Long-Term Disease Course of Pontocerebellar Hypoplasia Type 10.

BACKGROUND: Pontocerebellar hypoplasia type 10 (PCH10) due to CLP1 gene mutations is characterized by structural brain anomalies, progressive microcephaly, severe intellectual and physical disabilities, and spasticity. In this follow-up study, evolution of phenotypic and neurological characteristics of patients with PCH10 is discussed. METHODS: Phenotype, growth parameters, motor functions, developmental tests, spasticity assessments, functional independence assessments, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) of 10 patients with PCH10 were monitored on separate examinations. Alterations were recorded. RESULTS: Patients were followed-up for an average of 2.83 years. The tone of the upper extremities was significantly higher than that of the lower extremities, according to Modified Ashworth Scale (MAS) values. Sixty percent of patients could sit unsupported; 20% achieved supported sitting initially but lost the ability during follow-up. Absence of grabbing or sitting was observed in 20% of patients. During follow-up, one person achieved supported sitting and one person achieved head holding. Only one patient was able to speak a few words. Cerebellar atrophy (two of 10), pons hypoplasia (four of 10), cortical atrophy (seven of 10), enlarged ventricles (10 of 10), thinning of the corpus callosum (10 of 10), hypomyelination (six of 10), and increased white matter signal intensity (six of 10) were the observed MRI findings. CONCLUSIONS: Progressive cerebral and cerebellar atrophy was demonstrated radiologically for the first time in a PCH10 cohort. It is of crucial importance to identify these patients promptly with the help of dysmorphic findings and spasticity being pronounced in the upper extremities. Furthermore, we note that phenotypic and neurological examination findings tend to change slightly over time.

Evolution of EEG Findings in Pontocerebellar Hypoplasia Type 2A: Normal EEG in the First Few Months followed by Abnormal Tracing over the Years.

Pontocerebellar hypoplasia (PCH) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by cerebellar and pontine hypoplasia, progressive microcephaly, and developmental delay. Ten types of PCH have been described; PCH type 2A (PCH2A) due to a mutation in TSEN54 is the most frequent. Seizures have been reported in the large majority of patients. The probability of epilepsy developing increases with age, along with difficulties in differentiating seizures from dyskinetic movements. The aim of the present report was to describe the clinical symptoms and electroencephalogram (EEG) changes over time in three patients of Israeli Arab origin with PCH2A. All three, including two siblings and their first cousin, were homozygous for the TSEN54 p.A304S mutation. The patients demonstrated profound psychomotor retardation, severe spasticity and contractures, choreoathetoid movements, and seizures. The magnetic resonance imaging (MRI) scans and EEGs were reviewed by an experienced neuroradiologist and epileptologist, respectively. The MRI scans revealed a dragonfly-like cerebellar pattern in all patients. Despite the normal early EEG findings, all patients had characteristic features of epilepsy, with tonic seizures starting in the first days to months followed by focal to bilateral tonic-clonic seizures in early childhood which continued to adolescence. In conclusion, patients with PCH2A due to the missense mutation p.A304S in TSEN54 exhibit profound psychomotor delay, movement disorders, and intractable epilepsy. An evolution of EEG abnormalities and seizure semiology occurs over time. Similar to several other genetic epileptic encephalopathies, the normal early EEG tracing does not rule out the later occurrence of epilepsy.

A patient with pontocerebellar hypoplasia type 6: Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome.

Pontocerebellar hypoplasia type 6 (PCH6) is a rare infantile-onset progressive encephalopathy caused by biallelic mutations in RARS2 that encodes the mitochondrial arginine-tRNA synthetase enzyme (mtArgRS). The clinical presentation overlaps that of PEHO syndrome (Progressive Encephalopathy with edema, Hypsarrhythmia and Optic atrophy). The proband presented with severe intellectual disability, epilepsy with varying seizure types, optic atrophy, axial hypotonia, acquired microcephaly, dysmorphic features and progressive cerebral and cerebellar atrophy and delayed myelination on MRI. The presentation had resemblance to PEHO syndrome but sequencing of ZNHIT3 did not identify pathogenic variants. Subsequent whole genome sequencing revealed novel compound heterozygous variants in RARS2, a missense variant affecting a highly conserved amino acid and a frameshift variant with consequent degradation of the transcript resulting in decreased mtArgRS protein level confirming the diagnosis of PCH6. Features distinguishing the proband's phenotype from PEHO syndrome were later appearance of hypotonia and elevated lactate levels in blood and cerebrospinal fluid. On MRI the proband presented with more severe supratentorial atrophy and lesser degree of abnormal myelination than PEHO syndrome patients. The study highlights the challenges in clinical diagnosis of patients with neonatal and early infantile encephalopathies with overlapping clinical features and brain MRI findings.

