Classic "PCH" Genes are a Rare Cause of Radiologic Pontocerebellar Hypoplasia.

The term Pontocerebellar Hypoplasia (PCH) was initially used to designate a heterogeneous group of fetal-onset genetic neurodegenerative disorders. As a descriptive term, PCH refers to pons and cerebellum of reduced volume. In addition to the classic PCH types described in OMIM, many other disorders can result in a similar imaging appearance. This study aims to review imaging, clinical and genetic features and underlying etiologies of a cohort of children with PCH on imaging. We systematically reviewed brain images and clinical charts of 38 patients with radiologic evidence of PCH. Our cohort included 21 males and 17 females, with ages ranging between 8 days to 15 years. All individuals had pons and cerebellar vermis hypoplasia, and 63% had cerebellar hemisphere hypoplasia. Supratentorial anomalies were found in 71%. An underlying etiology was identified in 68% and included chromosomal (21%), monogenic (34%) and acquired (13%) causes. Only one patient had pathogenic variants in an OMIM listed PCH gene. Outcomes were poor regardless of etiology, though no one had regression. Approximately one third of patients deceased at a median age of 8 months. All individuals had global developmental delay, 50% were non-verbal, 64% were non-ambulatory and 45% required gastrostomy feeding. This cohort demonstrates that radiologic PCH has heterogenous etiologies and the "classic" OMIM-listed PCH genes underlie only a minority of cases. Broad genetic testing, including chromosomal microarray and exome or multigene panels, is recommended in individuals with PCH-like imaging appearance. Our results strongly suggest that the term PCH should be used to designate radiologic findings, and not to imply neurogenerative disorders.

New insights into CC2D2A-related Joubert syndrome.

PURPOSE: In this study, we describe the phenotype and genotype of the largest cohort of patients with Joubert syndrome (JS) carrying pathogenic variants on one of the most frequent causative genes, CC2D2A. METHODS: We selected 53 patients with pathogenic variants on CC2D2A, compiled and analysed their clinical, neuroimaging and genetic information and compared it to previous literature. RESULTS: Developmental delay (motor and language) was nearly constant but patients had normal intellectual efficiency in 74% of cases (20/27 patients) and 68% followed mainstream schooling despite learning difficulties. Epilepsy was found in only 13% of cases. Only three patients had kidney cysts, only three had genuine retinal dystrophy and no subject had liver fibrosis or polydactyly. Brain MRIs showed typical signs of JS with rare additional features. Genotype-phenotype correlation findings demonstrate a homozygous truncating variant p.Arg950* linked to a more severe phenotype. CONCLUSION: This study contradicts previous literature stating an association between CC2D2A-related JS and ventriculomegaly. Our study implies that CC2D2A-related JS is linked to positive neurodevelopmental outcome and low rate of other organ defects except for homozygous pathogenic variant p.Arg950*. This information will help modulate patient follow-up and provide families with accurate genetic counselling.

Recurrent, founder and hypomorphic variants contribute to the genetic landscape of Joubert syndrome.

BACKGROUND: Joubert syndrome (JS) is a neurodevelopmental ciliopathy characterised by a distinctive mid-hindbrain malformation, the 'molar tooth sign'. Over 40 JS-associated genes are known, accounting for two-thirds of cases. METHODS: While most variants are novel or extremely rare, we report on 11 recurring variants in seven genes, including three known 'founder variants' in the Ashkenazi Jewish, Hutterite and Finnish populations. We evaluated variant frequencies in ~550 European patients with JS and compared them with controls (>15 000 Italian plus gnomAD), and with an independent cohort of ~600 JS probands from the USA. RESULTS: All variants were markedly enriched in the European JS cohort compared with controls. When comparing allele frequencies in the two JS cohorts, the Ashkenazim founder variant (TMEM216 c.218G>T) was significantly enriched in American compared with European patients with JS, while MKS1 c.1476T>G was about 10 times more frequent among European JS. Frequencies of other variants were comparable in the two cohorts. Genotyping of several markers identified four novel European founder haplotypes.Two recurrent variants (MKS1 c.1476T>G and KIAA0586 c.428delG), have been detected in homozygosity in unaffected individuals, suggesting they could act as hypomorphic variants. However, while fibroblasts from a MKS1 c.1476T>G healthy homozygote showed impaired ability to form primary cilia and mildly reduced ciliary length, ciliary parameters were normal in cells from a KIAA0586 c.428delG healthy homozygote. CONCLUSION: This study contributes to understand the complex genetic landscape of JS, explain its variable prevalence in distinct geographical areas and characterise two recurrent hypomorphic variants.

