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Glycogen storage disease type II

Glycogen storage disease type II (also called Pompe disease or infantile acid maltase deficiency) is a rare genetic disorder caused by a deficiency in the enzyme acid alpha-glucosidase (GAA), which is needed to break down glycogen, a stored form of sugar used for energy. It is the only glycogen storage disease with a defect in lysosomal metabolism, and was the first glycogen storage disease to be identified—in 1932. The build-up of glycogen causes progressive muscle weakness throughout the body and affects various body tissues, particularly in the heart, skeletal muscles, liver and nervous system. Transmission is by autosomal recessive inheritance. more...

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Children have a 1 in 4 chance of inheriting the disease when both parents carry the abnormal gene. It is estimated to occur in about 1 in 40,000 births.


Pompe disease has three forms defined by age of onset and progression of symptoms:

Infantile, or early onset, is noticed shortly after birth. Symptoms include severe lack of muscle tone, weakness, and enlarged liver and heart. Mental function is not affected. Development appears normal for the first weeks or months but slowly declines as the disease progresses. Swallowing may become difficult and the tongue may protrude and become enlarged. Most children die from respiratory or cardiac complications before 2 years of age.

Juvenile onset symptoms appear in early to late childhood and include progressive weakness of respiratory muscles in the trunk, diaphragm and lower limbs, as well as exercise intolerance. Intelligence is normal. Most patients do not live beyond the second or third decade of life.

Adult onset symptoms also involve generalized muscle weakness and wasting of respiratory muscles in the trunk, lower limbs, and diaphragm. Many patients report respiratory distress, headache at night or upon waking, diminished deep tendon reflexes, and proximal muscle weakness, such as difficulty in climbing stairs. Intellect is not affected. A small number of adult patients live without major symptoms or limitations


Cardiac and respiratory complications are treated symptomatically. Physical and occupational therapy may be beneficial for some patients. Alterations in diet may provide temporary improvement but will not alter the course of the disease. Genetic counseling can provide families with information regarding risk in future pregnancies.


The prognosis for individuals with Pompe disease varies according to the onset and severity of symptoms. The disease is particularly lethal in infants and young children.


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A waist is a terrible thing to mind: central obesity, the metabolic syndrome, and sleep apnea hypopnea syndrome - editorials
From CHEST, 9/1/02 by Lee K. Brown

In this issue of CHEST (see page 829), Schafer and colleagues report on a consecutive sample of men who had been referred for suspected sleep apnea-hypopnea syndrome (SAHS) and were subjected to overnight polysomnography, anthropomorphic measurements reflecting obesity and body fat distribution, and blood testing for various cardiovascular risk factors as well as the measurement of serum leptin levels. They found significant associations between apnea-hypopnea index (AHI) and the following: body weight, body mass index (BMI), the sum of fat skin folds, and the percentage of body fat; levels of fasting blood glucose, uric acid, and fibrinogen; and leptin levels. The correlation of AHI with leptin levels disappeared when it was corrected for collinearities with indexes of obesity. The authors found no correlation between AHI and hypertension, smoking, age, and dyslipidemia. These data comprise the latest contribution to an expanding literature relating sleep-disordered breathing with the so-called metabolic syndrome, a constellation of obesity and metabolic abnormalities that are associated with increased cardiovascular morbidity. This increasing body of evidence suggests that the metabolic syndrome may be a "final common pathway" linking SAHS with vascular disease.

