Acidmaltasedeficiency: case study andreview ...

Journal of Neurology, Neurosurgery, and Psychiatry 1986;49:1011-1018

Acid maltase deficiency: a case study and review of thepathophysiological changes and proposed therapeuticmeasures

HYAM ISAACS,* NERINA SAVAGE,t MARGARET BADENHORST,:TONI WHISTLER:

From the Departments ofPhysiology,* and Medical Biochemistry,f and the Clinical Neuromuscular ResearchLaboratory, Department ofPhysiology, Witwatersrand University Medical School, South Africa

SUMMARY An adult patient with lysosomal acid alpha-glucosidase deficiency was fully investigated,and then placed on various forms of therapy with favourable response to a high protein, lowcarbohydrate diet. The rationale for the employment of this therapy, the problem of acid maltasedeficiency and the relationship to weakness and glycogenosome formation with accumulation orotherwise of glycogen within the muscle fibres is discussed.

Deficiency of lysosomal acid alpha-glucosidase (acidmaltase) is in most cases associated with abnormalaccumulation of glycogen in skeletal muscle. Theexcessive concentration of glycogen viewed ultra-microscopically is obvious in the sarcoplasm as free-lying glycogen and as membrane-bound glycogen sacsknown as glycogenosomes. These are seen to be dis-tended lysosomes, some of which have ruptured theirglycogen content into the sarcoplasm. On lightmicroscopy the muscle appearance is that of a vacu-olar myopathy which on histochemical study showsthe presence of excessive acid phosphatase.' In 1932Putschar2 and Pompe3 were the first to describe thisdisorder of glycogen metabolism in infants. Sub-sequently a late onset or adult form was described byEngel and Dale.4 Hers' ascribed the glycogen storageto acid alpha-glucosidase deficiency. Acid maltasedeficiency is classified as glycogenolysis Type I6 andis one of the six major causes of glycogen storage dis-ease.

It has become established over the years that thisrecessively inherited abnormality of lysosomal acidalphaglucosidase may present clinically in two forms.This subdivision is based on the age of onset,differences in severity, the course of the illness and thefact that these presentations seldom overlap in theaffected members of a particular family. The severe

Address for reprint request: Dr H Isaacs, NMRU, Department ofPhysiology, University of the Witwatersrand Medical School, YorkRoad, Parktown, 2193 South Africa.

Received 6 June 1985 and in revised form 7 October 1985.Accepted 20 October 1985

form of the disease occurs in infancy and presentswith severe cardiomegaly, hepatomegaly, neuro-logical involvement and the baby seldom lives formore than 2 years. The more benign form occurs injuveniles and in adults and is compatible with a rea-sonable lifespan.The observations of an affected adult patient who

has been studied and treated on a high protein, carbo-hydrate restricted diet over a 6 year period, arepresented.

Patient's history & examination

The patient, a caucasian female (fig 1) was first seen at theage of 29 years. She is the only child of healthy parents andthere was no history of neuromuscular disease in the family.She complained of.weakness of her thigh muscles and statedthat this symptom had been slowly progressive over the past16 years. At the age of 26 years her left quadriceps was biop-sied and a diagnosis of limb-girdle dystrophy was made.

Clinical examination revealed that the skeletal muscleswere generally weaker than normal, the proximal moreinvolved than the distal and the quadriceps muscles of thethighs most severely affected. Her weakness was such thatshe was unable to get up from the consulting room chairwithout the aid of her arms, was unable to climb a single 6"(15 cm) step without utilising the banister and could notelevate her legs against gravity when lying in the supine pos--ition. Respiration was laboured and accessory respiratorymuscle use was obvious. The tendon reflexes, with the excep-tion of the knee jerks, were present and equal. In particular,the eye muscles were normal, the tongue was of normal sizeand the rest of the cranial nerves normal. Sensation andcoordination were normal. No other abnormalities werenoted.

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(normal control 12-8 g/mg protein). Iodine spectral analysisof the glycogen was normal. Myophosphorylase activity wasnormal. The glucose tolerance test in response to a 50 g loadwas abnormal at 30 minutes, reaching a level of 260 mg/dl.The plasma insulin and growth hormone responses were

normal. The blood glucose response to epinephrine and glu-cagon was normal. Amino acid response to a protein load(lean beef) of 4 g/kg body weight after a 24-hour period offasting produced a considerable increase in branded chainamino acid activity (BCAA) peaking at 3 hours (fig 2). Theseresults for BCAA are similar to those described by Slonimet al in 1983.7Electromyography The abnormal findings were mostsevere in the proximal muscles of the lower limbs. Themotor-unit potentials were of short duration, mostly poly-phasic and of low voltage. Occasional myotonic-like burstsof activity were recorded. In the less severely involved mus-

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Plasma Valine

:Plasma Leucine

Fig 1 Side-view ofthe patient taken at the age of33 yearsin the early stages ofher pregnancy. Her lordotic stance isnoted.

