Zimprich et al. (2003) sought to replicate the study of Le et al. (2003) by sequencing exon 1 of the NR4A2 gene in 44 cases of familial PD. All index patients, who were of Caucasian ethnicity and from central Europe, were diagnosed with PD according to United Kingdom brain bank criteria. The mean age at onset was 58 years. Family history was regarded as positive in all cases, since levodopa-responsive rest tremor and/or hypokinetic symptoms were reported in at least 1 first-degree relative. Of 44 cases, 14 had at least 1 affected sib and 30 showed a parent-child transmission. All patients were negative for a mutation in parkin ( 602544 ). Neither of the 2 NR4A2 mutations identified by Le et al. (2003) occurred in any of these patients. Zimprich et al. (2003) concluded that sequence alterations in exon 1 of the NR4A2 gene are not a major cause of familial PD in central Europe.
This would occur most likely through each cell shrinking in size in response to the energy deficit (and/or in extreme situations from some cells dying via either apoptosis or necrosis, depending on location).  This may occur as a result of there not being enough ATP to maintain cellular functions: notably failure of the Na/K ATPase, resulting in a loss of the gradient to drive the Na/Ca antiporter which normally keeps Ca +
2 out of cells so that it does not build to toxic levels that will rupture cell lysosomes leading to apoptosis. An additional feature of a low energy state is failure to maintain axonal transport via Dynein/Kinesin ATPases, which in many diseases results in neuronal injury to both the brain and/or periphery.