Glycogen storage disease due to muscle phosphofructokinase deficiency
General Information (adopted from Orphanet):
Synonyms, Signs:
PFKM DEFICIENCY
MUSCLE PHOSPHOFRUCTOKINASE DEFICIENCY
GSD VII
GSD7
GSD due to muscle phosphofructokinase deficiency
GSD type 7
Glycogenosis type 7
Glycogenosis due to muscle phosphofructokinase deficiency
Glycogen storage disease type 7
tarui disease
Glycogen storage disease VII is an autosomal recessive metabolic disorder characterized clinically by exercise intolerance, muscle cramping, exertional myopathy, and compensated hemolysis. Myoglobinuria may also occur. The deficiency of the muscle isoform of PFK results in a total and ...Glycogen storage disease VII is an autosomal recessive metabolic disorder characterized clinically by exercise intolerance, muscle cramping, exertional myopathy, and compensated hemolysis. Myoglobinuria may also occur. The deficiency of the muscle isoform of PFK results in a total and partial loss of muscle and red cell PFK activity, respectively. Raben and Sherman (1995) noted that not all patients with GSD VII seek medical care because in some cases it is a relatively mild disorder
Tarui et al. (1965) first described this disorder in 3 affected Japanese sibs, a 20-year-old female and 23- and 27-year-old males. The parents were first cousins. The affected sibs complained of easy fatigability and inability to keep pace with ...Tarui et al. (1965) first described this disorder in 3 affected Japanese sibs, a 20-year-old female and 23- and 27-year-old males. The parents were first cousins. The affected sibs complained of easy fatigability and inability to keep pace with other persons. Physical examination revealed marked weakness and stiffness in muscle groups subjected to vigorous or prolonged exertion. Venous lactate failed to rise with the ischemic exercise test; 1 sib had myoglobinuria following the test. PFK activity was entirely absent in muscle and about half normal in erythrocytes. Layzer et al. (1967) reported an 18-year-old male with muscle PFK deficiency and red cell hemolysis. The erythrocytes of both unaffected parents showed partial enzyme activity. Layzer et al. (1967) suggested that red cell PFK is composed of 2 types of subunits, 1 of which is the sole subunit present in muscle PFK. The authors concluded that the genetic defect likely involves a subunit common to both the muscle and the red cell enzyme, and furthermore postulated autosomal recessive inheritance. Satoyoshi and Kowa (1967) described myopathy in 2 affected brothers. Family history revealed that myopathy was also present in a sister, their mother, and a son of 1 sister. Onset was about age 35 years with delayed muscle pain and stiffness on exertion, but absence of contracture or weakness on ischemic exercise. Phosphofructokinase activity was about 40% of normal in skeletal muscle. Oral ingestion of fructose relieved the symptoms. Satoyoshi and Kowa (1967) suggested the possible role of an inhibitor in the disease process. Waterbury and Frenkel (1972) found an intermediate level (60% of normal) of the PFK enzyme in the red cells of a physician with chronic compensated hemolysis and in his mother and grandmother who lacked evidence of hemolysis. The proband had 9% reticulocytes. PFK of the proband showed markedly increased lability on in vitro studies. The absence of muscle disease was atypical of the usual phenotype associated with type VII glycogen storage disease. Vora et al. (1980) studied a patient with the rare Tarui disease, in which myopathy and hemolysis are associated with PFK deficiency. The proband was a 31-year-old man who suffered from muscular weakness and myoglobinuria on exertion. He showed mild erythrocytosis despite laboratory evidence of hemolysis. His red cell PFK was exclusively of the L (liver) type (PFKL; 171860). Decreased production of 2,3-DPG was held responsible for the paradoxic erythrocytosis. Tani et al. (1983) studied 2 unrelated Japanese kindreds with PFKM deficiency associated with congenital nonspherocytic hemolytic anemia and mild myopathy. Both probands had jaundice, gallstones, and slight to moderate exercise intolerance. Both also had decreased red cell PFK activity and no increase of blood lactate during ischemic exercise testing. Electrophoresis of red cell PFK showed complete absence of the PFK muscle isozyme. Etiemble et al.(1976), Etiemble et al. (1980), Miwa et al. (1972), and Kahn et al. (1975) reported cases of hereditary nonspherocytic hemolytic anemia associated with partial erythrocyte phosphofructokinase deficiency (about 60% of normal). Although none of the patients had muscle symptoms, studies showed that the PFKM isoform was unstable. Vora et al. (1980) speculated that the heterogeneous group of hemolytic syndromes associated with partial red cell PFK deficiency without myopathy (Boulard et al., 1974; Kahn et al., 1975) may represent total absence of PFKL subunits or qualitative defects of M or L subunits. Vora et al. (1983) suggested that GSD VII could be classified clinically into 5 phenotypic subtypes: type I is the classic syndrome characterized by exertional myopathy and hemolysis; type II by isolated myopathy; type III by isolated hemolysis; and type IV by asymptomatic partial deficiency of red cell PFK. Type V could represent the rare progressive, fatal myopathy of infancy (see below). Hays et al. (1981) described muscle phosphofructokinase deficiency in a 61-year-old woman who had mild limb weakness all her life but no cramps or myoglobinuria. Limb weakness had worsened progressively in the previous 5 years. An abnormal polysaccharide was identified in muscle and thought to be related to a greatly elevated concentration of muscle