InvestigationsRoutine blood tests which included liver, thyroid and renalfunction studies were normal. The serum creatine kinase waselevated to 1455 IU/l (normal 0-170 IU/1), serum aldolase17-5 IU/l (normal 0-53-1 IU/1). The ECG showed inversionof the T waves in Std. III and AVF and right axis deviation.Vital capacity in the standing position was 2-4 litres, FEV,70% of predicted normal. Chest radiographs were normal.

Muscle studiesBiochemistry Alpha 1-4 glucosidase activity determinedradioactivity5 was 52-6 dpm/min/g (control values of 309 3± 54-9) measured by the incorporation of C14 maltase intoglycogen. The glycogen content was 904 g/mg protein

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0 1 2 3 5Hours post beef

Fig 2 The plasma valine, leucine and isoleucine levels afterlean beefconsumption (4 gm/kg body weight).(O 0-control subjectsA -before protein diet treatment* 0-3 years after protein diet treatment

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cles there were occasional high-voltage polyphasic unitsmixed with low voltage activity.

Nerve conduction studies of both motor and sensorymodalities in both upper and lower limbs were normal aswas the myoneural junctional response to repetitive stimu-lation varying between 2 and 20 H2.Histology & histochemistry The left quadriceps muscle wasbiopsied under local anaesthesia. The histology revealedgross distortion of the muscle fibres (fig 3). Most of the fibreswere vacuolated, some entirely disrupted and fibrous andfatty infiltration was prominent. The vacuole contentsstained blue with haematoxylin and eosin (H & E) and redwith a modified trichrome stain. The PAS stain revealed thepresence of excessive glycogen which appeared to be totallyremoved by diastase (spit) digestion. Widespread presence ofacid phosphatase was noted. There was no evidence of meta-chromatic or of acid mucopolysaccharide material present.

Histochemical staining for phosphorylase, NADdiaphorase, succinic dehydrogenase and ATPases at pH 9-4,4 3 and 4-6 confirmed that both fibre types were involved,though the Type 1 fibres were far more severely affected anduniversally smaller than the Type 2 (fig 4).

Fig 3 H & Epreparation demonstrating the markedvariability in fibre size, the extreme vacuolation ofthe fibresand centralisation ofmany of the nuclei. ( x 100).

Fig 4 NADpreparation demonstrating that the Type Ifibres are more affected than the Type 2fibres and are presentin greater numbers. ( x 100).

Electron microscopy On electron microscopic examinationthe massive glycogen accumulation was observed in both thesarcoplasm and in lysosomal vacuoles (fig 5). The swollenlysosomes possessed a single limiting membrane, someintact, others ruptured having discharged their glycogencontents into the sarcoplasm. Glycogen was also seen inoccasional distended, intact and also in disrupted mito-chondria. Membrane-bound glycogen sacs were also presentin the satellite cells. There was marked depletion and dis-tortion of the myofibrils by internal and external glycogen(fig 6). The lysosomal glycogen was frequently seen as beingclumped together in a regular pattern (fig 7). Some of theclumped material could be identified under highermagnification as closely packed glycogen granules but manyof these bodies had transformed into the electron denseunstructured material (fig 8).

Fig5qDmnstain th detrcto of th-e myfiriar

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pattern by distended glycogen-containing sacs andfree-lyingglycogen accumulating between the musck fibres. Markedfolding of the basement membrane is also noted. Acentrally-lying nucleus is also seen.(x3000).

Fi 6 Exrm dirutin oftemoirX, th radwnofnoma mitchrndral riste and the acuulto of

Fglycge wionthaingthemitohonrucianaswelasithemoirla

sacoptrasm-lin(xceu8000) sen.(x00)

Al.'*& Su *X-B.s A_.,<;.e3j.,.,. S ~~...

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Fig 6 Extreme disruption ofthe myofibrils, the breakdownofnormal mitochrondrial cristae and the accwnulation ofglycogen within the milochondria as well as in thesarcoplasm. ( x 8000).

