Loss of dopamine phenotype among midbrain neurons in Lesch-Nyhan disease

Lesch–Nyhan disease (LND) is an inherited disorder with a characteristic neurobehavioral phenotype that includes a movement disorder dominated by generalized dystonia, intellectual disability, and recurrent self-injurious behavior.1–4 The disorder is caused by mutations in the HPRT1 gene, leading to deficiency of the purine recycling enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt).5,6 The mechanisms by which HGprt deficiency leads to the neurological and behavioral problems are not well understood. However, there is strong evidence that they arise from dysfunction of basal ganglia circuits, and particularly dopaminergic pathways.7,8 Neurochemical studies of LND brains collected at autopsy have revealed 60 to 80% loss of dopamine throughout the basal ganglia.9–11 Positron emission tomography studies have demonstrated similar reductions of dopamine transporters and dopamine uptake.12,13 These studies have led to suggestions that dopamine neurons or their axonal projections are damaged.9,13 However, several histopathological studies of autopsied brains have not revealed any consistent loss of neurons in the substantia nigra.1,11,14 The reason for profound loss of dopamine-related measures with apparently preserved nigral dopamine neurons has never been established. Dysfunction of dopaminergic pathways also is observed in animal and cell models of HGprt deficiency.15 The HGprt knockout (HGprt−) mouse model has a 30 to 60% loss of striatal dopamine and associated biochemical markers such as homovanillic acid, dihydroxyphenylacetic acid, tyrosine hydroxylase (TH), aromatic amino acid decarboxylase, and dopamine transporters.16–18 However, quantitative stereological studies of these mutant mice have revealed no loss of midbrain dopamine neurons or their axonal projections.19 Several HGprt-deficient cell models also have shown loss of dopaminergic markers with no apparent loss of viability.20–25 In these cell models, mRNA expression profiling has revealed broad disruption of the neurotransmitter phenotype. These findings from cell and animal models have led to suggestions that HGprt deficiency disrupts early developmental programs that lead to the expression of the dopaminergic neurochemical phenotype. This hypothesis was explored in the current studies by examining the integrity of midbrain dopamine neurons in the brains of 5 LND brains collected at autopsy. Key findings were confirmed in the HGprt− mouse model19 and the MN9D cell model21 of HGprt deficiency.