Extension of the phenotype of biallelic loss-of-function mutations in SLC25A46 to the severe form of pontocerebellar hypoplasia type I.

Biallelic mutations in SLC25A46, encoding a modified solute transporter involved in mitochondrial dynamics, have been identified in a wide range of conditions such as hereditary motor and sensory neuropathy with optic atrophy type VIB (OMIM: *610826) and congenital lethal pontocerebellar hypoplasia (PCH). To date, 18 patients from 13 families have been reported, presenting with the key clinical features of optic atrophy, peripheral neuropathy, and cerebellar atrophy. The course of the disease was highly variable ranging from severe muscular hypotonia at birth and early death to first manifestations in late childhood and survival into the fifties. Here we report on 4 patients from 2 families diagnosed with PCH who died within the first month of life from respiratory insufficiency. Patients from 1 family had pathoanatomically proven spinal motor neuron degeneration (PCH1). Using exome sequencing, we identified biallelic disease-segregating loss-of-function mutations in SLC25A46 in both families. Our study adds to the definition of the SLC25A46-associated phenotypic spectrum that includes neonatal fatalities due to PCH as the severe extreme.

Natural course of pontocerebellar hypoplasia type 2A.

INTRODUCTION: Pontocerebellar hypoplasia Type 2 (PCH2) is a rare autosomal recessive condition, defined on MRI by a small cerebellum and ventral pons. Clinical features are severe developmental delay, microcephaly and dyskinesia.Ninety percent carry a p.A307S mutation in the TSEN54-gene. Our aim was to describe the natural course including neurological and developmental features and other aspects of care in a homogeneous group of PCH2 patients all carrying the p.A307S mutation. PATIENTS AND METHODS: Patients were recruited via the German patients' organizations. Inclusion criteria were imaging findings of PCH2 and a p.A307S mutation. Data were collected using medical reports and patient questionnaires discussed in a standardized telephone interview. RESULTS: Thirty-three patients were included. When considering survival until age 11 years, 53% of children had died Weight, length and head circumference, mostly in the normal range at birth, became abnormal, especially head circumference (-5.58 SD at age 5 yrs). Neurologic symptoms: Choreathetosis was present in 88% (62% with pyramidal signs), 12% had pure spasticity. Epileptic seizures were manifest in 82%, status epilepticus in 39%. Non-epileptic dystonic attacks occurred in 33%. General symptoms: feeding difficulties were recorded in 100%, sleep disorder in 96%, apneas in 67% and recurrent infections in 52%; gastroesophageal reflux disease was diagnosed in 73%, 67% got percutaneous endoscopic gastrostomy and 36% a Nissen-fundoplication. Neurodevelopmental data: All children made progress, but on a low level: such as fixing and following with the eyes was seen in 76%, attempting to grasp objects (76%), moderate head control (73%), social smile (70%), rolling from prone to supine (58%), and sitting without support (9%). Ten percent lost achieved abilities on follow-up. The presence of prenatal symptoms did not correlate with outcome. CONCLUSION: Phenotype of this genetically homogeneous group of PCH2 children was severe with reduced survival, but compatible with some developmental progress. Our data support the hypothesis of an early onset degeneration which thereafter stabilizes.

Effects of olivo-ponto-cerebellar atrophy (OPCA) on finger interaction and coordination.

