Additional clinical features specific for the INAD/NBIA phenotypic spectrum include cerebellar atrophy and iron accumulation in the globus pallidus, both of which can be observed on magnetic resonance imaging of the brain. In contrast, dystonia-parkinsonism Nutlin-3 Mdm2 inhibitor begins primarily as a movement disorder in the age range of 15–30 years old, and is further distinguished from NBIA/INAD by the absence of cerebellar atrophy and iron accumulation. A combination of dystonia and parkinsonism are the common presenting features, and similar to idiopathic PD, the parkinsonism is responsive to levodopa or a dopamine receptor agonist. Cognitive impairment is observed with disease progression. The PLA2G6 gene encodes group VIA calcium-independent phospholipase A2 also known as calcium-independent phospholipase A2 beta. The enzyme was originally identified in Chinese hamster ovary cells based on its ability to hydrolyze the sn-2 acyl groups of phospholipids, producing free fatty acids and lysophospholipids. Morgan et al originally mapped a gene locus containing PLA2G6 in multiple families with autosomal recessive inheritance of INAD or NBIA. Sequencing of the PLA2G6 gene in INAD and NBIA revealed a total of 44 unique mutations associated with disease. In all but one case in which PLA2G6 mutations were detected, mutations were present in both alleles, indicating that disease is caused by loss of function rather than a dominant gain of function. In some INAD/NBIA cases, both alleles were affected by early frame shift and stop codon mutations, suggesting a complete loss of protein function. However the majority of disease-associated mutations cause missense single amino acid substitutions. Subsequent studies identified PLA2G6 mutations in patients with dystonia-parkinsonism. Paisan-Ruiz et al identified regions of homozygosity on chromosome 22 in two families with dystoniaparkinsonism. Sequencing of genes in this region revealed missense mutations in PLA2G6, causing amino acid substitutions R741Q in one family and R747W in the other. In each case, affected patients were homozygous for the missense mutation in PLA2G6. A third missense mutation in PLA2G6, causing amino acid substitution R632W has been identified in association with dystonia-parkinsonism in 3 siblings. The three affected siblings in this family were homozygous for the missense mutation, while 3 unaffected siblings and parents were heterozygotes. Interestingly, the R632W mutation has been identified on one allele in an INAD patient with compound heterozygous mutations in PLA2G6. Distinct phenotypes associated with mutations in the same gene may result from the influence of additional genetic and environmental factors. Alternatively, individual PLA2G6 mutations may primarily determine phenotype through distinct effects on protein function, causing either different degrees of impairment in a single function, or perhaps affecting different functions of the same protein. To examine the hypothesis that disparate phenotypes are determined primarily by distinct effects of mutations on PLA2G6 enzyme function.