Mutations in phospholipase C eta-1 (PLCH1) are associated with holoprosencephaly.

BACKGROUND: Holoprosencephaly is a spectrum of developmental disorder of the embryonic forebrain in which there is failed or incomplete separation of the prosencephalon into two cerebral hemispheres. To date, dominant mutations in sonic hedgehog (SHH) pathway genes are the predominant Mendelian causes, and have marked interfamilial and intrafamilial phenotypical variabilities. METHODS: We describe two families in which offspring had holoprosencephaly spectrum and homozygous predicted-deleterious variants in phospholipase C eta-1 (PLCH1). Immunocytochemistry was used to examine the expression pattern of PLCH1 in human embryos. We used SHH as a marker of developmental stage and of early embryonic anatomy. RESULTS: In the first family, two siblings had congenital hydrocephalus, significant developmental delay and a monoventricle or fused thalami with a homozygous PLCH1 c.2065C>T, p.(Arg689*) variant. In the second family, two siblings had alobar holoprosencephaly and cyclopia with a homozygous PLCH1 c.4235delA, p.(Cys1079ValfsTer16) variant. All parents were healthy carriers, with no holoprosencephaly spectrum features. We found that the subcellular localisation of PLCH1 is cytoplasmic, but the p.(Cys1079ValfsTer16) variant was predominantly nuclear. Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome, all tissues producing or responding to SHH. Furthermore, the embryonic subcellular localisation of PLCH1 was exclusively cytoplasmic, supporting protein mislocalisation contributing to the pathogenicity of the p.(Cys1079ValfsTer16) variant. CONCLUSION: Our data support the contention that PLCH1 has a role in prenatal mammalian neurodevelopment, and deleterious variants cause a clinically variable holoprosencephaly spectrum phenotype.

Refining the mutational spectrum and gene-phenotype correlates in pontocerebellar hypoplasia: results of a multicentric study.

BACKGROUND: Pontocerebellar hypoplasias (PCH) comprise a group of genetically heterogeneous disorders characterised by concurrent hypoplasia of the pons and the cerebellum and variable clinical and imaging features. The current classification includes 13 subtypes, with ~20 known causative genes. Attempts have been made to delineate the phenotypic spectrum associated to specific PCH genes, yet clinical and neuroradiological features are not consistent across studies, making it difficult to define gene-specific outcomes. METHODS: We performed deep clinical and imaging phenotyping in 56 probands with a neuroradiological diagnosis of PCH, who underwent NGS-based panel sequencing of PCH genes and MLPA for CASK rearrangements. Next, we conducted a phenotype-based unsupervised hierarchical cluster analysis to investigate associations between genes and specific phenotypic clusters. RESULTS: A genetic diagnosis was obtained in 43 probands (77%). The most common causative gene was CASK, which accounted for nearly half cases (45%) and was mutated in females and occasionally in males. The European founder mutation p.Ala307Ser in TSEN54 and pathogenic variants in EXOSC3 accounted for 18% and 9% of cases, respectively. VLDLR, TOE1 and RARS2 were mutated in single patients. We were able to confirm only few previously reported associations, including jitteriness and clonus with TSEN54 and lower motor neuron signs with EXOSC3. When considering multiple features simultaneously, a clear association with a phenotypic cluster only emerged for EXOSC3. CONCLUSION: CASK represents the major PCH causative gene in Italy. Phenotypic variability associated with the most common genetic causes of PCH is wider than previously thought, with marked overlap between CASK and TSEN54-associated disorders.

SUFU haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum.

BACKGROUND: Joubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%-75%.In 2018, we reported homozygous hypomorphic missense variants of the SUFU gene in two families with mild JS. Recently, heterozygous truncating SUFU variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies. METHODS: We reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes. RESULTS: Heterozygous truncating and splice-site SUFU variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents. CONCLUSION: Heterozygous truncating or splice-site SUFU variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.

Heterozygous KIF1A variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders.

