Adult-onset Acid Maltase Deficiency Research Articles

ID 230 – Adult onset acid maltase deficiency – EMG aids diagnosis in Intensive Care Unit

A 25 year old man was admitted to Intensive Care Unit with the clinical problems of worsening shortness of breath and a history of progressive proximal limb weakness and bilateral ptosis. He was found to have marked type II respiratory failure and significant proximal weakness both the upper and lower limbs and also marked extra-ocular muscle weakness. Arterial Blood Gas Analysis was consistent with type II respiratory failure. Muscle enzymes – CK levels were elevated -1174 U. Acetyl Choline Receptor antibodies – Negative. Neurophysiological Studies – Normal nerve conduction studies; EMG evaluation demonstrated marked myopathic abnormalities in proximal and distal muscles in lower as well as upper limbs. Some muscles showed frequent pseudo-myotonic discharges. The clinical presentation of progressive muscle weakness and Type II respiratory failure along with EMG features raised the possibility of adult onset Acid Maltase deficiency. Muscle biopsy demonstrated accumulation of glycogen within membrane bound vacuoles consistent with adult onset Acid Maltase Deficiency (Pompe’s disease of adult onset). Awareness of clinical and neurophysiological features of Acid Maltase Deficiency aid the diagnosis of this disorder, particularly in the context of evaluation of respiratory failure cases in an Intensive Care Unit.

Electromyographic findings in 37 patients with adult-onset acid maltase deficiency.

In acid maltase deficiency (AMD), electrical myotonia (EM) may be restricted to paraspinal muscles. A comprehensive description of the electromyographic (EMG) findings in AMD is lacking. The purpose of this study is to describe the EMG features in adult-onset AMD, focusing on the distribution of EM. A retrospective chart review of AMD patients diagnosed at Mayo Clinic over age 18 years. Thirty-seven patients were included. Twenty-eight (76%) had EM in at least 1 muscle, and EM was more common in paraspinal and proximal limb muscles. The tensor fasciae latae (TFL) was equally sensitive to the paraspinals for EM. Three of 4 patients had EM identified in the diaphragm. Approximately three-quarters of adult-onset AMD patients display EM on EMG. The paraspinal muscles and TFL are the most likely to demonstrate EM, and EM can be detected in the diaphragm of adult onset AMD patients.

Systemic Metabolic Abnormalities in Adult-onset Acid Maltase Deficiency

The physiological relevance of acid maltase (acid α-glucosidase, an enzyme that degrades lysosomal glycogen) is well recognized in liver and muscle. In late (adult)-onset acid maltase deficiency (glycogen storage disease type II [GSD II]), glycogen accumulates inside muscular lysosomes in the context of reduced enzymatic activity present not only in muscle, but also throughout the organism. Yet, disease manifestations are commonly attributed to lysosomal disruption and autophagic vesicle buildup inside the myofiber due to a lack of obvious hepatic or broader metabolic dysfunction. However, current therapies primarily focused on reducing glycogen deposition by dietary or enzyme replacement have not been consistently beneficial, providing the motivation for a better understanding of disease mechanisms. To provide a systematic overview of metabolism and methylation capacity using widely available analytical methods by evaluating secondary compromise of (1) the citric acid cycle, (2) methylation capacity, and (3) nutrient sensor interaction in as many as 33 patients with GSD II (ie, not all patients were available for all assessments) treated with only a low-carbohydrate/high-protein, calorie-balanced diet. Case series including clinical and analytical characterization in an academic setting involving 33 enzymatically proved adults with GSD II treated only with a low-carbohydrate/high-protein, calorie-balanced diet. Biochemical analysis of blood and urine samples. Patients exhibited evidence for disturbed energy metabolism contributing to a chronic catabolic state and those who were studied further also displayed diminished plasma methylation capacity and elevated levels of insulin-like growth factor type 1 and its carrier protein insulin-like growth factor binding protein 3 (IGFBP-3). The simplest unifying interpretation of these abnormalities is nutrient sensor disturbance with secondary energy failure leading to a chronic catabolic state. Data also provide the framework for the investigation of potentially beneficial interventions, including methylation supplementation, as adjuncts specifically targeted to ameliorate the systemic metabolic abnormalities of this disorder.