glucose-6-phosphate, an activator of the chain-elongating enzyme glycogen synthase. Zanella et al. (1982) studied a 61-year-old man of northern Italian extraction, born of consanguineous parents, who had a lifelong intolerance for prolonged exercise and developed spontaneous muscle cramps. He also had intermittent mild jaundice from the age of 46: cholecystectomy was performed for gallstones at age 51, and, at age 54, he developed anemia and marked jaundice. Creatine phosphokinase levels were greatly increased. PFK activity was absent from muscle and was 39% of normal in red cells. Biochemical studies showed that the PFKM subunit was structurally abnormal and catalytically inactive. Vora et al. (1987) reported an 80-year-old man who presented with a 10-year history of progressive weakness of the legs as the only symptom. Residual red cell PFK showed the presence of a few M-containing isozymes in addition to the predominant L4 species, suggesting that the genetic lesion in this patient was a 'leaky' mutation of the gene coding for the M subunit. Danon et al. (1988) described a 75-year-old man with a 10-year history of slowly progressive limb weakness without cramps or myoglobinuria associated with PFKM deficiency. His asymptomatic daughter had 63% erythrocyte PFK activity. Argov et al. (1994) suggested that late-onset myopathy may represent a natural course of PFK deficiency rather than a separate nosologic entity because many patients give a history of easy fatigability and exercise intolerance since childhood. Tsujino et al. (1994) reported a 17-year-old Italian man who complained since childhood of myalgia and cramps after intense exercise. He had had no episodes of myoglobinuria. His red cell count and hemoglobin were normal, but he had reticulocytosis (6.1%), indicating compensated hemolysis. Muscle biopsy showed myopathic changes with subsarcolemmal glycogen accumulation. A brother was also affected. Nakagawa et al. (1995) and Hamaguchi et al. (1996) reported a 22-year-old Japanese man with a mild form of PFKM deficiency. He was brought to medical attention because of a gastric ulcer. While treated for the ulcer, he reported a history of mild fatigability and nausea and vomiting with strenuous exercise, and recurrent gouty arthritis, but no muscle pain, cramps, or dark urine. His parents were first cousins. Exercise testing resulted in increased serum creatine kinase, mild increase in serum lactate, and increased serum uric acid. Muscle studies showed almost complete absence of PFK activity and increased glycogen content. Molecular analysis identified a mutation in the PFKM gene (610681.0008). - Rapidly Progressive Fatal Infantile Form There are rare reports of a rapidly progressive fatal infantile form of PFKM deficiency. Servidei et al. (1986) reported an unusually severe case of PFKM deficiency. An affected girl had onset in infancy of limb weakness, seizures, cortical blindness, and corneal clouding, with death at age 7 months of respiratory failure. Amit et al. (1992) described a similar case of fatal infantile glycogen storage disease with multisystem manifestations in an infant girl born of consanguineous Bedouin parents. An older brother had suffered from similar weakness and cardiomyopathy; both sibs died at the age of 21 months. Phosphofructokinase activity was lacking in both liver and muscle. Amit et al. (1992) found reports of only 4 other cases (Danon et al., 1981) and 1 other family (Guibaud et al., 1978), and suggested that this multisystem form of phosphofructokinase deficiency may be related to the absence of an unknown activator common to all the PFK isozymes. Raben and Sherman (1995) noted that none of the patients with the rapidly progressive fatal infantile form of the disorder had evidence of hemolysis
In 1 of the original Japanese patients with glycogen storage disease type VII reported by Tarui et al. (1965), Nakajima et al. (1990) identified a homozygous mutation in the PFKM gene (610681.0001).
In 2 Ashkenazi Jewish sisters ...In 1 of the original Japanese patients with glycogen storage disease type VII reported by Tarui et al. (1965), Nakajima et al. (1990) identified a homozygous mutation in the PFKM gene (610681.0001). In 2 Ashkenazi Jewish sisters with GSD VII, Raben et al. (1993) identified a homozygous splice site mutation in the PFKM gene resulting in the deletion of exon 5 (610681.0005). Sherman et al. (1994) identified the exon 5 deletion mutation in 11 (61%) of 18 abnormal alleles in 9 Ashkenazi Jewish families with GSD VII, making it as the most common PFKM mutation in this population. In 4 Italian patients, including 2 brothers, with GSD VII, Tsujino et al. (1994) identified 3 novel mutations in the PFKM gene (610681.0002-610681.0004). The authors emphasized that these patients were not of Ashkenazi Jewish descent. Raben and Sherman (1995) tabulated 15 GSD VII disease-inducing mutations of the PFKM gene. In a 22-year-old Japanese man, born of consanguineous parents, with a mild form of GSD VII, Nakagawa et al. (1995) and Hamaguchi et al. (1996) identified a homozygous mutation in the PFKM gene (610681.0008)
Raben and Sherman (1995) tabulated 15 GSD VII disease-inducing mutations of the PFKM gene and noted that the disorder is especially prevalent among people of Ashkenazi Jewish descent. The authors found that the frequent exon 5 splicing defect (610681.0005) ...Raben and Sherman (1995) tabulated 15 GSD VII disease-inducing mutations of the PFKM gene and noted that the disorder is especially prevalent among people of Ashkenazi Jewish descent. The authors found that the frequent exon 5 splicing defect (610681.0005) accounted for approximately 68% of mutant alleles in Ashkenazim