OBJECTIVES: We investigated changes in finger interaction and coordination in patients with olivo-ponto-cerebellar atrophy (OPCA) using the recently developed approach to motor synergies based on the principle of motor abundance. METHODS: OPCA patients and control subjects performed sets of maximal and submaximal force production tasks by the fingers of each of the hands. Indices of multi-finger synergies were quantified within the framework of the uncontrolled manifold hypothesis. RESULTS: The patients showed lower maximal forces, higher indices of finger interdependence (enslaving), and lower indices of multi-finger synergies stabilizing total force in four-finger tasks. In addition, the patients showed an impaired ability to adjust synergies in preparation to a quick action (small and delayed anticipatory synergy adjustments). The synergy indices showed significant correlations with the clinical scores (both UPDRS total motor scores and ataxia related sub-scores). The observed changes in the indices of finger interaction and coordination were qualitatively similar to those reported earlier for patients with Parkinson's disease; however, the magnitude of the changes was much higher in the OPCA group. CONCLUSIONS: These findings fit the hypotheses on the role of the cerebellum in assembling motor synergies and in the feed-forward control of action. They suggest that the synergy index measured in artificial, constrained laboratory tasks may be predictive of more general changes in motor behavior. SIGNIFICANCE: The results suggest that studies of multi-digit synergies may be particularly sensitive to subcortical disorders and may provide a much-needed tool for quantitative assessment of impaired coordination in such patients.

Glutamate receptor block in Lurcher mutant mice during ontogeny and its effect on hippocampal long-term potentiation.

Basic evaluation of the effect of chronic NMDA glutamate receptor (NMDAR) blockade on the hippocampal long-term potentiation (LTP) was performed in an animal model of inborn olivo-cerebellar degeneration (Lurcher mutant mice, LMM). NMDA receptor antagonist MK-801 was administered to mice in the dose 0.2 mg/kg of body weight, daily during two periods of their ontogeny: D5-D26 and D91-D111. In the consecutive 15 days some behavioral characteristics were studied using special methods for physical activity testing. Then LTP was investigated in LMM and also in their healthy littermates which served as controls (wild-type, WT). LTP in animals pre-treated with MK-801 showed significant long-term suppression of NMDAR activity, in both WT and LMM despite certain small differences between them. Our results show that cerebellar pathology on one hand and a physical activity on the other hand can influence the LTP in hippocampal region. It can be concluded that the results support the ideas of close functional cooperation between the brain structures which are involved in mechanisms of learning and memory.

Changes of motor abilities during ontogenetic development in Lurcher mutant mice.

Lurcher mutant mice represent a natural model of olivocerebellar degeneration. This degeneration is caused by a mutation of the gene for the delta2 glutamate receptor. Lurcher mutants suffer from cerebellar ataxia and cognitive functions deficiency as a consequence of excitotoxic apoptosis of Purkinje cells in the cerebellar cortex and a secondary decrease of granule cells and inferior olive neurons. This process finishes by the 90th day of postnatal life, but already by 14 days, the Purkinje cells are damaged and the ataxia is fully developed. Purkinje cells die by apoptosis within the first 3 weeks of life. The aim of our work was to study the development of motor functions in the course of the ontogenetic development in Lurcher mutant mice of the B6CBA strain and to compare it with wild type mice of the same strain. Mice aged 2, 3, 6, 9, and 22 weeks were used in our experiment. Motor skills were examined using four standard tests: the horizontal wire, rotating cylinder, footbridge and slanting ladder. Our findings in Lurcher mutant mice show a significant increase of motor abilities up to the sixth postnatal week and selective decrease early after this period. This improvement of motor skills is caused by the physiological development of musculature and the nervous system, probably with some contribution of plasticity of the maturing brain. The cause of the decline of these abilities immediately after the completion of the development is unknown.

Challenge-oriented gait and balance training in sporadic olivopontocerebellar atrophy: a case study.

