adult acid maltase deficiency: an open trial with albuterol ...corrado angelini, elena pegoraro,...

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Adult Acid Maltase Deficiency: an Open Trial with Albuterol and Branched - Chain Aminoacids

Corrado Angelini, Elena Pegoraro, Sandro Zambito Marsala, Lodovica Vergani, Anna C. Nascimbeni, Luigi Fulizio and Marina Fanin

Department of Neurosciences, University of Padova, and Venetian Insitute of Molecular Medicine, Padova, Italy

Abstract We studied natural history and morphological features in 10 adult onset Acid Maltase Deficient (AMD) patients who were ambulant (age range 23-69 yrs), and 1 juvenile-onset AMD patient, who was wheelchair-bound and respirator-dependent (disease duration 36 yrs). Morphological features in muscle biopsy showed a vacuolar myopathy, there was Golgi apparatus proliferation within fibers, the autophagic vacuoles were positive at their periphery for caveolin-3 and dystrophin, documenting extensive protein turnover. We first clinically followed the patients periodically during the baseline period of the trial, by evaluating 5 limb-girdle muscles with the Medical Research Council Scale and monitored the performance of 4 functional tests (walking, climbing stairs, Gowers’ manoeuvre and rising from a chair). We then performed in 5 patients (4 adult-onset and 1 juvenile-onset) an open prospective clinical trial with a β2 agonist (albuterol) and pulsed branched-chain aminoacids (dose 500 ml 4% intravenous for 10 days subsequently every month) for six months. During this period, treated patients improved in functional score. In the 4 adult-onset patients no side effects were found, while the only respirator-dependent juvenile-onset patient, following an initial intravenous infusion of albuterol, presented signs of pulmonary oedema. He then well tolerated oral albuterol. The 5 treated patients continued oral albuterol treatment after the initial 6 months, for over 3 years. Our data suggest that in adult-onset AMD, the use of oral β2-agonist drug might be efficacious to antagonize muscle wasting and might be used as symptomatic therapy until enzyme replacement or aminoacid (leucine) therapy will be available. Key words: glycogen storage disease II, acid maltase, branched chain aminoacids, albuterol, clinical trial.

Basic Appl Myol 14(2): 71-78, 2004

Glycogen Storage Disease type II (GSD II) is caused by a deficiency of lysosomal α-glucosidase (acid maltase). This autosomal recessive disorder was the first described prototypical muscle lysosomal disorder. It can present in the classic infantile form (Pompe’s disease) with marked hypotonia and cardio-myopathy due to complete acid maltase deficiency [7] or in a juvenile/childhood onset form [5,6]. Adult onset AMD can simulate limb-girdle dystrophy or polymyositis, the late onset form is usually characteri-zed by respiratory involvement and shows a residual acid maltase activity [1]. Acid maltase is encoded by a 20 Kb gene mapped to chromosome 17q22-qter [4]; the gene encodes for a 110Kda peptide, that is translocated from Golgi apparatus to lysosomes and where it is shortened to a 70 kDa peptide. Mehler & Di

Mauro [14] and Reuser [16] demonstrated an inverse correlation between the level of residual acid α-glucosidase and clinical manifestations. The treatment of adult GSD II is still elusive while in Pompe’s disease a replacement treatment with α-glucosidase is under trial [20]. In juvenile and adult form of AMD Slonim [18] and Margolis and Hill [12] advocated high -protein diet as an effective treatment. Weight correction by a high-protein, low-carbohydrate diet was also used in GSD II by Isaacs [8]. We used β-2 agonists associated with intravenous branched-chain aminoacids to antagonize muscle protein waste.

Adult Acid Maltase Deficiency: an open trial with albuterol and branched - chain aminoacids

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Material and methods

Patients Case 1 (P.A.): this 69-year-old woman, complained of

weakness in upper extremities and at 55 years presented difficulty raising from the floor. At 58 years she had effort dyspnoea. A spirometry showed a restrictive lung disease, her forced vital capacity (FVC) was 56% of control. At age 69 her neurological exam showed waddling gait, there was mild weakness of deltoid, triceps and ileopsoas muscles. In the last years the patient developed a monoclonal M paraproteinemia and was diagnosed by bone marrow studies to suffer from a Waldenström’s macroglobulinemia. Her CPK was 218 U/l (n.v. < 170), an EMG was myopathic, EKG and ECHO were normal. She was hospitalized: muscle CT scan showed fatty substitution of thigh abductor muscles and bilateral hypotrophy of semitendinosus, gracilis and biceps femoralis muscles, there was a slight hypotrophy of biceps muscles. Muscle biopsy showed a vacuolar myopathy, with PAS positive vacuoles. Her muscle acid maltase was 8.42 picomoles/mg/ non collagen protein (normal values 31.4 – 173.4).

