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Progress and Problems in Muscle Glycogenoses

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Progress and Problems in Muscle Glycogenoses Acta Myologica • 2011; XXX: p. 96-102 Progress and problems in muscle glycogenoses S. DiMauro, R. Spiegel1 Department of Neurology, Columbia University Medical Center, New York, USA; 1 Department of Pediatrics, HaEmek Medical Center, Rappaport School of Medicine, Afula, Israel In this selective review, we consider a number of unsolved ques- to unravel why glycogen accumulation is not limitless in tions regarding the glycogen storage diseases (GSD). Thus, the muscle (2). The answer to the second question is an excit- pathogenesis of Pompe disease (GSD II) is not simply explained ing, if ancient, collaboration showing that both morpho- by excessive intralysosomal glycogen storage and may relate to a more general dysfunction of autophagy. It is not clear why de- logical and biochemical features of Pompe disease were brancher deficiency (GSD III) causes fixed myopathy rather than reproduced in muscle culture (3). The answer to the third exercise intolerance, unless this is due to the frequent accompa- question is a much more recent collaboration on a pa- nying neuropathy. The infantile neuromuscular presentation of tient who had phosphoglycerate kinase (PGK) deficiency branching enzyme deficiency (GSD IV) is underdiagnosed and (GSD IX) and a pure myopathy, or so we thought initially is finally getting the attention it deserves. On the other hand, the (see below) (4). late-onset variant of GSD IV (adult polyglucosan body disease APBD) is one of several polyglucosan disorders (including La- The truth is that GSD are still very much an open fora disease) due to different etiologies. We still do not under- chapter, where new entities are discovered (5, 6), appar- stand the clinical heterogeneity of McArdle disease (GSD V) or ently paradoxical myopathies due to lack, rather than the molecular basis of the rare fatal infantile form. Similarly, the excess, of glycogen (aglycogenosis or GSD 0) are being multisystemic infantile presentation of phosphofructokinase defi- reported (7, 8), old disorders, such as Lafora disease, are ciency (GSD VII) is a conundrum. We observed an interesting as- sociation between phosphoglycerate kinase deficiency (GSD IX) now recognized as GSD (9), and therapy based on enzyme and juvenile Parkinsonism, which is probably causal rather than replacement is reasonably successful in GSD II (10, 11). casual. Also unexplained is the frequent and apparently specific This is not meant to be a comprehensive review of the association of phosphoglycerate mutase deficiency (GSD X) and muscle glycogenoses. Rather, we will consider puzzling tubular aggregates. By paying more attention to problems than aspects of some GSD, following the Roman numerical to progress, we aimed to look to the future rather than to the past. order shown in Figure 1. Key words: glycogen storage diseases, GSD, polyglucosan disor- GSD II (acid maltase deficiency, ders Pompe disease) The first and oldest conundrum about this disorder Why writing of glycogen storage diseases (GSD), was its clinical heterogeneity, with a severe generalized which are “old hats” among the metabolic disorders af- infantile form and a later-onset form largely confined fecting skeletal muscle? Why writing of GSD to honor to skeletal muscle and presenting in children (juvenile Valerie Askanas and King Engel? Why writing with Ro- onset) or in adults (late-onset). As acid maltase (acid nen Spiegel? The answer to the first question is deeply α-glucosidase, GAA) is a single ubiquitous protein, it personal: the very first paper of the senior (chronologi- is not surprising that initial findings of different residual cally, not academically) author (SDM) described a lit- GAA activities in muscle (12) have been confirmed and tle girl with Pompe disease (1) and his first project as a related to the severity of GAA mutations, with nonsense postdoctoral fellow with Dr. Lewis P. (Bud) Rowland was mutations prevailing in the infantile form and missense Address for correspondence: Salvatore DiMauro, MD, 4-424B College of Physicians & Surgeons, 630 West 168th Street, New York, NY 10032, USA. Tel. +212 305 1662. Fax +212 305 3986. E-mail: [email protected] 96 Progress and problems in muscle glycogenoses “returns” to the cytoplasm the end product of lysosomal glycogen digestion, glucose. It is also telling that in mus- cle from patients with the infantile form of GSD II most glycogen is free in the cytoplasm, probably released by “burst lysosomes” (13). A more compelling scenario for the pathogenesis of GSD II, as well as other lysosomal storage disorders (16), involves a disruption of the vital autophagic process, with accumulation of autophagosomes resulting from defec- tive autophagosome-lysosome