While many investigators have observed that insulin resistance (either impaired glucose tolerance or unambiguous type II diabetes mellitus) resulting in hyperinsulinemia, abdominal (central) obesity, atherogenic dyslipidemias, essential hypertension, and microalbuminuria frequently coincide in individual patients, it was not until 1988 that Reaven (1) proposed that the coexistence of some of these disorders was not by chance but rather comprised what he termed "syndrome X." He was even able to hypothesize a direction of causality, citing data that suggested the following: (1) that obesity, sedentary lifestyle, and genetic propensity can cause insulin resistance; (2) that insulin resistance results in hyperinsulinemia; (3) that hyperinsulinemia can provoke catecholamine excess and renal retention of salt and water, either or both of which can raise BP; (4) that hyperinsulinemia results in elevated hepatic very low-density lipoprotein (VLDL) triglyceride secretion and inversely correlates with high-density lipoprotein (HDL) cholesterol concentrations; and (5) impaired glucose tolerance, hypertension, and elevated VLDL triglyceride/reduced HDL cholesterol are all associated with increased atherogenesis and cardiovascular risk. Kaplan (2) later suggested another mechanism by which hyperinsulinemia could provoke hypertension, by means of a direct effect on vascular smooth muscle. Since the name syndrome X had already been claimed 20 years earlier (describing patients with cardiac ischemia but angiographically normal coronary arteries), a variety of alternative appellations subsequently were brought forward, including the rather tame insulin resistance syndrome. More dramatic were "the deadly quartet" (2) and "CHAOS" (Coronary artery disease, Hypertension, Adult-onset diabetes, Obesity, and Stroke). (3) In 1998, an expert panel of the World Health Organization (4) finally agreed on the term metabolic syndrome, and that name and the syndrome definition that they developed seem to have stuck. The published definition requires glucose intolerance and/or insulin resistance plus two or more of the following conditions: hypertension; elevated plasma triglycerides and/or reduced HDL cholesterol; central obesity; and microalbuminuria. Hyperuricemia or gout, increased low-density lipoprotein cholesterol or the prevalence of small, dense low-density lipoprotein particles, disorders of fibrinolysis, and activation of inflammatory mechanisms also have been identified as probable or possible components of the metabolic syndrome, but some remain controversial. (5)

Teleologic considerations have given rise to the hypothesis that the metabolic syndrome is a remnant of evolutionary development under the pressures of a "feast-or-famine" existence. The theory holds that one or more "thrifty" genes emerged that act to conserve energy during times of famine. Examples of this include reducing thermogenesis or inhibiting pregnancy and lactation. The genotype also should enable the maximal storage of energy during times of plenty in the form of adipose tissue rather than glycogen since this type of energy storage provides more sustenance during periods of starvation. (6) The thrifty genes thus afford a survival advantage when the food supply is highly variable. However, this theory holds that the survival advantages of the genotype become liabilities when energy supplies are abundant and remain so. The metabolic syndrome results, and survival is impaired. Several putative mediators have been identified in support of this theory. One of them is leptin, which is a 167-amino acid protein produced by adipocytes and a variety of other tissues. Leptin has been shown to suppress hypothalamic neuropeptide Y in mice, (7) and, since neuropeptide Y stimulates appetite and thermogenesis, it is involved in a useful negative feedback mechanism. The ob gene has been identified as encoding for leptin, and the db gene as encoding for a hypothalamic leptin receptor in mice, and similar genes have been located in humans. (8) Interestingly, mice that are heterozygous for defective ob or db genes live longer when fasted than do normal mice, thus demonstrating the kind of survival advantage necessary for a thrifty gene. (8) Other possible mediators of the thrifty genotype are insulin receptor substrates (particularly insulin receptor substrate-1), phosphoinositide 3-kinase, hormone-sensitive lipase, endothelial lipoprotein lipase, mitochondrial uncoupling proteins, tumor necrosis factor (TNF)-[alpha], glycogen synthase, and others. (8,9)

As would befit the evolutionary pressure of a feast-or-famine existence lasting millennia as opposed to the constant abundance of (at most) the last few hundred years, metabolic syndrome is quite common. Most estimates place the prevalence of metabolic syndrome in nonobese individuals at 10%, and in obese subjects at > 50%. (10) Moreover, research in certain isolated populations with now-steady food supplies suggests that the higher mortality and lower fertility of individuals with glucose intolerance has been selecting for individuals without the thrifty gene, as is demonstrated by a decline in the incidence of glucose intolerance. (11) Not all is rosy in the land of the thrifty gene hypothesis, however. Several populations have been identified that are inordinately discordant for components of the syndrome. For instance, Pima Native Americans exhibit a very high prevalence of obesity and glucose intolerance, but a relatively low rate of dyslipidemia and hypertension. (12,13) In addition, a factor analysis of data from the Cardiovascular Health Study (14) suggested that body mass, glucose intolerance, dyslipidemia, and hypertension are independent, though overlapping, domains. The validity and objectivity of this analytic technique has been questioned, however. (5)

