Cr supplementaiton.

The dynamic 31 P-MRS experiments were performed prior to Cr supplementation and then at the end of each individual Cr supplementation period. During the initial MRS examination, CD was exhausted after 1.5 min of workload, even before the spectra showed PCr consumption and increase in Pi. During Cr supplementation, he always exercised until intracellular pH dropped beyond 6.8 which was associated with an increase in P^sub i^/PCr and ATP/PCr ratios (Figure 3). The time he was able to exercise in the magnet progressively increased from 3 min up to 11 min (Figure 28). Upon termination of work, the metabolite ratios rapidly returned to preexercise levels, demonstrating that mitochondrial function is, at least, not severely impaired11.


In this pilot study we aimed to put further weight upon the hypotheses, that (i) propose a relationship between disturbances in Cr metabolism and muscle disease, and that (ii) suggest that Cr supplementation holds potential to alleviate clinical symptoms. A 9-year-old patient with Duchenne muscular dystrophy received intermittent and continuous Cr supplementation over a period of 150 days.

For the non-invasive monitoring of intracellular PCr, ATP, P^sub i^ and PDE we performed, according to previous experiences8,10, 31P MRS of the gastrocnemious muscle, which is suited for standardized exercise in a whole body scanner. The gastrocnemius is not the most severely affected muscle in DMD, but 31P MRS of muscles with more advanced atrophy will yield insufficient signal from 31P compounds. The gastrocnemius muscle in our patient showed pseudohypertrophy and 70% of the proton signal derived from fat, reflects an advanced state of muscle degeneration. During all experiments, the patient was motivated and cooperative in the MRS examinations (20-30 min duration) and all spectra could be analysed (Figure 1).

To avoid influences of potential changes in relaxation times, a fully T1 relaxed spectrum was acquired at the beginning of each MRS experiment. At the baseline examination, the ratios of ATP/PCr, P^sub i^/PCr and PDE/PCr were abnormally elevated due to low intracellular PCr concentrations and increased PDE moieties, which is in accordance with previous investigations in DMD8,11. With the first Cr supplementation period, the ATP/PCr, P^sub i^/PCr and PDE/PCr (Figure 2A) ratios increased, most probably due to an increase in intracellular PCr concentrations. This was paralleled by a decrease in the serum CK and LDH activities. During intermittent Cr supplementation until day 120, the ratios gradually increased again, although the muscle performance further improved. This finding may indicate contributions from training effects. After institution of continuous Cr supplementation (from day 121 on), the intracellular PCr concentration showed a tendency to increase again.

The dynamic MRS experiments under Cr supplementation (Figure 3) showed a rapid breakdown of PCr and concomitant increase in the P^sub i^/PCr ratio during exercise, as well as rapid PCr recovery thereafter. This agrees with previous experiments11, that have shown no major defects in glycogenolysis and mitochondrial function in DMD. The dynamic MRS proved that our patient worked out at his best capacity and that motivation factors did not influence the muscle performance.

In the base-line MRS study, prior to Cr supplementation, the patient terminated exercise of the gastrocnemius muscle after 1.5 min because of muscle cramps, although no metabolic adaptation to work load could be observed on the spectra. This may be explained by increased lactic acid production during exercise in DMD, as has been reported by Kemp etal.' . With Cr supplementation, muscle performance (duration of exercise and rate of PCr utilisation in the spectra) improved in our patient. This indicates that the initial increase in intracellular PCr may have had a priming role for improved muscle performance and can facilitate muscle training. Later in the observation period, such training effects are likely to have further contributed to the continuous increase in exercise capability (Figure 2b).

Since dystrophin is not directly involved in Cr metabolism, a dramatic effect of Cr supplementation on the clinical symptoms could not be expected. However, the patient received continuous physiotherapy and training prior to and during this study, and he did better during Cr supplementation. This improvement was obvious on a subjective basis from the parents' point of view, but also found its expression in an increased walking distance on an ascending slope and significantly longer exercise times in dynamic MRS experiments (Figure 28).

This preliminary observation does not meet the requirements to test new therapies for DMD12, and cannot definitely prove a causative role of Cr supplementation for improvements in muscle performance. Therefore, no final conclusions about the future clinical role of Cr supplementation can be drawn. However, 31 P MRS was able to validate muscle performance on a metabolic level and could exclude simple motivation as the cause of clinical improvement. MRS showed that Cr supplementation could in fact increase intracellular PCr levels in a DMD patient. These findings are in line with previous Cr supplementation studies on normal subjects and trained athletes, which have demonstrated significant (up to 40%) increases in the intracellular Cr and PCr concentrations as well as increases in anerobic muscle performance4. Furthermore, pre-treatment of cultured mdx skeletal muscle cells with Cr for 8-10 days normalized Ca^sup 2+^ metabolism and enhanced both myotube formation and survival13.