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Fig 7 Accumulation ofglycogen in regular bapatterns. In the middle some show a dense chanstructure. (x 50 000).

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Fig 8 Marked disruption of the myofibrils wilbroken-down mitochondria and distended sarcareticulum together with large areas of vacuolatcentre a phagocvtic area where the glycogen haextremelv dense rounded material and can be nrecognised as glycogen. Scattered amongst theiare lighter ball-like collections ofglycogen andfree-lying glycogen. (x 4000).

Clinical course (table)The patient was placed on a high protein, lomdiet consisting of 45% carbohydrates, 20%protein with an approximate calorie value

improvement over the next 6 months was impressive. She^.t nhad lost 5 kg in weight, was able to climb six steps using the

banister and could get out of the same office chair withoutusing her arms. Serum CK levels had fallen to 258 IU/I. Aswe were not sure whether improvement was attributable tothe weight reduction, we then decided to let her return to hernormal diet for 3 months, though restricted to 1500 calories.The patient deteriorated. We then instituted therapy by pre-

scribing Eltroxin in the hope that thyroid hormone wouldincrease the activity of acid alphaglucosidase and so increaseglycogen utilisation. This therapeutic measure was

prompted by the knowledge that thyroid insufficiency causes

a fall in acid alpha-glucosidase.8 Over a period of 3 monthsshe gained 2 kg, became obviously weaker, the creatinekinase increased to 550 IU/l and the patient requested thatthe thyroid therapy, which by then had gradually been

ill-like increased to 0 3 daily, be stopped. During the period of

lge In thyroid administration, the patient watched closely for

evidence of thyrotoxicosis. This was not reflected clinicallyand the thyroid function studies at the height of her therapywere still within the upper range of normal. The acidalphaglucosidase measured at this time showed no

significant change. The thyroid medication was graduallydiscontinued and she remained on her normal diet of 1500calories per day (the carbohydrate content was estimated at60%, fats 20% and protein 15-20%) for the next threemonths, over which time she lost 1 kg in weight. She was

weaker, could barely climb three steps and could not get out.r5, of the same chair unaided. Her restricted calorie, high pro-

tein, low carbohydrate diet was restarted and consequentlyshe lost a further 2 kg but over the ensuing months herstrength gradually improved.Three years after diagnosis, the muscle biopsy was

repeated. At this stage the patient had been on a continuoushigh protein intake for 1 year. The biochemical and patho-logical studies produced results which were not significantly

th different from the initial studies. The CK level was 244 IU/Iplasmic and the glucose tolerance test had returned to normal. Pro-ion. In the tein utilisation showed a rapid rise in BCAA though herisformed basal levels were on the average 120 imol/l higher (fig 2).to longer Six years after initial diagnosis she is still stronger andse dense areas remains on her high protein diet. She is able to climb 20 stepsmuch with the aid of her arms pulling on the banister and gets up

out of the chair unaided. She can lift her legs against gravitywhen lying on her back and she can, with some difficulty, getup off the floor unaided, a function which was impossible6 years earlier. The patient, after many years, became

v carbohydrate pregnant (fig 1) and has given birth to a healthy daughter.fats and 35% Her vital capacity has improved to 2 6 litres in the standingof 1500. Her position and the FEV1 to 75-5% of predicted normal.

The changes in diet and therapy and the changes in muscle strength and the ability to climb stairs with the aid ofa banister

Time Weight (kg) Therapy Calories No ofstairs

0 mths 67 High protein low carbohydrate 1500 Nil6 mths 62 Normal diet 1500 69 mths 63 + Elthyroxin 0 1-0-3 mg 512 mths 63 Stopped thyroid medication Normal diet 1500 415 mths 62 High-protein diet 1500 327 mths 65 High-protein diet 1500 106 years 66 High-protein diet 1500 20 +