Case 2 (P.L.): 64 year old woman. She was the younger sister of case 1. Since age 44 she complained of lower limb weakness and since age 58 she presented effort dyspnoea. At age 63 she had atrial fibrillation, an echocardiogram showed bilateral atrial dilatation, a right ventricle dilatation and hypokinesia of ventricular septum. Her neurological exam showed a shuffling gait with a widened base, she had weakness in upper girdle

muscles, in ileopsoas and quadriceps muscles, her deep tendon reflexes were absent. Spirometry was normal. Muscle biopsy showed a vacuolar myopathy, with PAS positive vacuoles. A GSD type II was confirmed by acid maltase assay on leukocytes.

Case 3 (B.R.): this 56 year old woman, at age 40 complained of progressive difficulty in climbing stairs, walking and raising from the floor. Her 74 year older sister was also affected by GSD type II. On hospital admission at 43 years our patient walked with a cane, had a marked bilateral weakness of ileopsoas and quadriceps muscles, hypotrophy of thigh muscles; plantar and ankle reflexes were absent. EKG was normal. A spirometry showed a slightly restrictive pattern her forced vital capacity was decreased to 79%. CT scan showed hypotrophy of leg muscles particularly of gluteus, quadriceps and of posterior thigh muscles. Biopsy showed a vacuolar myopathy acid maltase was 5 picomoles/min/mg non collagen protein (normal values 31.4-173.4). This patient underwent a six month open trial then she continued albuterol alone and after 3 years her vital capacity improved.

Case 4 (Z.M.): This is a 43 year old woman who since 7 years complained of weakness in lower extremities and noticed difficulty in raising from the floor or climbing stairs. She tried acupuncture for her muscle complaints without benefit. A diagnosis of limb-girdle dystrophy was entertained, an EMG was myopathic. For this reason she was referred to our Center. On neurological exam she could raise from the floor using two hands and climb on a standardized set of stairs only using the rail. Her muscle biopsy showed a

Figure 1. Patient n. 5. Biceps brachii muscle biopsy at age 54 years. With H&E staining many fibers appear vacuolated

both in subsarcolemmal region and within the cytoplasm (A), show strong reaction for PAS (B) and acid phosphatase (C). Note that vacuolated degenerating fibers clearly reacted for Golgi (D) and overexpressed caveolin-3 (E) and dystrophin (F) at both the plasmalemma and the cytoplasm. Magnification x10.


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vacuolar myopathy. Acid α-glucosidase was 0.9 picomoles/min/mg. She was treated with 8 mg albuterol/day and had an excellent response within 3 months showing at the control that she was able to get up from the floor easily using only one hand. She in still on albuterol treatment after 3 years.

Case 5 (D.A.): this 54 year old woman, since 34 years of age presented difficulty walking, climbing stairs and raising from the floor. A first biopsy was done at 40 years and she was first diagnosed as limb-girdle dystrophy. A second biopsy was done at 44 years with the diagnosis of “autoimmune myositis, myocardiopathy and hepatic disorder”. Finally at 49 years, acid maltase deficiency was found. Acidic α-glucosidase activity was 1,8 picomoles min/mg/non collagen protein (2% of control). Since 50 years the patient has shown a progressive respiratory insufficiency: her vital capacity (FVC) decreased 13% every year. She then used overnight oxygen and had dyspnea at rest; she became respiratory dependent and finally died. A muscle CT scan showed “marked proximal muscle atrophy most prominent in posterior thigh muscles”.

On neurological exam at age 64 she had a lordotic gait (17 sec to walk 10 meters) was able to climb a set of stairs and to rise from a chair but not to lift legs from the bed. MRC strength on deltoid was 3+/5 bilaterally, on triceps 4+/5 bilaterally, external shoulder rotators 3+/5, ileopsoas and quadriceps 3/5. Her deep tendon reflexes were not evocable. Cranial nerves showed no abnormalities.

