Phosphoglycerate Kinase 1 Deficiency

A number sign (#) is used with this entry because phosphoglycerate kinase-1 deficiency is caused by mutation in the PGK1 gene (311800).

Description

Phosphoglycerate kinase-1 deficiency is an X-linked recessive condition with a highly variable clinical phenotype that includes hemolytic anemia, myopathy, and neurologic involvement. Patients can express 1, 2, or all 3 of these manifestations (Shirakawa et al., 2006).

Clinical Features

Kraus et al. (1968) attributed lifelong anemia in a 63-year-old Caucasian woman to deficiency of red cell phosphoglycerate kinase. Although no relatives were available for study, the proband's mother and 2 of her sibs had a history of anemia. Valentine et al. (1969) found hemolytic anemia with deficient red and white cell phosphoglycerate kinase in a large Chinese kindred. Mild hemolysis was present in presumed heterozygotes.

Guis et al. (1987) reported a boy with hemolytic anemia but no neuromuscular manifestations who was found to have a PGK variant termed 'San Francisco.' The anemia was severe and partially transfusion dependent. Guis et al. (1987) suggested that unusual stability of the mutant enzyme and a continuing ability to synthesize at least limited amounts of enzyme had protected nonerythroid tissues. In contrast, mature red cells, lacking the ability to synthesize new proteins, had a severely compromised life span.

Rosa et al. (1982) reported a man with episodes of rhabdomyolysis and acute renal failure who did not have hemolysis. He had a severe deficiency of PGK in muscle, white blood cells, red blood cells, and platelets. His mother and 2 daughters had a partial enzyme defect in red blood cells, suggesting X-linked recessive transmission. DiMauro et al. (1983) reported a 14-year-old boy with recurrent myoglobinuria and renal failure after intense exercise. Muscle PGK activity was 5% of normal values in the patient and was decreased in his mother but normal in his father.

Tonin et al. (1993) reported a 37-year-old man with exercise intolerance, myalgia, recurrent myoglobinuria, and retinitis pigmentosa who had decreased PGK activity.

Sugie et al. (1994) demonstrated PGK deficiency in 3 unrelated men who presented with myoglobinuria. All 3 were mentally retarded, and 2 had epilepsy. The patient who did not have epilepsy was the only one of the 3 who showed any hemolytic anemia. Sugie et al. (1994) noted that organ-specific isozymes or posttranslational modification are not the explanation for the variable involvement of hematopoietic, muscle and nervous tissue since enzymes derived from different tissues in the same individual do not differ in physical and biochemical characteristics. The variable clinical features of the disease were thought to be the consequence of the unique biochemical properties of the individual PGK mutants.

Noel et al. (2005) reported 2 unrelated boys of Spanish origin with PGK1 deficiency. At the age of 2 years, the first child was hospitalized for a febrile episode associated with severe anemia and jaundice, for which exchange transfusion was given. Subsequently, several similar hemolytic crises occurred, mainly due to viral infections, and exchange transfusion was required on 2 occasions. Due to the persistence of the microcytosis, a molecular study for thalassemia was performed, leading to the secondary diagnosis of heterozygosity for the alpha(-3.7) mutation. At 7 years of age the hemolytic crises were associated with a progressive neurologic impairment leading to mental deterioration. No muscular dystrophy could be demonstrated. The second child, who was from Murcia, had required blood transfusions from birth every 3 to 4 weeks for hemolytic anemia. The diagnosis of PGK deficiency was made when he was 6 years old. An older sister and younger brother were healthy and the mother had a history of 2 previous abortions. Accordingly, the patient's mother had been strictly monitored during the antenatal period because of the risk of abortion at the tenth week of gestation, and the patient was delivered by cesarean section. There was severe neonatal anemia, hyperbilirubinemia, hepatosplenomegaly, and purpura requiring intensive care. At 2 years of age, the patient was hospitalized due to a hemolytic crisis in association with severe encephalopathy without environmental cause, spastic tetraparesis, and psychomotor delay. The anemia was associated with severe and progressive encephalopathy with cortical and subcortical atrophy verified by cranial CT, and epileptic crises. He died of severe encephalopathy at 7 years of age.

Flanagan et al. (2006) reported 2 boys of a white American family with PGK1 deficiency who presented with hemolytic anemia, seizures, and developmental delay. One of the boys also had hemiplegic migraines, retinal dystrophy, and muscle fatigue after exertion. Erythrocyte PGK enzyme activity was less than 5% of normal. Genetic analysis identified a mutation in the PGK1 gene (311800.0013).

Shirakawa et al. (2006) reported a 33-year-old Japanese man with PGK1 deficiency manifesting as mental retardation and exertional myopathy, but without hemolytic anemia. He also had short stature, high-arched palate, and brachydactyly. Laboratory studies showed no evidence of hemolytic anemia, but serum creatine kinase and myoglobin were increased. PGK1 activity was 9.0% and 13.6% of control values in muscle and red blood cells, respectively. PGK1 activity in red blood cells of his mother was 60.7%.

Spiegel et al. (2009) reported an 18-year-old man of Arab Bedouin descent with PGK1 deficiency confirmed by genetic analysis (T378P; 311800.0015). He had a purely myopathic phenotype, with onset of muscle cramps and exercise-induced pigmenturia at age 7 years. He had no evidence of hemolytic anemia or neurologic involvement; serum creatine kinase was increased. Biochemical studies showed decreased PGK1 activity in muscle (0.9% of control values) and erythrocytes (1.6%). The patient's unaffected mother and 2 sisters were heterozygous for the mutation.

Molecular Genetics

In a patient with chronic hemolytic anemia associated with deficiency of PGK activity, Fujii and Yoshida (1980) used peptide mapping analysis to identify an R206P substitution (311800.0002) in the PGK1 protein.

In a 27-year-old Japanese male with PGK1 deficiency, Fujii et al. (1992) identified a mutation in the PGK1 gene (311800.0006). The patient had chronic hemolytic anemia and myoglobinuria, manifested by nausea, anorexia, and muscle weakness after exercise, beginning at the age of 10. There was no family history of anemia or neuromuscular disease.

In affected members of the Chinese family reported by Valentine et al. (1969), Turner et al. (1995) identified a mutation in the PGK1 gene (311800.0013).

In a patient with PGK1 deficiency manifest as myopathy (Sugie et al., 1989), Sugie et al. (1998) identified a mutation in the PGK1 gene (311800.0009).

In 2 unrelated patients of Spanish origin with PGK1 deficiency manifest as severe lifelong chronic hemolytic anemia and progressive neurologic impairment, Noel et al. (2005) identified 2 different mutations in the PGK1 gene (311800.0011 and 311800.0012, respectively).

In a Japanese man with PGK1 deficiency, Shirakawa et al. (2006) identified a mutation in the PGK1 gene (311800.0014). He had mental retardation and recurrent myoglobinuria, but no hemolytic anemia.