WEBVTT 00:00.000 --> 00:30.000 position:50% align:top line:0% *This machine-generated transcript may have errors. If remediation or a manually-generated transcript is needed, please contact NLM Support at https://support.nlm.nih.gov.* 00:59.140 --> 01:00.990 until a few years ago, 01:01.000 --> 01:03.820 a taco metabolic myopathy is would have been 01:03.820 --> 01:06.160 limited to the glycogen storage diseases 01:07.140 --> 01:08.210 in the last few years, 01:08.210 --> 01:08.850 however, 01:09.500 --> 01:11.970 the field has considerably expanded to 01:11.970 --> 01:14.560 include not only some variants of 01:14.560 --> 01:16.060 glycogen storage diseases, 01:16.440 --> 01:19.290 but also some newly recognize disorders 01:19.300 --> 01:20.460 of lipid metabolism. 01:23.440 --> 01:25.980 The first slide shows a 01:25.990 --> 01:28.530 very schematic overview of glycogen 01:28.530 --> 01:29.160 metabolism. 01:30.140 --> 01:32.690 Once glucose has been transferred 01:32.910 --> 01:33.950 into the cell, 01:34.340 --> 01:36.770 it is fast food related to glucose six 01:36.770 --> 01:38.290 fostered by an enzyme, 01:38.290 --> 01:40.660 an enzyme known as exogenous 01:42.240 --> 01:45.180 forceful glue commutes then converts glucose 01:45.180 --> 01:48.160 six phosphate to glucose one phosphate. 01:49.840 --> 01:50.860 At this point, 01:51.740 --> 01:52.550 like a gin, 01:52.940 --> 01:55.870 the process of glycogen synthesis starts 01:56.240 --> 01:58.730 and this is the only an 01:58.740 --> 02:01.300 obligatory process for glycogen 02:01.300 --> 02:01.910 synthesis. 02:02.440 --> 02:05.260 It takes place essentially in three 02:05.260 --> 02:05.890 steps. 02:06.540 --> 02:07.240 First. 02:07.470 --> 02:10.230 An enzyme known as you redeem defaults for 02:10.230 --> 02:12.150 glucose Piros for Elise 02:13.040 --> 02:15.710 convert glucose one fast fit to your 02:15.710 --> 02:17.250 eddine die fast food dye, 02:17.250 --> 02:17.730 phosphate, 02:17.730 --> 02:18.350 glucose. 02:19.240 --> 02:21.830 This is the substrate for the main 02:21.830 --> 02:24.660 glycogen of synthetic enzyme known as 02:24.660 --> 02:27.140 glycogen center days this 02:27.140 --> 02:30.020 enzyme attaches glucose units 02:30.940 --> 02:33.940 to the peripheral chains of glycogen molecule 02:34.210 --> 02:35.370 In an alpha 1, 02:35.370 --> 02:37.360 4 glucose citic link 02:38.330 --> 02:40.160 and this process goes on 02:40.740 --> 02:42.060 until the 02:42.940 --> 02:45.940 glycogen peripheral chain has reached 02:45.940 --> 02:47.160 a certain length. 02:47.540 --> 02:49.550 At this point, 02:49.560 --> 02:52.430 a third enzyme has to come into action 02:52.440 --> 02:54.760 and this is known as the branch er 02:55.740 --> 02:58.130 And what this enzyme does. 02:58.140 --> 03:00.870 It attach is a glucose 03:00.880 --> 03:03.860 unit in an alpha 1/6 position. 03:04.440 --> 03:07.390 And after this the sentences can 03:07.400 --> 03:09.060 then resume its action 03:09.440 --> 03:12.300 Elevating this new chain by 03:12.300 --> 03:15.240 adding glucose units in Alpha 1 4 03:15.250 --> 03:15.870 links. 03:16.540 --> 03:16.740 Yeah. 03:18.040 --> 03:18.920 While this is, 03:18.920 --> 03:19.560 as I said, 03:19.560 --> 03:22.390 the only an obligatory synthetic pathway as 03:22.390 --> 03:23.650 far as it is known, 03:23.660 --> 03:25.600 there are several glycogen, 03:25.600 --> 03:28.560 analytic or degrade active pathways 03:29.740 --> 03:32.710 for the energetic metabolism of 03:32.710 --> 03:33.350 the cell. 03:33.360 --> 03:36.240 Certainly the most important is the 03:36.250 --> 03:38.760 first Farrell is the branch or pathway. 03:39.640 --> 03:42.280 The first end the enzyme to act 03:42.290 --> 03:44.880 is force Farrell is and what it does in the 03:44.880 --> 03:47.700 presence of inorganic phosphate it falls for 03:47.700 --> 03:49.870 politically splits off 03:49.880 --> 03:52.480 stepwise glucose units from the 03:52.480 --> 03:54.270 peripheral change of glycogen. 03:54.280 --> 03:56.950 With liberation of glucose one phosphate, 03:57.640 --> 04:00.600 This enzyme can proceed until it 04:00.600 --> 04:03.100 has uh split off 04:03.110 --> 04:06.100 glucose units Up to about three 04:06.110 --> 04:08.830 or 4 units from the branching 04:08.830 --> 04:09.360 point. 04:10.040 --> 04:13.020 And at this point they partially chewed up 04:13.020 --> 04:15.750 glycogen if you want is known as a phosphorus 04:15.750 --> 04:16.140 limited. 04:16.140 --> 04:19.120 Extreme Now a second enzyme has to 04:19.120 --> 04:21.940 come into action and this is known as a deep Rancher. 04:22.260 --> 04:23.150 This enzyme, 04:23.150 --> 04:25.350 in a two step reactions reaction 04:25.840 --> 04:28.840 uh splits off the glucose unit 04:28.850 --> 04:31.240 in the alpha 1/6 position and 04:31.240 --> 04:34.080 therefore phosphorus can again 04:34.090 --> 04:36.560 act on a new uh 04:36.570 --> 04:39.330 peripheral chain of glycogen with further liberation of 04:39.330 --> 04:39.640 glucose. 04:39.640 --> 04:40.360 One fasted. 04:41.040 --> 04:43.550 The branch is a hydrologic 04:43.550 --> 04:46.420 enzyme and liberates glucose and glucose one 04:46.420 --> 04:46.950 phosphate. 04:47.440 --> 04:49.900 But this is of course a very small 04:49.910 --> 04:51.910 amount as compared to the glucose. 04:51.910 --> 04:54.160 One faster liberated by first parallels 04:55.740 --> 04:58.300 the other two pathways that I mentioned that I 04:58.300 --> 05:00.430 indicated here or 05:00.440 --> 05:03.340 anonymously are less important. 05:03.340 --> 05:05.860 Certainly for the sell one of them is 05:05.860 --> 05:08.250 catalyzed by alpha amylase. 05:09.040 --> 05:11.990 Although this enzyme is certainly present in all 05:11.990 --> 05:14.180 tissues and muscle as well. 05:14.230 --> 05:16.260 Its function is totally unknown. 05:16.840 --> 05:19.720 The biochemical action is known what it does. 05:19.720 --> 05:22.610 It randomly split alpha 14 glucose, 05:22.610 --> 05:25.460 citic links except the ones in maltose with 05:25.460 --> 05:26.380 liberation of olive, 05:26.380 --> 05:26.810 osaka, 05:26.810 --> 05:28.500 right small toes and glucose. 05:29.140 --> 05:29.890 But the function, 05:29.890 --> 05:31.770 as I mentioned is totally unknown. 05:32.360 --> 05:34.230 This other final pathway, 05:34.240 --> 05:35.860 which is indicated here 05:36.240 --> 05:39.200 Schematically wants to represent 05:39.210 --> 05:40.420 two enzymes. 05:40.430 --> 05:43.400 The neutral and the acid alpha 05:43.400 --> 05:46.210 glucose days is neutral because 05:46.220 --> 05:46.950 alpha glucose, 05:46.950 --> 05:49.370 it is is apparently linked to the 05:49.370 --> 05:50.510 cytoplasmic particular. 05:50.510 --> 05:53.080 Um while uh and its function is 05:53.080 --> 05:55.320 again completely unknown. 05:55.330 --> 05:58.010 While acid alpha 05:58.020 --> 06:00.910 14 glue cause it is actually it is an 06:00.910 --> 06:03.260 alpha 14 and 16 because it is, 06:03.260 --> 06:05.730 as you will see better known as acid 06:05.730 --> 06:08.250 maltese is Eliza Zuma enzyme 06:08.840 --> 06:11.790 and we'll talk about its function later on in the 06:11.800 --> 06:13.160 in this presentation. 