Elena Pretegiani

Pendular nystagmus, palatal tremor and progressive ataxia in GM2-gangliosidosis.

Progressive ataxia and palatal tremor (PAPT) is a neurodegenerative disorder described in both sporadic and familial cases [1,2]. Nystagmus is commonly associated. So far, only two genetic disorders (Alexander’s disease and SCA20) are recognized causes of familial PAPT, whilst most cases remain undiagnosed [1–3]. We report a 71-year-old man with adult-onset GM2-gangliosidosis type II (GM2-II, Sandhoff disease) who developed ocular pendular nystagmus and palatal tremor (OPT) besides progressive cerebellar ataxia, extrapyramidal signs and mild cognitive impairment. GM2-II results from HEXBmutations causing deficiency of b-hexosaminidase A and B, clinically indistinguishable from the more frequent Tay Sachs disease (GM2-gangliosidosis type I) whereHEXA mutations lead to sole b-hexosaminidase A deficiency [4]. GM2-ganglioside accumulates in neuronal as well as nonneuronal tissues causing a heterogeneous neuro-degeneration. Late-onset GM2gangliosidosis progresses more slowly and more mildly than infantile GM2-gangliosidosis with rare occurrence of retinal cherry-red spot and startle myoclonus, and with extrapyramidal and cerebellar dysfunction, upper and lower motor neuron impairment and neuro-psychiatric manifestations as the most prevalent symptoms [4]. Diagnosis may be difficult. Our patient belongs to a family of seven siblings, three of them affected by GM2-II and whose history and clinical features have been reported elsewhere [5]. In addition to his syndromic symptoms, the patient complained of gradually worsening oscillopsia and dysarthria. His recent history was negative for traumas, infections, inflammations or drugs associated with OPT [1,2]. Furthermore, clinical examination revealed a small amplitude vertical pendular nystagmus, masked by frequent blinking. Rhythmic palatal tremor was associated with tremor of the chin and branchial-derived muscles (Video S1). Surprisingly, despite a long history of progressive cerebellar impairment leading to clinically evident gait ataxia, dysmetria and blurred speech, brain magnetic resonance imaging (MRI) performed 14 years before (Fig. 1Aa), some weeks after, and several months after (Fig. 1Ab–e) did not show cerebellar or pontine atrophy and ruled out lesions in the Guillain Mollaret triangle as well as inferior olivary (pseudo) hypertrophy. Long echo time MR spectroscopy showed low NAA/Cr and Cho/ Cr ratios in both pons and cerebellar white matter. Therapy with clonazepam reduced the ocular tremor remarkably so that, after some weeks, it was possible to record the patient’s saccades. Horizontal saccades were hypometric with respect to healthy controls (Fig. 1B). The target was often reached through multistep saccades, suggesting a fastigial disinhibition as already hypothesized for hypometric saccades in late-onset Tay Sachs disease [6]. Vertical saccades were hypometric and slow, indicating moderate supranuclear vertical gaze palsy. This report extends to GM2-II the spectrum of inherited syndromes associated with PAPT. Notably, MRI was negative for lesions commonly associated with monophasic OPT [1,2,7], indicating GM2-II as the most likely cause of OPT. Interestingly, investigation for GM2-gangliosidosis in undiagnosed PAPT is also suggested by the finding of typical features of late-onset GM2-II in several cases of idiopathic PAPT. Indeed, optic atrophy without the macular cherry-red spot, pyramidal and extrapyramidal signs, autonomic failure and psychiatric disturbances characterize typical GM2gangliosidosis, particularly its late-onset variant, but they have often been reported also in sporadic and familial undiagnosed cases of PAPT [1,3,4]. The patient provided written informed consent.