Case 6 (D.C.G.): this 56 year old male patient presented at 16 years of age difficulty in climbing a rope during gym at school. The patient had at age 18 generalized weakness and could not climb on a rope or run during military service; at 29 years of age he presented respiratory insufficiency and poor appetite. His first muscle biopsy was interpreted as a “focal myositis” and therefore he was treated with steroids. Increasing respiratory insufficiency led to a tracheostomy and he was frequently hospitalized in intensive care unit. At age 52 a repeated muscle biopsy was performed which showed a vacuolar myopathy (Fig.1), acid maltase activity was 6% of control: 2.0 picomoles/mg/ non collagen protein (normal values: 31.4-173.4). At age 55 he was again hospitalized in the intensive care unit an ECG showed abnormal P waves. An echocardiogram showed signs of bi-atrial enlargement and of left ventricular hypertrophy. The patient was treated with intravenous albuterol and had a pulmonary oedema that was resolved with intravenous furosemide. He was switched to oral albuterol 6 mg, associated to pulsed branched-chain amino acids that he tolerated well. He is still overnight dependent on a ventilator. He has a prominent scoliosis with a right head tilting. He can sit and stand with support, raises his arms in a horizontal position. There is a slight atrophy of suprascapular and pectoral muscles and weakness of

quadriceps muscles but he has good strength (MRC 4 or 5) of other limb muscles. He has continued up to now oral albuterol treatment and is currently under stable conditions.

Case 7 (M.K.). This 28 year old man was brother of case 8. He had an uncertain and stepping uncertain gait and proximal weakness. CK was 3318 U/L and muscle CT scan showed atrophy in paraspinal and gluteus muscles. Spirometry showed moderate respiratory insufficiency. Acid maltase in muscle was 15% of control.

Case 8 (M.P.): this is 32 year old woman had myalgia and elevate CK (825 U/L). A biopsy showed a vacuolar myopathy and acid maltase was 17% of control.

Table 1 Protocol of functional tests

Muscle Function

1) Gait 1. normal 2. mild waddling, lordosis and/or toe walking 3. moderate waddling, lordosis and/or toe walking 4. severe waddling, lord sis and/or toe walking 5. walks only with assistance (i.e. braces, cane, crutches)6. stands, but unable to walk 7. confined to wheelchair

Time to walk 10 meters: .................sec.

2) Climbing Stairs 1. Climbs without assistance 2. Supports one hand on thigh 3. Supports both hands on thighs 4. Climb stairs in upright position but with aid of railing5. Climbs while clinging to the railing with both hands6. Manages to climb only a few steps 7. Unable to climb steps

Time to climb 4 steps: ……………..sec.

3) Arising from a chair 1. normal 2. with wide base and/or difficulty but without support 3. with support on one thigh 4. with support on both thighs 5. with support on arms of chair or on a table 6. not possible

Time to standing from sitting: ……………..sec.

4) From sitting to standing 1. normal 2. “butt first” manoeuvre, one hand on floor 3. “butt first” manoeuvre, two hands on floor 4. unilateral hand support on thigh 5. bilateral hand support on thighs 6. arises only with aid of an object (table, chair, etc.)7. unable to arise

Time to standing from sitting: ……………sec.


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Spirometry revealed slight respiratory insufficiency, muscle CT showed moderate atrophy of gluteus muscles.

Case 9 (P.M.): this 46 year old woman was diagnosed in 1978 at 23 years of age to suffer from AMD. Since 4 years she had myalgias, then she developed a severe limb-girdle weakness, particularly in thigh muscles and was not able to cross her legs. A muscle biopsy showed vacuolar myopathy and acid maltase deficiency. She has developed since 1990 a constrictive respiratory insufficiency and used an overnight ventilator. She was hospitalized for hypercapnia in January 1990 in an intensive care unit and since then she required a nocturnal ventilatory support. She is now following a high protein low carbohydrate diet.

Case 10 (D.C.O.): this 46 years old woman that works as a general physician from 4 years she has limb weakness and calf myalgia. Since 5 months she has difficulty rising from the floor or rising the arms to comb her hair. On neurological examination there was 4/5 weakness of external shoulder rotators and 4/5 bilaterally of ileopsoas muscle. Echocardiography revealed initial mitral valve prolapse, with no reflux. Her pulmonary tests were normal. Muscle CT scan shows some fat replacement in gluteus and thigh muscles. The muscle biopsy revealed a vacuolar myopathy; acid maltase was 0.33 µmol/gr wet weight muscle (normal mean value ± SD: 8.03 ± 1.48).