BACKGROUND: Dominant and recessive variants in the KIF1A gene on chromosome 2q37.3 are associated with several phenotypes, although only three syndromes are currently listed in the OMIM classification: hereditary sensory and autonomic neuropathy type 2 and spastic paraplegia type 30, both recessively inherited, and mental retardation type 9 with dominant inheritance. METHODS: In this retrospective multicentre study, we describe the clinical, neuroradiological and genetic features of 19 Caucasian patients (aged 3-65 years) harbouring heterozygous KIF1A variants, and extensively review the available literature to improve current classification of KIF1A-related disorders. RESULTS: Patients were divided into two groups. Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype. Fourteen different heterozygous missense variants were detected by next-generation sequencing screening, including three novel variants, most falling within the kinesin motor domain. CONCLUSION: The present study further enlarges the clinical and mutational spectrum of KIF1A-related disorders by describing a large series of patients with dominantly inherited KIF1A pathogenic variants ranging from pure to complex forms of hereditary spastic paraparesis/paraplegias (HSP) and ataxic phenotypes in a lower proportion of cases. A comprehensive review of the literature indicates that KIF1A screening should be implemented in HSP regardless of its mode of inheritance or presentations as well as in other complex neurodegenerative or neurodevelopmental disorders showing congenital or early onset ataxia.

Emerging concepts on bradykinesia in non-parkinsonian conditions.

BACKGROUND AND PURPOSE: Bradykinesia is one of the cardinal motor symptoms of Parkinson's disease. However, clinical and experimental studies indicate that bradykinesia may also be observed in various neurological diseases not primarily characterized by parkinsonism. These conditions include hyperkinetic movement disorders, such as dystonia, chorea, and essential tremor. Bradykinesia may also be observed in patients with neurological conditions that are not seen as "movement disorders," including those characterized by the involvement of the cerebellum and corticospinal system, dementia, multiple sclerosis, and psychiatric disorders. METHODS: We reviewed clinical reports and experimental studies on bradykinesia in non-parkinsonian conditions and discussed the major findings. RESULTS: Bradykinesia is a common motor abnormality in non-parkinsonian conditions. From a pathophysiological standpoint, bradykinesia in neurological conditions not primarily characterized by parkinsonism may be explained by brain network dysfunction. CONCLUSION: In addition to the pathophysiological implications, the present paper highlights important terminological issues and the need for a new, more accurate, and more widely used definition of bradykinesia in the context of movement disorders and other neurological conditions.

Profiles of Normal Cognition in Essential Tremor.

OBJECTIVES: Patients with essential tremor exhibit heterogeneous cognitive functioning. Although the majority of patients fall under the broad classification of cognitively "normal," essential tremor is associated with increased risk for mild cognitive impairment and dementia. It is possible that patterns of cognitive performance within the wide range of normal functioning have predictive utility for mild cognitive impairment or dementia. These cross-sectional analyses sought to determine whether cognitive patterns, or "clusters," could be identified among individuals with essential tremor diagnosed as cognitively normal. We also determined whether such clusters, if identified, were associated with demographic or clinical characteristics of patients. METHODS: Elderly subjects with essential tremor (age >55 years) underwent comprehensive neuropsychological testing. Domain means (memory, executive function, attention, visuospatial abilities, and language) from 148 individuals diagnosed as cognitively normal were partitioned using k-means cluster analysis. Individuals in each cluster were compared according to cognitive functioning (domain means and test scores), demographic factors, and clinical variables. RESULTS: There were three clusters. Cluster 1 (n = 64) was characterized by comparatively low memory scores (p < .001), Cluster 2 (n = 39) had relatively low attention and visuospatial scores (p < .001), and Cluster 3 (n = 45) exhibited consistently high performance across all domains. Cluster 1 had lower Montreal Cognitive Assessment scores and reported more prescription medication use and lower balance confidence. CONCLUSIONS: Three patterns of cognitive functioning within the normal range were evident and tracked with certain clinical features. Future work will examine the extent to which such patterns predict conversion to mild cognitive impairment and/or dementia.

[Acute vestibular syndrome following cerebellar stroke : Case report and literature review. German version]. / Akutes vestibuläres Syndrom nach Kleinhirninfarkt : Fallbericht und Literaturrecherche.

The current paper reports on a patient with recurrent rotational vertigo and persistent dizziness and imbalance lasting weeks, who underwent extensive neurootological and radiological examination. Pathological findings initially included right-sided benign paroxysmal positional vertigo (BPPV), persistent horizontal spontaneous nystagmus (SPN) to the left and a pathological bedside and video head impulse test (HIT) on the left. The pathological HIT on the left and SPN to the left indicated a central genesis. Therefore, cMRI was performed and revealed a left-sided cerebral infarction in the territory of the medial branch of the posterior inferior cerebellar artery (mPICA).

Preventive Suboccipital Decompressive Craniectomy for Cerebellar Infarction: A Retrospective-Matched Case-Control Study.

