Very Early Levodopa May Prevent Self-Injury in Lesch-Nyhan Disease.

Background: In Lesch-Nyhan disease (LND), early dopamine deficiency is thought to contribute to dystonia and self-injury, gradually developing over the first years of life. Previous attempts to restore dopamine levels in older patients have been unsuccessful. Based on the hypothesis that very early dopamine replacement can prevent full phenotypic development, we treated three patients with LND from infancy with levodopa.

Abnormalities of neural stem cells in Lesch-Nyhan disease.

Lesch-Nyhan disease (LND) is a neurodevelopmental disorder caused by variants in the gene, which encodes the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGprt). HGprt deficiency provokes numerous metabolic changes which vary among different cell types, making it unclear which changes are most relevant for abnormal neural development. To begin to elucidate the consequences of HGprt deficiency for developing human neurons, neural stem cells (NSCs) were prepared from 6 induced pluripotent stem cell (iPSC) lines from individuals with LND and compared to 6 normal healthy controls.

Induced pluripotent stem cells from subjects with Lesch-Nyhan disease.

Lesch-Nyhan disease (LND) is an inherited disorder caused by pathogenic variants in the HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt). We generated 6 induced pluripotent stem cell (iPSC) lines from 3 individuals with LND, along with 6 control lines from 3 normal individuals. All 12 lines had the characteristics of pluripotent stem cells, as assessed by immunostaining for pluripotency markers, expression of pluripotency genes, and differentiation into the 3 primary germ cell layers.

Deep brain stimulation in Lesch-Nyhan disease: outcomes from the patient's perspective.

Aim: To provide insight into outcome and long-term safety and efficacy of deep brain stimulation (DBS), from the perspective of individuals with Lesch-Nyhan disease (LND) and their families.

Method: We used patient-centered outcome measures to assess long-term outcomes of DBS for 14 individuals (mean [SD] age 10y 10mo [5y 6mo], range 5-23y, all males) with LND, after an average duration of 5y 6mo (range 11mo-10y 5mo) after surgery. We compared these results with a comprehensive review of previously published cases.

Physical Exercise Modulates L-DOPA-Regulated Molecular Pathways in the MPTP Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), resulting in motor and non-motor dysfunction. Physical exercise improves these symptoms in PD patients. To explore the molecular mechanisms underlying the beneficial effects of physical exercise, we exposed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP)-treated mice to a four-week physical exercise regimen, and subsequently explored their motor performance and the transcriptome of multiple PD-linked brain areas.

Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity.

Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature.

Validity of the MPTP-Treated Mouse as a Model for Parkinson's Disease.

Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron death in the substantia nigra (SN) and subsequent striatal adaptations. Mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) are widely used as a model for PD. To assess the validity of the MPTP mouse model for PD pathogenesis, we here identify the biological processes that are dysregulated in both human PD and MPTP-treated mice.

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

Objective: Lesch-Nyhan disease (LND) is caused by congenital deficiency of the purine recycling enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). Affected patients have a peculiar neurobehavioral syndrome linked with reductions of dopamine in the basal ganglia. The purpose of the current studies was to determine the anatomical basis for the reduced dopamine in human brain specimens collected at autopsy.

Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder.

Establishing meaningful relationships between genetic variations and clinical disease is a fundamental goal for all human genetic disorders. However, these genotype-phenotype correlations remain incompletely characterized and sometimes conflicting for many diseases. Lesch-Nyhan disease is an X-linked recessive disorder that is caused by a wide variety of mutations in the HPRT1 gene.

Levodopa is not a useful treatment for Lesch-Nyhan disease.

Lesch-Nyhan disease (LND) is characterized by dystonia, cognitive abnormalities, and self-injurious behavior. No effective therapies are available. LND is associated with a presynaptic dopaminergic deficit, but the reported effects of dopamine replacement therapy are conflicting.

Attenuated variants of Lesch-Nyhan disease.

Lesch-Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild.

Parkinson disease and comorbid cerebrovascular disease.

Optimal management of chronic diseases not only requires tackling of the primary disease processes, but also necessitates timely recognition and treatment of comorbid conditions. In this article, we illustrate this two-pronged approach for two common age-related disorders: Parkinson disease (PD) and cerebrovascular disease (CVD). We first discuss the pathophysiological mechanisms that could provide a link between PD and CVD.

The clinical utility of posturography.

