Case study
Juvenile parkinsonism associated with heterozygous frameshift ATP13A2 gene mutation

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Abstract

We report a case of levodopa-responsive juvenile parkinsonism (JP) associated with a heterozygous ATP13A2 gene frameshift mutation. The clinical phenotype of our case is more severe when compared with other published reports of symptomatic heterozygous ATP13A2 mutation carriers. To our knowledge, this is the youngest reported patient with JP associated with a heterozygous ATP13A2 mutation. Our findings expand the clinical phenotypic spectrum of JP associated with heterozygous ATP13A2 mutation.

Introduction

Juvenile parkinsonism (JP) is a term used to describe patients with parkinsonism with an onset under 21 years of age, whereas early-onset parkinsonism (EOP) refers to those with a disease onset between ages 21 and 40 years.1, 2, 3 Mutations in recessively inherited genes are common causes of both JP and EOP.1, 4 In general, the younger the age of onset of parkinsonism, the more likely the patient has an inherited form of parkinsonism.4 The most common cause of inherited JP and EOP are genetic Parkin mutations located on Chromosome 6q.1, 5

The majority of levodopa-responsive JP patients without multi-systemic involvement are due to a genetic cause that follows an autosomal recessive (AR) mode of inheritance.1, 4 To date, 4 genes responsible for AR JP have been identified (Parkin/PARK2, PINK1/PARK6, DJ-1/PARK7 and ATP13A2/PARK9) 4, 6, 7. Interestingly all 4 of these genes are linked to mitochondrial dysfunction and oxidative stress suggesting a common pathway of pathogenesis.6

Homozygous or compound heterozygous ATP13A2 gene mutations have been shown to cause AR JP and EOP associated with atypical features including dementia, pyramidal degeneration or supranuclear gaze paresis (Kufor-Rakeb syndrome (KRS)).8, 9, 10, 11, 12 Recent publications have highlighted that JP and EOP patients with heterozygous mutations in the ATP13A2 gene have a milder clinical presentation compared with the typical clinical phenotype of KRS.13, 14, 15, 16 These studies expand the clinical heterogeneity associated with ATP13A2 mutations and suggest that heterozygous ATP13A2 mutations may be associated with JP and EOP.

Due to the phenotypic heterogeneity associated with ATP13A2 mutations, several authors have advocated screening for the ATP13A2 gene in patients with EOP and in levodopa-responsive JP particularly with pyramidal signs or clinical features of KRS 13, 17. We now describe a case report of levodopa-responsive JP without additional clinical features of KRS associated with a novel heterozygous frameshift (truncating) mutation in the ATP13A2 gene.

Section snippets

Case report

An 11-year old Lithuanian boy first presented at 6 years of age with a 1-year history of dysarthria, progressive upper limb postural tremor, dystonia of upper limbs associated with a diurnal variation. He did not have any systemic involvement. His symptoms resolved with levodopa (250 mg/day) treatment in Lithuania. At 7 years of age, the family then moved to UK and he was transferred to our care.

After 1½ years of good response to levodopa, he developed progressive motor fluctuations consisting

Discussion

To our knowledge, this is the youngest published case report of JP associated with a heterozygous mutation in the ATP13A2 gene. The [123I] SPECT scan in our patient showed marked symmetrical reduction of activity in lentiform nuclei bilaterally indicating presynaptic dopaminergic dysfunction in the nigrostriatal system. This is consistent with other published SPECT and PET findings in Parkin, PINK1 and homozygous ATP13A2 mutations.5, 14, 18

Homozygous or compound heterozygous ATP13A2 gene

Conclusion

Our findings expand the clinical phenotypic spectrum of JP associated with heterozygous ATP13A2 gene mutations. It suggests that heterozygous ATP13A2 mutations may be a significant factor in the development of JP. This needs to be explored further in large-scale studies. It also highlights that more widespread screening of all cases of levodopa-responsive JP is warranted. Further functional studies are necessary to clarify the pathogenicity of this mutation.

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