The specific role of central obesity in patients with the metabolic syndrome also remains to be explained. The differentiation of obesity into two identifiable patterns dates back > 50 years, when Vague (15) defined "android" and "gynoid" types based on measurements of skin-fold thickness at various body locations and drew some interesting correlations with disease prevalence. Modern medicine currently uses the terms central and peripheral for these patterns (apple and pear may be used by those botanically inclined) and waist-to-hip girth ratio (WHR), CT imaging, and MRI scans have been added to the diagnostic armamentarium. Central and peripheral obesity differ in the type of adipose tissue that accumulates. The more metabolically active brown adipocytes accumulate in central locations, while white adipocytes are found peripherally. In addition, many studies have confirmed the existence of a tighter correlation of central obesity with insulin resistance, dyslipidemia, hypertension, and atherosclerotic heart disease than for obesity without regard to pattern. (2) A variety of theories have been proposed to explain this, including the increased production of various mediators by brown adipocytes (candidates include leptin and TNF-[alpha]), or increased lipolysis in abdominal adipocytes leading to excess free-fatty-acid transport to the liver. The mediators may reduce peripheral insulin sensitivity, or the free fatty acids may decrease hepatic insulin uptake, degradation, and sensitivity as well as affect peripheral insulin sensitivity. (8-10) Of possible relevance is the fact that leptin levels decline after suction lipectomy of subcutaneous abdominal fat deposits. (16)

The importance of the metabolic syndrome lies in its association with cardiovascular morbidity as well as other possible end-organ effects, such as nonalcoholic steatohepatitis. Although each of the components of the metabolic syndrome individually have been identified as risk factors for cardiovascular disease, an individual with three or more components is at particularly high risk. For instance, Wilson et al (17) have reported a prospective analysis of the Framingham Offspring Study looking for cardiovascular events in 2,406 men and 2,569 women between the ages of 18 to 74 years. Gender-specific quintiles for baseline values of HDL cholesterol, triglycerides, total cholesterol, BMI, systolic BP, and glucose (as a surrogate for insulin resistance) were computed, and the lowest quintile for HDL cholesterol and highest quintiles for the other variables were used to compute the risk. Clusters of three or more risk factors occurred in 17% of the subjects. Fully 20% of the cardiovascular events in men and 48% of the events in women could be attributed solely to the clustering of three or more factors.

The metabolic syndrome has not escaped the interest of the sleep medicine community, and the article by Schafer and coworkers in this issue of CHEST is but the latest in a series of reports. Early reports by Davies et al (18) and Stoohs et al (19) documented an increased prevalence of insulin resistance in small groups of subjects with SAHS, but differences in BMI accounted for the entire relationship. Similarly, Levinson and colleagues (20) published a small study in 1994 that failed to detect a relationship between central obesity using WHR and severity of SAHS, although patients did tend to have higher WHR when compared to normative values. Strohl et al (21) were able to demonstrate an association between hyperinsulinemia (as well as BP) and AHI independent of BMI in 386 men referred for polysomnography, and more recently, two relatively large prospective studies demonstrated a relationship between SAHS severity and insulin resistance that was independent of BMI. Ip and colleagues (22) studied 270 consecutive nondiabetic patients (73% men) who had been referred for evaluation of suspected SAHS and found such a quantitative relationship for both AHI and minimum oxyhemoglobin saturation with insulin resistance. Central obesity (ie, the WHR) also was correlated with SAHS severity. Not unexpectedly, given the previous discussion, hypertension was significantly related to insulin resistance in their subjects. Punjabi and associates (23) recruited 150 men with no history of diabetes, cardiac disease, or pulmonary disease and subjected them to polysomnography, oral glucose tolerance testing, and measurement of fasting insulin and lipid levels. They found a surprisingly high prevalence of SAHS, ranging from 40 to 60% depending on the value of AHI score used to define a case. Impaired glucose tolerance and insulin resistance were associated with SAHS severity, as represented by both AHI and the degree of oxyhemoglobin desaturation. The WHR bore no relationship to the degree of SAHS, but HDL cholesterol level decreased with increasing AHI.