Eye Movements in Parkinson’s Disease and Inherited Parkinsonian Syndromes

Despite extensive research, the functions of the basal ganglia (BG) in movement control have not been fully understood. Eye movements, particularly saccades, are convenient indicators of BG function. Here, we review the main oculomotor findings reported in Parkinson’s disease (PD) and genetic parkinsonian syndromes. PD is a progressive, neurodegenerative disorder caused by dopaminergic cell loss within the substantia nigra pars compacta, resulting in depletion of striatal dopamine and subsequent increased inhibitory BG output from the internal globus pallidus and the substantia nigra pars reticulata. Eye movement abnormalities are common in PD: anomalies are more evident in voluntary than reflexive saccades in the initial stages, but visually guided saccades may also be involved at later stages. Saccadic hypometria (including abnormally fragmented saccades), reduced accuracy, and increased latency are among the most prominent deficits. PD patients show also unusually frequent and large square wave jerks and impaired inhibition of reflexive saccades when voluntary mirror saccades are required. Poor convergence ability and altered pursuit are common. Inherited parkinsonisms are a heterogeneous group of rare syndromes due to gene mutations causing symptoms resembling those of PD. Eye movement characteristics of some parkinsonisms have been studied. While sharing some PD features, each syndrome has a distinctive profile that could contribute to better define the clinical phenotype of parkinsonian disorders. Moreover, because the pathogenesis and the underlying neural circuit failure of inherited parkinsonisms are often well defined, they might offer a better prospect than idiopathic PD to understand the BG function.

Eye movements in genetic parkinsonisms affecting the α-synuclein, PARK9, and manganese network

https://doi.org/10.1016/j.clinph.2017.09.107 1388-2457/Published by Elsevier Ireland Ltd on behalf of International Fe Abbreviations: PARK9, parkinson disease 9 PARK1, parkinson disease 1 HMNDYT1, hypermanganesemia with dystonia, polycythemia, and cirrhos PDG, genetic Parkinson disease CT, controls UPDRS, Unified Parkinson’s Disease Rating Scale Specific saccadic abnormalities follow basal ganglia dysfunction. Eye movements are indeed often analyzed to differentiate parkinsonian syndromes and to provide new insights into the modulatory role of the basal ganglia. Nevertheless, the oculomotor description of most inherited parkinsonisms is still lacking. Here, we analyzed the eye movement characteristics of three inherited parkinsonian syndromes (genetic Parkinson’s disease, PDG): Parkinson’s disease 9 (or Kufor-Rakeb syndrome, PARK9, #606693), due to recessive mutations in ATP13A2 encoding the lysosomal P-type ATPase PARK9 (Ramirez et al., 2006; Gitler et al., 2009); hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMNDYT1, #613280) due to recessive mutations in SLC30A10 leading to manganese accumulation in the liver, bone marrow, and nervous system (Quadri et al., 2012), and Parkinson’s disease 1 (PARK1, #168601) associated with dominant mutations in SNCA encoding a-synuclein (Golbe et al., 1990). Recently, PARK9, a-synuclein, and manganese have been interconnected in a functional network (Gitler et al., 2009; Peres et al., 2016). Loss of PARK9 increases a-synuclein accumulation and manganese toxicity. Manganese regulates a-synuclein homeostasis and accumulation (Peres et al., 2016). Alpha-synuclein normally protects against manganese toxicity, but its overexpression causes neurodegeneration (Peres et al., 2016). It is thus interesting to compare the phenotypes resulting from mutations in the three genes at the extremes of this metabolic network. Six patients with PDG were recruited. Two brothers (44 and 35yo) (PARK9) harbored homozygous ATP13A2 and heterozygous FBXO7 (PARK15) mutations. Both patients showed pyramidal, extrapyramidal, and cerebellar signs, hyposthenia, facial minimyoclonus, and cognitive decline (Santoro et al., 2011). Unified Parkinson’s Disease Rating Scale (UPDRS) score was 67 in the older brother and 16 in the younger. Mini Mental Status Examination in the younger brother was 19/30, Montreal Cognitive Assessment 13/30. Brain MRI revealed reduced gray and white matter in motor, prefrontal, and somatosensory cortex, cingulate, caudate, thalamus, and cerebellum. [123I] FP-CIT–SPECT showed decreased dopamine transport in the striatum.

