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.

Phosphoglycerate kinase deficiency: A nationwide multicenter retrospective study

“…When considering our series of patients with PGK deficiency, we found that the disease had a childhood‐onset and that enzymatic activity was markedly decreased (2.0%‐3.6% of lowest control value) in all cases (Table ). These results are in accordance with other published cases . It has been suggested that early‐onset and the remarkably low (usually <10% of normal) PGK activity observed in almost all patients are the results of a majority of PGK1 mutations heavily impairing thermal stability and, to a different extent, catalytic properties of the enzyme …”

“…Why is parkinsonism so frequently observed in PGK deficiency? It has been hypothesized that PGK1 ‐related parkinsonism may be the result of insufficient ATP regeneration in the substantia nigra resulting from low levels of PGK activity . Also, as the PGK1 gene lies within Xq21.1, a region that is known as a susceptibility locus for classical Parkinson's disease (PD) associated with PARK12 (OMIM #300557), it has been hypothesized that mutations in PGK1 may contribute to the pathogenesis of PARK12‐associated PD .…”

“…PGK deficiency was initially described as a rare cause of hereditary nonspherocytic hemolytic anemia (NSHA), but it is now recognized as a glycogenosis involving skeletal muscle and central nervous system (CNS) . Two main clinical pictures have been described: a syndrome characterized by NSHA and CNS involvement ‐including seizures, mental retardation, stroke, and parkinsonism‐; and a purely myopathic syndrome with exercise intolerance, cramps, and recurrent myoglobinuria . How such different clinical manifestations are caused by mutations in the same gene is unclear, although it was recently suggested that the level of impaired glycolysis in PGK deficiency was a major determinant of phenotype .…”

“…How such different clinical manifestations are caused by mutations in the same gene is unclear, although it was recently suggested that the level of impaired glycolysis in PGK deficiency was a major determinant of phenotype . Less than 50 patients with PGK deficiency have been described worldwide, including approximately 43 patients characterized at the molecular level . The variable phenotype in PGK deficiency is difficult to investigate because of the rarity of the condition, with almost only single‐family cases reported so far …”

A novel <i>PGK1</i> mutation associated with neurological dysfunction and the absence of episodes of hemolytic anemia or myoglobinuria

“…Recently, a PGK heterozygous carrier mother was reported to show parkinsonism, although she showed normal PKG activity (31). In the future, the disease characteristics associated with PGK1 mutations may expand as more patients with similar CNS symptoms are identified.…”