Phosphorylase deficiency

The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

Adenosine Deaminase Purine Nucleoside Phosphorylase Deficiency... 

Adenosine deaminase deficiency is associated with an immunodeficiency disease in which both thymus-derived lymphocytes (T cells) and bone marrow-derived lymphocytes (B cells) are sparse and dysfunctional. Purine nucleoside phosphorylase deficiency is associated with a severe deficiency of T cells but apparently normal B cell function. Immune dysfunctions appear to result from accumulation of dGTP and dATP, which inhibit ribonucleotide reductase and thereby deplete cells of DNA precursors. 

H4. Hershfield, M. S., and Mitchell, B. S., Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. In Metabolic and Molecular Bases of Inherited Disease, 7th ed. (C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, eds.), pp. 1725-1768. McGraw-Hill, New York, 1995. 

Phosphorylase deficiency (McArdle s disease, glycogenosis type V) is an autosomal recessive myopathy caused by a genetic defect of the muscle isoenzyme of glycogen phosphorylase (Fig. 42-1). Intolerance of strenuous exercise is present from childhood, but usually onset is in adolescence, with cramps after exercise [1, 5]. Myoglobinuria occurs in about one-half of patients. If they avoid intense exercise, most patients can live normal lives however, about one-third of them develop some degree of fixed weakness, usually as a late-onset manifestation of the disease. In a few patients, weakness rather than exercise-related cramps and myoglobinuria characterizes the clinical picture. 

In liver phosphorylase deficiency (glycogenosis type VI, Hers disease Fig. 42-1) and in two genetic forms of phosphorylase kinase deficiency, one of which is X-linked recessive, the other of which is autosomal recessive, hypoglycemia is either absent or mild. Symptoms of brain dysfunction do not usually occur (type VIII, Fig. 42-1) [1],... 

Hepatic Glycogen Phosphorylase Deficiency (Hers Disease)... 

Glycogen phosphorylase deficiency in muscle gives rise to muscle weakness, frequent cramp and ease of fatigue (McArdle s syndrome). It also gives rise to hypoglycae-mia if the liver enzyme is deficient (Chapter 6). 

Fairbanks LD, Marinaki AM, Carrey EA, Hammans SR, Duley JA (2002) Deoxyuridine accumulation in urine in thymidine phosphorylase deficiency (MNGIE) J Inherit Metab Dis 25 603-604... 

Giblett ER, Ammann AJ, Wara DW, Sandman R, Diamond LK (1975) Nucleoside-phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity. Lancet 1 1010-1013... 

D-1) Muscle phosphorylase deficiency (Type V GSD McArdle s Disease). Liver phosphorylase is normal, but muscle phosphorylase is deficient. The patient cannot break down muscle glycogen and experiences muscle cramps and weakness with exercise. Muscle biopsy may confirm the enzyme defect. There is no significant rise in lactate in an ischemic exercise test. Magnetic resonance spectroscopy may be useful in diagnosing changes in muscle metabolic function. 

D-l) Liver phosphorylase deficiency (Type VI GSD Hers Disease), There is glycogen accumulation in the liver and liver enlargement. There is growth retardation, as amino acids are shunted toward gluconeogenesis rather than growth. 

Hepatic glycogenosis (type VI) (G.H. Hers, 1959) is due to hepatic phosphorylase deficiency. Subtype Via is caused by a lack of phos-phorylase-B kinase, and it is transmitted by the x-chromosomal recessive route. Subtype Vib shows a deficiency in glycogen phosphorylase, and its transmission is autosomal recessive. In the musculature, the analogous enzyme is, however, intact. Nevertheless, there is pronounced genetic and phenotypical heterogeneity. 

Hepatomegaly increased hepatic glycogen stores probably X-linked, but there may be more than one type, with some autosomally inherited must be distinguished from glycogen phosphorylase deficiency. 

The answer is c. (Murray, pp 199-207. Scriver, pp 1521-1552. Sack, pp 121-138. Wilson, pp 287-317.) Muscle phosphorylase deficiency leads to a glycogen storage disease [McArdles disease (232600)] and, in young adults, an inability to do strenuous physical work because of muscular cramps resulting from ischemia. The compromised phosphorylation of muscle glycogen characteristic of McArdle s disease compels the muscles to rely on auxiliary energy sources such as free fatty acids and ambient glu-... 

In purine nucleoside phosphorylase deficiency, levels of purine nucleotides are high and synthesis of uric acid decreases. High levels of dGTP are apparently responsible for the impairment of T cells that is characteristic of this malady. 

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