Lewy body pathology and typical Parkinson disease in a patient with a heterozygous (R275W) mutation in the Parkin Gene (PARK2)

There are only two reports of neuropathological findings in heterozygotes for Parkin (PARK2) mutation [3, 5]. One was a normal individual bearing an exon 3 deletion, who at autopsy (at age 93) revealed the absence of a-synuclein pathology and no neuronal depletion in the substantia nigra (SN). The other case carried a single point mutation (C212Y, exon 6) and had been affected by neuropathologically confirmed PSP. We here report a patient with a heterozygous Parkin mutation (R275W, on exon 7), clinical features of typical Parkinson’s disease and a neuropathological picture of diffuse Lewy body disease. This patient had two offspring with compound heterozygous (R275W and exon 3 deletion) Parkin mutations (Fig. 1), both of which were affected by early-onset PD ([6], family 48). To our knowledge, this is the first report of diffuse Lewy body pathology associated with clinically typical PD in a patient with a heterozygous Parkin mutation. A 62-year-old man presented with asymmetric fine motor impairment and rigidity, which were followed by resting tremor. There was good, sustained response to levodopa. Single photon emission computed tomography with Ioflupane (SPECT-DaTSCAN), performed 14 years from disease onset, showed severe reduction in tracer uptake in the corpora striata (Fig. 2a). Fifteen years after disease onset, the patient gradually became demented. This was confirmed by neuropsychological testing (MMSE 19/30; ADL 2; IADL 2), while neuroimaging at this time showed diffuse atrophy on brain MRI (Fig. 2b) and diffuse cortical and subcortical hypoperfusion on ECD-Tc99mSPECT. He died at the age of 80. At autopsy, macroscopic examination of the brain revealed bilateral depigmentation of the SN and locus