Although the experiences from this observation in a single patient are preliminary, there is evidence that oral Cr supplementation may at least have a contributing effect to improve muscle performance in DMD.


Dipl. Ing. E. Artner and Dr Dipl. Ing. E. Wiesbauer (Chemie Linz Ges.m.b.H., St.-Peter-Strasse 25, A-4021 Linz, Austria) are gratefully acknowledged for the generous supply of creatine, and Prof. R. Margreiter (Department Transplant Surgery, University Hospital, Innsbruck) for continuous support. This work was sponsored by the Swiss National Science Foundation (fellowship No. 823A-037106), the Austrian Science Foundation (Lise Meitner fellowship No M00198MED), and the 'Ciba-Geigy-jubil5ums-Stiftung'.


1 Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM. Intracellular compartmentation, structure and function of creative kinase isoenzymes in tissues with high and fluctuating energy demands: The phosphocreatine circuit for cellular energy homeostasis. Biochem / 1992; 281: 21 40

2 Wyss M, Smeitink J, Wevers RA, Wallimann T. Mitochondrial creative kinase: A key enzyme of aerobic energy metabolism. Biochem Biophys Acta 1992; 1102: 119-166

3 Wyss M, Felber S, Skladal D, Koller A, Kremser CI, Sperl W. The therapeutic potential of oral creative supplementation in muscle disease. Med Hypotheses 1998; 51: 333-336

4 Wyss M, Kaddurah-Daouk R. Creative and creatinine metabolism. Physiol Rev Accepted for publication

5 Bittner RE, Shorny S, Ferlings R, Sperl WI, Kress W, Muller CR, Cremer M, Leger JJ, Voit T. Sarcolemmal expression of dystrophin C-terminus but reduced expression of 6Q-dystrophin-related protein in two DMD patients with large deletions of the dystrophin gene. Neuromusc Disord 1995; 5: 81-92

6 Seo Y, Murakami M, Watan H, Imai Y, Yoshizaki K, Nishikawa H, Morimoto T. Intracellular pH determination by a 31 P-NMR technique. The second dissociation constant of phosphoric acid in a biological system. J Biochem 1983; 94: 729-734

7 Delanghe ), De Slypere J-P, De Buyzere M, Robbrecht J, Wieme R, Vermeulen A. Normal reference values for creative, creatinine, and carnitine are lower in vegetarians. Clin Chem 1989; 35: 1802-1803

8 Griffith RD, Cady EB, Edwards RH, Wilkie DR. Muscle energy metabolism in Duchenne dystrophy studied by 31 P-NMR: Controlled trials show no effect of allopurinol or ribose. Muscle Nerve 1985; 8: 760-767

9 Barany M, Siegel I, Venkatasubramanian P, Mok E, Wilbur A. Human leg neuromuscular diseases: P-31 NMR spectroscopy. Radiology 1989; 172: 503-508

10 Younkin D, Berman P, Sladky J, Chee C, Bank W, Chance B. 31 P NMR studies in Duchenne muscular dystrophy: Age-related metabolic changes. Neurology 1987; 37: 165-169

11 Kemp G, Taylor D, Dunn J, Frostic S, Radda G. Cellular energetics of dystrophic muscle. J Neurol Sci 1993; 116: 201-206

12 Heckmatt JZ, Hyde SA, Gabain A, Dubowitz V. Therapeutic trial of isaxonine in Duchenne muscular dystrophy. Muscle Nerve 1988; 11: 838-847

13 Pulido SM, Passaquin AC, Wallimann T, Ru.egg UT. Creative supplementation improves intracellular Caz+ handling and survival in mdx skeletal muscle cells. Abstract Book of the 30th Annual Meeting of the Swiss Societies for Experimental Biology 1998: 20

Stephan Felber*, Daniela Skladal^, Markus Wyss^^, Christian Kremser*, Arnold Koller(sec) and Wolfgang Sperl(para)

*Department of Radiology II and Magnetic Resonance, ^Department of Pediatrics, ^^Department of Transplant Surgery, (sec)Department of Sports Medicine, University of Innsbruck, (para)Children's Hospital, LKH Salzburg, Austria

Correspondence and reprint requests to: S. Felber, MD, Department of Magnetic Resonance, Department of Radiology II, University of Innsbruck, Anichstr. 35, A-6020 Innsbruck, Austria. Accepted for publication August 1999.

Copyright Forefront Publishing Group Mar 2000
Provided by ProQuest Information and Learning Company. All rights Reserved

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