Cerebral dural arteriovenous fistulas in patients with PTEN-related hamartoma tumor syndrome.

Central nervous system (CNS) dural arteriovenous fistulas (DAVF) have been reported in PTEN-related hamartoma tumor syndrome (PHTS). However, PHTS-associated DAVF remain an underexplored field of the PHTS clinical landscape. Here, we studied cases with a PTEN pathogenic variant identified between 2007 and 2020 in our laboratory (n = 58), and for whom brain imaging was available. Two patients had DAVF (2/58, 3.4%), both presenting at advanced stages: a 34-year-old man with a left lateral sinus DAVF at immediate risk of hemorrhage, and a 21-year-old woman with acute intracranial hypertension due to a torcular DAVF. Interestingly, not all patients had 3D TOF/MRA, the optimal sequences to detect DAVF. Early diagnosis of DAVF can be lifesaving, and is easier to treat compared to developed, proliferative, or complex lesions. As a result, one should consider brain MRI with 3D TOF/MRA in PHTS patients at genetic diagnosis, with subsequent surveillance on a case-by-case basis.

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.

Dance Improves Motor, Cognitive, and Social Skills in Children With Developmental Cerebellar Anomalies.

In this multiple single-cases study, we used dance to train sensorimotor synchronization (SMS), motor, and cognitive functions in children with developmental cerebellar anomalies (DCA). DCA are rare dysfunctions of the cerebellum that affect motor and cognitive skills. The cerebellum plays an important role in temporal cognition, including SMS, which is critical for motor and cognitive development. Dancing engages the SMS neuronal circuitry, composed of the cerebellum, the basal ganglia, and the motor cortices. Thus, we hypothesized that dance has a beneficial effect on SMS skills and associated motor and cognitive functions in children with DCA. Seven children (aged 7-11) with DCA participated in a 2-month dance training protocol (3 h/week). A test-retest design protocol with multiple baselines was used to assess children's SMS skills as well as motor, cognitive, and social abilities. SMS skills were impaired in DCA before the training. The training led to improvements in SMS (reduced variability in paced tapping), balance, and executive functioning (cognitive flexibility), as well as in social skills (social cognition). The beneficial effects of the dance training were visible in all participants. Notably, gains were maintained 2 months after the intervention. These effects are likely to be sustained by enhanced activity in SMS brain networks due to the dance training protocol.

High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families.

PURPOSE: Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families. METHODS: We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. RESULTS: We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation. CONCLUSION: A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation.

Experience of follow-up, quality of life, and transition from pediatric to adult healthcare of patients with tuberous sclerosis complex.

INTRODUCTION: Tuberous sclerosis complex (TSC) is a multisystemic genetic disease with high clinical variability and age-related manifestations. These characteristics add to the complexity of transition to adulthood. This study aimed to explore the perception of medical follow-up and transition experience in a large group of patients with TSC who presented epilepsy in childhood. METHOD: This multicenter French study included patients with TSC aged 18 years or older who developed epilepsy before the age of 16 years. A questionnaire specifically designed for the study explored patients' opinion through 270 questions covering different aspects of their social, familial, professional, and medical courses. RESULTS: The questionnaire was sent to 72 patients, and 60 patients were included in the study (83% response rate) with a mean age of 32 years (18-55 years). Cognitive impairment was present in 80% of patients, and half of questionnaires were completed by the family. Pediatric care was coordinated by the child neurologist and was more regular and multidisciplinary than adult care. Epilepsy had the best follow-up followed by renal issues. Unmet needs were identified for psychiatric and behavioral disorders, both in children and adults. Respondents considered the help in achieving autonomy better in adult care. Only 50% of patients with a normal intellectual development had clear knowledge about their disease and the need for a regular monitoring. Two-thirds of respondents estimated that they had a transition experience between 16.5 and 21-year-old, considered as good in 60% of them. Seventy percent felt continuity between pediatric and adult care, and only 3% of respondents felt that their care would have been better if they were still followed in pediatric healthcare system. The change of care structure and/or caregivers was the most stressful factor during transition and transfer. CONCLUSION: This study highlights persistent issues in the regularity and coordination of the follow-up of patients with TSC despite established international guidelines. Although most patients had a positive transition experience, there is still an urgent need to optimize transition programs. This would be essential to maintain care continuity between pediatric and adult health systems, especially for patients with TSC with epilepsy and high rate of cognitive and psychiatric impairments.

Epilepsy in young Tsc1(+/-) mice exhibits age-dependent expression that mimics that of human tuberous sclerosis complex.

