Gali Heimer

Basal ganglia oscillations and pathophysiology of movement disorders

Low frequency rest tremor is one of the cardinal signs of Parkinsons disease and some of its animal models. Current physiological studies and models of the basal ganglia differ as to which aspects of neuronal activity are crucial to the pathophysiology of Parkinsons disease. There is evidence that neural oscillations and synchronization play a central role in the generation of the disease. However, parkinsonian tremor is not strictly correlated with the synchronous oscillations in the basal ganglia networks. Rather, abnormal basal ganglia output enforces abnormal thalamo-cortical processing leading to akinesia, the main negative symptom of Parkinsons disease. Parkinsonian tremor has probably evolved as a downstream compensatory mechanism.

Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios

Purpose:Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene–disease associations.Methods:We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of patients.Results:We obtained a genetic diagnosis for 29 (24%) of our patients. We showed that patients carried an excess of damaging de novo mutations in intolerant genes, particularly those shown to be essential in mice (P = 3.4 × 10−8). This enrichment is only partially explained by mutations found in known disease-causing genes.Conclusion:This work indicates that the application of appropriate bioinformatics analyses to clinical sequence data can also help implicate novel disease genes and suggest expanded phenotypes for known disease genes. These analyses further suggest that some cases resolved by whole-exome sequencing will have direct therapeutic implications.Genet Med 17 10, 774–781.

Statistical Properties of Pauses of the High-Frequency Discharge Neurons in the External Segment of the Globus Pallidus

The neurons of many basal ganglia nuclei, including the external and internal globus pallidus (GPe and GPi, respectively) and the substantia nigra pars reticulata (SNr) are characterized by their high-frequency (50–100 spikes/s) tonic discharge (HFD). However, the high firing rate of GPe neurons is interrupted by long pauses. We studied the extracellularly recorded spiking activity of 212 well-isolated HFD GPe and 52 GPi/SNr neurons from five monkeys during different states of behavioral activity. An algorithm that maximizes the surprise function was used to detect pauses and pauser cells (“pausers”). Only 6% of the GPi/SNr neurons versus as many as 56% of the GPe neurons were classified as pausers. The GPe average pause duration equals 0.62 s. The interpause intervals follow a Poissonian distribution with a frequency of 13 pauses/minute. No linear relationship was found between pause parameters (duration or frequency) and the firing rate of the cell. Pauses were preceded by various changes in firing rate but not dominantly by a decrease. The average amplitude and duration of the spike waveform was modulated only after the pause but not before it. Pauses of pairs of cells that were recorded simultaneously were not correlated. The probability of GPe cells to pause spontaneously was extremely variable among monkeys (30–90%) and inversely related to the degree of the monkeys motor activity. These findings suggest that spontaneous GPe pauses are related to low-arousal periods and are generated by a process that is independent of the discharge properties of the cells.

Synchronizing activity of basal ganglia and pathophysiology of Parkinson's disease

Early physiological studies emphasized changes in the discharge rate of basal ganglia in the pathophysiology of Parkinsons disease (PD), whereas recent studies stressed the role of the abnormal oscillatory activity and neuronal synchronization of pallidal cells. However, human observations cast doubt on the synchronization hypothesis since increased synchronization may be an epi-phenomenon of the tremor or of independent oscillators with similar frequency. Here, we show that modern actor/ critic models of the basal ganglia predict the emergence of synchronized activity in PD and that significant non-oscillatory and oscillatory correlations are found in MPTP primates. We conclude that the normal fluctuation of basal ganglia dopamine levels combined with local cortico-striatal learning rules lead to noncorrelated activity in the pallidum. Dopamine depletion, as in PD, results in correlated pallidal activity, and reduced information capacity. We therefore suggest that future deep brain stimulation (DBS) algorithms may be improved by desynchronizing pallidal activity.

CAOS—Episodic Cerebellar Ataxia, Areflexia, Optic Atrophy, and Sensorineural Hearing Loss: A Third Allelic Disorder of the ATP1A3 Gene

We describe the molecular basis of a distinctive syndrome characterized by infantile stress-induced episodic weakness, ataxia, and sensorineural hearing loss, with permanent areflexia and optic nerve pallor. Whole exome sequencing identified a deleterious heterozygous c.2452 G>A, p.(E818K) variant in the ATP1A3 gene and structural analysis predicted its protein-destabilizing effect. This variant has not been reported in context with rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood, the 2 main diseases associated with ATP1A3. The clinical presentation in the family described here differs categorically from these diseases in age of onset, clinical course, cerebellar over extrapyramidal movement disorder predominance, and peripheral nervous system involvement. While this paper was in review, a highly resembling phenotype was reported in additional patients carrying the same c.2452 G>A variant. Our findings substantiate this variant as the cause of a unique inherited autosomal dominant neurologic syndrome that constitutes a third allelic disease of the ATP1A3 gene.