BACKGROUND AND PURPOSE: Sporadic olivopontocerebellar atrophy (OPCA) is a rare and debilitating neurologic disease of insidious onset. It is characterized by atrophy of the cerebellum, pons, and inferior olivary nuclei with concomitant ambulation deficits and dyscoordination. To our knowledge, there has been no published study investigating any aspect of rehabilitation in OPCA. Therefore, the purpose of this study was to investigate the use of challenge-oriented gait and balance training to improve gait and balance in OPCA. CASE DESCRIPTION: An otherwise healthy 19-year-old woman with moderate to severe upper and lower extremity ataxia, secondary to sporadic OPCA, participated in this prospective case study. She also had a vestibulotoxic treatment procedure to decrease the severity of her vertigo. INTERVENTION: This individual participated in a 12-week gait and balance training program (five times per week), which consisted of one to two hours of various challenging static and dynamic balance tasks. To measure her progress, the following scales and tests were used: Berg Balance Scale, Dynamic Gait Index, Activities-Specific Balance Confidence Scale, computerized dynamic posturography (sensory organization test and limits of stability), and self-selected gait velocity. OUTCOMES: : Improvements were noted in all the dependent measures (pre to post): Berg Balance Scale (34/56 to 39/56), Dynamic Gait Index (1/24 to 7/24), Activities-Specific Balance Confidence Scale (50.6%-85.1%), sensory organization test (composite score, 31/100 to 47/100), limits of stability (maximum excursion, 89-105; endpoint excursion, 57-93; directional control, 60-78), and SSGV (0.375-0.526 m/sec). DISCUSSION: Results from this case study suggest that a gait and balance training program may be beneficial to individuals with ataxia from OPCA. This early evidence warrants further investigation using more rigorous methods.

The effect of nitric oxide synthase inhibitors nitro-L-arginine and 7-nitroindazole on spatial learning and motor functions in Lurcher mutant and wild type mice.

Nitric oxide (NO) is an intercellular messenger that, among other things, plays an important role in the nervous system as a gaseous neurotransmitter, modulating long-term potentiation (LTP) induction of synaptic transmission. LTP has been suggested to be the basis of memory formation. On the other hand NO also participates in excitotoxic processes which play an important role in many neuropathological states. The aim of this work was to observe the effect of two NO synthase (NOS) inhibitors (N omega-Nitro-L-arginine, NA; 7-nitroindazole, NI) on spontaneous behaviour, spatial learning and motor functions in Lurcher (+/Lc) and wild type (+/+) mice, derived from the B6CBA strain. Heterozygous Lurcher mutant mice represent a natural model of the olivocerebellar degeneration. They suffer from postnatal, practically total, extinction of cerebellar Purkinje cells (due to the excitotoxic apoptosis) and a partial decrease of granule cells and inferior olive neurons (ION) because of the lost target of their axons. +/+ animals are healthy littermates of +/Lc. NA is a nonselective NOS inhibitor which influences, except neuronal (n), also endothelial (e) NOS with an impact on blood pressure, NI is a selective nNOS inhibitor without any circulatory effect. The adult animals of both types (+/Lc; +/+) were influenced by acute administration of both inhibitors (25 mg/kg i.p. 30 min. before experiments) and newborns only by both acute and long-term administration of NI (1 month, starting from postnatal day 2, P2). Control solutions - saline or solvents of both NA and NI inhibitors--diluted 1M HCl and dimethyl sulfoxide (DMSO) respectively, were given at a relevant volume in the same way. The effect of both inhibitors and control solutions on motor functions was tested using four standard procedures (horizontal wire, slanting ladder, rotating cylinder, foot-bridge); in newborns at the age of 14 days. Spatial learning ability was examined in five-day long procedure in the Morris water maze (MWM) (in newborns started on P21). Spontaneous behaviour was studied only in adult animals (after acutely influencing them) employing the open field method. The results showed, that neither the Lurcher mutant, nor wild type mice derived from the B6CBA strain were significantly affected by NOS inhibitors NA and NI in spatial learning after both the acute and long-term application. Only significant decrease of swimming speed was found in both types of mice after the acute administration of NI and in the wild type animals after the acute administration of NA. Motor functions were significantly negatively affected only in the Lurcher mutants after both the acute and chronic application of NI.

Selective, circuit-wide sparing of floccular connections in hereditary olivopontine cerebellar atrophy with slow saccades.

We present a systems-oriented histopathologic analysis of the ocular motor control circuits in the cerebellum and brainstem from a patient with a hereditary form of olivopontine cerebellar atrophy of the Wadia type, which has a characteristic ocular motor presentation of slow saccades but relative preservation of smooth pursuit and gaze-holding. This differential pattern of clinical involvement is associated with a lobule-specific pattern of cerebellar degeneration. We asked whether these patterns of sparing and degeneration were consistent throughout the associated deep cerebellar and brainstem structures. Specimens were fixed in formalin, embedded in paraffin, and stained for various markers. We found that elements of the floccular and nodular pathways, controlling smooth pursuit and vestibular reflexes, were relatively spared, particularly those structures that are interconnected with the medial regions. Conversely, the elements of the dorsal vermis pathway controlling saccade adaptation were relatively involved. This subregional specificity of degeneration further defines possible areas of investigation for elucidating pathophysiology, testing biomarkers of disease, and developing areas for therapeutic intervention.