Case 11 (M.W.): this 67 year old woman presented at age 52 a sudden onset of thigh myalgias and upper limb muscle involvement with reduction of lung vital capacity. Her FVC was 83%. At neurological examination she had 4/5 weakness of proximal muscles in upper and lower girdle. The muscle biopsy showed a

vacuolar myopathy and acid maltase was 0.33 µmol/gr wet weight.

Methodology of trial The study was done according to the principles of the

Declaration of Helsinki and informed consent was obtained from patients before participation to the clinical trial.

We evaluated five limb muscles (deltoid, biceps, triceps, quadriceps, ileopsoas) according to Medical Research Council (MRC) scale and the percent compound MRC score was calculated. At the beginning of our trial we obtained a baseline score of all our adult patients since we timed and graded four functional performances (Table 1), i.e. walking for 10 meters, climbing 4 steps on a stair, Gowers’ manoeuvre, rising from a chair, lifting arms, according to a standard protocol [2]. Each patient was evaluated by routine blood exams, EKG, spirometry and muscle CT scan. Control clinical score and spirometry were done every 3 months during the first six months and then every 6 months. The clinical evaluation of pulmonary tests was blinded. The criteria by which adult patients have been selected were the informed consent and the possibility to come to periodic examination. Only 5 patients (4 adult-onset and 1 juvenile-onset) fulfilled these criteria. The other additional patients were only evaluated on their natural history.

Morphological and biochemical studies Muscle biopsies were examined in five patients

applying routine histological and histochemical techniques. The diagnosis of AMD deficiency was confirmed biochemically using standard fluorimetric

Figure 2. Patient n. 6. Quadriceps muscle biopsy at age 52 years. Serial cross sections show vacuolated fibers with

H&E staining (A) filled with PAS positive material (B) and with diffuse reaction with acid phosphatase (C). The same vacuoles stain positive with Golgi zone antibody (D), whereas sarcolemma and a few inner membrane stain with caveolin-3 (E) and dystrophin (F). Magnification x20.


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technique with α-methyl-umbelliferone-α-glucoside or maltose as previously described [1].

Serial cross sections were collected for immuno-histochemistry.

Antibodies and immunohistochemistry The following primary antibodies were diluted in PBS

and incubated for 1 hour used at 1:100 dilution (Transduction Lab): anti-caveolin-3, anti-dystrophin at 1:100 dilution (C-terminal) (Novacastra Lab) anti Golgi zone at 1:200 dilution (Chemicon). Immuno-fluorescence labeling was developed using secondary anti-mouse Cy-3 coniugated Ig (Caltag) at 1:100 dilution, for 1 hour incubation. Sections were analyzed and photographed with a Zeiss fluorescence Axioplan microscope with Cool-Snap Nikon digital camera.

Molecular studies Genomic DNA was analyzed in all patients. All adult-

onset cases resulted compound heterozygote for a common leaky splice site T to G transversion in intron 1 and a second unidentified mutation of GSD II gene. The only patient where the second mutant allele was identified was patient 6 with juvenile onset. In this patient the mutations detected were IVS 1-13 and T→G /2604 ∆G; the latter is a new undescribed mutation in GSD gene (Hirshorm, personal communication).

Results

Morphological data The biopsies taken before treatment showed vacuoles

of different size and shape, with strong acid phosphatase activity (Fig. 1-3). However not all muscle fibers in the same section were equally affected and there was wide intra patient variability. Vacuolated fibers show increase in glycogen concentration and increased autophagy. Golgi apparatus was strongly reactive with Golgi zone antibodies and both caveolin-3 and dystrophin appear at the periphery of vacuoles, therefore an extensive fiber remodeling was observed.

Clinical trial During therapy in 4 adult AMD patients, the

compound functional score (Table 1 and 2) decreased in all patients indicating a better ability in walking, climbing stairs or performing Gowers’ manoeuvre. MRC index obtained by compounding the MRC score of three muscles in upper limbs (deltoid, biceps, triceps muscles) and two in lower limbs (quadriceps, ileopsoas muscles) showed a consistent increase in strength. MRC increased in case 1 from 90 to 95%, in case 2 from 82,5 to 95, in case 3 from 67,5 to 92, 5%, in case 4 from 80 to 90%. In our patients at a three months interval we obtained a control spirometry. In our four adult patients albuterol dosage ranged from 8 to 12 mg daily, reaching the maximum tolerated dose. We also used in the first 6 months branched chain aminoacids 4% 500 ml intravenous, pulsed for 10 subsequent day every month; the intravenous sly treatment was then discontinued. After this 6 months period treatment in AMD patients was continued only with albuterol. Results of our global functional score are shown in Table 2 and Fig.4.