OBJECTIVE: To describe the epileptic phenotype of Tsc1(+/-) mice pups in comparison with age-related seizures in human tuberous sclerosis complex (TSC). METHODS: Tsc1(+/-) and control mice underwent intracranial electroencephalography (EEG) recording at postnatal ages (P)8 to P33, with linear silicon probe implanted in the somatosensory cortex of one or both hemispheres for 8-24 h. Ictal events were classified visually by independent analyzers; distinct EEG patterns were related to age and analyzed to quantify field potential characteristics and signal dynamics between hemispheres. We collected retrospectively 20 infants with prenatally diagnosed TSC and EEG before seizure onset, and analyzed the electroclinical course of epilepsy, taking into account a first-line treatment by vigabatrin. RESULTS: Spontaneous seizures were disclosed in 55% of Tsc1(+/-) mice at P9-18. Three ictal patterns were identified: from P9 to P12 "spike clusters" consisted of recurring large spikes without clinical correlate; "spasm-like" discharges dominated from P13 to P16 consisting of high amplitude large field potential superimposed with or followed by fast activity repeated every 2-10 s for at least 20 s, accompanied by rhythmic limb contractions; from P14 to P18 a "tonic-clonic like" pattern comprised rhythmic spikes of increasing amplitude with tonic-clonic movements. Early onset "spike clusters" were mainly unilateral, whereas "spasm-like" and "tonic-clonic like" patterns were bilateral. Interhemispheric propagation was significantly faster for "tonic-clonic like" than for "spasm-like" events. In infants diagnosed prenatally with TSC, clusters of sharp waves or spikes preceded the first seizure, and vigabatrin prevented the development of seizures. Patients treated after seizure onset developed spasms or focal seizures that were pharmacoresistant in 66.7% of cases. SIGNIFICANCE: Tsc1(+/-) mice pups exhibit an age-dependent seizure pattern sequence mimicking early human TSC epilepsy features. Spike clusters before seizure onset in TSC should be considered as a first stage of epilepsy reinforcing the concept of preventive antiepileptic therapy.

Renal involvement in tuberous sclerosis complex with emphasis on cystic lesions.

INTRODUCTION: Tuberous sclerosis complex (TSC) involves frequently the kidneys. Lesions encompass mainly angiomyolipoma and cysts. The disease can be associated with autosomal dominant polycystic kidney disease leading to the contiguous gene syndrome (CGS) The objectives of the present study were to review the US appearances of the renal involvement in children affected by classical TSC or by the CGS and to verify whether it is possible to differentiate between both entities. The evolution of the lesions through time was also studied. MATERIALS AND METHODS: 55 cases of patients <16 years with STB were reviewed by two pediatric radiologists. Clinical data reviewed included age at diagnosis, genetic assessment and complications; US data reviewed included renal size, type of lesions (angiomyolipoma-AML, or cysts), number and location as well as their evolution with time. Complications were also analyzed. RESULTS: 30 patients (56 %) had at least one kidney lesion (27 classical TSC and 3 CGS). On the basis of the US findings, these patients were separated into four groups. Group 1 (9 patients) displayed microscopic (diffuse) AML; group 2 (3 patients) displayed macroscopic AML; group 3 (9 patients) displayed only renal cysts and group 4 (9 patients) displayed the association of AML and cysts. Increased renal size, the large number and size of cystic lesions were suggestive of the CGS. The isolated AML were suggestive of classical STB. The average growth of angiomyolipoma was low before age of 12 and exceeded 4 mm/year thereafter. CONCLUSION: In children with TSC, renal involvement is common. Some US criteria can help to suggest the diagnosis of CGS. The growth of angiomyolipoma is slow before 12 years and accelerates thereafter. Complications are rare.

Epileptic patients with de novo STXBP1 mutations: Key clinical features based on 24 cases.