Sporadic ataxias in Japan--a population-based epidemiological study.

Sporadic spinocerebellar ataxias (SCAs) comprise heterogeneous diseases with poorly understood epidemiologies and etiologies. A population-based epidemiological analysis of sporadic ataxias in the Japanese population was described. The prevalence rate of SCAs in the Japanese population is estimated to be 18.5/100,000. Sporadic SCAs account for 67.2% of total SCAs including hereditary SCAs, with olivopontocerebellar atrophy (OPCA) being the most common form sporadic ataxia (64.7%). The natural history analysis conducted on the basis of International Cooperative Ataxia Rating Scale (ICARS) showed that only 33% of patients with OPCA were able to walk at least with one stick 4-5 years after the onset of OPCA, which is much less than that of patients with cortical cerebellar atrophy (CCA). Similarly, 43% of patients with OPCA were able to stand alone 4-5 years after the onset, while 76% of patients with CCA were able to stand alone at the same disease duration. A population-based epidemiological analysis should provide essential information on the natural history of SCAs.

The effect of repeated rotarod training on motor skills and spatial learning ability in Lurcher mutant mice.

Lurcher mutant mice represent a model of olivocerebellar degeneration. Due to loss of Purkinje cells, they suffer from functional cerebellar decortication resulting in ataxia and deterioration of cognitive functions. The aim of the work was to assess the effect of enforced physical activity represented by rotarod training on motor skills and spatial learning in young and adult B6CBA Lurcher mice. These functions were compared with those in untrained wild type mice of the same age. We examined motor skills using bar, ladder and rotarod tests. Spatial learning was tested in the Morris water maze. Motor skills of Lurchers were found to be worse than in wild type mice, but they showed motor learning in the course of training. The training did not significantly influence the results on the bar and ladder. In the rotarod test, young trained Lurchers achieved only slightly better results than untrained ones. In adult mice, the improvement was insignificant. Lurchers failed in spatial learning test compared to the wild type mice. In the wild type mice there was no difference in learning between young and adult individuals, while young Lurchers learned better than older ones. Enforced motor activity led to spatial learning improvement in older Lurchers, but not in young ones. The experiments showed that effects of enforced physical activity in Lurcher mice mitigated the deficit in the water maze task related to age so that trained older Lurchers showed as good performance as younger ones but still worse than the wild type mice.

Rhabdomyolysis in pontocerebellar hypoplasia type 2 (PCH-2).

Pontocerebellar hypoplasia type 2, an autosomal recessive neurodegeneration with prenatal onset, is characterised by progressive microcephaly and chorea/dystonia and has not previously been associated with muscular involvement. The gene associated with PCH-2 is unknown. An episode of rhabdomyolysis is reported in two non-related children with PCH-2, fatal in one, precipitated by intercurrent disease. Muscle biopsies in two other PCH-2 patients, and in one rhabdomyolysis patient whose biopsy antedated this complication showed areas of myofibrillar disruption or necrosis. Postmortem muscle sampled in another case without neuromuscular symptoms revealed focal necrosis, regenerating small fibres and upregulation of HLA-ABC. Random serum creatine kinase values in six other PCH-2 patients without clinical signs of neuromuscular involvement were increased in four. Collected data provide preliminary evidence of a subclinical myopathy associated with PCH-2.

The time-dependent block of NMDA glutamate receptor influences hippocampal LTP in inborn cerebellar degeneration mouse model.

The effect of single dose of NMDA glutamate receptor blockage administration on the hippocampal LTP was evaluated in animal model of inborn cerebellar degeneration. We compared the level of possible LTP blockade in two groups of animals, Lurcher mutant mice and their healthy littermates which served as controls. In the second part of the study we tested group of mice which were influenced repeatedly by the same NMDA blocker (MK-801) during behavioral experiments. Our results suggest a similar effect of blockade either after single or chronic MK-801 administration; both of them practically disrupted LTP generation with differences between healthy and neurodegenerative animals.