Figure 3. Patient n. 7. Quadriceps femoris muscle biopsy at age 28 years. The asterisc indicates the same fiber in

serial sections. Serial cross sections show some atrophic and vacuolated fibers with H%E stain (A), filled with PAS postive material (B) and reacting for acid phospthatase (C). Immunolabeling with Golgi zone antibody (D) was positive in vacuolated fibers within the cytoplasm; similar reaction is observed with caveolin-3 (E) and dystrophin (F). Caveolin-3 labeling is present at the sarcolemma, in inner membranes, and faintly in the cytoplasm. Magnification x10.


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Side effects were also monitored during control examinations. With albuterol we observed occasional side effects such as flushing, tremor, agitation, palpitation, but they disappeared when we decreased the dose of albuterol in order to avoid these symptoms. Only in the juvenile respirator-dependent man, we observed a severe initial complication by intravenous albuterol treatment, i.e. a pulmonary edema. The intravenous albuterol was stopped while patient was in intensive care. Our patient was then treated with furosemide and improved, and subsequently was switched to 6 mg oral albuterol, that he tolerated well and stabilized his clinical condition. He is now under stable condition in an hospice were he uses an overnight ventilation.

Discussion Our morphological results indicate that variable

membrane bound glycogen storage is characteristic for adult AMD. Fibers containing vacuolated glycogen stain for both a lysosomal marker (acid phosphatase) and for the trans-Golgi network, indicating an high membrane turnover. We observed that both caveolin-3 and dystrophin participate to this membrane rearrangement, suggesting a T tubule or sarcolemmal involvement. The loss of acid maltase enzyme has a wide effect on skeletal muscle morphology. The role of acid maltase in muscle is likely not completely understood and these morphological correlates indicate

that muscle weakness might be due to extensive muscle remodelling [15].

The primary objective of our trial was to reduce skeletal muscle protein waste, that is a prominent feature of adult glycogenosis type II. We used a β2 adrenergic agonist to inhibit skeletal muscle hypercatabolism due to the activation of lysosomal proteases and of the ATP – ubiquitin-dependent proteolytic pathway. β2 adrenergic agonists have been used as powerful muscle growth promoters in many animal species, since they promote skeletal muscle hypertrophy and cause reduction of body fat and favour the redistribution of energy substrates for a better utilization by skeletal muscle. According to Martineau [13] and Costelli [3], in their metabolic action, β2 agonists stimulate also the release of free fatty acids. Several studies have documented the effect of β2 agonists on skeletal muscle: in one placebo-controlled study, 12 healthy volunteers were given albuterol, and muscle strength improved on average of 22% at 21 days. In 20 knee surgery patients, the use of clenbuterol resulted in a more rapid recovery of strength to baseline than placebo [11]. Increased muscle strength was observed by Signorile [17] in a group of 10 patients, with muscular atrophy, who were paralized following a spinal injury; these patients were treated in a double blind, placebo-controlled crossover study with metaproterenol.

Table 2. AMD PATIENTS IN NATURAL HISTORY OR TREATED WITH ALBUTEROL

Pt., sex Age (yrs)

Age of onset (yrs)

Disease duration

(yrs)

FVC (%)

CK (U/L)

Natural history / treated

Basalscore

Score at 3 months

Score at 6 months

Score at12

months

Albuteroldose (mg)

1 (PA), F* 69 55 14 56 218 treated 13 11 11 8 12

2 (PL), F* 64 44 19 100 274 treated 22 21 21 21 12

3 (BR), F 56 40 16 79 323 treated 24 21 20 20 10

4 (ZM), F 43 36 7 88 1242 treated 17 16 15 15 6

5 (DA), F 54 40 14 Resp. 161 Natural hist.

6 (DCG), M 56 16 40 Resp. 60 treated 25 25 25 25 6

7 (MK), M° 28 27 1 100 3118 Natural hist.

8 (MP), F° 32 32 0,5 100 825 Natural hist.

9 (PM), F 46 19 27 Resp. 360 Natural hist.

10 (DGO), F 46 42 4 100 714 Natural hist.

