Acid maltase deficiency

ABSTRACT. Background: A 30-year-old woman with celiac sprue had progressive weight loss, myalgia, limb-girdle weakness, and dysphagia. Methods and Results: Barium swallow showed an atonic esophagus, and scintigraphic study confirmed esophageal dysmotility. Skeletal muscle biopsy showed characteristic appearances of acid maltase deficiency, which was confirmed by a re

duction of leukocyte acid alpha-glucosidase activity. Conclusions: Nutritional factors may have accelerated the presentation of the lysosomal storage disorder. This is the first reported case of dysphagia caused by esophageal motor weakness in acid maltase deficiency. (Journal of Parenteral and Enteral Nutrition 21:046049, 1997)

Acid maltase deficiency (glycogen storage disease type II or Pompe's disease) is the paradigm of the lysosomal storage disorders. Inherited deficiency of acid alpha-glucosidase leads to the accumulation of glycogen within lysosomes; the extent of this accumulation depends on the relative deficiency of the acid hydrolase and the rate of accumulation of the substrate macromolecule within any given cell type. Although Pompe originally described a severe infantile form of the disease characterized by profound hypotonia, myopathy, and heart failure,1 milder forms of the condition with onset in childhood and adult life have now been recognized. Partial deficiency of acid a-glucosidase activity is associated with skeletal muscle weakness causing progressive proximal myopathy and diaphragmatic weakness that leads to respiratory embarrassment in the absence of cardiac abnormalities. Muscle bulk is preserved early in the course of the disorder despite progression of the weakness. Ultimately muscle atrophy is associated with overt loss of somatic bulk.

The degree of glycogen deposition in slowly progressive disease seems insufficient to account for observed muscle weakness. The increased clearance of branchedchain amino acids, which is a feature of the condition, suggests that muscle protein catabolism is increased. It has been postulated that altered intracellular metabolism of skeletal muscle glycogen is the cause of a shift in the balance between protein synthesis and degradation.2

In the absence of definitive treatment dietary therapy may arrest progress of this disorder. The original observation that in the short term a diet high in branched-chain amino acids could improve exercise tolerance2 has subsequently been reproduced in other patients3,4 and this intervention appears to reduce requirements for ventilatory assistance in patients with advanced disease.5,6 Although institution of a high-protein diet induces a reduction in muscle protein turnover, there is often no symptomatic improvement7 and in severely affected infants progressive weakness continues unabated.8

We report the coincidence of symptomatic gluten-sensitive enteropathy with rapid weight loss and progression of disability in a young adult with acid maltase deficiency. The weight loss was initially arrested by institution of a gluten-free diet. Progressive deterioration in the ability to swallow because of esophageal weakness over 3 years led to a vicious circle of reduced intake and further rapid weight loss (Fig. 1).

CASE PRESENTATION

A 30-year-old woman with celiac disease diagnosed 2h years previously had noted a 5-kg weight loss and aching and weakness in the muscles of her lower limb girdle; there had been progressive dysphagia for solids for 1 year without regurgitation, recently accompanied by heartburn.

The patient was married with two normal children by uneventful deliveries. In 1989, 5 years previously, she had been investigated for weight loss accompanied by generalized myalgia and tenderness. At this time serum alanine transferase was noted to be elevated (213 IU/L, normal

In 1992, because of further weight loss and diarrhea accompanied by an anemia of 10.5 g/dL, investigations for celiac disease were undertaken; serology showed positive anti-gliadin and endomysial antibodies. Duodenal biopsy (Fig. 2) showed villous atrophy, crypt hyperplasia, and increased intraepithelial lymphocytes. A gluten-free diet was instituted but subsequent failure to gain weight with continuing malaise prompted further investigations. Dietary review indicated compliance with gluten exclusion and an average daily intake of 8.4 MJ. Her anemia had improved and repeat duodenal biopsy confirmed restoration of villous pattern. Serum antibody to gliadin and endomysium became undetectable. By November 1994, after 2 1/2 years ingesting a gluten-free diet, there was a further 2-kg in weight loss; symptomatic muscle weakness was such that the patient was unable to climb stairs unaided. There was no history of rash, arthralgia or Raynaud's phenomenon; dysphonia, cramps, and visual symptoms were absent. The patient was a nonsmoker and rarely consumed alcohol. As an infant she had reached normal developmental and academic milestones and was able to participate in sports activities at school, although performance at running and jumping events was poor. There was no family history of neurological disease. Her siblings were well, and her two children had reached normal developmental milestones at ages 3 and 6 years.

Clinical examination showed selective loss of muscle bulk at the shoulder girdle and in the adductor compartment of the thighs; tone was normal. There was bilateral weakness of hip flexion with normal distal power; no weakness of the upper extremities was detected. The patient was unable to rise to the seated position unaided or from the floor without grasping the thighs to push the body erect (Gower's maneuver). Gait was normal and coordination and sensation were intact.

