Enzyme activity and brain anatomy: lessons from HPRT deficiency.

Lesch-Nyhan disease is a rare, X-linked disorder, related to defi ciency of the purine salvage enzyme hypoxanthineguanine phosphoribosyltransferase (HPRT). In addition to uric acid overproduction, HPRT defi ciency aff ects motor and cognitive function and is associated with behavioural disturbances caused by unknown pathophysiological changes. Since it was fi rst described, it has been known that one of the most conspicuous manifestations of Lesch-Nyhan disease is self-injurious behaviour, which manifests between 18 months and 13 years of age, causing severe lesions, mainly on the lips, tongue, and fi ngers. This behaviour is of an obsessive-compulsive nature and is not present in patients with partial HPRT defi ciency (those with Lesch-Nyhan variant disease). Diff erences between patients with the classic Lesch-Nyhan disease phenotype and Lesch-Nyhan variant disease might help to elucidate the pathophysiological changes behind the neurological manifestations, including self-injurious behaviour. In The Lancet Neurology, David Schretlen and colleagues report results of their study of regional brain abnormalities in Lesch-Nyhan disease and its variants to identify aff ected brain regions and regions that diff er between the two disease forms. Previous autopsy and imaging studies have focused on the basal ganglia because the main clinical manifestations implicate basal ganglia dysfunction. Various results have been reported, including decreased dopamine concentrations, a mean 17% reduction of total cerebral volume, and reduced basal ganglia volume. However, the brain structure in patients with HPRT defi ciency has not been fully described. Schretlen and colleagues report for the fi rst time brain regional volumes, examined by voxel-based morphometry, in a complete range of HPRT-defi cient patients (21 with classic Lesch-Nyhan disease and 17 with Lesch-Nyhan variant disease). Since 1995, voxel-based morphometry has been used to defi ne structural patterns of brain damage in patients with movement disorders. The results of Schretlen and colleagues’ study show a mean 20% decrease in intracranial volumes (17% in grey matter and 26% in white matter) in patients with classic Lesch-Nyhan disease compared with healthy controls, and a mean 14% reduction (16% in grey matter and 14% in white matter) in patients with Lesch-Nyhan variant disease, which directly correlated with the severity of the clinical manifestations. Detailed anatomical brain regional analysis showed not only basal ganglia reductions, but also reductions in other connecting cortical and subcortical cerebral regions, such as limbic and frontotemporal structures, without aff ecting the occipital and parietal cortical areas. Unfortunately, no anatomical lesions could clearly distinguish patients with classic disease from those with the variant form. These fi ndings suggest that the clinical manifestations related to HPRT defi ciency are associated with specifi c anatomical modifi cations that might be related to impaired brain development. The neurological indications of HPRT defi ciency have been associated with dopaminergic system impairment. However, the extensive neuroanatomical abnormalities shown by Schretlen and colleagues cannot be explained by an isolated nigrostriatal dopamine pathway disturbance; other neurotransmitters, such as serotonin or adenosine, might also be pathogenic. This result renders a crucial unanswered question: what is the relation between HPRT defi ciency and regional brain volume reduction? The results of this study provide insight into this association. First, the investigators present new information for enhanced assessment of the neuroanatomical phenotype in patients with HPRT defi ciency. Since 1984, we have diagnosed 45 patients with HPRT defi ciency (32 [70%] of whom had classic Lesch-Nyhan disease). Most of these patients presented before their fi rst birthday with reddish sandy urine, hyperuricaemia, or neurodevelopmental retardation. Some patients had a normal HPRT1 coding region but decreased HPRT1 mRNA expression of unknown cause. To the parent of such a patient, we could not readily answer questions such as: “Will my son bite himself?” The considerable overlap in grey matter reduction between classic and variant Lesch-Nyhan disease does not allow these disease types to be distinguished. However, the comparison of aff ected brain regions in both groups in this study showed several areas, including the posterior cingulate, the ventral striatum, Published Online October 24, 2013 http://dx.doi.org/10.1016/ S1474-4422(13)70247-3