ABSTRACT
BACKGROUND: Lesch-Nyhan disease is a rare, X-linked, neurodevelopmental metabolic disorder that is caused by abnormalities in the levels of hypoxanthine-guanine phosphoribosyltransferase enzyme activity. The neural substrates associated with Lesch-Nyhan disease remain poorly understood. We aimed to use voxel-based morphometry to identify affected brain regions in classic Lesch-Nyhan disease and Lesch-Nyhan variant disease, and to identify regions that differ between the two disease types. METHODS: In this cross-sectional study, we recruited patients with classic Lesch-Nyhan disease or Lesch-Nyhan variant disease from clinics, referrals, the Lesch-Nyhan Syndrome Registry, and the Matheny School and Hospital (Peapack, NJ, USA), and healthy controls from the Baltimore metropolitan area (MD, USA). We used voxel-based morphometry to analyse grey matter volume between groups using a three-group ANCOVA, followed by six pairwise post-hoc group comparisons. FINDINGS: Between Oct 3, 1993, and April 29, 2013, we recruited 21 patients with classic Lesch-Nyhan disease, 17 patients with variant disease, and 33 healthy controls. Patients with classic Lesch-Nyhan disease had a 20% reduction in intracranial volume (17% reduction in grey matter volume; 26% reduction in white matter volume) compared with healthy adults. The largest differences were in basal ganglia, and frontotemporal and limbic regions, with sparing of parieto-occipital regions. Grey matter volumes of patients with Lesch-Nyhan variant disease were invariably between those of patients with classic Lesch-Nyhan disease and healthy controls. Compared with healthy controls, patients with classic disease showed additional grey matter volume reductions in the temporal lobe and left lateralised structures, and patients with variant disease showed additional reductions in lingual and precuneus regions with sparing of right frontal and temporal regions. Patients with classic disease had reductions of volume in the ventral striatum and prefrontal areas compared with those with the variant form. INTERPRETATION: We noted regional abnormalities associated with known neurological and behavioural deficits in patients with classic Lesch-Nyhan disease. Patients with Lesch-Nyhan variant disease show milder grey matter abnormalities in many of the same brain regions and preservation of grey matter volume in other regions, which could provide important clues to the neural substrates of differences between the phenotypes. FUNDING: National Institute of Child Health and Human Development, Therapeutic Cognitive Neuroscience Fund, and Benjamin and Adith Miller Family Endowment on Aging, Alzheimer's and Autism Research.
Subject(s)
Brain/pathology , Lesch-Nyhan Syndrome/pathology , Adolescent , Adult , Basal Ganglia/pathology , Cerebral Cortex/pathology , Cross-Sectional Studies , Female , Humans , Lesch-Nyhan Syndrome/classification , Magnetic Resonance Imaging , Male , Middle Aged , Organ Size , Phenotype , Young AdultABSTRACT
La deficiencia de HPRT es un trastorno que se hereda ligado al cromosoma X y se caracteriza por producción excesiva de ácido úrico y alteraciones neurológicas variables. La deficiencia completa de HPRT se denomina síndrome de Lesch-Nyhan y se manifiesta por coreatetosis, espasticidad, retraso mental y automutilación. En otros pacientes con déficit de HPRT la deficiencia parece ser parcial y los síntomas neurológicos pueden variar de ausentes a severos (síndrome de Kelley-Seegmiller). La deficiencia de HPRT se clasifica en dos grupos síndrome de Lesch-Nyhan y síndrome de Kelley-Seegmiller, pero esta clasificación es confusa. Nosotros hemos analizado nuestra experiencia con 22 pacientes con déficit de HPRT pertenecientes a 18 familias españolas diagnosticados en el Hospital La Paz de Madrid en los últimos 16 años. Los estudios clínicos, bioquímicos, enzimáticos y moleculares realizados en estos pacientes nos han permitido delinear una nueva clasificación de la deficiencia de HPRT. Esta clasificación según un espectro continuo puede ser de utilidad para un mejor conocimiento de la enfermedad (AU)
Subject(s)
Female , Male , Child , Humans , Lesch-Nyhan Syndrome/classification , Hypoxanthine Phosphoribosyltransferase/deficiency , Lesch-Nyhan Syndrome/diagnosisABSTRACT
In humans, mutations in the gene encoding the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) are associated with a spectrum of disease that ranges from hyperuricemia alone to hyperuricemia with profound neurological and behavioral dysfunction. Previous attempts to correlate different types or locations of mutations with different elements of the disease phenotype have been limited by the relatively small numbers of available cases. The current article describes the molecular genetic basis for 75 new cases of HPRT deficiency, reviews 196 previously reported cases, and summarizes four main conclusions that may be derived from the entire database of 271 mutations. First, the mutations associated with human disease appear dispersed throughout the hprt gene, with some sites appearing to represent relative mutational hot spots. Second, genotype-phenotype correlations provide no indication that specific disease features associate with specific mutation locations. Third, cases with less severe clinical manifestations typically have mutations that are predicted to permit some degree of residual enzyme function. Fourth, the nature of the mutation provides only a rough guide for predicting phenotypic severity. Though mutation analysis does not provide precise information for predicting disease severity, it continues to provide a valuable tool for genetic counseling in terms of confirmation of diagnoses, for identifying potential carriers, and for prenatal diagnosis.
Subject(s)
Hypoxanthine Phosphoribosyltransferase/genetics , Mutation , Amino Acid Substitution , Cells, Cultured , Codon/genetics , DNA Mutational Analysis , DNA, Complementary/genetics , Exons/genetics , Fibroblasts/enzymology , Genotype , Gout/classification , Gout/diagnosis , Gout/enzymology , Gout/genetics , Humans , Hypoxanthine Phosphoribosyltransferase/deficiency , Kinetics , Lesch-Nyhan Syndrome/classification , Lesch-Nyhan Syndrome/diagnosis , Lesch-Nyhan Syndrome/enzymology , Lesch-Nyhan Syndrome/genetics , Lymphocytes/enzymology , Phenotype , Point Mutation , Severity of Illness Index , Syndrome , Terminology as Topic , Uric Acid/bloodABSTRACT
El síndrome de Lesch-Nyhan es una enfermedad genética ligada al cromosoma X, originada por un defecto en el gen que codifica la hipoxantia guanina fosforribosiltransferasa (HGPRT). Esta enzima participa en la recuperación de la guanina e hipoxantina. La deficiencia enzemática conlleva una acumulación exagerada del ácido úrico. La deficiencia total o casi total de la enzima, produce el síndrome de Lesch-Nyhan, el cual se caracteriza por hiperruricemia, hiperaciduria, coreoatetosis, hiperreflexia, retardo mental y autoagresividad. La deficiencia parcial de la enzima ocasiona artritis gotosa y nefrolitiasis sin daño neurológico.
