Clinical and Biochemical Analysis of Glutamate-Cysteine Ligase Deficiency Presented with Late-Onset Spinocerebellar Ataxia and Hemolytic Anemia.

INTRODUCTION

Glutamate-cysteine ligase catalytic subunit (GCLC), previously known as gamma-glutamyl-cysteine synthetase, is an essential rate-limiting step in glutathione synthesis. Glutathione modulates multitudes of critical cellular processes and scavenges free radicals. Its deficiency is reported to cause hemolysis of variable severity and is a rare cause of neurological abnormalities such as spinocerebellar ataxia.

CLINICAL PRESENTATION

We report a 55-year-old female patient with progressive late-onset ataxia, lower limb spasticity, and chronic hemolytic anemia found to have a GCLC pathogenic variant and low glutathione level. Magnetic resonance imaging of the head and cervical spine showed global cerebellar atrophy with widened folia and decreased diameter of the upper cervical spine. Blood workup revealed hemolytic anemia with genetic testing confirmed a homozygous variant, c.514 T>A in exon 4 of the GCLC gene, resulting in Ser172Thr (TCC>ACC). Management encompassed a multidisciplinary approach with a trial of high-dose alpha-lipoic acid, glutathione supplement, and physical therapy.

CONCLUSIONS

GCLC deficiency manifesting with hemolysis has been reported in 12 cases worldwide from 6 independent families, with only 4 cases having additional neurological manifestations. To date, no specific GCLC gene mutation has been attributed to the reported neurological constellation of symptoms. To the best of our knowledge, this is the first case report of late-onset spinocerebellar degeneration as a manifestation of c.514T>A (p. S172T) GCLC pathological variant genetic mutation.