SLC1A4 mutations cause a novel disorder of intellectual disability, progressive microcephaly, spasticity and thin corpus callosum

Two unrelated patients, presenting with significant global developmental delay, severe progressive microcephaly, seizures, spasticity and thin corpus callosum (CC) underwent trio whole‐exome sequencing. No candidate variant was found in any known genes related to the phenotype. However, crossing the data of the patients illustrated that they both manifested pathogenic variants in the SLC1A4 gene which codes the ASCT1 transporter of serine and other neutral amino acids. The Ashkenazi patient is homozygous for a deleterious missense c.766G>A, p.(E256K) mutation whereas the Ashkenazi‐Iraqi patient is compound heterozygous for this mutation and a nonsense c.945delTT, p.(Leu315Hisfs*42) mutation. Structural prediction demonstrates truncation of significant portion of the protein by the nonsense mutation and speculates functional disruption by the missense mutation. Both mutations are extremely rare in general population databases, however, the missense mutation was found in heterozygous mode in 1:100 Jewish Ashkenazi controls suggesting a higher carrier rate among Ashkenazi Jews. We conclude that SLC1A4 is the disease causing gene of a novel neurologic disorder manifesting with significant intellectual disability, severe postnatal microcephaly, spasticity and thin CC. The role of SLC1A4 in the serine transport from astrocytes to neurons suggests a possible pathomechanism for this disease and implies a potential therapeutic approach.

Computational physiology of the basal ganglia in Parkinson's disease.

The normal activity of basal ganglia neurons is characterized by Poisson-like (random) firing patterns. Correlations between neurons of the same structure are weak or non-existent. By contrast, synchronous oscillations are commonly found in the basal ganglia of human patients and animal models of Parkinsons disease. The frequency of these oscillations is often similar to that of the parkinsonian tremor, but their role in generating the tremor or other parkinsonian symptoms is still under debate. The tremor is intermittent and does not appear in all human patients. Similarly, primate models tend to develop tremor as a function of species of monkey. African green (vervet) monkeys usually demonstrate a high-amplitude, low-frequency (4-7Hz) tremor beyond their akinesia and bradykinesia, whereas macaques tend to be akinetic rigid and rarely demonstrate a low-amplitude high-frequency (10-12Hz) action-postural tremor. We took advantage of this fact and studied the appearance of the synchronicity and oscillations in six monkeys, three vervets and three macaques, before and after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) systemic treatment and induction of parkinsonism. Multiple extracellular recordings were conducted in the primary motor cortex of two monkeys and in the globus pallidus (GP) of all six monkeys. All the monkeys became akinetic and bradykinetic as a result of the MPTP treatment, but only vervets demonstrated prolonged episodes of low-frequency (4-6Hz) tremor, whereas macaques were non-tremulous. The GP population exhibited approximately 5Hz oscillatory activity in all six monkeys, whereas approximately 10Hz neural oscillations were only detected in the tremulous monkeys. The activity of the cortical neurons became strongly oscillatory at approximately 10Hz in one of these monkeys, but not the other, although both were tremulous and exhibited comparable pallidal oscillatory activity. Finally, synchronous oscillations, when present, were centred around the higher frequencies of oscillations. These findings suggest that there is a correlation between high-frequency GP neural oscillations and tremor. Furthermore, these pallidal 10Hz oscillations are probably transferred to the periphery through cortical and brainstem pathways.

Liver Disease in Pediatric Patients With Ataxia Telangiectasia: A Novel Report.