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Discussion

Acid alpha-glucosidase deficiency originallvdescribed in children by Pompe3 is not confined to thehuman species. The deficiency occurs in the Laplanddog,9 the cat,' in cattle" and in sheep.'2 Thesereports have indicated that the deficiency iswidespread in the animal world.A diagnosis of glycogen storage disease Type Ilb

was established in our patient. The clinical course ofacid maltase deficiency in general has been welldescribed.' The virtual non-occurrence of more thanone distinctive type occurring in a family, apart fromthose described by Bush et al'3 and the character-istics of the molecular defects14 14b of this disordervindicates the separation of Type II glycogenolysisinto the severe non-surviving infantile (Type Ila) andthe relatively benign adult variety (Type IIb). Thisconcept is strongly held by Mehler and Dimauro"who believe that the sub-groups are inherited as dis-tinct autosomal recessive abnormalities. An inter-mediate or juvenile form characterised by improvedsurvival, though organomegaly due to glycogen accu-mulation is not infrequent, tends to merge with theadult variety.A challenging contradiction adding complexity to

this disorder is the reports of lysosomal glycogen stor-age disease in patients with normal acid maltase lev-els 16 1 The particularly severe involvement of cer-tain muscles is unexplained as is the excessiveinvolvement of Type I fibres in AMD (fig 2) andmany explanations have been offered to account forthe varying severity and the pathogenesis.The deficiency of acid alpha-glucosidase remains

the main reason for glycogen accumulation in thisdisorder.6

Mehler and Dimauro'5 obtained small amounts ofacid maltase from muscle in their long survivingpatients but none in the infantile form and theauthors state that "the residual acid maltase activityfound in the muscles of Type Ilb deficiency may notbe high enough to be functionally significant." Lowlevels of acid alpha-glucosidase have been found inother disease states such as myxoedema, in two casesof myotonia congenita. in patients suffering fromhypokalaemic periodic paralysis as well as in healthyheterozygotes. none of whom has shown evidence ofabnormal glycogen storage.8 The induction of hypo-thyroidism in rats'8 failed to evoke glycogen storagedespite the depletion of acid alpha-glucosidase. Gly-cogen storage however could be induced in rat liver.heart and skeletal muscle'9 by the use of an alpha-glucosidase inhibitor. Acarbose. The inhibitor, apseudotetrasaccharide, was administered intra-peritoneally. The accumulation of glycogen could bereversed by withdrawing the inhibitor.'9 The failure

to produce glycogen accumulation by inducing acidalpha-glucosidase deficiency in induced hypothyroid-ism, suggests that thyroid hormone may be necessaryfor the process of glycogen accumulation. This inter-pretation could explain the clinical deteriorationwitnessed in our patient when placed on thyroidsupplementation in an attempt to increase the acidalpha-glucosidase level.

Smith et al20 and others' 15 21 suggested a compen-satory mechanism to account for the slow progressionof weakness and correlated this with the level of neu-tral acid maltase which is markedly decreased in skel-etal muscle in the infantile form but normal in theadult. This theory, though playing a role, does notexplain the cases with normal acid alpha-glucosidase.Neutral maltase as opposed to acid alpha glucosidaseis not located in the lysosomes but is bound to thesarcoplasmic reticulum.20

Other hypotheses of importance suggest that a leakof acid hydrolysates from lysosomes into the cytoceldamages myofibrils and in doing so the acid glu-cosidase escaping into the sarcoplasm became in-active as the pH alters.22 that lysosomal rupture andglucase accumulation causes enlargement, ruptureand eventual destruction of the fibrils,23 that phos-phorylase deficiency aggravates the disorder.24 Thisdeficiencv however was not found by otherauthors.25-27 Furthermore it is established that theamount of glycogen accumulation in muscle differsfrom patient to patient and may even be normal.' 21Variation in glycogen concentration does not cor-relate with the loss of power or elucidate the reasonfor glycogenosome formation or autophagy which areprominent features of this disorder.The formation of glycogenosomes, a prominent

feature of this disorder warrants comment. Glyco-genosomes are not confined to acid maltase deficiencybut also occur in the glycogen storage Type III and IX'variants, in phosphorylase B kinase deficiency andrarely in normal muscle (fig 9).28 In these other forms

4.' />.X ,....... e

t'I

Fig 9 A glycogenosome seen in normal muscle. x 6000).