Motor and visuospatial abilities in a model of olivocerebellar and retinal degeneration--Lurcher mutant mice of C3H strain.

Lurcher mutant mice represent a natural model of olivocerebellar degeneration. They suffer from loss of Purkinje cells and decreased number of granule cells and inferior olive neurons. The degeneration leads to cerebellar ataxia and deterioration of cognitive functions. Some animals of the C3H strain have also the retinal degeneration. The aim of the study was to analyze the morphology of cerebellar and retinal degeneration and to evaluate the ability of motor coordination and visuospatial orientation in C3H Lurcher mutant mice. Cerebella of Lurcher mutant and wild type mice were examined with several histological, histochemical and immunohistochemical methods. Motor coordination was tested on a bar, ladder and rotarod. Spatial orientation and learning were tested in the Morris water maze with visible or hidden platform. Histological examinations showed decreased numbers of Purkinje cell in Lurchers. Various histological methods brought different information about the course or stage of the cerebellar degeneration. Retinal degeneration was identified with hematoxyline-eosine staining very well. Lurchers performed worse in motor coordination tests and in both the spatial orientation and learning test. Retinal degeneration influenced negatively both the spatial learning and orientation. Motor tests were influenced by retinal degeneration only in the wild type mice. Wild type mice showed some ability of idiothetic navigation, which was not found in Lurchers.

Topographic brain mapping of the international cooperative ataxia rating scale. A positron emission tomography study.

The International Cooperative Ataxia Rating Scale (ICARS) is a 100-point semiquantitative scale designed primarily to assess cerebellar dysfunction. However, little is known of the metric properties of this scale. We assessed the ICARS by rating the severity of cerebellar dysfunction in 27 patients with spinocerebellar ataxias (SCA), three patients with sporadic olivopontocerebellar ataxia and 24 healthy control subjects. [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) study was also performed on each subject. The statistical parametric mapping analyses revealed a significant correlation between the ICARS scores and functional impairment of the frontal regions within SCA patients. The glucose metabolism in the cerebellum, thalamus and caudate nucleus had significant differences between SCA patients and healthy control subjects. The results suggested that the clinical severity of SCA patients correlated with the functional impairment in the frontal regions, the targets of cerebellar efferent projections.

[Study of brainstem auditory evoked potentials and its correlation with pontine volume in olivopontocerebellar atrophy].

AIM: To investigate the change of latency and interpeak latency of each component of BAEP (brainstem auditory evoked potential, BAEP) and its correlation with PV/PFV (pontine volume/posterior fossa volume, PV/PFV) ratio in OPCA (olivopontocerebellar atrophy, OPCA). METHODS: We used Keypoint EMG/EP to determine waves I PL (peak latency, PL), III PL, V PL and I - III IPL (interpeak latency, IPL), III - V IPL, I - V IPL and used 1.5TMR 3D volume rendering software to determine PV (pontine volume, PV), CV(cerebellar volume, CV) and PFV (posterior fossa volume,PFV). Then calculated PV/PFV ratio, CV/PFV ratio and PV/ CV ratio in OPCA group and control group. RESULTS: Compared with control group, in OPCA group wave IIII PL, I - III IPL were significantly elongated (P < 0.05), III - V IPL was significantly shorten (P < 0.05), PV/PFV ratio was significantly decreased (P < 0.01); there was a positive correlation between III-V IPL and PV/PFV ratio (r = 0.83, P < 0.01). CONCLUSION: In patients with OPCA, III PL, I - III IPL of BAEP were elongated and III - V IPL of BAEP was shorten. III - V IPL became shorter when the volume of pontine decreased.

Does transplantation of cerebellar embryonic tissue influence hippocampal LTP in adult Lurcher mutant mice?

Possible influence of embryonic cerebellar graft transplanted into the adult neurodegenerative brain in Lurcher mutant mice on long-term potentiation (LTP) in hippocampus was investigated. Evaluation of LTP ability and comparison with the tests of motor learning suggests similarities between magnitude of LTP and criteria of motor learning. Also interstrain differences were described. Our results support ideas about tight cooperation among brain structures which are involved in mechanisms of learning and memory.