BACKGROUND AND PURPOSE: No evidence is available on the benefits of preventive suboccipital decompressive craniectomy (SDC) for patients with cerebellar infarction. The purpose of this matched case-control study was to investigate whether preventive SDC was associated with good clinical outcomes in patients with cerebellar infarction and to evaluate its predisposing factors. METHODS: Between March 2007 and September 2015, 28 patients underwent preventive SDC. We performed propensity score matching to establish a proper control group among 721 patients with cerebellar infarction during the same period. Group A (n=28) consists of those who underwent preventive SDC, and group B (n=56) consists of those who did not undergo preventive SDC. We analyzed and compared clinical outcomes between groups. RESULTS: Clinical outcomes were better in group A than in group B at discharge (P=0.048) and 12-month follow-up (P=0.030). Group B had more deaths within 12 months than group A (log-rank, P<0.05). Logistic regression analysis showed that preventive SDC (odds ratio, 4.815; P=0.009) and the absence of brain stem infarction (odds ratio, 2.862; P=0.033) were independently associated with favorable outcomes (modified Rankin Scale score of 0-2) at 12-month follow-up. CONCLUSIONS: Favorable clinical outcomes including overall survival can be expected after preventive SDC in patients with a volume ratio between 0.25 and 0.33 and the absence of brain stem infarction. Among these patients, preventive SDC might be better than the best medical treatment alone.

Imaging spectrum of cerebellar pathologies: a pictorial essay.

The cerebellum is a crucial structure of hindbrain which helps in maintaining motor tone, posture, gait and also coordinates skilled voluntary movements including eye movements. Cerebellar abnormalities have different spectrum, presenting symptoms and prognosis as compared to supratentorial structures and brainstem. This article intends to review the various pathological processes involving the cerebellum along with their imaging features on MR, which are must to know for all radiologists, neurologists and neurosurgeons for their prompt diagnosis and management.

Bipolar Camouflage: A Cerebellar Cognitive Affective Syndrome Case Report.

The cerebellar cognitive affective syndrome is a neuropsychiatric syndrome composed of affective (anxiety, depression, euphoria, and emotional lability) and cognitive symptoms (executive, attentional, and visuospatial deficits) that was described in the 1990s. We present the case of a 49-year-old woman with a history of an acute neurological episode at the age of 28, after which she reported a change in personality, brief and alternating periods of depression, hypomania, and mixed episodes, and cognitive impairment that had a major impact on her personal and occupational level of functioning. She was initially diagnosed with bipolar disorder, but a clinical, neuropsychological, and imaging re-evaluation prompted a diagnostic reconsideration in favor of a cerebellar cognitive affective syndrome. This enabled therapeutical and prognostic refinement. Here, we discuss the diagnostic challenges of this syndrome and the implications that an accurate diagnosis has for patients.

Cerebellar Cognitive-Affective Syndrome Secondary to Epstein-Barr Virus Infection: A Case Report.

Throughout history, the cerebellum was initially perceived as potentially vestigial until the 19th century. However, subsequent research illuminated its pivotal role in coordination. Over the course of the 20th century, it became predominantly associated with motor functions. Nevertheless, in the latter half of the century, Schmahmann's pioneering research expanded the understanding of the cerebellum to encompass its involvement in cognition and emotions. In light of this evolving background, the primary objective of this paper is to present a clinical case featuring a 60-year-old male with a history of Epstein-Barr virus. This patient underwent a comprehensive neuropsychiatric assessment at a tertiary care hospital, involving thorough clinical, paraclinical, and neuroimaging examinations. The extensive medical findings strongly indicate the presence of a cognitive-affective cerebellar syndrome.

Phenytoin and damage to the cerebellum - a systematic review of published cases.

INTRODUCTION: The antiseizure medication phenytoin has been associated with changes in the cerebellum, cerebellar signs, and permanent cerebellar damage. We have systematically reviewed the clinical and radiological features, and their correlation. AREAS COVERED: We identified sixty case reports and case series of the effects of phenytoin on the cerebellum by searching Medline and Embase and relevant reference lists. The reports described 92 [median 1, range 1-5] cases, documented median age 28 [2.7-78] years. Eighty-one cases described one or more clinical sign of ataxia (present in 96%), dysarthria (63%), and nystagmus (70%). The neurological outcome (in 76 cases): 10 (13%) recovered by 12 months; 55 (72%) suffered residual disability; and 11 (14%) died. Median serum phenytoin concentration (48 cases) was 50 (interquartile range 31-66) mg/L; only three values were below 20 mg/L. The radiological findings included cerebellar atrophy in 41 of 61 patients (67%) with at least one scan. EXPERT OPINION: Evidence mainly comes from case reports, and is inevitably biased. Most patients with cerebellar dysfunction have phenytoin concentrations above the reference range. Clinical signs of ataxia can persist without radiological evidence of cerebellar atrophy, and cerebellar atrophy is seen without any clinical evidence of cerebellar dysfunction.