Myalgic phenotype and preserved muscle strength in adult-onset acid maltase deficiency

Adult-onset acid maltase deficiency is a rare disorder characterized by progressive proximal muscle weakness and early respiratory insufficiency. We present a case of a 53-year-old woman who presented with several years of severe, diffuse myalgia and no evidence of weakness on examination. Further testing revealed a mildly elevated serum creatine kinase, a subtle vacuolar myopathy, decreased skeletal muscle α-glucosidase activity, and causative mutations in the responsible GAA gene. While likely very uncommon, adult-onset acid maltase deficiency may present with diffuse strength-sparing myalgia.

Adult-Onset Acid Maltase Deficiency With Isolated Axial Muscle Involvement

We report a patient with acid maltase deficiency who presented with subacute respiratory failure as the first symptom without significant extremity weakness. Electromyography of extremities was normal but showed myopathic changes and myotonic discharges limited to axial muscles only. Muscle biopsy confirmed the diagnosis. It is essential to examine axial muscles during electromyography if a patient presents with respiratory failure of unclear etiology even if the clinical examination does not show significant weakness in the extremities and electromyographic findings in the extremities are unremarkable.

Glycoengineered Acid α-Glucosidase With Improved Efficacy at Correcting the Metabolic Aberrations and Motor Function Deficits in a Mouse Model of Pompe Disease

Improving the delivery of therapeutics to disease-affected tissues can increase their efficacy and safety. Here, we show that chemical conjugation of a synthetic oligosaccharide harboring mannose 6-phosphate (M6P) residues onto recombinant human acid alpha-glucosidase (rhGAA) via oxime chemistry significantly improved its affinity for the cation-independent mannose 6-phosphate receptor (CI-MPR) and subsequent uptake by muscle cells. Administration of the carbohydrate-remodeled enzyme (oxime-neo-rhGAA) into Pompe mice resulted in an approximately fivefold higher clearance of lysosomal glycogen in muscles when compared to the unmodified counterpart. Importantly, treatment of immunotolerized Pompe mice with oxime-neo-rhGAA translated to greater improvements in muscle function and strength. Treating older, symptomatic Pompe mice also reduced tissue glycogen levels but provided only modest improvements in motor function. Examination of the muscle pathology suggested that the poor response in the older animals might have been due to a reduced regenerative capacity of the skeletal muscles. These findings lend support to early therapeutic intervention with a targeted enzyme as important considerations in the management of Pompe disease.

Visual Hallucinations in a Patient with Adult Onset Acid Maltase Deficiency Disorder

A 66-year-old male presented with visual hallucinations. He had chronically elevated serum creatine kinase (CK) levels without muscle weakness. His hospital course was complicated by hypercapnic respiratory failure requiring mechanical ventilation. His hallucinations completely subsided on mechanical ventilation. Elevated CK levels prompted a muscle biopsy, which showed myopathy consistent with acid maltase deficiency disorder (AMDD). This is the first reported case of adult onset AMDD presenting with psychiatric symptoms. Our objective in reporting this case is to encourage early recognition of neuromuscular respiratory failure in AMDD and to reinforce that respiratory failure may develop without associated extremity muscle weakness.