Postural instability and falls are common and devastating features of ageing and many neurological, visual, vestibular or orthopedic disorders. Current management of these problems is hampered by the subjective and variable nature of the available clinical balance measures. In this narrative review, we discuss the clinical utility of posturography as a more objective and quantitative measure of balance and postural instability, focusing on several areas where clinicians presently experience the greatest difficulties in managing their patients: (a) to make an appropriate differential diagnosis in patients presenting with falls or balance impairment; (b) to reliably identify those subjects who are at risk of falling; (c) to objectively and quantitatively document the outcome of therapeutic interventions; and (d) to gain a better pathophysiological understanding of postural instability and falls, as a basis for the development of improved treatment strategies to prevent falling.

Subthalamic nucleus stimulation and levodopa-resistant postural instability in Parkinson's disease.

We examined the effect of bilateral subthalamic nucleus stimulation on levodopa-resistant balance impairment in 14 patients with Parkinson's disease and 18 matched controls. Instability was quantitatively assessed using standardized multidirectional dynamic posturography. Patients were tested after taking a suprathreshold dose of levodopa, both with stimulators turned on and off.

Quantification of trunk rotations during turning and walking in Parkinson's disease.

Objective: To develop a reliable, objective and sensitive measure of axial trunk rotations in PD, which can be applied in an ambulatory setting.

Methods: To quantify turning motion, two angular velocity transducers attached to the lower back measured angular velocity of the trunk in the yaw plane (i.e.

PRKCG mutation (SCA-14) causing a Ramsay Hunt phenotype.

Progressive myoclonic ataxia, also referred to as Ramsay Hunt syndrome, is characterized by a combination of myoclonus and cerebellar ataxia, infrequently accompanied by tonic-clonic seizures. Its differential diagnosis overlaps with progressive myoclonic epilepsy, a syndrome with myoclonus, tonic-clonic seizures, progressive ataxia and dementia. In patients with progressive myoclonic epilepsy, specific diseases can frequently be recognized, but the diagnostic yield in progressive myoclonic ataxia is much lower.

Postural responses to multidirectional stance perturbations in cerebellar ataxia.

Previous studies of patients with focal cerebellar damage underscored the importance of the cerebellum for balance control. These studies were restricted to postural control in the pitch plane, and focused mainly on leg muscle responses. Here, we examined the effect of degenerative cerebellar lesions on postural control in multiple directions, and studied how such lesions affect intersegmental coordination of the legs, trunk and arms.

Delineation of the motor disorder of Lesch-Nyhan disease.

Lesch-Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Affected individuals exhibit over-production of uric acid, along with a characteristic neurobehavioural syndrome that includes mental retardation, recurrent self-injurious behaviour and motor disability. Prior studies involving relatively small numbers of patients have provided different conclusions on the nature of the motor disorder.

Role of the basal ganglia in balance control.

In this review paper, we summarize the important contributions of the basal ganglia to the regulation of postural control. After a brief overview of basal ganglia circuitries, the emphasis is on clinical observations in patients with focal lesions in parts of the basal ganglia, as the impairments seen here can serve to highlight the normal functions of the basal ganglia nuclei in postural control. Two particularly relevant functions are discussed in detail: first, the contribution of the basal ganglia to flexibility and to gaining control of balance-correcting responses, including the ability to lend priority to the elements of a postural task; and second, processing afferent information by the basal ganglia, which is increasingly recognized as being highly relevant for postural control.

The motor disorder of classic Lesch-Nyhan disease.

Reports describing the neurological features of Lesch-Nyhan disease (LND) vary widely, thereby implying the involvement of different neurological substrates. The movement abnormalities in 20 patients with LND were investigated. Dystonia was the most frequent and severe movement disorder.

Falls and freezing of gait in Parkinson's disease: a review of two interconnected, episodic phenomena.

Falls and freezing of gait are two "episodic" phenomena that are common in Parkinson's disease. Both symptoms are often incapacitating for affected patients, as the associated physical and psychosocial consequences have a great impact on the patients' quality of life, and survival is diminished. Furthermore, the resultant loss of independence and the treatment costs of injuries add substantially to the health care expenditures associated with Parkinson's disease.

Oxidative stress and dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease.

Lesch-Nyhan disease, a neurogenetic disorder caused by congenital deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyl transferase, is associated with a prominent loss of striatal dopamine. The current studies address the hypothesis that oxidant stress causes damage or dysfunction of nigrostriatal dopamine neurons in a knockout mouse model of the disease, by assessing several markers of oxidative damage and free radical scavenging systems. Some of these measures provided evidence for an increase in oxidative stress in the mutant mice (aconitase activity, oxidized glutathione, and lipid peroxides), but others did not (superoxide dismutase, protein thiol content, carbonyl protein content, total glutathione, glutathione peroxidase, catalase, and thiobarbituric reducing substances).