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1016of glycogen storage disease, the level of acid alpha-glucosidase is normal and this confirms the belief thatthe formation of glycogenosomes need not depend onacid alpha-glucosidase deficiency.29That the glycogen in acid maltase deficiency may

have undergone some change or be present in a formwhich is not available for glycolysis has beenpostulated30 and an abnormality of the short outerbranches of the glycogen has been found.30 Thoughthe extracted glycogen appears to be chemically nor-mal, the electron dense change seen in many of theclosely packed glycogen balls, suggests a physicalchange (figs 7, 8). The way the lysosomes handle thischange is of the utmost importance.The lysosomal enzymes play a major role in this

disorder; for example cleavage of the outer branchesof glycogen up to the alpa 1-6 linkage is a function ofneutral maltase. Lysosomal enzymes31 32 must becovalently labelled with a sugar phosphate for incor-poration of the enzyme into the lysosome. Failure inlabelling results in the acid alpha-glucosidase remain-ing in the neutral pH media of the sarcoplasm where,as previously stated, it becomes inactive. The local-isation of acid alpha-glucosidase compartmentallyhas as yet not been adequately achieved."7 Perme-ability and incorporation of glycogen into thelysosome does not seem to be at fault and this aspecthas been fully studied.33 The mechanism whereby thelysosomes ingest such vast quantities of glycogen andare able to do so in occasional cases even in the pres-ence of normal levels of acid alpha-glucosidase,remains obscure. It has been shown that most of thenormal glycogen is not digested in the lysosome butthat the extremely large molecular-sized glycogenbodies are.34 3 In the light of our present knowledgeit appears that a deficiency of alpha-glucosidase doesnot initiate autophagy but the large glycogen mole-cule itself seems able to stimulate this process.36 Thereason why large glycogen macromolecules areformed is unknown and whether glycogen autophagyand degradation depend upon the same or differentsystems is still to be established. Failure of utilisationof glycogen is not the cause of the muscle weakness inacid maltase deficiency and the process of gluco-neogenesis is intact.

Therapy

Prevention of the disease by in utero detection of aninvolved foetus has become an important con-tribution in the control of this disorder. Detection ofAMD Type IIa in a known carrier may be achievedby culturing cells extracted from the amniotic fluidand demonstrating glycogen accumulation.37 Morerecently a rapid diagnostic method has beendescribed;38 amniocentesis is carried out at 15-18


weeks and the affected amniotic fluid cells are foundto show glycogen accumulation on electron micro-scopic study. Identifying the involved foetus in thismanner offers the parents the option of abortion.As is the case in many neuromuscular disorders, the

sufferers often neglect to make full use of theirremaining muscle, for example pulmonary functionmay be improved by means of diaphragm training byusing forced expiratory exercises.39

Since the recognition of acid maltase deficiency,various therapies have been tried. Restriction of car-bohydrate in the diet was attempted without avail.'Attempts at mobilisation of glycogen by the adminis-tration of ephedrine and glucagon were equallyunsuccessful.' Fructose feeding was of no realvalue.26 Attempts at stimulating acid alpha-glucosidase by the administration of thyroid hormonein our patient caused deterioration. Treatment withprednisone in conjunction with a low carbohydratediet was of no value.40 Vitamin A, progesterone andhyperbaric oxygen used as lysosome unstabilisingagents, ketogenic diets and oral acid alpha-glucosidase derived from fungi have been valueless.4'Administration of oral acid maltase prepared frombacteria42 as well as acid alpha-glucosidase preparedfrom human placenta43 proved to be of no value.Administration of lysosome labelling agents com-bined with acid alpha-glucosidase prepared from bac-teria was unsuccessful.44 The administration of acidalpha-glucosidase entrapped in liposomes has beenused45 but again the liposomes failed to reach themuscle tissue. Gregoriadis46 suggested that the lipo-somes could be directed to muscle tissue by attachingspecific antigens to the liposomal surface. This pro-cess and the use of enzyme polymers has as yet notmet with success.47

Slonim et a17 suggested that the disturbance in gly-cogen metabolism caused protein utilisation to occuras an alternate energy source which ultimately leadsto a state of relative protein deficiency and muscleweakness. They demonstrated the early rise and fallof BCAA as occurred in our case. That this is notindicative of increased degradation is shown bycalculations7 which demonstrated a concurrent fall inCethepsin D and H and proteinase activity suggestingan increase in tissue utilisation of BCAA which arethe principal amino-acids for muscle proteinsynthesis.

This glycogenogenic switch seems to have meritand our patient's progress substantiates this. Towardsthe end of three years of treatment, our patient'sresting level of BCAA had increased by more than120 pmol/l (fig 2).The improvement in strength at the 3 year period

was not associated with improvement histologicallyor with higher acid alpha-glucosidase activity but the



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CK and aldolase fell significantly and remain at alevel just above normal. It is suggested that this regi-men be tried more extensively.

We gratefully acknowledge the financial support ofthe Medical Research Council of South Africa, theUniversity of the Witwatersrand and the MuscularDystrophy Research Foundation of South Africa forthis study.

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