Brain Volume Abnormalities in Lesch-Nyhan Disease
Abstract & Commentary
By Sotirios Keros, MD, PhD
Instructor, Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medical College
Dr. Keros reports no financial relationships relevant to this field of study.
Synopsis: Subjects with Lesch-Nyhan disease and Lesch-Nyhan variant have significant reductions in brain size in the basal ganglia as well as several cortical areas.
Source: Schretlen DJ, et al. Regional brain volume abnormalities in Lesch-Nyhan disease and its variants: A cross-sectional study. Lancet Neurol 2013;12:1151-1158.
Lesch-nyhan disease is an x-linked recessive disorder caused by mutations that cause hypoactivity of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). This defect in HGPRT activity results in the overproduction of uric acid which then leads to hyperuricemia, tophi, and gout. Most children with the classic form of Lesch-Nyhan disease present in the first year of life with neurodevelopmental delays, and typically go on to develop mental retardation, self-injurious behaviors, and both pyramidal and extra-pyramidal motor disabilities such as dystonia, choreoathetosis, ballismus, dysarthria, hypotonia, and spasticity. Less severe mutations result in a Lesch-Nyhan "variant," which is notable for the absence of self-injury and is otherwise a less severe phenotype that correlates with enzyme activity.
The neurological symptoms in Lesch-Nyhan disease are diverse, and likely are a result of dysfunction in several different brain regions or circuits. Previous work has concentrated on the basal ganglia, revealing dysfunction of dopaminergic basal ganglia pathways. However, basal ganglia abnormalities do not fully explain the spectrum of symptoms seen in Lesch-Nyhan disease.
In this study, the authors used voxel based morphometry on brain MRIs obtained from subjects with classic Lesch-Nyhan disease (n = 21), Lesch-Nyhan variant (n = 17), and healthy controls (n = 33) using either a 1.5 tesla or 3.0 tesla MRI machine. The analysis was performed using the VBM8 toolkit of the SPM8 software package using manual alignment to the anterior commissure posterior commissure line. Diagnoses were confirmed with either fibroblast testing of HPRT enzyme activity or with genetic analysis of the HPRT1 gene. Subjects underwent examination by a specialist in movement disorders as well as cognitive testing by a neuropsychologist. Additionally, informants such as a family member or caregiver were asked to rate each subject's behavior, adaptive functioning, and personality.
Compared to healthy controls, those with Lesch-Nyhan disease had lower IQ scores (KBIT-2 score of 54 vs 112) and higher BFM dystonia scale ratings (73 vs. 1.4), while subjects with Lesch-Nyhan variant had intermediate values (KBIT-2 of 85; BFM of 24). The total brain volume of Lesch-Nyhan patients was 20% less than controls and 14% less in variant disease. Brain volume measurements in the classic disease, variant disease, and controls was (in cm3) 1003, 1077, and 1267, respectively. Grey matter volumes were 601, 611, and 724, while white matter volumes were 402, 466, and 543. In all cases, the disease group values were statistically significant with respect to controls. Total brain volume to total intracranial volume ratio was identical in all three groups.
Grey matter reductions were most prominent in the caudate, thalamus, and anterior putamen, with the general basal ganglia structures in classic Lesch-Nyhan approximately 75% as large as controls and 85% of controls for variant disease. However, significant reductions were also found in several cortical areas within the temporal and frontal lobes. These areas included the left and right dorsolateral prefrontal cortex, left inferior frontal gyrus, left and right orbital frontal cortex, right and left amygdala, right and left hippocampus, right and left parahippocampal gyrus, and left middle temporal gyrus. In addition, reductions were found in the anterior cingulate cortex and the cingulate gyrus. In all cases, the sizes of these structures in variant disease was intermediate between the classic form and controls. However, the primary regions where classic disease differed from variant disease were the cingulate gyrus, ventral striatum, and orbitofrontal cortex. No differences between any groups were seen in the parietal and occipital lobes. In addition, no brain regions were larger in Lesch-Nyhan patients compared to controls. Basal ganglia size was strongly correlated to dystonia severity in both classic and variant disease.
This study, which represents the largest analysis of brain volumes in Lesch-Nyhan disease, confirms that the effects of HPRT deficiency are not limited to the basal ganglia and nigrostriatal pathways and demonstrates abnormalities in areas previously not known to be affected. The fact that brain-to-intracranial volume ratios were similar also strongly implies that this disorder is developmental in nature rather than degenerative. It still remains unclear why certain structures and brain regions are affected while others are spared. Do all the observed affected structures depend on HPRT activity for optimum development? Or rather, perhaps only a subset of brain structures are directly affected by HPRT deficiency, and all connections to these structures also suffer, such that the collection of deficits observed reflect all the connections within the affected circuit.
The variant form of the disease exhibits less severe brain volume reductions than the classic form, and this is congruent with the intermediate phenotype seen in the variant form. However, one key distinction between the classic and variant form is the self-injurious behavior. As the authors point out, this study may give some clues as to the anatomic origin of this phenomenon. The greatest differences seen between the classic and variant form were in the cingulate, as well as the ventral striatum and orbitofrontal cortex. The cingulate is known for its involvement in negative emotions, such as fear and anxiety, while the ventral striatum orbitofrontal cortex pathway has previously been suspected to contribute to self-injury. This study further implicates these areas and will hopefully lead to advances in determining underlying anatomical structures involved in self-injury in Lesch-Nyhan and other neuropsychiatric diseases.