A GABAergic Dysfunction in the Olivary–Cerebellar–Brainstem Network May Cause Eye Oscillations and Body Tremor. II. Model Simulations of Saccadic Eye Oscillations

Eye and body oscillations are shared features of several neurological diseases, yet their pathophysiology remains unclear. Recently, we published a report on two tennis players with a novel presentation of eye and body oscillations following self-administration of performance-enhancing substances. Opsoclonus/flutter and limb tremor were diagnosed in both patients. Common causes of opsoclonus/flutter were excluded. High-resolution eye movement recordings from one patient showed novel spindle-shaped, asymmetric saccadic oscillations (at ~3.6 Hz) and ocular tremor (~40–60 Hz). Based on these findings, we proposed that the oscillations are the result of increased GABAA receptor sensitivity in a circuit involving the cerebellum (vermis and fastigial nuclei), the inferior olives, and the brainstem saccade premotor neurons (excitatory and inhibitory burst neurons, and omnipause neurons). We present a mathematical model of the saccadic system, showing that the proposed dysfunction in the network can reproduce the types of saccadic oscillations seen in these patients.

Anti-Saccades in Cerebellar Ataxias Reveal a Contribution of the Cerebellum in Executive Functions

Objective Increasing evidence suggests a cerebellar contribution to modulate cognitive aspects of motor behavior and executive functions. Supporting findings come from studies on patients with neurodegenerative diseases, in which however, given the extent of the disease, the specific role of the cerebellum, could not be clearly isolated. Anti-saccades are considered a sensitive tool to test executive functions. The anti-saccade underlying neural network, consisting of different cortical areas and their downstream connections including the lateral cerebellum, has been largely clarified. To separate the role of the cerebellum with respect to other cortical structures in executive control, we compared the anti-saccade performances in two distinct cohorts of patients with cerebellar disorders (with and without cerebral cortical involvement). Methods Eye movements during the execution of anti-saccades were recorded in 12 patients with spinocerebellar ataxia type 2 (a cortical-subcortical neurodegenerative disease), 10 patients with late onset cerebellar ataxia (an isolated cerebellar atrophy), and 34 matched controls. Results In the anti-saccade task, besides dynamic changes already demonstrated in the pro-saccades of these patients, we found in both groups of cerebellar patients prolonged latency with larger variability than normal and increased directional error rate. Errors, however, were corrected by cerebellar patients as frequently as normal. No significant differences were found in patients with and without cortical involvement. Conclusion Our results indicate, in a large cohort of cerebellar patients, that the cerebellum plays a critical role in the regulation of executive motor control not only, as well known, by controlling the end of a movement, but also modulating its initiation and reducing reflexive responses that would perturb voluntary actions.

Characteristic Eye Movements in Ataxia-Telangiectasia-Like Disorder: An Explanatory Hypothesis

Objective To investigate cerebellar dysfunctions and quantitatively characterize specific oculomotor changes in ataxia-telangiectasia-like disorder (ATLD), a rare autosomal recessive disease caused by mutations in the MRE11 gene. Additionally, to further elucidate the pathophysiology of cerebellar damage in the ataxia-telangiectasia (AT) spectrum disorders. Methods Saccade dynamics, metrics, and visual fixation deficits were investigated in two Italian adult siblings with genetically confirmed ATLD. Visually guided saccades were compared with those of 40 healthy subjects. Steady fixation was tested in primary and eccentric positions. Quantitative characterization of saccade parameters, saccadic intrusions (SI), and nystagmus was performed. Results Patients showed abnormally hypermetric and fast horizontal saccades to the left and greater inaccuracy than healthy subjects in all saccadic eye movements. Eye movement abnormalities included slow eye movements that preceded the initial saccade. Horizontal and vertical spontaneous jerk nystagmus, gaze-evoked, and rebound nystagmus were evident. Fixation was interrupted by large square-wave jerk SI and macrosaccadic oscillations. Conclusion Slow eye movements accompanying saccades, SI, and cerebellar nystagmus are frequently seen in AT patients, additionally our ATLD patients showed the presence of fast and hypermetric saccades suggesting damage of granule cell-parallel fiber-Purkinje cell synapses of the cerebellar vermis. A dual pathogenetic mechanism involving neurodevelopmental and neurodegenerative changes is hypothesized to explain the peculiar phenotype of this disease.