INVESTIGATIONS

Urine analysis was normal. Hematocrit was 41% with normal red cell indices, white cell count was 5.9 x 10 ^ sup 9^/L with normal differential count. Random blood glucose was 6.0 mmol/L (normal 3.5 to 9.0 mmol/L). Alanine and aspartate transferases were 177 and 150 IU/L (normal

An double-contrast upper barium series showed an atonic esophagus with retarded passage of barium in association with free gastroesophageal reflux. A combined scintigraphic esophageal and gastric emptying study showed bolus obstruction at the midesophagus with active retroperistalsis and spasm (Fig. 3). Gastric emptying was rapid. Chest radiography showed normal heart and lungs. Forced vital capacity was 2.35 L falling to 1.55 L in the supine position, consistent with diaphragmatic impairment. Resting electrocardiogram and transthoracic echocardiography were normal.

Light microscopy of the left quadriceps muscle biopsy showed vacuolated fibers (Fig. 4A) with focally increased acid phosphatase activity representing abundant secondary lysosomes (Fig. 4B) that were associated with strong periodic acid-Schiff staining marking the presence of glycogen. These findings are suggestive of acid maltase deficiency, which was further supported by electron microscopy showing abundant membrane-bound glycogen granules in muscle fibrils. Leukocyte acid oe-glucosidase activities were measured in peripheral leukocytes from the patient, her mother, and two siblings. Leukocyte extracts were precipitated at pH 5 to remove neutral alpha-glucosidase also present and Beta-galactosidase was measured as a reference enzyme (Table I). Enzymatic assays demonstrated deficiency of alpha-1,4-glucosidase in the patient, confirming the suspected diagnosis of acid maltase deficiency.

DISCUSSION

Dysphagia in association with proximal limb girdle weakness has not been previously described in acid maltase deficiency. The recent onset of dysphagia and retrosternal chest pain after meals in our patient were related to profoundly disordered esophageal motility as shown by an upper barium series and radioisotopic esophageal emptying study. No evidence of cardiac involvement was demonstrated. When the cause of dysphagia arises is distal to the pharynx, solid boluses are more likely to cause symptoms because they require greater propulsive force. Relatively preserved pharyngeal function could explain the observation that liquids could be swallowed without difficulty.

Esophageal scintigraphy performed in this way has a high sensitivity for detecting esophageal motor disorders.9 Esophageal manometry could have corroborated this abnormality although it was not performed in this case. Although full thickness esophageal biopsy would also have been instructive in confirming the underlying pathology, it was rejected because of the risk of this invasive procedure and unlikely benefit to the patient.

In two necropsy studies of adults with a progressive form of acid maltase deficiency, glycogen deposits were identified within the smooth muscle of the intestine,'o and it is notable that in a 19-year-old woman of Chinese origin diarrhea for which no cause was found in life may have been ascribable to intestinal smooth muscle disease." Smooth muscle dysfunction due to acid maltase deficiency has been documented at other sites; in six patients from three pedigrees cerebral aneurysms were detected and shown to be due to vacuolar abnormalities of smooth muscle within the walls of the affected arteries.12

Presentation of acid maltase deficiency after the age of 20 years is very unusual. It causes a slowly progressive proximal myopathy that may mimic polymyositis or limbgirdle dystrophy, although up to one third of patients suffer respiratory failure at presentation. It is characteristic that muscle involvement is selective, and in most cases diaphragmatic and axial and proximal limb muscles are most severely affected. Ultimately the condition progresses to involve the respiratory muscles and the usual cause of death appears to be ventilatory failure. Survival has been documented, however, into the seventh decade of life.

Acid maltase deficiency is an autosomal recessive disease of lysosomal storage. The severe infantile form of the disease affects between 1 in 50,000 and 1 in 150,000 live births6 and is fatal within the first 2 years of life; the progressive adult form of the disease described here is less common. After the discovery by Hers"3 that the accumulation of glycogen is due to a specific deficiency of acid alpha-glucosidase,13 it was suggested that other obscure diseases would result from heritable deficiencies of lysosomal acid hydrolases. The prediction has proved to be correct and more than 30 distinct storage diseases apparently due to the deficiency of a single lysosomal protein have been identified.14 The extent to which any given tissue is affected depends on the degree of enzymatic deficiency in the lysosome and the rate of turnover of the substrate. Autophagy of glycogen into lysosomes within muscle cells is a normal feature of its function as an intracellular energy store. In acid maltase deficiency progressive accumulation occurs presumably because of continued production of the substrate in the face of reduced hydrolysis. Although the function of lysosomal glycogenolysis is not known, it may be important in resting muscle, when the cytosolic phosphorylation pathway, responsible for glycogenolysis in exercising muscle, is not activated. It is notable that inherited deficiency of the lysosomal a-glucosidase is not associated with exercise-induced muscle pain and myoglobinuria, which are features of enzyme defects in the phosphorylation pathway of glycogenolysis.