06:19.640 --> 06:20.650 The next slide 06:21.940 --> 06:23.860 represents a 06:24.440 --> 06:27.040 uh summary of the glycogen storage 06:27.040 --> 06:27.820 diseases. 06:27.830 --> 06:29.290 There are eight, 06:29.300 --> 06:32.000 as you see known glycogen oh sis 06:32.010 --> 06:32.830 of these. 06:32.830 --> 06:33.730 However, 06:33.740 --> 06:34.730 type one like oh, 06:34.730 --> 06:37.490 gino sis or fungal disease and 06:37.490 --> 06:40.410 type type six glycogen Oh sis hers disease 06:40.410 --> 06:42.910 and type eight click on geonosis or hooks disease 06:43.270 --> 06:46.180 do not affect muscle Type one is due 06:46.180 --> 06:48.950 to a defect of glucose six phosphate days. 06:48.990 --> 06:51.350 An enzyme which is not present in muscle 06:51.740 --> 06:54.700 Types six is due to a defect of 06:54.800 --> 06:57.280 liver force Farrelly's and enzyme 06:57.290 --> 07:00.260 different genetically different from from 07:00.260 --> 07:03.250 muscle force Farrelly's and type eight Geico 07:03.250 --> 07:06.180 geonosis is due to A defect of one of the 07:06.180 --> 07:09.020 enzymes involved in the activation of 07:09.020 --> 07:10.090 Liverpool's Farrelly's. 07:10.100 --> 07:10.910 Again, 07:10.920 --> 07:12.650 this does not involve muscle, 07:13.140 --> 07:14.840 so when we exclude these, 07:14.890 --> 07:17.520 we are left with five glycogen 07:17.520 --> 07:18.610 storage diseases, 07:19.140 --> 07:21.820 all of which affect muscle Again. 07:21.820 --> 07:22.490 However, 07:22.790 --> 07:25.540 type three glycogen Asus and type 07:25.540 --> 07:26.480 four glycogen oh, 07:26.480 --> 07:27.370 sis do, 07:27.370 --> 07:28.170 respectively, 07:28.180 --> 07:28.780 respectively, 07:28.780 --> 07:31.660 to a defect of the deep branch er 07:32.240 --> 07:34.260 and the branch er enzyme 07:35.740 --> 07:38.670 are dominated by the liver 07:38.670 --> 07:41.670 involvement and muscle symptoms 07:41.670 --> 07:43.660 and signs are generally minimal. 07:44.040 --> 07:46.650 So we will ignore 07:46.650 --> 07:48.960 these for this time and 07:48.960 --> 07:51.840 concentrate on The 07:51.850 --> 07:54.850 residual three glycogen storage diseases. 07:54.860 --> 07:57.410 Type To type five and type 07:57.410 --> 07:58.010 seven, 07:58.020 --> 08:00.720 which indeed cause a major 08:00.730 --> 08:02.950 major neuromuscular 08:02.960 --> 08:05.440 disorder and 08:05.450 --> 08:07.190 the muscle disorder. 08:07.190 --> 08:07.730 Really, 08:07.740 --> 08:10.530 the clinical picture pictures fall 08:10.530 --> 08:12.640 basically into two groups, 08:13.140 --> 08:15.970 one which is dominated by muscle 08:15.980 --> 08:18.820 cramps and myoglobin urea, 08:18.830 --> 08:21.470 and the other which is dominated by muscle 08:21.470 --> 08:21.960 weakness, 08:21.960 --> 08:23.350 progressive muscle weakness. 08:26.240 --> 08:29.130 It is I think historically correct 08:29.140 --> 08:31.870 to start the description with glycogen Asus, 08:31.870 --> 08:34.460 type five because this was 08:34.840 --> 08:36.990 the first muscle glycogen noses 08:37.440 --> 08:40.360 uh studied biochemically by 08:40.360 --> 08:42.360 bryan McArdle in England in 08:42.360 --> 08:44.250 1951 08:44.940 --> 08:47.590 and um Accardo very elegantly 08:47.600 --> 08:49.050 described. 08:49.080 --> 08:50.760 They 08:52.340 --> 08:55.150 the metabolic block If 08:55.150 --> 08:56.510 not the enzyme defect, 08:56.510 --> 08:59.160 which was discovered about eight years later. 08:59.840 --> 09:02.430 There are about 50 cases reported in the 09:02.430 --> 09:05.220 literature and Uh most of 09:05.220 --> 09:07.190 them affect males, 09:07.190 --> 09:09.350 as you see in the proportion of about 4-1. 09:10.740 --> 09:11.430 Type five. 09:11.430 --> 09:14.280 Black vaginosis is do as I mentioned before, 09:14.290 --> 09:16.650 to a defect of muscle force Farrellys 09:17.540 --> 09:19.990 in view of the central role played by this 09:19.990 --> 09:22.100 enzyme in glycogen metabolism. 09:22.100 --> 09:23.960 As I pointed out in the first slide, 09:24.440 --> 09:27.280 it is somewhat surprising that the symptoms symptom a 09:27.280 --> 09:28.730 theology in this disease, 09:28.740 --> 09:30.950 is not very dramatic. 09:31.940 --> 09:34.610 The symptoms consist mainly in 09:34.610 --> 09:37.610 exercise intolerance soon after 09:37.610 --> 09:39.550 starting vigorous exercise. 09:40.640 --> 09:43.170 These patients experience muscle 09:43.170 --> 09:44.650 stiffness and egg. 09:45.340 --> 09:48.340 Most patients soon learn what their limits are 09:48.570 --> 09:50.360 and if they do not overdo, 09:50.360 --> 09:52.860 they can enjoy a reasonably normal life. 09:54.040 --> 09:54.950 However, 09:54.960 --> 09:56.790 when they exceed their limits, 09:56.800 --> 09:59.060 they experience painful cramps, 09:59.070 --> 10:01.670 which electro maya graphically appear to be 10:01.680 --> 10:04.620 silent and therefore fit the definition of 10:04.620 --> 10:05.460 contractors. 10:06.640 --> 10:07.750 In some instances, 10:07.760 --> 10:10.180 contractors are followed by muscle 10:10.180 --> 10:11.100 breakdown, 10:11.110 --> 10:13.060 and this is reflected muscle necrosis, 10:13.060 --> 10:15.850 and this is reflected by myoglobin urea. 10:17.860 --> 10:20.480 We have seen two cases 10:20.490 --> 10:23.160 who presented with renal shutdown 10:23.540 --> 10:25.720 requiring him on dialysis 10:26.210 --> 10:28.820 and in whom the diagnosis of 10:28.820 --> 10:30.550 McArdle disease was made. 10:31.040 --> 10:32.450 Uh Subsequently 10:34.440 --> 10:35.680 McArdle disease. 10:35.760 --> 10:38.580 Patients with McArdle disease have 10:38.590 --> 10:40.710 rarely problems in childhood. 10:42.240 --> 10:43.470 While on the other hand, 10:43.690 --> 10:46.520 permanent myopathy with weakness has been 10:46.520 --> 10:48.660 described either as a late 10:49.140 --> 10:52.110 uh consequence of the disease or 10:52.120 --> 10:54.960 as a late onset form of this disease. 10:56.840 --> 10:59.760 Most patients with McArdle disease experience 10:59.770 --> 11:02.260 a characteristic second wind phenomenon. 11:03.040 --> 11:05.140 If they take a brief rest 11:05.270 --> 11:07.940 after muscle pain and 11:07.940 --> 11:10.560 weakness occur during strenuous 11:10.560 --> 11:11.420 exercise, 11:11.840 --> 11:14.740 they can then resume physical activity 11:14.750 --> 11:17.650 more vigorously and for a longer 11:17.650 --> 11:19.760 period of time without any problem. 11:20.540 --> 11:22.940 two factors apparently are 11:22.950 --> 11:24.560 responsible for this phenomenon. 11:24.940 --> 11:27.650 One an increased mobilization of free 11:27.650 --> 11:29.940 fatty acids to provide 11:29.950 --> 11:32.890 muscle with alternative fuel and the 11:32.890 --> 11:35.390 second and increased blood flow to the 11:35.390 --> 11:36.650 exercising muscles. 11:38.240 --> 11:41.060 The pathogenesis of contracture and 11:41.060 --> 11:41.650 myoglobin. 11:41.650 --> 11:44.370 Urea in McArdle disease Is generally 11:44.370 --> 11:47.210 attributed to a critical shortage of 11:47.210 --> 11:49.750 80 p during strenuous exercise. 11:49.760 --> 11:52.260 When most of the energy for muscle 11:52.270 --> 11:55.160 contraction derives from glycogen breakdown 11:55.540 --> 11:56.460 and black colleges. 