M.P.2.14 Muscle gene expression profile in adult onset acid maltase deficiency

M.P.2.14 Muscle gene expression profile in adult onset acid maltase deficiency

Modification of the natural history of adult‐onset acid maltase deficiency by nutrition and exercise therapy

Adult-onset acid maltase deficiency is an inherited lysosomal skeletal-muscle disease characterized by progressive myopathy and respiratory failure, for which there is no known therapy. In an uncontrolled, prospective study, we evaluated whether adherence to high-protein and low-carbohydrate nutrition and exercise therapy (NET) can slow the progressive deterioration of muscle function in this disease. Thirty-four patients have been treated with NET for periods of 2-10 years (mean 4.5 +/- 2.5). Pre-NET rate of muscle function deterioration, as measured by the Walton scale, was compared to post-NET rate. Twenty-six patients were deemed to be consistently compliant with NET. Difference between pre-NET slope of muscle function deterioration to that of post-NET slope in compliant patients was -0.29 (95% CI -0.19, 0.39) (P < 0.0001). We conclude that compliance with NET can slow deterioration of muscle function and improve the natural history of adult-onset acid maltase deficiency. Muscle Nerve, 2006.

Muscle MRI in adult-onset acid maltase deficiency

We report the spectrum of muscle involvement on magnetic resonance imaging in 11 patients with a molecularly confirmed diagnosis of adult-onset acid maltase deficiency at different clinical stages. Muscle magnetic resonance imaging showed a selective progressive pattern of muscle involvement with a constant involvement of the adductor magnus and semimembranosus at the early stage of the disease and a later fatty infiltration of the long head of the biceps femoris, semitendinosus and of the anterior thigh muscles. In the advanced phases a selective sparing of sartorius, rectus, and gracilis muscles and peripheral portions of the vastus lateralis was also evident. Muscle strength and magnetic resonance imaging findings were positively correlated. The results suggest that muscle magnetic resonance imaging may provide valuable diagnostic guidance for the assessment of accurate selective muscular involvement in acid maltase deficiency and may help monitor the progression of the disorder. Further control studies in a larger cohort are needed to evaluate the specificity of these findings.

Evaluation of muscle glycogen content by 13C NMR spectroscopy in adult-onset acid maltase deficiency

Muscle glycogen storage was measured by in vivo, natural abundance 13C nuclear magnetic resonance spectroscopy in distal and proximal lower limb segments of patients suffering from adult-onset acid maltase deficiency. Interleaved T1-weighted acquisitions of glycogen and creatine served to quantify glycogen excess. For acid maltase deficient patients ( n=11), glycogen:creatine was higher than controls ( n=12), (1.20±0.39 vs. 0.83±0.18, P=0.0005). Glycogen storage was above the normal 95% confidence limits in at least one site for 7/11 patients. The intra-individual coefficient of reproducibility was 12%. This totally atraumatic measurement of glycogen allows repeated measurement at different muscle sites of acid maltase deficient patients, despite selective fatty replacement of tissue. This could provide an additional parameter to follow the development of disease in individual patients, including in the perspective of forthcoming therapeutic trials. It may also offer an appropriate tool to study the role of glycogen accumulation in progression of the pathology.

Juvenile and adult-onset acid maltase deficiency in France: genotype-phenotype correlation.

To characterize the phenotypes of patients with juvenile and adult-onset acid maltase deficiency (AMD) in the French population and correlate them with genetic defects. AMD is an autosomal recessive disorder caused by the absence of the enzyme acid a-glucosidase (GAA). Patients are generally compound heterozygotes for various mutations in the GAA gene. The most common mutant allele is a -13T to G transversion in intron 1. The authors performed a clinical, biochemical, and genetic study on 21 unrelated patients with juvenile and adult-onset AMD. Although onset of progressive muscle weakness occurred during adulthood in all cases but one, presence of mild, nonprogressive muscular symptoms appearing during childhood was detected in 16 patients. Eighteen patients had a similar clinical pattern with pelvic girdle muscle weakness predominating in glutei and thigh adductors. Restrictive respiratory insufficiency with vital capacity less than 60% was noted in eight patients, and respiratory failure was the first manifestation in two cases. All patients but one were compound heterozygotes, and 17 carried the IVS1 (-13T ---> G) transversion (one patient was homozygous for this mutation). The two mutated alleles were identified in 10 cases, with 13 different mutations detected in the GAA gene. There was no clear correlation between the type of mutation and phenotype. This study shows a high genetic heterogeneity of juvenile and adult AMD in the French population. The absence of genotype-phenotype correlation suggests a complex physiopathology that requires further investigations.