Several studies have previously examined plasma leptin levels, with or without indexes of the metabolic syndrome, in patients with SAHS. Vgontzas and colleagues (24) were able to demonstrate higher values of leptin in a small sample of obese middle-aged men with SAHS compared to age-matched and BMI-matched control subjects, and TNF-[alpha] and interleukin-6 levels were similarly increased. AHI also correlated with insulin resistance and CT scan measurements of central obesity. Another small study by Phillips et al (25) confirmed the presence of increased leptin levels in SAHS patients compared with similarly overweight control subjects. Two studies have demonstrated a fall in plasma leptin levels in SAHS patients who had been treated with nasal continuous positive airway pressure. Chin et al (26) found that this had occurred after only 3 to 4 days of treatment, although a decrease in central obesity (without a decrease in BMI) required 6 months. Ip and colleagues (27) demonstrated initially elevated leptin concentrations in SAHS patients (compared to nonapneic control subjects with similar BMI) that fell after 6 months of therapy with continuous positive airway pressure. Triglyceride levels also fell in the treated patients in the latter study, but fasting insulin and glucose concentrations did not change.

From these data, it is reasonable to conclude that potentially significant degrees of insulin resistance and hyperleptinemia are associated solely with SAHS, although it is certainly true that other factors (such as increased BMI) also play an important role. Consequently, insulin resistance and the metabolic syndrome become prime suspects in the search for a mechanism by which SAHS could cause increased cardiovascular morbidity, along with other possible mediators that may or may not act independently, such as leptin, TNF-[alpha], and interleukin-6 levels. The current study by Schafer and colleagues unfortunately does not add a great deal to our knowledge in this respect. Many previously well-demonstrated associations were not supported by their data, including those between AHI and hypertension, smoking, and age, presumably due to a lack of sufficient power. Other relationships that are relatively new to the SAHS literature, but which have been supported by multiple well-performed studies, also were not corroborated, such as those between AHI and leptin. However, the study by Schafer and coworkers does add a new suspect, elevated fibrinogen levels, as a mediator between SAHS and cardiovascular morbidity. Their data also failed to "connect the dots" between SAILS and parapharyngeal fat pad size, and it is the largest and most precise study to examine this relationship. Consequently, it will be necessary for future studies to look at mechanisms by which obesity (and central obesity, in particular) could provoke SAHS without a direct effect on upper airway anatomy, as well as to further delineate the intriguing relationships between SAHS and the metabolic syndrome.


(1) Reaven GM. Banting lecture 1988: role of insulin resistance in human disease. Diabetes 1988; 37:1595-1607

(2) Kaplan NM. The deadly quartet: upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 1989; 149:1514-1520

(3) Davidson MB. Clinical implications of insulin resistance syndromes. Am J Med 1995; 99:420-426

(4) Alberti KGMM, Zimmer PZ. Definition, diagnosis and classification of diabetes mellitus and its complications: WHO Consultation. Geneva, Switzerland: World Health Organization, 1999; 31-33

(5) Meigs JB. Invited commentary: insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors. Am J Epidemiol 2000; 152:908-911

(6) Neel V. Diabetes mellitus: a "thrifty" genotype rendered detrimental by progress? Am J Hum Genet 1962; 14:352-362

(7) Friedman J, Halaas J. Leptin and the regulation of body weight in mammals. Nature 1998; 395:763-770