Our patient had biopsy-proven celiac sprue and showed a histologic, immunologic, and clinical response to a gluten-free diet. During the 2 years before the diagnosis of sprue, there was loss of >10% of body weight (Fig. 1). There was rapid progression of symptomatic weakness and profound loss of somatic muscle bulk. Despite persistent elevation of transaminase the diagnosis of muscle disease was not suspected. After 2 years ingesting a glutenfree diet, her previously relentless weight loss was much reduced. The onset of the new symptom of dysphagia prompted investigation that led to the diagnosis of acid maltase deficiency. At the time of diagnosis of enzyme deficiency we instituted a program of hypercaloric dietary supplementation with increased protein content, in an attempt to arrest further progression. In spite of this a gradual deterioration in swallowing eventually led to reduced oral intake and a further marked decline in weight.

Because of this symptomatic deterioration further investigations were performed. Endoscopic examination of esophagus and lower esophageal sphincter relaxation were normal. Histologic examination of duodenal biopsies was normal, and antibody titers to gliaden and endomysium were not elevated and negative, respectively, in serum. Deterioration was ascribed to progression of disability due to acid maltase deficiency.

We considered the possibility that reduced calcium absorption and altered vitamin D metabolism, which occur in untreated celiac sprue, could have induced osteomalacia and contributed to proximal muscle weakness, but this was excluded in our patient. It is more probable that the interaction is related to the increased protein catabolism that occurs in the malnourished state.15 There is a precedent for exacerbation of weakness due to acid maltase deficiency by malnutrition. Demey et al 6 described a 28year-old woman who had adopted a severely inadequate diet. Rapid weight loss of 6 kg appeared to accelerate the progress of her muscle disorder and induced acute respiratory insufficiency that required ventilation, in the absence of an infective cause. After institution of a hypercaloric, low-carbohydrate diet, muscle strength improved and there was a decreased requirement for ventilatory support.

Unlike lysosomal disorders affecting the mononuclear phagocyte system such as Gaucher's disease, marrow transplantation has no demonstrable role in either human or bovine muscle disease due to acid maltase deficiency.16,17 However, the ability of phosphorylated high-mannose acid a-glucosidase to complement the functional deficiency and reverse glycogen storage in cultured fibroblasts of patients with type II glycogenosis 18-20 provides a rational basis for human trials of enzyme replacement using suitably glycosylated forms of recombinant human protein. Pending the possible availability of such treatment, and given the demonstrable correlation between malnutrition and clinical deterioration, it is of critical importance to maintain the nutritional integrity of patients with this storage disorder.

Received for publication, March 25, 1996.

Accepted for publication, September 4, 1996. Correspondence and reprint requests: Timothy S. King, MRCP, Addenbrooke's Hospital Cambridge, Department of Gastroenterology, Unit E7, Box 201A, Cambridge CB2 2QQ, United Kingdom.

REFERENCES

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4. Umpleby AM, Wiles CM, Trend PStJ, et al: Protein turnover in acid maltase deficiency before and after treatment with a high protein diet. J Neurol Neurosurg Psychiatry 50:587-592, 1987 5. Mobarhan S, Pintozzi RL, Damle P, et al: Treatment of acid maltase deficiency with a diet high in branched-chain amino acids. JPEN 14:210-212,1990

6. Demey HE, Van Meerbeeck JP, Vandewoude MJF, et al: Respiratory insufficiency in acid maltase deficiency: The effect of high protein diet. JPEN 13:321323, 1989

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14. Scriver CR, Beaudet AL, Sly WS, et al (eds): The Metabolic Basis of Inherited Disease, 7th ed. McGraw-Hill, 1994 15. Picou D, Taylor-Roberts T: The measurement of total protein synthesis and catabolism and nitrogen turnover in infants in different nutritional states and receiving different amounts of dietary protein. Clin Sci 36:283-296, 1969

16. Howell JMcC, Dorling PR, Shelton JN, et al: Natural bone marrow transplantation in cattle with Pompe's disease. Neuromuscular Disorders 1:449454, 1991

17. Watson JG, Gardner-Medwin D, Goldfinch ME, et al: Bone marrow transplantation for glycogen storage disease type II (Pompe's disease). N Engl J Med 314:385 (letter), 1986

18. Di Marco PN, Howell JMcC, Dorling PR. Bovine generalised glycogenosis type II. Uptake of lysosomal a-glucosidase by cultured skeletal muscle and reversal of glycogen accumulation. FEBS Lett 190:301-304,1985

19. Van der Ploeg AT, Bolhuis PA, Wolterman RA, et al: Prospect for enzyme therapy in glycogenosis II variants: A study on cultured muscle cells. J Neurol 235:392-396, 1988

20. Van der Ploeg AT, Kroos MA, Willemsen R, et al: Intravenous administration of phosphorylated acid a-glucosidase leads to uptake of enzyme in heart and skeletal muscle of mice. J Clin Invest 87:513 518,1991

TIMOTHY S. KING, MRCP*; JANICE R. ANDERSON, FRCPATH^; E. PHILIP WRAIGHT, FRCR ^^; JOHN 0. HUNTER, FRCP*; AND TIMOTHY M. Cox, FRC (sec)

From the *Department of Gastroenterology; ^Department of Histopathology; ^^Department of Nuclear Medicine; and (sec) Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom

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