OBJECTIVE: Mutations in the syntaxin binding protein 1 gene (STXBP1) have been associated mostly with early onset epileptic encephalopathies (EOEEs) and Ohtahara syndrome, with a mutation detection rate of approximately 10%, depending on the criteria of selection of patients. The aim of this study was to retrospectively describe clinical and electroencephalography (EEG) features associated with STXBP1-related epilepsies to orient molecular screening. METHODS: We screened STXBP1 in a cohort of 284 patients with epilepsy associated with a developmental delay/intellectual disability and brain magnetic resonance imaging (MRI) without any obvious structural abnormality. We reported on patients with a mutation and a microdeletion involving STXBP1 found using array comparative genomic hybridization (CGH). RESULTS: We found a mutation of STXBP1 in 22 patients and included 2 additional patients with a deletion including STXBP1. In 22 of them, epilepsy onset was before 3 months of age. EEG at onset was abnormal in all patients, suppression-burst and multifocal abnormalities being the most common patterns. The rate of patients carrying a mutation ranged from 25% in Ohtahara syndrome to <5% in patients with an epilepsy beginning after 3 months of age. Epilepsy improved over time for most patients, with an evolution to West syndrome in half. Patients had moderate to severe developmental delay with normal head growth. Cerebellar syndrome with ataxic gait and/or tremor was present in 60%. SIGNIFICANCE: Our data confirm that STXBP1 mutations are associated with neonatal-infantile epileptic encephalopathies. The initial key features highlighted in the cohort of early epileptic patients are motor seizures either focal or generalized, abnormal initial interictal EEG, and normal head growth. In addition, we constantly found an ongoing moderate to severe developmental delay with normal head growth. Patients often had ongoing ataxic gait with trembling gestures. Altogether these features should help the clinician to consider STXBP1 molecular screening.

Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A.

Mutations in the KCNQ2 and KCNQ3 genes encoding for Kv 7.2 (KCNQ2; Q2) and Kv 7.3 (KCNQ3; Q3) voltage-dependent K(+) channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug-resistant seizures with psychomotor retardation, electroencephalogram (EEG) suppression-burst pattern (Ohtahara syndrome), and distinct neuroradiological features, a condition that was named "KCNQ2 encephalopathy." In the present article, we describe clinical, genetic, and functional data from 17 patients/families whose electroclinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three insertions/deletions and three large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies.

Mono and biallelic variants in HCN2 cause severe neurodevelopmental disorders.

Hyperpolarization activated Cyclic Nucleotide (HCN) gated channels are crucial for various neurophysiological functions, including learning and sensory functions, and their dysfunction are responsible for brain disorders, such as epilepsy. To date, HCN2 variants have only been associated with mild epilepsy and recently, one monoallelic missense variant has been linked to developmental and epileptic encephalopathy. Here, we expand the phenotypic spectrum of HCN2- related disorders by describing twenty-one additional individuals from fifteen unrelated families carrying HCN2 variants. Seventeen individuals had developmental delay/intellectual disability (DD/ID), two had borderline DD/ID, and one had borderline DD. Ten individuals had epilepsy with DD/ID, with median age of onset of 10 months, and one had epilepsy with normal development. Molecular diagnosis identified thirteen different pathogenic HCN2 variants, including eleven missense variants affecting highly conserved amino acids, one frameshift variant, and one in-frame deletion. Seven variants were monoallelic of which five occurred de novo, one was not maternally inherited, one was inherited from a father with mild learning disabilities, and one was of unknown inheritance. The remaining six variants were biallelic, with four homozygous and two compound heterozygous variants. Functional studies using two-electrode voltage-clamp recordings in Xenopus laevis oocytes were performed on three monoallelic variants, p.(Arg324His), p.(Ala363Val), and p.(Met374Leu), and three biallelic variants, p.(Leu377His), p.(Pro493Leu) and p.(Gly587Asp). The p.(Arg324His) variant induced a strong increase of HCN2 conductance, while p.(Ala363Val) and p.(Met374Leu) displayed dominant negative effects, leading to a partial loss of HCN2 channel function. By confocal imaging, we found that the p.(Leu377His), p.(Pro493Leu) and p.(Gly587Asp) pathogenic variants impaired membrane trafficking, resulting in a complete loss of HCN2 elicited currents in Xenopus oocytes. Structural 3D-analysis in depolarized and hyperpolarized states of HCN2 channels, revealed that the pathogenic variants p.(His205Gln), p.(Ser409Leu), p.(Arg324Cys), p.(Asn369Ser) and p.(Gly460Asp) modify molecular interactions altering HCN2 function. Taken together, our data broadens the clinical spectrum associated with HCN2 variants, and disclose that HCN2 is involved in developmental encephalopathy with or without epilepsy.

Paroxysmal Tonic Upgaze in a Patient With Congenital Ataxia due to a De Novo Missense Variant of CACNA1G.

BACKGROUND: Paroxysmal tonic upgaze (PTU), defined as an involuntary upward movement of the eyes, has been considered as a benign phenomenon but may also be associated with ataxia and developmental delay. To date, CACNA1G mutations have been reported in autosomal dominant spinocerebellar ataxia designated SCA42 and in early encephalopathies with cerebellar atrophy but never in periodic childhood manifestations of PTU type. METHODS AND RESULTS: We report the case of a two-month-old infant with a de novo pathogenic variation of CACNA1G who presented with PTU associated with congenital ataxia and other periodic neurological manifestations. CONCLUSIONS: Although the link between CACNA1G mutations and periodic neurological manifestations remains unclear, we provide detailed video documentations of PTU, paroxysmal torticollis, and ataxia in a patient with a CACNA1G mutation. This case allows a better understanding of the underlying mechanisms of PTU and suggests potential new avenues for clinical treatments.

