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CACNA1A, ataxias, DEE42, epilepsy, neurogenetics In contrast, cryptogenic PTU may have only coordination difficulties during its ictal phase.[10] In conclusion, CACNA1A sequencing should also be considered in the settings of early epilepsy and/or developmental delay when chronic cerebellar signs are present. Keywords: CACNA1A; ataxias; DEE42; epilepsy; neurogenetics EN CACNA1A ataxias DEE42 epilepsy neurogenetics 1225 1227 3 08/29/23 20230801 NES 230801 The gene CACNA1A encodes the a1A pore-forming subunit of the neuronal calcium channel P/Q.[1] CACNA1A-related disorders include the allelic episodic neurological disorders, familial hemiplegic migraine type 1 and episodic ataxia type 2, and the spinocerebellar ataxia type 6, which is a late-onset and progressive cerebellar ataxia. [Extracted from the article]

Background: Biallelic loss‐of‐function NDUFA12 variants have hitherto been linked to mitochondrial complex I deficiency presenting with heterogeneous clinical and radiological features in nine cases only. Objectives: To fully characterize, both phenotypically and genotypically, NDUFA12‐related mitochondrial disease. Methods: We collected data from cases identified by screening genetic databases of several laboratories worldwide and systematically reviewed the literature. Results: Nine unreported NDUFA12 cases from six pedigrees were identified, with presentation ranging from movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. MRI showed basal ganglia abnormalities (n = 6), optic atrophy (n = 2), or was unremarkable (n = 1). All carried homozygous truncating NDUFA12 variants, three of which are novel. Conclusions: Our case series expands phenotype–genotype correlations in NDUFA12‐associated mitochondrial disease, providing evidence of intra‐ and inter‐familial clinical heterogeneity for the same variant. It confirms NDUFA12 variants should be included in the diagnostic workup of Leigh/Leigh‐like syndromes – particularly with dystonia – as well as isolated optic atrophy. [ABSTRACT FROM AUTHOR]

This article discusses the prevalence of spinocerebellar ataxia type 6 (SCA6) in Japanese immigrants in Brazil. The authors compare the frequency of SCA6 in Japan and Brazil, finding that it is relatively uncommon in Brazil compared to other subtypes of SCA. They also note that all of the SCA6 patients in their study had Japanese ancestry. The authors suggest that genetic diseases should be considered and investigated in individuals with Japanese ancestry, and that this guidance should be applied in other countries as well. [Extracted from the article]

Background: Ataxia telangiectasia is one of the most common causes of autosomal recessive cerebellar ataxias. However, absence of telangiectasia, normal levels of alpha‐fetoprotein and negative genetic test may direct to alternative diagnosis with similar phenotypes such as ataxia telangiectasia‐like disorders (ATLD). Cases: We report two instructive cases of ATLD: the first case with ataxia telangiectasia‐like disorder type 1 related to MRE11A gene, and the second case with ataxia telangiectasia‐like disorder type 2 related to PCNA gene. Literature Review: ATLD is an unusual group of autosomal recessive diseases that share some clinical features and pathophysiological mechanisms with ataxia telangiectasia (AT). ATLD may be associated with mutations in the MRE11A (ATLD type 1) and PCNA (ATLD type 2) genes. ATLD belongs to the group of chromosomal instability syndromes. The reason for the term ATLD is related to the similar pathophysiological mechanisms observed in AT, which is characterized by chromosomal instability and radiosensitivity. Conclusions: In this review, the main clinical features, biomarkers, brain imaging and genetics of ATLD are discussed. Mutations in the MRE11A and PCNA genes should be included in the differential diagnosis for early onset cerebellar ataxia with absence of telangiectasia and normal levels of alpha‐fetoprotein. View Supplementary Video 1 [ABSTRACT FROM AUTHOR]

Background: Molecular imaging has proven to be a powerful tool to elucidate degenerated paths in a wide variety of neurological diseases and has not been systematically studied in hereditary spastic paraplegias.Objectives: To investigate dopaminergic degeneration in a cohort of 22 patients with hereditary spastic paraplegia attributed to SPG11 mutations and evaluate treatment response to l-dopa.Methods: Patients and controls underwent single-photon emission computed tomography imaging utilizing 99m Tc-TRODAT-1 tracer. A single-blind trial with 600 mg of l-dopa was performed comparing UPDRS scores.Results: Reduced dopamine transporter density was universal among patients. Nigral degeneration was symmetrical and correlated with disease duration and motor and cognitive handicap. No statistically significant benefit could be demonstrated with l-dopa intake during the trial.Conclusion: Disruption of presynaptic dopaminergic pathways is a widespread phenomenon in patients with SPG11 mutations, even in the absence of parkinsonism. Unresponsiveness to treatment could be related to postsynaptic damage that needs to be further investigated. [ABSTRACT FROM AUTHOR]