Congenital and metabolic myopathies of childhood or adult onset

Objectives: To investigate the clinical presentation, histological findings, and outcome of patients with congenital and metabolic myopathies (CM and MM) in whom the disease was diagnosed in childhood or adulthood. Patients and Methods: We reviewed the diagnosis of all skeletal muscle biopsies performed by our group between 1984 and 1996 (13 years). All patients with CM and MM of childhood or adult onset were included in the study. Patients with mitochondrial myopathies were excluded because they are multisystemic disorders with a more distinct picture than that observed in other MM. We retrospectively reviewed the clinical history, with special emphasis on the clinical patterns of presentation, histological findings, and outcome. Results: Among 1,865 biopsies, 28 (1.5%) fulfilled the diagnostic criteria for CM(seven nemaline myopathies, four multicore myopathies, three centronuclear myopathies) or MM (five adult-onset acid maltase deficiency, three myophosphorylase deficiency, three phosphofructokinase deficiency, two carnitine palmitoyl transferase deficiency, and one carnitine deficiency). In nearly half of the patients, mild stable weakness was the major complaint, whereas in one third muscular symptoms were intermittent and related to exercise. In a small number of cases, a persistently raised serum creatinkinase in an asymptomatic patient was the reason for muscle biopsy. Histological examination of skeletal muscle was highly indicative of a specific muscle disease in 26 of the 28 cases. After a mean follow-up of 7 years, the outcome has generally been good, and in most patients the myopathy did not worsen, most remaining ambulatory. Conclusion: CM and MM presenting in childhood or adulthood are infrequent; the symptoms are usually mild or moderate, and the prognosis generally is good.

Muscle computed tomography in adult-onset acid maltase deficiency

Nine patients with adult-onset acid maltase deficiency (Pompe's disease) were examined clinically and with computed tomography (CT). The CT scan showed early and severe involvement of the muscles of trunk and thighs, with selective sparing of the tensor fasciae latae, short head of biceps femoris, gracilis, and sartorius muscles. Shoulder and leg muscles were less affected. The disease spread over the years from trunk to extremities. Muscle strength and CT findings were positively correlated.

Genotype‐phenotype correlation in adult‐onset acid maltase deficiency

We performed a clinical, biochemical, and genetic study in 16 patients from 11 families with adult-onset acid maltase deficiency. All patients were compound heterozygotes and carried the IVS1(-13T --> G) transversion on one allele; the second allele harbored either a deletion of a T at position 525 in exon 2 (7 probands, 64%) or a deletion of exon 18 (1 proband, 9%). Deterioration of handicap was related to age, and decrease in vital capacity to duration of the symptomatic stage. Respiratory insufficiency was never the first manifestation. The levels of activity of serum creatine kinase and of alpha-glucosidase in peripheral blood cells or muscle were helpful for the diagnosis, but did not have prognostic value. The adult form of acid maltase deficiency appears to be both clinically and genetically rather homogeneous; decrease of alpha-glucosidase activity is the final common pathway leading to destruction of muscle fibers and progression of muscle weakness over a period of years.

Sarcoid myopathy presenting with diaphragm weakness

Sarcoidosis involving muscle occurs frequently, but it is infrequently symptomatic. The clinical, electromyographic, and histologic features of sarcoidosis involving muscle in a 63-year-old woman presenting with diaphragm weakness are described. An electromyogram revealed wide-spread myotonia and an inflammatory myopathic process, suggestive of adult-onset acid maltase deficiency disease. Muscle biopsy showed noncaseating granulomas consistent with sarcoidosis. Clinical improvement followed the initiation of oral prednisone therapy. This case illustrates that muscular sarcoidosis may mimic adult-onset acid maltase deficiency in both its clinical and electromyographic features.