Differentiating Genetic Forms of Pontocerebellar Hypoplasia From Acquired Lesions Resembling Pontocerebellar Hypoplasia: Clinical, Neurodevelopmental, and Imaging Insight From 19 Extremely Premature Patients.

It is well established that extreme prematurity can be associated with cerebellar lesions potentially affecting the neurologic prognosis. One of the commonly observed lesions in these cases is pontocerebellar hypoplasia resulting from prematurity, which can pose challenges in distinguishing it from genetically caused pontocerebellar hypoplasia. This confusion leads to unacceptable and prolonged diagnostic ambiguity for families as well as difficulties in genetic counseling. Therefore, it is crucial to identify the clinical and neuroradiologic features allowing to differentiate between acquired and genetic forms of pontocerebellar hypoplasia in order to guide clinical practices and improve patient care. In this regard, we report in the present manuscript the clinical, developmental, and radiologic characteristics of 19 very premature children (gestational age <28 weeks, now aged 3-14 years) with cerebellar lesions and discuss the causal mechanisms. Our findings support the notion that a combination of specific clinical and radiologic criteria is essential in distinguishing between acquired and genetic forms of pontocerebellar hypoplasia.

Musical abilities in children with developmental cerebellar anomalies.

Developmental Cerebellar Anomalies (DCA) are rare diseases (e.g., Joubert syndrome) that affect various motor and non-motor functions during childhood. The present study examined whether music perception and production are affected in children with DCA. Sixteen children with DCA and 37 healthy matched control children were tested with the Montreal Battery for Evaluation of Musical Abilities (MBEMA) to assess musical perception. Musical production was assessed using two singing tasks: a pitch-matching task and a melodic reproduction task. Mixed model analyses showed that children with DCA were impaired on the MBEMA rhythm perception subtest, whereas there was no difference between the two groups on the melodic perception subtest. Children with DCA were also impaired in the melodic reproduction task. In both groups, singing performance was positively correlated with rhythmic and melodic perception scores, and a strong correlation was found between singing ability and oro-bucco-facial praxis in children with DCA. Overall, children with DCA showed impairments in both music perception and production, although heterogeneity in cerebellar patient's profiles was highlighted by individual analyses. These results confirm the role of the cerebellum in rhythm processing as well as in the vocal sensorimotor loop in a developmental perspective. Rhythmic deficits in cerebellar patients are discussed in light of recent work on predictive timing networks including the cerebellum. Our results open innovative remediation perspectives aiming at improving perceptual and/or production musical abilities while considering the heterogeneity of patients' clinical profiles to design music-based therapies.

Corrigendum: Musical abilities in children with developmental cerebellar anomalies.

[This corrects the article DOI: 10.3389/fnsys.2022.886427.].

CACNA1A-associated epilepsy: Electroclinical findings and treatment response on seizures in 18 patients.

CACNA1A pathogenic mutations are involved in various neurological phenotypes including episodic ataxia (EA2), spinocerebellar ataxia (SCA6), and familial hemiplegic migraine (FHM1). Epilepsy is poorly documented. We studied 18 patients (10 males) carrying de novo or inherited CACNA1A mutations, with median age of 2,5 years at epilepsy onset. Eight mutations were novel. Two variants known leading to gain of function (GOF) were found in 5 patients. Five other patients had non-sense variants leading to loss of function (LOF). Seizures were most often revealed by either status epilepticus (SE) (n = 8), eventually triggered by fever (n = 5), or absences/behavioural arrests (n = 7). Non-epileptic paroxysmal events were frequent and consisted in recurrent hemiplegic accesses (n = 9), jitteriness in the neonatal period (n = 6), and ocular paroxysmal events (n = 9). Most of the patients had early permanent cerebellar dysfunction (n = 16) and early moderate to severe global developmental delay (GDD)/intellectual deficiency (ID) (n = 17). MRI was often abnormal, with cerebellar (n = 8) and/or cerebral (n = 6) atrophy. Stroke-like occurred in 2 cases. Some antiepileptic drugs including topiramate, levetiracetam, lamotrigine and valproate were effective on seizures. Acetazolamide and calcium channel blockers were often effective when used. More than half of the patients had refractory epilepsy. CACNA1A mutation should be evoked in front of 2 main electro-clinical phenotypes that are associated with permanent cerebellar dysfunction and moderate to severe GDD/ID. The first one, found in all 5 patients with GOF variants, is characterized by intractable seizures, early and recurrent SE and hemiplegic accesses. The second, less severe, found in 5 patients with LOF variants, is characterized by refractory early onset absence seizures.

