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

Satoshi Sakaue,Shinya Osone,Toshihiko Imamura,Masanori Nakagawa,Masaya Suematsu,Masafumi Morimoto,Toshiki Mizuno,Takahiko Tokuda,Hajime Hosoi,Hitoshi Kanno,Yumiko Azuma,Takashi Kasai,Ikuko Mizuta,Omar M A El-Agnaf

doi:10.1038/s41531-017-0014-4

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.

Highlights

Phosphoglycerate kinase 1 (PGK-1) is a key enzyme in the glycolytic pathway and is encoded by PGK-1 (Online Mendelian Inheritance in Man (OMIM) #311800), which maps to the X chromosome and is expressed in all somatic tissues
We report a boy with PGK-1 deficiency and his mother, a heterozygous carrier of a PGK-1mutation, both of whom presented with early-onset parkinsonism
We previously reported that this patient was diagnosed with PGK-1 deficiency at 3 years of age based on decreased PGK activity in erythrocytes (16 IU/g Hb, normal: 255–325 IU/g Hb) and the novel PGK-1 missense mutation c.1060G > C; p.A354P.4 (Notably, this mutation was originally described as A353P, which indicates an amino-acid substitution at the 353rd position from the NH2-terminal serine residue.4)

Summary

Introduction

Phosphoglycerate kinase 1 (PGK-1) is a key enzyme in the glycolytic pathway and is encoded by PGK-1 (Online Mendelian Inheritance in Man (OMIM) #311800), which maps to the X chromosome and is expressed in all somatic tissues. We report a boy with PGK-1 deficiency and his mother, a heterozygous carrier of a PGK-1mutation, both of whom presented with early-onset parkinsonism. A 16-year-old boy with PGK-1 deficiency developed parkinsonism.

Results

Conclusion