Respiratory involvement in primary muscle disorders: assessment and management

Eighty-four patients with primary disorders of muscle were referred for assessment of respiratory insufficiency between 1978 and 1991. The eventual diagnoses were: 'limb girdle syndromes' (18 patients), adult onset acid maltase deficiency (14), dystrophia myotonica (13), inflammatory disorders (10), congenital myopathies (nine), rigid spine syndromes (five), dystrophies (Duchenne (six), facioscapulohumeral (four), Becker (one)) and miscellaneous (four). Presentations were often insidious, with progressive nocturnal hypoventilation culminating in respiratory failure or arrest, recurrent respiratory tract infections, or obstructive sleep apnoea. Respiratory symptoms developed relatively early in patients with acid maltase deficiency and inflammatory disorders but parallelled the development of limb weakness in limb girdle, myotonic and congenital syndromes. Sixty-six patients received respiratory support for a median of 5 years (1-34 years) using various techniques of negative and positive pressure ventilation. Fourteen patients received short-term support for an episode of respiratory failure before being weaned, 51 required nocturnal domiciliary ventilation and one was dependent on continuous domiciliary support. Tracheostomy was performed in 32 patients and used for domiciliary nocturnal ventilation in 25. Twenty-eight patients have subsequently died.

Lysosomal glycogen storage disease without acid maltase deficiency. A lectin-histochemical study of an unusual type of lysosomal glycogen storage disease.

Lectin histochemical studies were performed on frozen sections of biopsied skeletal muscle from two unrelated patients with lysosomal glycogen storage disease without acid maltase deficiency. The clinical manifestations of these patients, myopathological features and biochemical characteristics are similar to those first reported by Danon et al. in 1981. Routine myopathological findings showed vacuolar myopathy and excess of glycogen with or without glycogenosomes resembling acid maltase deficiency (AMD), but the biochemical activity of acid α-glucosidase was normal.Ten lectins with varying sugar specificities were used as probes. The results were compared with normal muscle and with one patient who had the typical manifestations of adult onset AMD. Though myofibers themselves were never stained in normal muscle, positively stained myofibers with or without vacuolations were found in diseased muscle. Vacuolar membranes and their contents were strongly stained by almost all the lectins applied. Ulex europaeus agglutinin-I (UEA-I) specific to L-fucose stained the perimeter of the disturbed muscle in addition to the vacuoles.The staining pattern of the vacuolations and perimeter of disturbed myofibers was different from that found in AMD. In AMD, Triticum vulgaris agglutinin (WGA) and Limax flavus aggutinin (LFA) faintly stained the vacuolar membranes and contents. These preliminary investigations of abnormal lectin staining patterns may provide a key to understanding the pathomechanism of this unique lysosomal glycogen storage disease.

Immunohistochemical localization of AMP deaminase in rimmed vacuoles in human skeletal muscle.

High AMP deaminase reactivity was detected in the rimmed vacuoles in skeletal muscles in adult onset acid maltase deficiency and distal myopathy with rimmed vacuole formation histochemically as well as immunohistochemically. Acid phosphatase activity was positive but myosin ATPase activity was negative in the vacuoles. AMP deaminase found in rimmed vacuoles does not seem to be associated with myosin but is possibly bound to lysosomes or other related organelles in accordance with the proliferation of autophagic vacuoles.

Respiratory Insufficiency in Adult-Onset Acid Maltase Deficiency

Although the adult form of acid maltase deficiency is characterized by weakness of the limb girdle muscles, weakness of the respiratory muscles out of proportion to that of the limb muscles may make the diagnosis less obvious. We present four patients aged 35 to 57 with respiratory muscle weakness associated with signs of cor pulmonale and symptoms of alveolar hypoventilation. Each had symptoms of fatigue, hypersomnolence, morning headache, and orthopnea, the cause of which was misdiagnosed. The key to diagnosis was paradoxic abdominal motion on inspiration. This finding, consistent with diaphragmatic paralysis, led to neurologic evaluation, electromyographic examination, and muscle biopsy to confirm the diagnosis. The symptoms of alveolar hypoventilation were reversed with chronic nocturnal ventilation, which assisted in rehabilitating some patients.