Anesthetic considerations of Joubert syndrome in patients with mitochondrial disease - A case report.

BACKGROUND: Joubert syndrome and mitochondrial disease are rare congenital diseases in which a wide range of symptoms affects multiple organs. Patients with these diseases present characteristic symptoms related to the musculoskeletal, respiratory, and neurological systems, which make it difficult for anesthesiologists to manage the patient's airway and choose appropriate anesthetic drugs. CASE: A 13-year-old male patient with Joubert syndrome and mitochondrial disease underwent elective surgery to insert a continuous ambulatory peritoneal dialysis catheter. Anesthesia was induced and maintained with propofol, remifentanil, and rocuronium. An I-gel was inserted to secure the airway; however, the fitting did not work properly, so the patient was intubated. The operation was completed without any major problems, and the intubated patient was transferred to the intensive care unit. CONCLUSIONS: Anesthesiologists should determine the method of anesthesia and prepare for unintended complications based on a full understanding of these congenital diseases.

Physical Activity as a Predictor of Cognitive Decline in an Elderly Essential Tremor Cohort: A Prospective, Longitudinal Study.

Background: Essential tremor (ET), one of the most common neurological diseases, is associated with cognitive impairment. Surprisingly, predictors of cognitive decline in ET remain largely unidentified, as longitudinal studies are rare. In the general population, however, lower physical activity has been linked to cognitive decline. Objectives: To determine whether baseline physical activity level is a predictor of cognitive decline in ET. Methods: One hundred and twenty-seven ET cases (78.1 ± 9.5 years, range = 55-95), enrolled in a prospective, longitudinal study of cognition. At baseline, each completed the Physical Activity Scale for the Elderly (PASE), a validated, self-rated assessment of physical activity. Cases underwent an extensive battery of motor-free neuropsychological testing at baseline, 1.5 years, and 3 years, which incorporated assessments of cognitive subdomains. Generalized estimating equations (GEEs) were used to assess the predictive utility of baseline physical activity for cognitive change. Results: Mean follow-up was 2.9 ± 0.4 years (range = 1.3-3.5). In cross-sectional analyses using baseline data, lower physical activity was associated with lower overall cognitive function as well as lower cognitive scores in numerous cognitive domains (memory, language, executive function, visuospatial function and attention, all p < 0.05). In adjusted GEE models, lower baseline physical activity level significantly predicted overall cognitive decline over time (p=0.047), and declines in the subdomains of memory (p = 0.001) and executive function (p = 0.03). Conclusions: We identified reduced physical activity as a predictor of greater cognitive decline in ET. The identification of risk factors often assists clinicians in determining which patients are at higher risk of cognitive decline over time. Interventional studies, to determine whether increasing physical activity could modify the risk of developing cognitive decline in ET, may be warranted.

Rate of progression from mild cognitive impairment to dementia in an essential tremor cohort: A prospective, longitudinal study.

BACKGROUND: Essential tremor (ET), among the most common neurological diseases, is associated with cognitive dysfunction. Yet, nearly all knowledge of ET-related cognitive impairment is static and cross-sectional (e.g., prevalence), with virtually no dynamic information (i.e., course and progression, conversion rates, and clinical outcomes). OBJECTIVES: To quantify the rate of progression from mild cognitive impairment (MCI) to dementia in a cohort of elderly ET cases. METHODS: 167 ET cases, enrolled in a prospective, longitudinal, clinical-pathological study, underwent an extensive neuropsychological testing battery at baseline (T1), 1.5 years (T2), and 3 years (T3). Results of these assessments informed clinical diagnoses of normal cognition (ET-NC), MCI (ET-MCI), and dementia (ET-D). RESULTS: At baseline, 26 cases (82.7 ± 7.7 years) were diagnosed with ET-MCI and were available for follow-up at T2. At T2, three of 26 (11.5%) had converted to ET-D. At the start of T2, 23 cases (83.6 ± 7.7 years) were diagnosed with ET-MCI and were available for follow-up at T3. At T3, six of 23 (26.1%) converted to ET-D. The average annual conversion rate from ET-MCI to ET-D was 12.5%. CONCLUSIONS: The study of cognitive impairment in ET is a nascent field, with limited data. We show that the conversion rate from ET-MCI to ET-dementia was 12.5%. Available studies on historical controls have reported conversion rates of 2.6-6.3%. Data such as these systematically fill gaps in knowledge, creating a scientifically-derived knowledge base to guide physicians and patients in clinical settings.