11:57.540 --> 12:00.300 A defect of 80P could impair muscle 12:00.300 --> 12:03.060 relaxation by affecting the energy 12:03.060 --> 12:05.520 dependent calcium uptake of the 12:05.520 --> 12:06.190 cytoplasmic, 12:06.190 --> 12:06.750 ridiculous, 12:07.740 --> 12:09.930 more severe or prolonged the ATP 12:09.940 --> 12:12.610 depletion could alter the integrity of 12:12.620 --> 12:14.660 muscle membranes and cause 12:15.100 --> 12:16.660 necrosis and myoglobin O'Ryan. 12:18.340 --> 12:19.750 This better genetic mechanism, 12:19.750 --> 12:20.430 however, 12:20.440 --> 12:23.310 has not been verified experimentally and in one 12:23.310 --> 12:26.210 study shown here in the old the 12:26.210 --> 12:28.900 results of which are shown in this slide in one study 12:28.900 --> 12:29.870 by DR. 12:29.870 --> 12:31.160 Roland and his colleagues, 12:32.940 --> 12:35.840 um the concentrations of 12:35.850 --> 12:38.290 adenine nucleotides creating phosphate, 12:38.290 --> 12:41.180 creating an inorganic phosphate were 12:41.190 --> 12:43.810 all found to be normal in two 12:43.810 --> 12:46.690 patients before in the muscle 12:46.690 --> 12:49.450 from two patients before and after or 12:49.450 --> 12:50.760 during contracture. 12:55.440 --> 12:57.960 The possibility was also considered 12:58.340 --> 13:01.020 that a compartmentalized as it were the 13:01.020 --> 13:03.720 effect of ATP may cause irreversible 13:03.720 --> 13:06.350 damage of circa plastic articular membranes 13:06.740 --> 13:09.430 responsible for the sometime rather 13:09.430 --> 13:11.000 prolonged contractors. 13:11.740 --> 13:12.770 However, 13:12.780 --> 13:15.290 no defect of calcium uptake 13:15.300 --> 13:18.010 nora Tps activity in cytoplasmic 13:18.010 --> 13:20.300 critical um vesicles 13:20.310 --> 13:22.090 isolated from 13:22.100 --> 13:24.980 a muscle was 13:24.980 --> 13:27.590 found in dr Brodus lab or in our own 13:27.590 --> 13:30.540 lab in a patient before and during 13:30.540 --> 13:31.260 contractor 13:33.540 --> 13:36.380 McArdle disease is not a single 13:36.380 --> 13:37.350 genetic entity, 13:37.840 --> 13:40.140 although in most cases the mode of 13:40.140 --> 13:42.230 inheritance appears to be autism. 13:42.230 --> 13:45.050 A recessive autos normal dominant 13:45.060 --> 13:47.550 inheritance was observed in one family, 13:48.240 --> 13:50.840 and the genetic basis for the large 13:50.840 --> 13:52.940 prevalence of male patients 13:52.950 --> 13:55.050 remain to be explained. 13:56.140 --> 13:58.300 A more striking example of genetic 13:58.300 --> 14:00.960 heterogeneity is the finding that in some 14:00.960 --> 14:01.690 patients, 14:01.700 --> 14:04.580 no enzyme protein is detectable by immunological 14:04.580 --> 14:05.170 methods, 14:05.180 --> 14:06.490 while in others, 14:06.500 --> 14:08.820 enzyme protein seems to be present. 14:08.830 --> 14:11.350 Although inactive or at least 14:11.360 --> 14:12.960 partially active, 14:14.640 --> 14:17.550 the relative proportion of patients and the mode 14:17.550 --> 14:20.510 of transmission will have to be determined for each of 14:20.510 --> 14:21.550 these conditions. 14:21.560 --> 14:22.860 This has not been done yet. 14:24.140 --> 14:26.250 Another genetic puzzle is the 14:26.250 --> 14:28.610 finding in dr king angles 14:28.610 --> 14:31.510 laboratory that force formulas activity was 14:31.520 --> 14:32.560 demonstrable. 14:32.570 --> 14:35.570 His to chemically at least in regenerating 14:35.580 --> 14:38.490 and cultured muscle fibers from three patients with 14:38.490 --> 14:39.650 McArdle disease. 14:41.540 --> 14:44.540 The fact that symptoms and signs of McArdle 14:44.540 --> 14:47.160 disease are intermittent and in most 14:47.170 --> 14:49.250 cases transitory as I mentioned, 14:50.340 --> 14:53.330 makes the need of effective therapy less 14:53.340 --> 14:55.950 dramatic for this disorder than for 14:55.950 --> 14:58.950 other progressively crippling metabolic diseases. 14:59.540 --> 15:00.310 However, 15:00.320 --> 15:03.270 because of the severe limitation of exercise in 15:03.270 --> 15:06.230 otherwise healthy people and the risk 15:06.240 --> 15:09.050 of extensive muscle necrosis and myoglobin urea 15:09.440 --> 15:12.250 several therapeutic measures have been tried in 15:12.250 --> 15:13.290 McArdle disease. 15:14.640 --> 15:17.230 Initial attempts to bypass the 15:17.230 --> 15:18.560 metabolic block, 15:19.340 --> 15:20.410 and here, 15:20.420 --> 15:23.070 let me point out again here is where the metabolic block 15:23.070 --> 15:25.150 is this is glycogen breakdown. 15:25.160 --> 15:26.260 This is like colleges. 15:27.140 --> 15:30.000 Initial attempts were aimed at bypassing this 15:30.000 --> 15:32.830 metabolic block by providing muscle 15:32.840 --> 15:35.170 with glucose or 15:35.170 --> 15:36.460 fructose. 15:37.240 --> 15:39.910 This was based on some observations that both 15:39.910 --> 15:42.770 glucose and fructose seems to prolong 15:42.780 --> 15:44.850 or to uh to prolong the 15:44.850 --> 15:47.650 capacity to exercise for these patients. 15:48.640 --> 15:51.300 Uh Another alternative 15:51.310 --> 15:53.670 therapy would consist in administration 15:53.680 --> 15:54.960 of uh 15:55.440 --> 15:57.600 drugs that would cause 15:58.940 --> 16:00.860 hyper glossy mia. 16:01.640 --> 16:04.510 Um like 16:04.520 --> 16:04.960 broken down. 16:05.740 --> 16:06.740 However, 16:06.750 --> 16:09.480 these drugs have been tried and have not proven to be 16:09.480 --> 16:11.840 very effective. 16:12.740 --> 16:15.050 The sugars tend to 16:15.540 --> 16:17.920 cause weight gain without much 16:17.930 --> 16:20.860 clinical response and the blue bag on the 16:20.870 --> 16:23.190 parental administration of glucose gonna certainly 16:23.200 --> 16:24.060 impractical 16:26.240 --> 16:28.750 other potential therapeutic approaches 16:28.760 --> 16:30.410 remain to be evaluated. 16:31.140 --> 16:33.830 one is suggested by the studies on the 16:33.830 --> 16:36.450 second Wind phenomenon that I briefly mentioned before 16:36.940 --> 16:39.930 and that would consist in raising the concentration 16:39.940 --> 16:42.640 of serum free fatty acid and ketone 16:42.640 --> 16:45.430 bodies either by dietary regimen like a 16:45.430 --> 16:47.880 ketogenic diet or by pharmacological 16:47.880 --> 16:48.450 means, 16:48.460 --> 16:49.270 for instance, 16:49.280 --> 16:50.750 by sublingual eyes. 16:50.750 --> 16:51.460 Oprah Torino 16:54.640 --> 16:57.210 Glycogen noses type seven or to Ruiz 16:57.210 --> 16:59.420 disease is due to an effect of 16:59.650 --> 17:02.560 muscle foster flew to kindness and this 17:02.560 --> 17:04.860 is shown here schematically. 17:05.240 --> 17:05.950 So as you see, 17:05.950 --> 17:08.190 the defect is lower down in the psychologist. 17:09.700 --> 17:12.280 six cases have been reported and we have 17:12.280 --> 17:13.860 recently started to more, 17:14.340 --> 17:16.990 the clinical picture is identical to that of 17:16.990 --> 17:19.790 macarthur's disease and consists of exercise 17:19.790 --> 17:20.560 intolerance, 17:20.570 --> 17:22.460 cramps and myoglobin area, 17:23.740 --> 17:26.200 muscle morphology and the degree of glycogen 17:26.200 --> 17:28.570 accumulation are also very similar in these two 17:28.570 --> 17:29.260 disorders. 