Nicolaides–Baraitser syndrome: defining a phenotype

We report here on an adult patient affected by Nicolaides– Baraitser syndrome (NCBRS, OMIM #601358) who also presented with multiple cerebral cavernous malformations and insulin resistance and we discuss the relevance of these findings for NCBRS patients. NCBRS is an increasingly recognized cause of intellectual disability linked to a defective epigenetic mechanism [1, 2]. A typical picture of NCBRS is emerging after the recent identification of the responsible gene SMARCA2 [3]. SMARCA2 encodes a subunit of the switch/sucrose non-fermenting (SWI/SNF) chromatin remodeling complex which is involved in gene transcription, cell differentiation, and DNA repair [3]. Beside intellectual delay, seizures, facial coarsening, short stature, microcephaly, sparse scalp hair, and prominent interphalangeal joints seem to be cardinal features [4]. Nevertheless, NCBRS phenotype delineation is still based on a limited number of reported cases. This makes difficult the attribution of uncommon features as syndromic or coincidental to the disease. Moreover, somatic and germline mutations of the SWI/SFN complex have been associated with tumor suppression, raising the question whether patients with intellectual disability harboring SWI/SNF mutations might have increased risk of developing neoplasias [5]. A lack of reported cancers in these patients may be due to the fact that many of them are juveniles that have been not followed after their childhood [5]. Mari et al. described recently the clinical and molecular details of a cohort of Italian patients [2]. Patient 2 in their report is a 35 years old woman with a heterozygous c.2554G[A mutation in exon 18. Her clinical picture largely overlapped those of other NBS patients: she presented with cognitive delay and limited speech, epilepsy, microcephaly, short stature, decreased subcutaneous fat, coarse facial features, sparse scalp hair and dense eyebrows, and facial and dorsal hypertrichosis. Further investigations, however, led to two additional interesting findings. First, a brain MRI showed cerebral atrophy with frontal lobe hypoplasia and multiple cerebral cavernous malformations (CCMs). Both the proband and her mother, who also suffered from headache and CCMs, were found to harbor a c.2012 insCAAC in the exon 17 of KRIT1 (CCM1). While the two genetic diseases were likely inherited independently by the proband, they might hypothetically have reciprocally influenced the proband’s phenotype. A two-hit mechanism (germline and somatic) leading to the inactivation of both alleles within affected cells has been proposed for the genesis of CCMs and other vascular malformations [6]. In the two-hit model, a germline mutation is inherited in one allele and lesions occur in cells in which also the wild-type allele is inactivated [7]. We wonder, then, if SMARCA2 mutations might favor the development of vascular malformations by contributing to inactivate the spared allele at a somatic level. Indeed, SMARCA2 mutations associated with NCBRS generate a & Elena Pretegiani elena.pretegiani@nih.gov

Shuffled data in the investigation of complex dynamics of the neuromotor saccadic system

Saccadic temporal data series were examined for evidence of chaotic behavioral trend. To do this, we analyzed the saccadic data series recorded from healthy voluntary subject in special experimental design. Some computational tests based on chaos theory, as phase-space portrait reconstruction and estimation of its correlation dimension and Lyapunov exponent, were applied on saccadic raw data series, in comparison to the shuffled data of the same signal leading to evidence of chaotic dynamics in both cases. Comparison with theoretic chaotic data, quasi-periodic signal and pure random series was also discussed considering corresponding raw and shuffled data.