11 (MW), F 67 52 15 Resp. n.d. Natural hist.

*, °: pairs of affected siblings. Resp.: on respirator overnight.


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Clenbuterol has been shown to have an anabolic action on muscle cancer cachexia of the rat ascites hepatoma cells [3]. β2 agonists are undergoing clinical trials in other human neuromuscular disorders: in a double-blind placebo controlled trial, albuterol [10] gave encouraging results in patients with facio-scapular humeral dystrophy (FSHD). There was an increase of lean mass measured by DEXA scan after 52 weeks in two FSHD groups with both a low albuterol dosage (8 mg x twice a day) and high dosage (16 mg x twice a day), but there was no consistent increase in strength except for grip score. One possible explanation to these results is that the proximal muscle groups, which are extremely weak in FSHD, did not respond. We also observed a poor response in our juvenile-onset AMD patient, while 4 adult-onset AMD patients better tolerated albuterol. A pilot trial has also been done with albuterol at a dose 8-16 mg/day in amyotrophic lateral sclerosis [9] and by our group [19]. In adult GSD type II patients β2 adrenergic agonists have not been used so far: their metabolic mechanism of action might be attributed to the fact that they contribute to a reduction of body fat by FFA and insulin mobilization, and that they activate muscle phosphorylase, increasing glycogen breakdown. We observed a long term beneficial effect of albuterol in our four patients. β2 adrenergic drugs should be used cautiously in case of hyperthyroidism, diabetes, hypertension, severe cardiovascular disorders, which may be sometimes part of an AMD picture, in fact in our juvenile patient relevant side effects were observed by IV albuterol treatment, i.e. pulmonary oedema. This juvenile-onset AMD patient was first treated by intravenous mean in intensive care because of his poor ventilatory condition.

The exact mechanism by which intracellular muscle proteins are degraded is largely unknown, although it is generally accepted that proteolysis occurs both inside and outside the lysosomes. The catabolism of proteins

has not been studied in detail in adult AMD, and our morphological data suggest that membrane protein turnover should be analyzed. Also little is known, as to whether β2 agonists increase the anabolic process or depress the catabolic ones. In GSD II it seems important to achieve both the redistribution of energy substrates and inhibition of proteolysis in order to restore protein synthesis. β2 agonists represent a convenient pharmacological approach in this lysosomal myopathy and in a number of pathological conditions, where muscle protein catabolism is critical. In our pilot trial, since branched chain aminoacids and albuterol treatment overlapped in the first six months, it is difficult to clarify which one of the two was the most efficacious drug. However, the subsequent benefit observed with albuterol alone in functional performances suggests a possible symptomatic use with this β2 adrenergic agonists in GSD type II. Treatment with enzyme replacement therapy (ERT) of infantile Pompe’s disease cases has been started from a few years using recombinant human α-glucosidase from rabbit milk [20]. ERT yields variable results in different tissues (e.g. skin and nerve seem to benefit before skeletal muscle) and improved mostly in infantile patients in good conditions; therefore, it seems important to maintain AMD patients in the most favourable clinical conditions. Protein or leucine aminoacid supplementation or albuterol therapy might be therefore useful until ERT becomes available for adult AMD patients.

Acknowledgments This paper was supported by Telethon grant bank #

GTF02009 and MURST grant # 2001068328.

Address correspondence to: Corrado Angelini, M.D., Neuromuscular Center,

Department of Neurosciences, University of Padova, Via Giustiniani 5, 35128 Padova Italy.

References [1] Angelini C, Engel AG. Comparative study of acid

maltase deficiency. Biochemical differences between infantile, childhood and adult types. Arch.Neurol. 1972; 26: 344-349.

[2] Angelini C, Ringel SP, Micaglio GF, Trevisan CP. Italian multicenter therapeutic trials in Duchenne dystrophy. I protocol. Ital.J.Neurol.Sci. 1984; 4: 137-142.

[3] Costelli P, Garcia Martinez C, Leovera M, Carbo N, Lopez-Soriano FL, Agell N, Tessitore L, Bacceno ML, Argiles JM. Muscle protein waste in tumor-bearing rats is effectively antagonized by a β2 adrenergic agonist (clenbuterol). J.Clin.Invest. 1995;. 95: 2367-2374.

[4] D'Ancona GG, Wurn J, Croce CM. Genetics of type Il glycogenosis: assignment of the human gene for

Figure 4. Functional score in 4 treated AMD patients

derived from the sum of grades in 4 functional tests (walking 10 meters, Gowers manoeuvre, rising from a chair, climbing 4 steps of a stair). When functional index decreases, a better performance is recorded.