17:30.040 --> 17:32.850 Differential diagnosis may be suggested by 17:32.850 --> 17:35.400 Eritrea's side studies because a partial 17:35.400 --> 17:38.210 defect of red blood cell fossil fuel to kindness has 17:38.210 --> 17:40.940 been shown consistently in all cases 17:40.940 --> 17:42.850 of fossil fuel to kindness deficiency. 17:43.240 --> 17:43.450 Mhm. 17:44.320 --> 17:47.270 No therapy has been attempted so far in this disease 17:47.740 --> 17:49.660 and as the metabolic block 17:50.140 --> 17:52.900 is at the level of like colleges and 17:52.900 --> 17:54.400 not of glycogen policies, 17:54.410 --> 17:57.170 there is of course no rationale for the use of 17:57.170 --> 17:59.600 glucose or fructose in this disease. 17:59.610 --> 18:00.550 However, 18:00.940 --> 18:03.730 dietary regiments or drugs causing 18:03.730 --> 18:06.370 increase of increased levels of plasma free fatty 18:06.370 --> 18:09.260 acids and ketone bodies again could prove 18:09.260 --> 18:11.700 beneficial in this disorder as well as in McArdle 18:11.700 --> 18:12.270 disease. 18:14.440 --> 18:17.410 A valuable lab test for the diagnosis of both 18:17.410 --> 18:20.110 glycogen oh sis type five and type seven 18:20.120 --> 18:22.960 is the response of venus blood lactate 18:22.970 --> 18:24.560 to ischemic exercise. 18:24.570 --> 18:27.310 And this is schematically shown here if the 18:27.310 --> 18:29.310 patient is asked to exercise, 18:29.320 --> 18:31.910 generates forearm exercise 18:32.340 --> 18:34.260 uh in ischemia. 18:35.140 --> 18:37.860 What happens is that either 18:37.870 --> 18:40.350 through the action of various 18:40.740 --> 18:42.860 hormones like epinephrine 18:43.240 --> 18:46.060 or more directly by a shift 18:46.070 --> 18:48.920 of calcium from the inside of the 18:48.920 --> 18:50.000 cytoplasmic article. 18:50.000 --> 18:52.860 Um Into the site is all there is a 18:53.740 --> 18:56.350 cascading of reactions of activating 18:56.350 --> 18:59.250 reactions of force foreigners from 18:59.250 --> 19:01.960 the less active form to the more active form. 19:02.440 --> 19:05.420 This in turn activates glycogen breakdown 19:05.430 --> 19:08.010 and psychologists and in ischemic 19:08.010 --> 19:10.440 conditions there is a production of 19:10.440 --> 19:13.230 lactate which results in an increase 19:13.330 --> 19:15.950 of venus lactate in normal individuals. 19:16.340 --> 19:18.260 In patients with a block 19:19.140 --> 19:21.730 either at the level of phosphoric or foster filter 19:21.730 --> 19:22.280 kindness. 19:22.740 --> 19:23.700 This X. 19:23.710 --> 19:24.070 S. 19:24.070 --> 19:26.870 Chemical exercise results in no increase 19:27.010 --> 19:28.460 in venus lock date. 19:31.740 --> 19:34.430 A very different picture is offered by like a 19:34.430 --> 19:34.940 geonosis, 19:34.940 --> 19:37.670 type two or acid maltese deficiency 19:38.240 --> 19:40.770 in the classical or infantile or 19:40.770 --> 19:42.560 generalized form. 19:42.570 --> 19:45.530 The disease is rapidly progressive 19:45.540 --> 19:48.210 and death occurs before a year of 19:48.210 --> 19:48.770 age. 19:49.640 --> 19:51.770 This is indicated here 19:53.240 --> 19:54.850 old tissues are affected, 19:54.860 --> 19:57.600 but particularly there is a massive accumulation of 19:57.600 --> 19:59.390 glycogen in the heart, 19:59.400 --> 20:01.990 skeletal muscle and both central and 20:01.990 --> 20:03.260 peripheral nervous system. 20:06.640 --> 20:08.860 The clinical picture is dominated by 20:08.860 --> 20:11.710 profound weakness and 20:11.710 --> 20:13.950 really floppy nous and 20:13.960 --> 20:15.060 uh 20:16.640 --> 20:19.270 and sometimes macro close to 20:26.040 --> 20:26.850 recently. 20:26.850 --> 20:27.560 However, 20:28.340 --> 20:30.840 a more benign form of the 20:30.840 --> 20:33.740 disease has been recognized onset 20:33.750 --> 20:35.770 is either in childhood 20:36.440 --> 20:37.960 or in adult life, 20:38.640 --> 20:40.180 and the clinical picture, 20:40.190 --> 20:42.930 with very few exceptions is really 20:42.940 --> 20:45.540 limited to skeletal muscle 20:45.540 --> 20:47.730 involvement and consist of a 20:47.730 --> 20:48.560 progressive, 20:48.940 --> 20:51.770 generally approximate limb muscle weakness, 20:52.090 --> 20:54.940 simulating muscular dystrophy 20:54.950 --> 20:56.330 or polymer anxieties 20:59.940 --> 21:00.760 sometimes, 21:00.760 --> 21:01.310 however, 21:01.310 --> 21:04.190 and rather often in about 50% of these patients, 21:04.200 --> 21:07.120 respiratory muscles are involved and 21:07.120 --> 21:09.750 this may result in severe ventilatory 21:09.750 --> 21:12.120 insufficiency serum, 21:12.120 --> 21:14.460 creating fast for kindness is consistently 21:14.460 --> 21:16.790 elevated in all of these patients 21:16.890 --> 21:19.820 with late 21:19.820 --> 21:21.430 onset as in motors deficiency, 21:21.440 --> 21:24.320 as well as in the infantile cases and 21:24.330 --> 21:25.570 characteristically, 21:25.580 --> 21:28.190 the electro maya electro my ah graffiti 21:28.190 --> 21:30.370 shows milestone is discharged. 21:30.380 --> 21:33.270 My Tony discharges without clinical my 21:33.270 --> 21:33.760 antonia. 21:36.140 --> 21:38.940 The history pathological features are those 21:38.950 --> 21:41.660 of a vascular myopathy 21:42.140 --> 21:45.140 and glycogen is variably increased in this late 21:45.140 --> 21:46.060 onset forms, 21:46.640 --> 21:49.190 but this may escape routine histological 21:49.190 --> 21:49.950 observation. 21:50.740 --> 21:53.580 It is therefore of great importance to 21:53.580 --> 21:56.050 consider late onset as emotive deficiency 21:56.540 --> 21:59.090 in the differential diagnosis of my pathetic 21:59.090 --> 21:59.730 syndromes 22:01.540 --> 22:03.270 1963 22:04.540 --> 22:07.250 hers in Belgium described 22:07.410 --> 22:09.360 the absence of acid maltese 22:10.740 --> 22:13.260 in tissues of patients with the generalist or 22:13.260 --> 22:16.190 infantile form of the disease and 22:16.190 --> 22:19.120 formulated the concept of the inborn listeners 22:19.120 --> 22:20.060 normal disease. 22:21.240 --> 22:22.580 As far as Guy Pacino's, 22:22.580 --> 22:24.270 this type two is concerned. 22:26.740 --> 22:29.160 This concept is based on 22:29.160 --> 22:31.710 the phenomenon of 22:31.720 --> 22:34.640 tautology in the course of the 22:34.640 --> 22:37.210 physiological renewal of the cell 22:37.640 --> 22:40.490 portions of the cytoplasm are surrounded 22:40.490 --> 22:43.160 by vesicles and form 22:43.170 --> 22:45.450 what is known as an automatic 22:45.940 --> 22:47.770 vacuum or 22:48.640 --> 22:51.600 auto fake ozone. 22:51.720 --> 22:53.370 In the terminology of DR airs, 22:54.340 --> 22:57.220 the merging of primary lizzo zones containing a 22:57.220 --> 22:59.670 whole battery of acid idolizes 22:59.680 --> 23:02.650 with this automatic vacuums 23:02.660 --> 23:05.530 transforms or forms what is known 23:05.530 --> 23:07.950 as a digestive vacuum or 23:07.960 --> 23:09.750 auto Liz ozone. 