Glycogen storage diseases

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Hydrolyse Glykogen

Fig. 26. Acid maltase deficiency. The muscle contains vacuoles filled with glycoprotein (arrow)

Fig. 27. McArdles disease. Sub-sarcolemmal vacuoles with stained glycogen (small arrows), and evidence of dener-vation atrophy (large arrows)

There is either no weakness, or proximal muscles are involved. Distribution

Slowly progressive in most cases. Time course

Onset depends on the specific glycogen storage disease (GSD) and can range Onset/age from infantile to adult onset as outlined below

Clinical syndrome Type I (GSD I - von Gierke disease) is characterized by growth retardation,

Type I (GSD I) hypoglycemia, hepatomegaly, kidney enlargement, hyperlipidemia, hyperuri cemia, and lactic acidemia. Deficiencies in glucose-6-phosphatase (G6Pase) and glucose-6-phosphate transporter (G6PT) cause GSD Ia and GSD Ib. GSD Ib patients also suffer from chronic neutropenia and functional deficiencies of neutrophils and monocytes, resulting in recurrent bacterial infections as well as ulceration of the oral and intestinal mucosa.

Type II (GSD II) Type II (GSD II - acid maltase deficiency) - 3 types:

- Infantile onset: cardiomegaly and heart failure, liver disease, weakness and hypotonia.

- Childhood onset: proximal symmetrical weakness with enlarged muscles due to glycogen accumulation, with respiratory failure (RF).

- Adult onset: fatigue early in the disease followed by proximal weakness, and eventually RF. RF may the presenting feature in 30% of patients. Other features include basilar cerebral aneurysms, pulmonary hypertension, sleep hypercapnia with headache on waking.

Type III (GSD III) Type III (GSD III - debrancher deficiency) is more common in men than women

(~ 3:1). GSD IIIa (85%) have liver and muscle involvement and GSD IIIb (15%) have only liver involvement. Wasting of leg and intrinsic hand muscles along with slowing of nerve conduction studies and mixed myopathic and neurogenic units may lead to a mistaken diagnosis of motor neuron disease.

- Infantile form associated with deposition in muscle and liver, with hypoglycemia, recurrent seizures, severe cardiomegaly, and hepatomegaly.

- Childhood form associated with hypoglycemia, seizures, growth retardation, weakness, liver dysfunction and hepatomegaly.

- Adult form develops in the 3rd to 6th decade and is slowly progressive. It is associated with distal leg and proximal weakness, fatigue and myalgia, exercise intolerance, respiratory failure, milder cardiomyopathy, hepatic dysfunction. Patients may develop axonal neuropathy due to glycogen storage in endoneurial cells and axons.

GSD IV GSD IV (brancher deficiency) is associated with myopathy, cardiomyopathy, and liver disease. In addition brain and spinal cord can be affected resulting in progressive involvement of the upper and lower motor neurons, sensory loss, sphincter problems, and dementia. GSD IV can be associated with adult poly-glucosan body disease and is seen especially in Ashkenazi Jews.

GSD V GSD V (McArdle's disease) usually starts in the early teens and is more common in males. It is characterized by exercise intolerance, and severe cramping that may last several hours, myoglobinuria, proximal muscle involvement, and a "second wind" phenomenon in which the patient's symptoms may temporarily resolve. In the infantile form severe weakness and respiratory failure may be seen, and late onset GSD IV may be associated with only mild fatigue.

GSD VII GSD VII (Tarui's disease) occurs predominantly in males of Ashkenazi Jewish or

Italian ancestry. Clinical features are similar to McArdle's although the "second wind" is less common than in McArdle's. High carbohydrate meals exacerbate exercise intolerance, because the patient cannot metabolize glucose and ends up depleting free fatty acids and ketones - the "out of wind" phenomenon.

Myoglobinuria is less frequent than in McArdle's. Occasionally in children there may be a severe myopathy, respiratory failure, cardiomyopathy, arthrogryposis, seizures, and corneal opacification. GSD VII is also associated with accumulation of polyglucosan bodies over time and may result in a further deterioration in strength later in life that resembles IBM.

GSD VIII-XIII are characterized by intolerance to intense exercise, cramps and/ GSD VIII-XIII or myoglobinuria. GSD X occurs almost exclusively in blacks and heterozygotes may also have exercise intolerance.

GSD are a group of predominantly autosomal recessive disorders. GSD I is Pathogenesis caused by deficiencies in the activity of G6Pase system consisting of two membrane proteins that work in concert to maintain glucose homeostasis, G6PT (11q23) and G6Pase (17q21). G6PT translocates glucose-6-phosphate (G6P) from cytoplasm to the lumen of the endoplasmic reticulum and G6Pase catalyzes the hydrolysis of G6P to produce glucose and phosphate. Deficiencies in G6Pase and G6PT cause GSD Ia and GSD Ib, respectively.

GSD II is an autosomal recessive disorder due to deficiency of l acid a-1,4-glucosidase coded by a gene on chromosome 17q23. GSD III results from nonsense mutations, small deletions or insertions, or splice site changes on chromosome 1p21. There is a deficiency of amylo-1,6-glucosidase (AGL) that catalyzes both a transferase and a hydrolysis reaction. In GSD V several missense, stop, start codon or frameshift mutations of 11q13 have been described. There is a deficiency of muscle phosphorylase resulting in impaired ATP generation from aerobic and anaerobic glycolysis and reduced production of pyruvate. GSD VII is due to a deficiency of 6-Phosphofructokinase (PFK - 1cen-q32). Other listed enzyme deficiencies resulting in defects of glycogen storage include: GSD XII - Aldolase A: 16q22, GSD XIII - P-Enolase: 17pter, GSD XI-Lactate dehydrogenase: 11p15, GSD IX - Phosphoglycerate Kinase: Xq13, X -Phosphoglycerate Mutase: 7p12, and GSD VIII - Phosphorylase P kinase: Xq12.

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