fusion (16, 17). In fact, Nishino and colleagues went as far as stating that “Pompe disease can no longer be viewed simply as a glycogen storage disease,” but rather as a problem in handling ex- cessive numbers of autophagosomes (13). A unique feature of GSD II is the availability of a generally effective – and now widely utilized – enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). There is already a vast literature on the subject (10), and a few problems have emerged, such as the immune reaction to rhGAA in infants with null muta- tions and no GAA protein (i.e. no cross-reactive immuno- logical material, CRIM) (18). Assumption of rhGAA into lysosomes is probably hindered by the more general au- tophagic dysfunction mentioned above and several strata- gems have been proposed to improve uptake, including conjugation of rhGAA with a synthetic oligosaccharide harboring mannose-6-phosphate (19), combining ERT Figure 1. Scheme of glycogen metabolism and glyco- lysis. Roman numerals denote muscle glycogenoses due with chaperones (20), and inhibition of glycogen synthe- to defects in the following enzymes: II, acid α-glucosidase sis (21, 22). (AAG); III, debrancher; IV, brancher; V, myophosphoryla- One final clinical note: besides skeletal muscle, se; VI, liver phosphorylase; VII, muscle phosphofructoki- smooth muscle must also be affected in late-onset GSD II nase (PFK); VIII, phosphorylase b kinase (PHK); IX, phos- because there have been a few reports of cerebral arterio- phoglycerate kinase (PGK); X, phosphoglycerate mutase pathies, often affecting the basilar artery (23, 24). (PGAM); XI, lactate dehydrogenase (LDH); XII, aldolase; XIII, β-enolase; IV, triosephosphate isomerase (TPI). Sym- bols in regular typeface denote glycogenoses character- GSD III (debrancher enzyme ized by exercise intolerance, cramps, and myoglobinuria. deficiency; Cori-Forbes disease) Symbols in italics denote glycogenoses characterized by fixed weakness. The debrancher is a “double duty” enzyme, with two catalytic functions, oligo-1,4-1,4-glucantransferase and amylo-1,6-glucosidase. Once phosphorylase has short- and splicing (i.e. “leaky”) mutations prevailing in later ened the peripheral chains of glycogen to about four onset cases (13, 14). glucosyl units (this partially digested glycogen is called A second riddle regarded the pathogenesis of weak- phosphorylase-limit dextrin, PLD), the debrancher en- ness: was it simply due to the mechanical disarray of zyme removes the residual stumps in two steps. First, a the contractile material caused by the glycogen-laden maltotriosyl unit is transferred from a donor to an accep- lysosomes or to an energy defect? The former mecha- tor chain (transferase activity), leaving behind a single nistic hypothesis is questionable both because it does glucosyl unit, which is then hydrolyzed by the amylo-1- not explain the weakness of later onset GSD II and be- ,6-glucosidase, at which point the branch is off. A single- cause equally disruptive overloads of lipid droplets in copy gene, AGL, encodes the debrancher enzyme. muscle were compatible with normal strength in a pre- A comprehensive summary of clinical features and clinical case of neutral lipid storage disease with my- therapeutic options has been published recently (25). opathy (NLSDM) (15). The latter energetic hypothesis Considering the predominantly myopathic presenta- is supported by the notion that GAA activity normally tion of GSD III, a clinician would likely question why 97 S. DiMauro, R. Spiegel the defect of an enzyme that acts hand-in-hand with myo- and the nucleus ambiguus. Similar findings were reported phosphorylase should cause weakness rather than cramps in two more infants (32, 33). The motor neurons of the and myoglobinuria, the clinical hallmarks of McArdle spinal cord are also severely affected (32), explaining how disease. One reason for this discrepancy may be that in one of the patients we studied was initially diagnosed as McArdle disease glycogen cannot be metabolized at all, spinal muscular atrophy type I (SMA I) until mutations in whereas in GSD III the peripheral chains of normal gly- the SMN1 gene were ruled out (34). cogen can be utilized. However, this explanation postu- At the other end of the clinical spectrum, there is lates that the intact glycogenosynthetic pathway allows adult polyglucosan body disease (APBD), a neurological some turnover between normal glycogen and PLD, which variant of GSD IV presenting late in life with progres- is not unreasonable. sive upper and lower motor neuron dysfunction (simu- Another explanation for the fixed and mostly dis- lating amyotrophic lateral sclerosis), sensory neuropathy, tal weakness of patients with GSD III (26) is the si- neurogenic bladder (APBD patients often see a urolo- multaneous involvement of muscle and nerve, as gist before
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