23:09.760 --> 23:10.230 Again, 23:10.230 --> 23:11.770 in the terminology of daughter earth, 23:13.040 --> 23:13.980 after all, 23:13.990 --> 23:16.720 the appropriate substrates have been digested 23:16.720 --> 23:19.050 by the specific 23:19.050 --> 23:19.880 hydrologists, 23:21.340 --> 23:23.460 The residual 23:23.940 --> 23:26.850 building blocks or smaller molecules that may 23:26.850 --> 23:29.660 be formed through this process are either released 23:29.660 --> 23:32.560 into the cell and re utilized 23:32.940 --> 23:34.940 like glucose from glycogen for instance, 23:34.950 --> 23:37.440 or if larger 23:37.440 --> 23:40.310 molecules and digestible structures are 23:40.320 --> 23:41.010 left, 23:41.020 --> 23:43.940 they will remain indefinitely in what are known as 23:43.950 --> 23:46.450 residual or dense bodies in the cell 23:50.540 --> 23:51.320 now. 23:51.330 --> 23:51.770 Uh 23:55.640 --> 23:58.530 in like a generous this type to the absence 23:58.530 --> 23:59.860 of acid maltese, 23:59.870 --> 24:02.790 which has both alpha 14 and alpha 24:02.790 --> 24:04.580 16 glucose. 24:04.580 --> 24:07.490 It is activity as we mentioned before and is 24:07.490 --> 24:10.310 therefore capable of digesting glycogen all the way to 24:10.310 --> 24:12.540 glucose results in continuous 24:12.540 --> 24:15.300 accumulation of undigested glycogen 24:15.300 --> 24:18.080 within lizzo zones until the cell is 24:18.090 --> 24:20.270 literally engorged with this 24:21.000 --> 24:23.410 and sometimes are called glycogen ISMs. 24:24.640 --> 24:27.340 While there is little doubt that this is the 24:27.340 --> 24:30.130 basic pathogenesis In type two 24:30.130 --> 24:31.110 black vaginosis, 24:31.440 --> 24:33.960 some observations remain difficult to explain. 24:34.740 --> 24:37.690 One question which probably merely merely 24:37.690 --> 24:40.420 reflects our ignorance of the functional role 24:40.470 --> 24:41.070 of lizards. 24:41.070 --> 24:42.540 Normal glycogen metabolism, 24:42.550 --> 24:45.270 normal muscle is why this tissue, 24:45.740 --> 24:47.010 which is normally, 24:47.020 --> 24:49.720 which normally appears to have very few lizzo soames 24:50.090 --> 24:52.190 is so severely affected in this disease. 24:53.440 --> 24:55.200 A more impor important question, 24:55.200 --> 24:55.770 however, 24:56.140 --> 24:58.500 is why such a large 24:58.500 --> 25:01.240 proportion of the accumulated glycogen is 25:01.240 --> 25:04.220 not internalize omo As one would expect 25:04.220 --> 25:05.140 from the theory, 25:05.150 --> 25:07.170 but rather free the cytoplasm, 25:07.640 --> 25:09.770 a phenomenon which is particularly 25:09.770 --> 25:12.630 apparent in infantile form of the 25:12.630 --> 25:14.600 disease and particularly muscle. 25:14.610 --> 25:17.170 And this is exemplified in the slide. 25:18.340 --> 25:19.520 As you see here, 25:19.530 --> 25:22.370 you can see only the first of all notice the great 25:22.370 --> 25:23.650 accumulation of glycogen. 25:23.660 --> 25:26.150 You can only see here some mile five 25:26.150 --> 25:28.770 brill's group here in one isolated here 25:29.240 --> 25:32.150 and but notice particularly how 25:32.150 --> 25:34.930 most of the glycogen is freeing the cytoplasm and 25:34.930 --> 25:36.170 only in certain areas. 25:36.170 --> 25:37.960 You can see one or two 25:38.340 --> 25:40.040 bodies or 25:40.050 --> 25:41.460 vesicles 25:42.840 --> 25:44.060 enclosing glycogen 25:50.040 --> 25:52.750 further irrespective of the mechanism by 25:52.750 --> 25:53.990 which the glycogen? 25:54.000 --> 25:55.780 The free glycogen accumulates? 25:56.640 --> 25:59.090 Another question is why is it not 25:59.090 --> 26:01.360 degraded by the normal, 26:01.360 --> 26:03.860 like a generalistic pathways of the cytoplasm. 26:05.640 --> 26:07.460 In other puzzling question, 26:07.470 --> 26:10.200 regards the biochemical basis for the clinical 26:10.200 --> 26:13.070 differences between infantile and late onset, 26:13.070 --> 26:14.270 as in motors deficiency. 26:17.340 --> 26:18.760 In a comparative study. 26:18.770 --> 26:21.370 Angelini and dangle found lower than 26:21.370 --> 26:24.030 normal neutral multi activity in several 26:24.030 --> 26:26.960 tissues from the infantile but not the late onset 26:26.970 --> 26:29.720 late onset AMG patients as emotive 26:29.720 --> 26:32.590 deficiency patients and suggested a possible 26:32.590 --> 26:35.270 compensatory role for neutral maltese. 26:36.140 --> 26:38.990 In our laboratory determination of acid 26:38.990 --> 26:41.910 maltese by a very sensitive floor O Matic asset 26:41.920 --> 26:44.420 using the artificial substrate for 26:44.420 --> 26:46.580 methylene Bellisario alpha, 26:46.590 --> 26:47.180 the glucose, 26:47.180 --> 26:50.020 glucose glucose side revealed the presence 26:50.020 --> 26:52.970 of some residual activity variable 26:52.970 --> 26:55.790 From between three and 12 in 26:55.790 --> 26:58.250 15 cases in muscle from 15 26:58.250 --> 27:00.660 cases with late onset as in motives 27:00.660 --> 27:01.490 deficiency, 27:01.500 --> 27:04.030 but no residual Activity in 27:04.040 --> 27:06.680 in muscle from three patients with 27:06.690 --> 27:08.920 infantile form of the disease. 27:12.040 --> 27:14.570 This phenomenon is even more apparent in Lucas 27:14.570 --> 27:17.410 sides where enzyme activity, 27:17.420 --> 27:20.060 acid motives activity is either normal 27:20.070 --> 27:22.630 or only partially reduced in late 27:22.630 --> 27:25.130 onset but undetectable in 27:25.130 --> 27:27.230 infantile forms of the disease. 27:27.940 --> 27:29.200 These observations, 27:29.210 --> 27:32.040 and the fact that no cases of infantile and 27:32.040 --> 27:34.890 late onset as emotive deficiency have been so far 27:34.890 --> 27:36.590 reported in the same family, 27:36.600 --> 27:39.590 suggest that these are two different genetic 27:39.590 --> 27:42.160 diseases affecting the same enzyme. 27:42.540 --> 27:45.090 Another example of genetic virginity. 27:47.140 --> 27:49.770 Several different therapeutic strategies have been 27:49.770 --> 27:50.470 tried, 27:50.480 --> 27:52.650 particularly the infantile form, 27:52.660 --> 27:55.560 including liberalization of liposomes, 27:55.570 --> 27:58.310 stimulation of glycogen analysis and 27:58.310 --> 27:59.450 enzyme replacement, 28:00.540 --> 28:01.700 vitamin A. 28:01.710 --> 28:04.690 Progesterone hyperbaric oxygen are 28:04.690 --> 28:07.290 among the list goes on liberalising agents 28:07.340 --> 28:09.850 used to make the trapped glycogen. 28:10.050 --> 28:12.580 This is the rationale behind it to make the trapped 28:12.580 --> 28:15.270 glycogen available to cytoplasmic digestion. 28:16.540 --> 28:19.460 These agents were clinically ineffective and the 28:19.460 --> 28:22.330 rationale of this approach may be questionable in 28:22.330 --> 28:23.700 infantile MD. 28:23.710 --> 28:25.670 where as I showed before, 28:25.680 --> 28:28.210 much extra lies omar 28:28.210 --> 28:30.650 glycogen is already present in most tissues 28:32.040 --> 28:34.950 stimulation of psychoanalysis by administration of 28:34.950 --> 28:37.240 epinephrine resulted in 28:37.240 --> 28:40.170 decrease of cytoplasmic but 28:40.170 --> 28:41.100 not centralized. 