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acid alpha-glucosidase to chromos 17. Proc. Nat. Acad. Sci 1979; 76: 4526-4529.

[5] Engel AG. Acid maltase deficiency in adults: studies in four cases of a syndrome which may mimic muscular dystrophy or other myopathies. Brain 1970; 93: 599-616.

[6] Engel AG, Gomez MR, Seybold ME, Lambert EH. The spectrum and diagnosis of acid maltase deficiency. Neurology 1973; 23: 95-100.

[7] Hers HG. α-glucosidase deficiency in generalized glycogen-storage disease (Pompe's disease). Biochem. J 1963; 86: 11-16.

[8] Isaacs H, Savage N, Badenhorst M, Whistler T. Acid maltase defíciency: a case study and review of the pathophysiological changes and proposed therapeutic measures. J Neurol. Neurosurg. Psych. 1986; 49: 1011-1018.

[9] Juhsz-Poisine K, Merryfield YJ, Sarejak M, Belden DS, Vaclawik AJ, Brooks BR (1999). Beta-2 adrenergic against (albuterol) ergotropic effect on neck estension (ME) and neck flexion (NF) maximal voluntary isometric contraction (MVIC) strength in amyotrophic lateral sclerosis (ALS) patients: quasi experimental prospective non-randomized control pilot study using Medical Research Council (MRC) Grading Scale and computerized isometric muscle testing (CIMT). Neurology 52 (suppl.2), A526.

[10] Kissel JT, McDermott MP, Mendell JR, King WM, Pandya S, Griggs RC, Tawil R, the FSH-DY Group Randomized, double-blind, placebo-controlled trial of albuterol in facioscapulohumeral dystrophy. Neurology 2001; 57: 1434-1440.

[11] Maltin CA, Delday MI, Watson JS, Heys SD, Nevisan JM, Kitchie IK, Gibson PH Clenbuterol, a beta-adrenoceptor agonist, increases relative muscle strength in orthopaedic patients. Clin Sci (Colch) 1993; 84 (6): 651-654.

[12] Margolis ML, Hill AR Acid maltase defíciency in an adult: evidence for improvement in respiratory

function with high-protein dietary therapy. Am Rev.Resp.Dis. 1986; 134: 328-331.

[13] Martineau L, Horan MA, Rothwell NJ, Little RA Salbutamol, a beta 2-adrenoceptor agonist, increases skeletal muscle strength in young men. Clin Sci (Colch) 1992; 82 (5): 615-621.

[14] Mehler M, DiMauro S Residual acid maltase activity in late-onset acid maltase defíciency. Neurology 1977; 27: 178-184.

[15] Orth M, Mindegar RR Effect of acid maltase deficiency at the endosomal/lysosomal system and glucose transporter 4. Neuromuscular Disorder 2003; 13: 49-54.

[16] Reuser AJ, Kroos M, Willemsen R, Swallow D, Tager JM, Galjaard H. Clinical diversity in glycogenosis type 11: biosynthesis and in situ localization of acid alpha-glucosidase mutant fibroblasts. J Clin. Invest. 1987; 79: 1689-1699.

[17] Signorile JF, Banovac K, Gomez M, Flipse D, Caruso JF, Lowenstein I. Increased muscle strength in paralyzed patients after spinal cord injury: effect of beta 2-adrenergic agonist. Arch. Phys. Med. Rehabil. 1995; 76(1): 55-58.

[18] Slonim AE, Coleman RA, McElligot MA, Najjar J, Hirrschorn K, Labadie GU, Mrak R, Evans OB, Shipp E, Pressu R Improvement of muscle function in acid maltase deficiency by high-protein therapy. Neurology 1983; 33: 34-38.

[19] Sorarù G, Pegoraro E, Spinella P, Turra S, D’Ascenzo C, Angelini C. Pilot trial with clenbuterol in amyotrophic lateral sclerosis. (manuscript submitted)

[20] Winkel LPF, Kamphoven JHJ, Van Den Hout HJMP, Severijnen LA, Van Doorn PA, Reuser AJJ, Van Der Ploeg AT. Morphological changes in muscle tissue of patients with infantile Pompe’s disease receiving enzyme replacement therapy. Muscle Nerve 2003; 27: 743-751.

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