Objective: Machado-Joseph disease (SCA3/MJD) is the most frequent spinocerebellar ataxia worldwide and characterized by brainstem, basal ganglia, and cerebellar damage. However, little is known about the natural history of the disease. This motivated us to determine the extension and progression of central nervous system involvement in SCA3/MJD using multimodal magnetic resonance imaging (MRI)-based analyses in a large cohort of patients (n = 79) and presymptomatic subjects (n = 12).Methods: All subjects underwent MRI in a 3T device to assess gray and white matter. To evaluate the cerebral and cerebellar cortices, we used measures from FreeSurfer and SUIT. T1-multiatlas assessed deep gray matter. Diffusion tensor imaging multiatlas was used to investigate cerebral white matter (WM) and SpineSeg to assess the cervical spinal cord.Results: There was widespread WM and cerebellar damage, in contrast to the restricted motor cortex involvement when all patients are compared to age- and sex-matched controls. Presymtomatic patients showed WM microstructural abnormalities mainly in the cerebellar and cerebral peduncles and volumetric reduction of midbrain, spinal cord, and substantia nigra. To assess the disease progression, we divided patients into four subgroups defined by time from ataxia onset. There was a clear pattern of evolving structural compromise, starting in infratentorial structures and progressing up to the cerebral cortex.Conclusion: Structural damage in SCA3/MJD begins in the spinal cord, cerebellar peduncles, as well as substantia nigra and progresses to cerebral areas in the long term. These structural differences reveal some insights into the pathogenesis of SCA3/MJD and suggest a staging scheme to map the progression of the disease. Ann Neurol 2018;84:401-408. [ABSTRACT FROM AUTHOR]

The association of young-adult-onset cerebellar ataxia, vertical supranuclear gaze palsy, bulbar dysfunction, and cognitive impairment suggest the diagnosis of NPC. SP 2 sp In our patient, molecular testing disclosed the homozygous variant NM 000271.4 ( I NPC1 i ): c.2292G>A;(Silent), classified as pathogenic, and confirmed the diagnosis. Ataxia, gaze palsy Keywords: ataxia; gaze palsy EN ataxia gaze palsy 397 398 2 04/05/22 20220401 NES 220401 A 28-year-old woman presented with progressive gait ataxia and speech impairment that started 7 years ago. [Extracted from the article]

The clinical features of multiple system atrophy (MSA) include four domains: autonomic failure/urinary dysfunction, Parkinsonism, cerebellar ataxia, and corticospinal tract dysfunction. Although the diagnosis of definite MSA requires pathological confirmation, magnetic resonance imaging (MRI) studies have been shown to contribute to the diagnosis of MSA. Although pyramidal tract dysfunction is frequent in MSA patients, signs of pyramidal tract involvement are controversially demonstrated by MRI. We evaluated the pyramidal involvement in 10 patients (7 women) with clinically probable MSA, detecting the presence of spasticity, hyperreflexia, and Babinski sign, as well as demonstrating degeneration of the pyramidal tract and primary motor cortex by MRI in all of them. Our article also discusses key radiological features of this syndrome. In MSA, pyramidal tract involvement seems to be more frequent than previously thought, and the clinicoradiological correlation between pyramidal tract dysfunction and degeneration may contribute to the understanding of the clinical hallmarks of MSA. MRI may also add information regarding the differential diagnosis of this syndrome. © 2006 Movement Disorder Society [ABSTRACT FROM AUTHOR]

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The article discusses a case of hereditary truncal dystonia associated with an ANO3 gene variant. The patient, a 67-year-old woman, presented with flexion of the thoracolumbar spine and a family history of late-onset camptocormia. Genetic testing revealed a likely pathogenic variant in the ANO3 gene, broadening the phenotypic spectrum of ANO3-related dystonias. The study highlights the importance of genetic testing for patients with truncal dystonia and a positive family history, offering insights into the genetic basis of movement disorders. [Extracted from the article]