28:41.100 --> 28:42.770 Uzoma glycogen in liver. 28:43.240 --> 28:44.380 In one case 28:46.330 --> 28:48.850 this only demonstrates that astral is is normal. 28:48.850 --> 28:50.990 Glycogen breakdown is normal. 28:50.990 --> 28:53.760 In this disease administration of 28:53.760 --> 28:54.550 alpha glucose, 28:54.550 --> 28:57.360 it is prepared either from aspergillus *** 28:57.740 --> 29:00.590 or from human placenta was 29:00.590 --> 29:02.050 attempted in a few cases. 29:02.740 --> 29:05.680 In one patient centralizes omo glycogen 29:05.810 --> 29:08.770 decreased significantly in liver and the 29:08.770 --> 29:09.400 morphology. 29:09.400 --> 29:12.090 The infrastructure of this organ reverted essentially to 29:12.090 --> 29:12.550 normal. 29:15.040 --> 29:15.810 In no case, 29:15.810 --> 29:16.440 however, 29:16.450 --> 29:17.650 did the exotic, 29:17.660 --> 29:20.550 did exogenous enzyme enter either 29:20.550 --> 29:23.510 skeleton or cardiac muscle and the clinical 29:23.510 --> 29:25.660 course was unchanged by this treatment. 29:26.740 --> 29:29.530 In patients with the late onset form of the disease, 29:29.940 --> 29:32.760 ketogenic diet associated or not 29:32.770 --> 29:35.660 with epinephrine administration has been suggested 29:35.660 --> 29:38.480 as a means of slowing down glycogen 29:38.480 --> 29:41.170 accumulation in Mosul and its effectiveness is 29:41.170 --> 29:44.060 presently under investigation in several laboratories. 29:46.640 --> 29:49.390 While a great amount of work has been done over the 29:49.390 --> 29:52.190 past 25 years on glycogen metabolism of 29:52.190 --> 29:54.750 muscle and if disorders as I think 29:54.760 --> 29:57.170 became apparent from this presentation, 29:57.740 --> 30:00.580 relatively little attention has been directed to 30:00.580 --> 30:01.460 lipid metabolism. 30:02.340 --> 30:05.330 This is surprising because lipid metabolism is at least as 30:05.330 --> 30:07.860 important as glycogen metabolism as a source of 30:07.860 --> 30:09.660 energy for muscle contraction. 30:10.540 --> 30:13.430 While glycogen breakdown is an ideally suited 30:13.430 --> 30:16.000 metabolic system for the rapid provision of 30:16.000 --> 30:16.560 energy, 30:17.240 --> 30:19.540 which is crucial in flight or fly 30:19.540 --> 30:22.230 situations or in strenuous exercise in 30:22.230 --> 30:22.780 humans, 30:24.540 --> 30:27.530 it cannot sustain exercise for more than a few minutes. 30:28.620 --> 30:30.990 The energy for prolonged exercise 30:31.040 --> 30:33.360 derives mainly from lipid metabolism, 30:33.840 --> 30:36.830 which is largely an intra mitochondria process, 30:36.840 --> 30:39.770 as shown schematically in the slide. 30:40.420 --> 30:42.080 Once free fatty acids, 30:42.090 --> 30:44.380 which are the so to the lipid 30:44.380 --> 30:46.570 currency of the sale. 30:46.580 --> 30:47.850 For the sale 30:49.240 --> 30:51.870 have been transported into the cell. 30:51.880 --> 30:54.830 They are activated by an enzyme known as 30:54.840 --> 30:56.260 fatty acid coenzyme, 30:56.260 --> 30:59.130 a center days at the expense of ATP 30:59.140 --> 31:01.860 to form fatty acid coenzyme A. 31:04.340 --> 31:05.360 At this point 31:06.540 --> 31:09.460 in an enzyme known as car 31:09.460 --> 31:11.340 knitting performative transfers, 31:11.840 --> 31:14.470 one which is located on the outer 31:14.470 --> 31:16.820 face of the inner mitochondrial membrane 31:16.890 --> 31:18.260 mitochondrial membrane. 31:18.270 --> 31:21.240 And this this structure here 31:21.240 --> 31:22.950 is supposed to represent the mitochondria 31:23.840 --> 31:26.820 um attach is the 31:26.820 --> 31:28.770 fatty acid oil residue 31:29.340 --> 31:32.160 to a molecule of carnitine 31:32.940 --> 31:34.370 to form fatty acids. 31:34.380 --> 31:36.890 Carnegie in this form, 31:36.900 --> 31:39.440 and only this form long chain fatty 31:39.440 --> 31:42.330 acids can go across 31:42.330 --> 31:45.060 or penetrate into the mitochondria. 31:46.340 --> 31:48.960 Once inside the mitochondria in a second 31:48.960 --> 31:51.740 enzyme known as car knitting permitted 31:51.740 --> 31:54.730 transfers to which is attached to the interface 31:54.740 --> 31:56.360 or the inner mitochondrial membrane 31:56.940 --> 31:59.190 catalyze is the reverse reaction. 31:59.200 --> 32:02.180 Detaches the fatty acid residue or the long chain 32:02.190 --> 32:05.030 fatty acid residue from carnitine and reattach, 32:05.030 --> 32:07.940 is it to a coenzyme coenzyme a 32:07.940 --> 32:10.560 to form again fatty acid coenzyme a. 32:11.040 --> 32:13.710 This now can undergo within the mitochondria in 32:13.840 --> 32:16.350 the stepwise process of better oxidation 32:16.940 --> 32:17.740 at each step. 32:17.740 --> 32:18.640 In this process, 32:18.650 --> 32:21.530 there is liberation of a molecular velocity coenzyme 32:21.530 --> 32:21.910 A, 32:21.920 --> 32:24.260 which then can enter the Krebs cycle 32:30.640 --> 32:33.510 to disorders of lipid metabolism or to 32:33.510 --> 32:36.450 specific disorders of lipid metabolism have been 32:36.460 --> 32:38.560 affecting muscle have been reported, 32:39.140 --> 32:41.060 one of them causing 32:42.940 --> 32:45.100 intolerance to exercise if you want. 32:45.110 --> 32:48.090 Or intermittent myoglobin urea and the other 32:48.100 --> 32:49.860 causing progressive muscle weakness. 32:50.440 --> 32:50.940 Again, 32:50.940 --> 32:51.460 as you see, 32:51.460 --> 32:54.060 the muscle seems to have but a few ways of crime. 32:55.640 --> 32:58.500 1973 at the University of Pennsylvania, 32:58.500 --> 33:01.460 we started two brothers 33 and 33:01.460 --> 33:02.960 29 years old. 33:03.340 --> 33:04.170 As you see here, 33:04.640 --> 33:07.550 with a similar with similar syndromes 33:08.540 --> 33:09.670 in the syndrome, 33:09.670 --> 33:11.560 the clinical picture 33:12.140 --> 33:14.560 consisted really of recurrent myoglobin urea, 33:15.040 --> 33:16.600 convincing around puberty. 33:17.140 --> 33:20.130 Unlike muscle for foreigners and fossil fuel tokens 33:20.140 --> 33:20.980 deficiency, 33:20.980 --> 33:23.570 there was no history of painful cramps or 33:23.570 --> 33:24.690 intolerance to strangers, 33:24.690 --> 33:26.770 exercise of short duration 33:27.540 --> 33:30.380 myoglobin urea generally followed sustained 33:30.380 --> 33:33.320 exercise of about two hours duration, 33:33.330 --> 33:34.950 like mountain hiking, 33:35.440 --> 33:37.770 unloading lumber painting walls. 33:40.040 --> 33:40.640 Also, 33:40.650 --> 33:42.240 unlike McArdle disease, 33:42.360 --> 33:44.270 fasting contribute to the pierre. 33:44.270 --> 33:46.820 Myoglobin urea and the two most severe 33:46.820 --> 33:49.380 attacks were induced 33:49.390 --> 33:52.310 by were indeed precipitated by a combination of 33:52.310 --> 33:55.270 prolonged exercise and inadequate diet. 33:56.640 --> 33:58.690 The diagnosis of glycogen, 33:58.690 --> 34:01.530 Osi's type five Or seven was ruled out 34:01.530 --> 34:04.110 by the normal rise of Venus lactate after 34:04.110 --> 34:06.990 ischemic exercise and more directly 34:07.000 --> 34:09.960 by the normal level of glycogen and the normal 34:09.960 --> 34:12.710 activities of phosphorus and fossil fuel tokens in 34:12.710 --> 34:15.220 muscle biopsies morphology of 34:15.220 --> 34:16.860 muscle was essentially normal. 