(8) Groop L, Orho-Melander M. The dysmetabolic syndrome. J Intern Med 2001; 250:105-120

(9) Abate N. Obesity and cardiovascular disease: pathogenetic role of the metabolic syndrome and therapeutic implications. J Diabetes Complications 2000: 14:154-174

(10) Mantzoros CS, Flier JS. Insulin resistance: the clinical spectrum. Adv Endocrinol Metab 1995; 6:193-232

(11) Dowse GK, Zimmet PZ, Finch CF, et al. Decline in incidence of epidemic glucose intolerance in Naurnans: implications for the "thrifty genotype." Am J Epidemiol 1991; 133:1093-1104

(12) Howard BV, Davis MP, Pettit DJ, et al. Plasma and lipoprotein cholesterol and triglyceride concentrations in the Pima Indians: distributions differing from those of Caucasians. Circulation 1983; 68:714-724

(13) Howard BV, Lee ET, Yeh JL, et al. Hypertension in adult American Indians: the Strong Heart Study. Hypertension 1996; 18:256-264

(14) Sakkinen PA, Wahl P, Cushman M, et al. Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol 2000; 152:897-907

(15) Vague J. The degree of masculine differentiation of obesities: a factor determining predisposition to diabetes, atherosclerosis, gout, and uric calculous disease. Am J Clin Nutr 1956; 4:20-34

(16) Chen M-D, Ou L-F, Song Y-M. Postoperative plasma leptin levels in women undergoing suction lipectomy [letter]. Mayo Clin Proc 2001; 76:1177-1178

(17) Wilson PWF, Kannel WB, Silbershatz H, et al. Clustering of metabolic factors and coronary heart disease. Arch Intern Med 1999; 159:1104-1109

(18) Davies RJ, Turner R, Crosby J, et al. Plasma insulin and lipid levels in untreated obstructive sleep apnea and snoring: their comparison with matched controls and response to treatment. J Sleep Res 1994; 3:180-185

(19) Stoohs RA, Facchini F, Guilleminault C. Insulin resistance and sleep-disordered breathing in healthy humans. Am J Respir Crit Care Med 1996; 154:170-174

(20) Levinson PD, McGarvey ST, Carlisle CC, et al. Adiposity and cardiovascular risk factors in men with obstructive sleep apnea. Chest 1993; 103:1336-1342

(21) Strohl KP, Novak RD, Singer RD, et al. Insulin levels, blood pressure and sleep apnea. Sleep 1994; 17:614-618

(22) Ip MSM, Lam B, Ng MMT, et al. Obstructive sleep apnea is independently associated with insulin resistance. Am Rev Respir Crit Care Med 2002; 165:670-676

(23) Punjabi NM, Sorkin JD, Katzel LI, et al. Sleep-disordered breathing and insulin resistance in middle-aged and overweight men. Am Rev Respir Crit Care Med 2002; 165:677-682

(24) Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 2000; 85:1151-1158

(25) Phillips BG, Kato M, Narkiewicz K, et al. Increases in leptin levels, sympathetic drive, and weight gain in obstructive sleep apnea. Am J Physiol Heart Circ Physiol 2000; 279:H234-H237

(26) Chin K, Shimizu K, Nakamura T, et al. Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy. Circulation 1999; 100: 706-712

(27) Ip MSM, Lam KSL, Ho C-M, et al. Serum leptin and vascular risk factors in obstructive sleep apnea. Chest 2000; 118: 580-586

Dr. Brown is Medical Director, New Mexico Center for Sleep Medicine, Lovelace Health Systems, and The Division of Pulmonary, Allergy, and Critical Care, Department of Internal Medicine, University of New Mexico School of Medicine.

Correspondence to: Lee K. Brown MD, FCCP, Medical Director, New Mexico Center for Sleep Medicine, Lovelace Health Systems, 4700 Jefferson Blvd NE, Suite 800, Albuquerque, NM 87109; e-mail:

COPYRIGHT 2002 American College of Chest Physicians
COPYRIGHT 2003 Gale Group

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