Objective: Ataxia telangiectasia (A-T) is a rare genetic multiorgan disease. Although gastrointestinal involvement is known, hepatic involvement in A-T has not been investigated. We aimed to study the hepatic involvement in a large cohort of patients with A-T. Methods: A retrospective review of patients, studied from January 1986 to January 2015 at a National A-T Center. Clinical data including demographic, genetic, laboratory, nutritional, radiographic, and histological data were retrieved. Results: Fifty-three patients, 27 (49%) boys, age 14.6 ± 5.2 years (range 5.9–26.1 years), were included. Twenty-three patients (43.4%), age 9.9 ± 5.1 years, had consistently abnormal liver enzymes. The mean enzyme levels were alanine aminotransferase 76.8 ± 73.8 IU/L, aspartate aminotransferase 70 ± 50 IU/L, alkaline phosphatase 331 ± 134 IU/L, and gamma glutamyl transferase 114.7 ± 8 IU/L. Evaluation of other etiology of liver disease was negative. Ultrasonography revealed fatty liver in 9 of them (39%). Liver biopsy was performed in 2 patients, revealing mild-to-moderate steatosis in both, and fibrosis in 1 patient. Progression to advanced liver disease occurred in 2 of 23 (9%) patients within 2 to 5 years. Dyslipidemia was significantly associated with abnormal liver enzymes: 3 of 30 (10%) patients without abnormal liver enzymes versus 10 of 23 (45.5%) patients with abnormal liver enzymes, respectively (P < 0.05, Fisher exact test). No correlation was found between hepatic involvement and HbA1C, sex, presence of malignancy, or type of mutation. Conclusions: Abnormal liver enzymes and fatty liver are common in patients with A-T and may progress to advanced liver disease at a young age. These findings are novel and implicate that patients with A-T with abnormal liver enzymes should be evaluated for the presence of liver disease.

Female polysomy-X and systemic lupus erythematosus

OBJECTIVES Systemic lupus erythematosus (SLE) occurs more commonly in females than in males. Recent evidence suggests that genetic factors transmitted by the X-chromosome may confer increased risk for autoimmune disease in general, and for SLE in particular. It is therefore possible that X-chromosome polysomy might confer further increased risk for lupus. In addition to describing the clinical and immunologic features of a young woman with polysomy-X and SLE, we sought to review all other published cases associating female or male polysomy-X with SLE or other forms of autoimmunity. METHODS We report a case of a prepubertal girl with polysomy-X and SLE. We performed a systemic literature review for cases of polysomy-X and SLE and summarize previously published cases. In addition, we reviewed reports concerning the possible association between SLE and other connective tissue diseases and male polysomy-X. RESULTS An 11-year-old girl with tetrasomy-X (48 XXXX karyotype) presented with prolonged fever. Workup led to the diagnosis of SLE, and subsequent renal biopsy revealed mild diffuse mesangial proliferative glomerulonephritis. Two additional cases of SLE in women with 47 XXX and one of 48 XXXX karyotype were found in a literature review and compared to the present case. We identified studies that found X-chromosome polysomy to be over-represented in male patients with SLE and case descriptions of connective tissue diseases occurring in patients with polysomy-X. CONCLUSION No consistent pattern of disease was observed in female polysomy patients with SLE. Taken together with the data concerning the frequency of polysomy-X among males with SLE, our findings provide additional support for the hypothesis that X-chromosome polysomy may confer increased susceptibility to SLE. Molecular mechanisms that might account for this phenomenon are discussed.

Neighboring pallidal neurons do not exhibit more synchronous oscillations than remote ones in the MPTP primate model of Parkinson's disease

In the healthy primate, neurons of the external and internal segments of the globus pallidus (GP) present a primarily irregular firing pattern, and a negligible level of synchrony is observed between pairs of neurons. This holds even for neighboring cells, despite their higher probability to receive common inputs and to innervate each other via lateral connectivity. In the Parkinsonian primate, this changes drastically, and many pairs of GP cells show synchronous oscillations. To address the relation between distance and synchrony in the Parkinsonian state, we compared the synchrony of discharge of close pairs of neurons, recorded by the same electrode, with remote pairs, recorded by different ones. However, spike trains of neighboring cells recorded by the same extracellular electrode exhibit the shadowing effect; i.e., lack of detection of spikes that occur within a few milliseconds of each other. Here, we demonstrate that the shadowing artifact can both induce apparent correlations between non-correlated neurons, as well as conceal existing correlations between neighboring ones. We therefore introduced artificial shadowing in the remote pairs, similar to the effect we observed in the close ones. After the artificial shadowing, neighboring cells did not show a higher tendency to oscillate synchronously than remote ones. On the contrary, the average percentage (over all sessions) of artificially shadowed remote pairs exhibiting synchronous oscillations was 35.4% compared to 17.2% in the close ones. Similar trend was found when the unshadowed remote pairs were separated according to the estimated distance between electrode tips: 29.9% of pairs at approximate distance of less than 750 μm were significantly synchronized, in comparison with 28.5% of the pairs whose distance was more than 750 μm. We conclude that the synchronous oscillations in the GP of MPTP treated primates are homogenously distributed.