34:19.040 --> 34:21.510 The concentration of carnitine was slightly 34:21.510 --> 34:23.970 elevated in this 34:23.980 --> 34:24.660 patient 34:26.940 --> 34:29.570 as compared to normal and the activity of 34:29.570 --> 34:32.360 parliamentary coenzyme a center days and acetyl 34:32.370 --> 34:34.860 carnitine transfers were normal 34:38.840 --> 34:39.400 muscle. 34:39.400 --> 34:39.980 Carnitine. 34:39.980 --> 34:42.610 Parliamentary transfer is for the long chain. 34:42.620 --> 34:43.470 If you remember. 34:43.480 --> 34:44.060 Arsenal. 34:44.740 --> 34:47.170 Canada transfers was Measured 34:47.170 --> 34:49.380 by three methods, 34:49.390 --> 34:52.220 2 of which are shown in this slide in 34:52.230 --> 34:54.200 both crude muscle or margin. 34:54.200 --> 34:56.470 It's and in mitochondria preparation 34:56.940 --> 34:59.120 and in the patients, 34:59.120 --> 35:00.860 the activities varied between 35:01.240 --> 35:03.790 undetectable to about 20% of 35:03.790 --> 35:05.200 normal at most 35:07.540 --> 35:08.180 the enzyme. 35:08.180 --> 35:10.610 The fact was also expressed in leukocyte. 35:12.130 --> 35:13.230 In both patients, 35:13.250 --> 35:15.810 where activities were below 20% of 35:15.810 --> 35:18.660 normal and intermediate activities 35:18.660 --> 35:20.980 were found in the leukocyte of their 35:20.990 --> 35:22.250 symptomatic mother. 35:23.740 --> 35:26.380 This pattern seems to suggest an auto xoma 35:26.380 --> 35:27.980 recessive model transmission, 35:27.990 --> 35:29.450 although at present, 35:29.600 --> 35:32.560 next link transmission cannot be excluded. 35:34.940 --> 35:37.920 Plasma free fatty acids were normal 35:37.930 --> 35:39.260 on a balanced diet, 35:39.640 --> 35:42.040 but cholesterol was slightly 35:42.040 --> 35:44.520 increased And tried 35:44.520 --> 35:47.060 illiterates were increased between three 35:47.440 --> 35:50.050 and five fold in the patient, 35:52.440 --> 35:54.690 Each patient then underwent a 35:54.690 --> 35:56.950 72 hour fast without 35:56.950 --> 35:57.750 exercise. 35:58.040 --> 36:00.350 Both patients remained a symptomatic, 36:01.130 --> 36:04.040 but one of them had a marked increase 36:04.040 --> 36:06.410 of CPK after 72 hours of 36:06.410 --> 36:07.050 fasting, 36:07.060 --> 36:09.670 which was again present at a 36:09.670 --> 36:12.120 subsequent trial of fasting 36:12.210 --> 36:15.060 and myoglobin traces of myoglobin became 36:15.060 --> 36:16.440 apparent in both plasma, 36:16.440 --> 36:19.390 enduring in both patients. 36:19.450 --> 36:20.750 After fasting 36:23.230 --> 36:24.850 ketone bodies production 36:25.630 --> 36:27.810 was also abnormal. 36:27.820 --> 36:28.970 As you see Here, 36:28.980 --> 36:31.410 Ketone bodies did not rise in 36:31.410 --> 36:34.110 plasma until about the 3rd 36:34.110 --> 36:35.160 day of fasting. 36:35.530 --> 36:38.460 While administration of medium change like this right 36:38.470 --> 36:41.370 produced a very prompt increasing ketone bodies as in 36:41.370 --> 36:43.050 normal individuals. 36:45.230 --> 36:47.980 This would suggest that the side effect may 36:47.980 --> 36:49.140 affect the liver as well. 36:49.150 --> 36:51.120 Although this was not directly tested, 36:52.530 --> 36:55.050 how can we now tie all this data together? 36:55.730 --> 36:56.090 Well, 36:56.090 --> 36:58.950 long chain fatty acid oxidation in men at 36:58.950 --> 37:01.870 rest and on a regular diet provides 37:01.870 --> 37:03.120 more than 50%. 37:03.120 --> 37:05.540 Certainly of the energy required by muscle 37:06.130 --> 37:09.030 impairment of fatty acid utilization. 37:09.030 --> 37:11.710 By muscle may cause an increase of free 37:11.710 --> 37:13.460 fatty acids in the blood. 37:14.130 --> 37:16.060 And this would be the free fatty acids, 37:16.060 --> 37:18.970 which are potentially toxic substances would be handled by 37:18.970 --> 37:19.610 the liver, 37:19.620 --> 37:21.850 which would then s terrify them to 37:21.850 --> 37:22.860 triglycerides, 37:22.870 --> 37:24.530 and this may cause secondary 37:24.540 --> 37:25.950 hypercholesterolemia. 37:27.130 --> 37:29.750 The sequence of events would be magnified 37:29.760 --> 37:31.040 during fasting, 37:31.050 --> 37:33.880 which normally causes increased utilization of 37:33.880 --> 37:36.040 fatty acids released from multiple sides 37:37.430 --> 37:39.080 during normal activity. 37:39.240 --> 37:40.640 And on a normal diet, 37:40.650 --> 37:43.410 these patients can utilize muscle glycogen and 37:43.410 --> 37:44.170 blood glucose. 37:45.430 --> 37:48.420 Normal activity and moderate or short exercise 37:48.420 --> 37:49.560 are very well tolerated 37:51.030 --> 37:52.810 after unusual exercise. 37:52.810 --> 37:53.350 However, 37:53.360 --> 37:55.320 especially with some degree of fasting, 37:55.510 --> 37:58.500 glycogen stores are probably depleted and due 37:58.500 --> 38:01.280 to the defect of carnitine permitted transfers long 38:01.280 --> 38:03.740 chain fatty acids cannot enter muscle 38:03.740 --> 38:05.750 mitochondria to serve a source of energy. 38:06.920 --> 38:09.700 The pathogenesis of myoglobin urea is as 38:09.700 --> 38:12.580 Hypothetical as it is in like a diagnosis type five and 38:12.580 --> 38:12.950 7. 38:13.720 --> 38:14.290 Again, 38:14.290 --> 38:15.280 in this disorder, 38:15.580 --> 38:18.480 it can be postulated that acute muscle 38:18.480 --> 38:19.080 necrosis, 38:19.080 --> 38:22.000 maybe related to the defect 38:22.000 --> 38:24.380 of ATP do in this case to a 38:24.380 --> 38:26.910 block of lipid rather than glycogen 38:27.150 --> 38:27.830 metabolism 38:33.020 --> 38:36.000 In 1972 Andrew Angle and 38:36.000 --> 38:38.920 Zeke Erred reported the case of a young woman, 38:38.920 --> 38:41.620 19 year old woman with severe 38:41.620 --> 38:43.640 generalized muscle weakness, 38:44.320 --> 38:47.240 Which started apparently in childhood 38:47.240 --> 38:49.960 but became rapidly wars around 38:49.960 --> 38:51.250 90 age 19. 38:56.020 --> 38:58.680 They main feature of this 38:58.680 --> 39:00.980 patient was in the morphology of her muscle, 39:00.990 --> 39:03.940 which showed tremendous accumulation of lipids, 39:03.950 --> 39:06.950 a real lipid storage myopathy and 39:06.950 --> 39:07.670 next slide, 39:07.670 --> 39:09.570 which is not from the same patient, 39:09.580 --> 39:12.530 but from a patient that we recently studied the Columbia 39:12.530 --> 39:14.640 University shows this phenomenon. 39:15.220 --> 39:16.030 As you see, 39:16.720 --> 39:19.100 these great accumulation 39:19.270 --> 39:22.140 of lipids in these three portions of these three 39:22.140 --> 39:24.890 fibers is remarkable in 39:24.890 --> 39:25.830 normal muscle. 39:25.840 --> 39:28.220 You could see just a few of these 39:28.230 --> 39:31.140 vacuums containing lipids originally here and 39:31.140 --> 39:31.440 there 39:36.220 --> 39:38.840 the following year angle and 39:38.840 --> 39:41.690 Angelini found that in 39:41.690 --> 39:44.650 vitro utilization of long chain fatty 39:44.650 --> 39:47.010 acids by the 39:47.020 --> 39:49.790 patient muscle was defective as compared to 39:49.790 --> 39:52.600 normal in the absence of of 39:52.610 --> 39:53.820 added Carnegie. 