Early-onset parkinsonism in a pedigree with phosphoglycerate kinase deficiency and a heterozygous carrier: do PGK-1 mutations contribute to vulnerability to parkinsonism?

Abstract

Phosphoglycerate kinase 1 (PGK-1) is a glycolytic enzyme encoded by PGK-1, which maps to the X chromosome. PGK-1 deficiency causes X-linked recessive hereditary chronic hemolytic anemia, myopathy, and neurological disorders due to insufficient ATP regeneration. Early-onset parkinsonism has occasionally been reported as a neurological complication of this condition. However, heterozygous carriers of PGK-1 deficiency were thought to be neurologically asymptomatic. Here, we report a boy with PGK-1 deficiency and his mother, a carrier of a heterozygous mutation in PGK-1, both of whom presented with early-onset parkinsonism. The boy developed parkinsonism at 9 years of age. His parkinsonism partially responded to levodopa treatment. ¹²³l-metaiodobenzylguanidine (MIBG) uptake was normal. His mother, who exhibited normal PGK-1 activity in erythrocytes, developed parkinsonism at 36 years of age. Her symptoms were undistinguishable from those of Parkinson's disease (PD), despite her normal uptake of MIBG. Neither a point mutation in nor multiplication of SNCA was found. Additionally, hotspots of LRRK2 and GBA were not mutated. To our knowledge, this report provides the first description of parkinsonism in a carrier of PGK-1 deficiency. Interestingly, PGK-1 is located within the confirmed susceptibility locus for PD known as PARK12. These observations suggest that PGK-1 mutations confer susceptibility to PD.

Fig. 1

The patient’s pedigree is presented in accordance with standardized human pedigree nomenclature. Solid black indicates the phenotype of classical symptoms of PGK-1 deficiency (i.e., hemolytic anemia and myopathy). The checkerboard pattern indicates the phenotype of parkinsonism. Members with asterisks were neurologically examined by the authors. Cases 1 (III₁) and 2 (II₂) were also genetically and enzymatically examined. The results of genetic and enzymatic testing for PGK-1 are presented below these cases. X^mt and X⁺ indicate an allele with the c.1060G>C mutation and the wild-type allele on the X chromosome, respectively

Fig. 2

DAT images for case 1 (a) and case 2 (b) are presented. Both images reveal decreased DAT uptake in the striatum. Specific binding ratios were semiquantitatively calculated using DaT View software (Nihon Medi-Physics, Tokyo, Japan) based on Bolt’s method. The right and left specific binding ratios were 1.87 and 1.71, respectively, in (a) and 2.50 and 4.19, respectively, in (b). The reported cut-off value was 4.5.