Levetiracetam-induced depression in a 5-year-old child with partial epilepsy.

Depression in children and adolescents with epilepsy is common. Depression worsen quality of life in epilepsy patients. Neurobiological, social, and iatrogenic factors may play a role in depressive disorder development. We report a patient with partial epilepsy secondary to neonatal stroke, who developed depressive disorder as a result of levetiracetam (LEV) treatment. Our report illustrates the possible implication of iatrogenic factors in depression among epilepsy patients. However, recent data suggest that LEV may be effective in case of affective disorders. We discuss the factors linking epilepsy with depression. Because of its high incidence and its multiple physiopathologic factors, psychiatric comorbidity should be always assessed in pediatric epileptic patients.

Relapsing encephalopathy with cerebellar ataxia are caused by variants involving p.Arg756 in ATP1A3.

Mutations in ATP1A3 lead to different phenotypes having in common acute neurological decompensation episodes triggered by a specific circumstance and followed by sequelae. Alongside Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss syndrome (CAPOS), a new Relapsing Encephalopathy with Cerebellar Ataxia (RECA) phenotype was published in 2015. We describe herein eight new pediatric cases. Most of them had no specific history when the first neurological decompensation episode occurred, before the age of 5 years, triggered by fever with severe paralytic hypotonia followed by ataxia with or without abnormal movements. Neurological sequelae with ataxia as the predominant symptom were present after the first episode in three cases and after at least one subsequent relapse in five cases. Five of the eight cases had a familial involvement with one of the two parents affected. The phenotype-genotype correlation is unequivocal with the causal substitution always located at position 756. The pathophysiology of the dysfunctions of the mutated ATPase pump, triggered by fever is unknown. Severe recurrent neurological decompensation episodes triggered by fever, without any metabolic cause, should lead to the sequencing of ATP1A3.

Epilepsia partialis continua and defects in the mitochondrial respiratory chain.

UNLABELLED: Epilepsia partialis continua (EPC) is characterized by continuous myoclonic or clonic jerks repeated at short intervals followed by a slowly progressive neurological disorder. We report three patients with EPC and a defect in the mitochondrial respiratory chain. METHODS: Clinical, neuroradiological, and biochemical data were reported. RESULTS: The patients presented continuous myoclonic jerks at age of 8 months, 11 months and 6 years, respectively. Two of the three patients had a previous developmental delay. Neurological examination at first admission revealed extrapyramidal symptoms in all patients. Initial biological investigations suggested mitochondrial dysfunction. Initial EEG showed a continuous discharge of periodic spikes (0.5-1Hz). MRI studies were initially normal then progressed to cerebral hemiatrophia. EEG revealed both correlation and absence of correlation between spikes or sharp waves and myoclonic jerks. The activity of one or several complexes of the mitochondrial respiratory chain was reduced in the muscle samples of the three patients. No mutation of mtDNA was found. CONCLUSION: Our report suggests that EPC can be due to mitochondrial respiratory chain disorders. Some clinical findings and initial investigations were indicative of a disorder of mitochondrial metabolism. Previous developmental delay, extrapyramidal symptoms and other organ involvement should suggest a possible mitochondrial etiology of EPC. In case of infant presenting EPC, mitochondrial respiratory chain disorder should be considered first.

Expanding the phenotype of SCA19/22: Parkinsonism, cognitive impairment and epilepsy.

INTRODUCTION: Spinocerebellar ataxia types 19 and 22 (SCA19/22) are rare conditions in which relatively isolated cerebellar involvement is frequently associated with cognitive impairment. Here, we report on new clinical features and provide details of the cognitive profile in two SCA19/22 families. METHODS: Two families displaying an autosomal-dominant form of cerebellar ataxia underwent clinical examinations and genetic testing. RESULTS: In addition to the classical clinical features of SCA, a wide spectrum of cognitive disorders (including visuospatial impairments) was observed. Eight patients had mild Parkinsonism, and five had epilepsy. Genetic testing showed that the KCND3 mutation (c.679_681delTTC, p.F227del) was present in both families. CONCLUSIONS: Our findings broaden the phenotypic spectrum of SCA19/22, and suggest that KCND3 should be included in the list of candidate genes for epilepsy, Parkinsonism and cognitive impairment.