39:53.830 --> 39:56.520 But when carnitine was added to the medium, 39:56.530 --> 39:59.130 then utilization of fatty 39:59.130 --> 40:01.440 acids became essentially normal. 40:02.610 --> 40:05.250 This observation led them to measure the 40:05.250 --> 40:08.110 concentration of carnitine in the patient muscle in the 40:08.110 --> 40:10.710 patient's muscle and in several occasions they 40:10.710 --> 40:13.710 found that the carnitine levels were very 40:13.710 --> 40:16.630 low as compared to normal muscles. 40:17.610 --> 40:17.820 Mhm. 40:18.910 --> 40:21.780 Carnitine is sympathized exclusively or 40:21.780 --> 40:24.650 predominantly in the liver and then sort of 40:24.650 --> 40:27.480 exported through the blood to other 40:27.480 --> 40:28.030 tissues. 40:29.310 --> 40:32.170 The much higher concentration of carnitine in muscle 40:32.170 --> 40:33.250 than in plasma. 40:33.260 --> 40:36.260 Further suggests that the uptake of carnitine, 40:36.260 --> 40:37.830 maybe an active process 40:40.010 --> 40:41.910 depending on energy, 40:41.910 --> 40:44.430 possibly as serum carnitine 40:44.430 --> 40:45.140 levels. 40:45.810 --> 40:47.700 We are normal in the patient, 40:47.710 --> 40:50.240 the effect of this transport mechanism 40:50.910 --> 40:53.560 appear to be the most likely explanation for the 40:53.560 --> 40:54.950 defect of muscle carnitine. 40:55.160 --> 40:57.660 In the patient of Andrew Anglin 40:57.660 --> 40:58.230 Angelini, 41:02.410 --> 41:05.230 four more patients with this syndrome have 41:05.230 --> 41:06.950 been described and actually 41:07.190 --> 41:09.730 it is almost difficult to 41:10.110 --> 41:12.840 uh to keep Up with the literature. 41:12.840 --> 41:13.400 A 5th, 41:13.410 --> 41:16.280 a fifth patient or six patient in all, 41:16.290 --> 41:19.060 has been now described in Lancet and we have seen, 41:19.070 --> 41:21.800 as I mentioned in other patients that we're following. 41:21.800 --> 41:22.230 Now. 41:22.610 --> 41:23.470 In any event, 41:23.780 --> 41:25.440 there are several, 41:25.450 --> 41:27.720 some common features between these patients, 41:27.900 --> 41:28.520 namely, 41:29.000 --> 41:31.760 they all showed muscle weakness more or less 41:31.770 --> 41:34.650 generalized and all of them had 41:34.660 --> 41:37.380 lipid storage in their muscle lipid 41:37.380 --> 41:39.440 story picture of lipid storage myopathy. 41:40.010 --> 41:40.640 However, 41:41.610 --> 41:44.330 the disorders seem to be rather 41:44.330 --> 41:45.190 heterogeneous. 41:45.190 --> 41:48.030 As far as other parameters are concerned. 41:48.410 --> 41:50.340 Age of onset varied. 41:50.350 --> 41:52.770 The number of tissues involved 41:52.780 --> 41:55.720 varied very much in some cases. 41:55.730 --> 41:58.620 In some cases the disorder seems to be limited to 41:58.620 --> 41:59.720 skeletal muscle. 41:59.730 --> 42:02.470 In other it seemed to affect 42:02.480 --> 42:03.520 peripheral nerve, 42:03.530 --> 42:04.010 uh, 42:04.400 --> 42:05.370 leukocyte, 42:06.600 --> 42:09.540 it's on the most important 42:09.550 --> 42:12.530 difference uh is reflected by a patient 42:12.530 --> 42:15.010 described by car party and 42:15.020 --> 42:16.880 collaborators in Montreal. 42:16.890 --> 42:19.670 This was a child where carnitine was 42:19.670 --> 42:21.220 not only low in muscle, 42:21.230 --> 42:23.970 but it was only law in uh 42:23.980 --> 42:26.320 zero and in living 42:27.200 --> 42:30.120 and this would therefore suggest that in this case we are 42:30.120 --> 42:33.010 dealing with a defect in carnitine synthesis 42:33.020 --> 42:35.480 in the liver rather than an effect of carnitine 42:35.490 --> 42:36.620 transport. 42:39.900 --> 42:42.650 The genetic nature of the disease was 42:42.650 --> 42:44.510 demonstrated in one case, 42:45.200 --> 42:47.660 this is the pedigree of the patients studied 42:47.670 --> 42:50.460 by Dr van Dyke and his collaborators 42:50.470 --> 42:53.130 here in Rochester and as the 42:53.130 --> 42:55.990 numbers indicate carnitine levels, 42:56.000 --> 42:58.650 carnitine concentration in muscle and as you 42:58.650 --> 42:59.190 see, 42:59.200 --> 43:01.820 both parents of the pra positives 43:01.830 --> 43:04.230 and a maternal and 43:04.600 --> 43:07.510 all had definitely lower than 43:07.510 --> 43:09.230 normal levels of comedy, 43:09.800 --> 43:12.340 suggesting because this pattern strongly 43:12.340 --> 43:15.030 suggest an auto xoma recessive model transmission 43:16.800 --> 43:19.280 regardless of what the primary biochemical 43:19.290 --> 43:20.740 error or errors. 43:20.750 --> 43:21.460 Really, 43:21.470 --> 43:23.470 maybe these disorders, 43:23.640 --> 43:25.220 the effect of muscle committee, 43:25.230 --> 43:28.200 which is the indispensable carrier of fatty acids 43:28.200 --> 43:30.140 across the inner mitochondrial membrane, 43:30.180 --> 43:33.180 as I showed before in the scheme may 43:33.180 --> 43:36.020 easily account for the defect of lipid metabolism 43:36.100 --> 43:38.520 observed in these patients and for the lipid 43:38.520 --> 43:39.110 storage. 43:40.600 --> 43:43.490 What is not easily explained is why to 43:43.490 --> 43:46.280 biochemical defects affecting the same 43:46.280 --> 43:47.440 metabolic pathway, 43:47.450 --> 43:50.360 namely carnitine positive transference deficiency 43:50.370 --> 43:53.320 and carnitine deficiency should cause 43:53.320 --> 43:55.510 such dissimilar clinical pictures. 43:56.800 --> 43:59.730 Therapy with corticosteroids has 43:59.730 --> 44:02.580 been beneficial in Carnitine deficiency in two cases 44:02.990 --> 44:05.720 for reasons that are still largely unknown 44:06.490 --> 44:09.310 replacement therapy with oral carnitine 44:09.690 --> 44:12.480 has also been very effective in at least two patients 44:13.190 --> 44:15.680 and the rationale for such a therapy appears to 44:15.680 --> 44:16.250 be, 44:16.260 --> 44:16.830 of course, 44:16.840 --> 44:19.390 obvious particularly in the case in the 44:19.390 --> 44:21.010 cases with low serum 44:21.990 --> 44:22.610 Carnegie. 44:23.190 --> 44:23.810 However, 44:24.190 --> 44:26.290 in spite of the good clinical response, 44:26.500 --> 44:29.250 no increase of either liver or muscle 44:29.250 --> 44:31.780 carnitine was observed suggesting the 44:31.780 --> 44:34.770 defective sentences of carnitine in the liver 44:34.780 --> 44:37.610 may not be the sole biochemical abnormality, 44:38.190 --> 44:39.080 particularly this. 44:39.080 --> 44:42.020 This is true for the case of Car party 44:42.030 --> 44:43.610 and collaborators in Montreal, 44:45.190 --> 44:47.520 the area of lipid metabolism of muscle, 44:47.530 --> 44:50.490 and it's disorders is still largely uncharted 44:50.490 --> 44:51.100 territory, 44:51.990 --> 44:54.860 and it is likely that a number of different disease 44:54.870 --> 44:57.300 entities will be recognized in the near 44:57.300 --> 44:57.900 future, 44:57.910 --> 45:00.600 just as it happened for the glycogen storage diseases. 45:01.090 --> 45:03.830 And this is certainly a challenging and exciting 45:03.830 --> 45:05.010 perspective for the future.