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Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an autosomal recessive neurodegenerative disease, usually caused by biallelic AAGGG repeat expansions in RFC1. In this study, we leveraged whole genome sequencing data from nearly 10 000 individuals recruited within the Genomics England sequencing project to investigate the normal and pathogenic variation of the RFC1 repeat. We identified three novel repeat motifs, AGGGC (n = 6 from five families), AAGGC (n = 2 from one family) and AGAGG (n = 1), associated with CANVAS in the homozygous or compound heterozygous state with the common pathogenic AAGGG expansion. While AAAAG, AAAGGG and AAGAG expansions appear to be benign, we revealed a pathogenic role for large AAAGG repeat configuration expansions (n = 5). Long-read sequencing was used to characterize the entire repeat sequence, and six patients exhibited a pure AGGGC expansion, while the other patients presented complex motifs with AAGGG or AAAGG interruptions. All pathogenic motifs appeared to have arisen from a common haplotype and were predicted to form highly stable G quadruplexes, which have previously been demonstrated to affect gene transcription in other conditions. The assessment of these novel configurations is warranted in CANVAS patients with negative or inconclusive genetic testing. Particular attention should be paid to carriers of compound AAGGG/AAAGG expansions when the AAAGG motif is very large (>500 repeats) or the AAGGG motif is interrupted. Accurate sizing and full sequencing of the satellite repeat with long-read sequencing is recommended in clinically selected cases to enable accurate molecular diagnosis and counsel patients and their families., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene was recently identified in two/third of patients with cerebellar ataxia, sensory neuropathy, and bilateral vestibular areflexia syndrome (CANVAS). The phenotypic spectrum has expanded since (i.e., parkinsonism, motor neuron involvement, cognitive decline); no behavioral symptoms have been reported yet., Case Report: We report an Italian family that met the diagnostic criteria for CANVAS, and RFC1-expansion was detected in five of seven. All the affected members presented behavioral-psychiatric symptoms (anxiety, panic attacks, alcohol abuse) before the multisystemic RFC1-expansion manifestation. The disease course was progressive, with ataxia and behavioral-cognitive aspects as the most disabling symptoms., Conclusion: These behavioral-cognitive observations may broaden the RFC1-expansion phenotypic spectrum and highlight the importance of investigating the whole non-motor symptoms in ataxic patients., (© 2022. Fondazione Società Italiana di Neurologia.)

Pathogenic variants in polynucleotide kinase 3'-phosphatase (PNKP) gene have been associated with two distinct clinical presentations: autosomal recessive microcephaly, seizures, and developmental delay (MCSZ; MIM 613402) and ataxia with oculomotor apraxia type 4 (AOA4; MIM 616267). More than 40 patients have been reported so far, and their clinical presentations revealed a continuum phenotypic spectrum ranging from congenital microcephaly and early-onset intractable seizures, to adult onset slowly progressive sensory-motor neuropathy and cerebellar ataxia. We describe three unrelated Italian patients with different phenotypes and novel or recurrent pathogenic variants in PNKP gene. Patient 1, homozygous for the recurrent frameshift variant (p.Thr424Glyfs*49), had an early-onset MCSZ phenotype. Late in the disease progression, cerebellar ataxia and peripheral neuropathy were recognized. Patient 2, homozygous for a frameshift variant (p.Ala429Thrfs*42), presented a phenotype partially consistent with MCSZ including microcephaly and developmental delay, but without seizures. Patient 3 is one of the oldest patients described to date and presented polyneuropathy, and cerebellar signs. Biochemical tests showed abnormalities of cholesterol, albumin, or alpha-fetoprotein plasma levels. The clinical presentation of our patients encompassed early-to-adult-onset manifestations. For these cases, the long clinical follow-up allowed an in-depth phenotypic characterization and a better delineation of the natural history of patients carrying PNKP pathogenic variants., (© 2019 Wiley Periodicals, Inc.)

Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause a relatively pure, slowly progressive cerebellar recessive ataxia mostly identified in Quebec, Canada. Combining next-generation sequencing techniques and deep-phenotyping (clinics, magnetic resonance imaging, positron emission tomography, muscle histology), we here established the frequency, phenotypic spectrum and genetic spectrum of SYNE1 in a screening of 434 non-Canadian index patients from seven centres across Europe. Patients were screened by whole-exome sequencing or targeted panel sequencing, yielding 23 unrelated families with recessive truncating SYNE1 mutations (23/434 = 5.3%). In these families, 35 different mutations were identified, 34 of them not previously linked to human disease. While only 5/26 patients (19%) showed the classical SYNE1 phenotype of mildly progressive pure cerebellar ataxia, 21/26 (81%) exhibited additional complicating features, including motor neuron features in 15/26 (58%). In three patients, respiratory dysfunction was part of an early-onset multisystemic neuromuscular phenotype with mental retardation, leading to premature death at age 36 years in one of them. Positron emission tomography imaging confirmed hypometabolism in extra-cerebellar regions such as the brainstem. Muscle biopsy reliably showed severely reduced or absent SYNE1 staining, indicating its potential use as a non-genetic indicator for underlying SYNE1 mutations. Our findings, which present the largest systematic series of SYNE1 patients and mutations outside Canada, revise the view that SYNE1 ataxia causes mainly a relatively pure cerebellar recessive ataxia and that it is largely limited to Quebec. Instead, complex phenotypes with a wide range of extra-cerebellar neurological and non-neurological dysfunctions are frequent, including in particular motor neuron and brainstem dysfunction. The disease course in this multisystemic neurodegenerative disease can be fatal, including premature death due to respiratory dysfunction. With a relative frequency of ∼5%, SYNE1 is one of the more common recessive ataxias worldwide., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) is an autosomal recessive neurodegenerative disease, usually caused by biallelic AAGGG repeat expansions in RFC1. In this study, we leveraged whole genome sequencing data from nearly 10 000 individuals recruited within the Genomics England sequencing project to investigate the normal and pathogenic variation of the RFC1 repeat. We identified three novel repeat motifs, AGGGC (n = 6 from five families), AAGGC (n = 2 from one family) and AGAGG (n = 1), associated with CANVAS in the homozygous or compound heterozygous state with the common pathogenic AAGGG expansion. While AAAAG, AAAGGG and AAGAG expansions appear to be benign, we revealed a pathogenic role for large AAAGG repeat configuration expansions (n = 5). Long-read sequencing was used to characterize the entire repeat sequence, and six patients exhibited a pure AGGGC expansion, while the other patients presented complex motifs with AAGGG or AAAGG interruptions. All pathogenic motifs appeared to have arisen from a common haplotype and were predicted to form highly stable G quadruplexes, which have previously been demonstrated to affect gene transcription in other conditions. The assessment of these novel configurations is warranted in CANVAS patients with negative or inconclusive genetic testing. Particular attention should be paid to carriers of compound AAGGG/AAAGG expansions when the AAAGG motif is very large (>500 repeats) or the AAGGG motif is interrupted. Accurate sizing and full sequencing of the satellite repeat with long-read sequencing is recommended in clinically selected cases to enable accurate molecular diagnosis and counsel patients and their families. [ABSTRACT FROM AUTHOR]

A wide spectrum of neurodegenerative diseases has been associated with pathogenic variants in the PNPLA6 (patatin-like phospholipase domain-containing protein 6) gene, including spastic paraplegia type 39, Gordon—Holmes, Boucher—Neuhauser, Oliver—Mc Farlane, and Laurence—Moon syndromes. These syndromes present variable and overlapping clinical symptoms, encompassing cerebellar ataxia, hypogonadotropic hypogonadism, chorioretinal dystrophy, spastic paraplegia, muscle wasting, peripheral neuropathy, and cognitive impairment. In the present study, we performed a wide genetic screening in 292 patients presenting with ataxia or spastic paraplegia using a probe-based customized gene panel, covering >200 genes associated with spinocerebellar diseases. We identified six novel and four recurrent PNPLA6 gene variants in eight patients (2.7%). Six patients presented an infantile or juvenile onset (age <18), and two patients had an adult onset. Cerebellar ataxia was observed in seven patients and spastic paraplegia in one patient. Progression of cerebellar symptoms was slow in all patients, who retained ambulation even after a mean disease duration of 15 years. Brain MRI showed cerebellar atrophy in 6/8 patients, more pronounced in superior and dorsal vermis lobules (I to VII). Additional clinical features included hypogonadotropic hypogonadism (5/8), growth hormone deficiency (2/8), peripheral axonal neuropathy (4/8), cognitive impairment (3/8), chorioretinal dystrophy (2/8), and bilateral vestibular areflexia with a reduced visual vestibule-ocular reflex (1/8). In accordance with previous studies, chorioretinal dystrophy was the most frequent presenting symptom in early onset patients, hypogonadotropic hypogonadism in juvenile onset cases, and cerebellar ataxia in adult patients. One patient had an initial clinical presentation compatible with Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS), but no pathological expansions in the RFC1 gene. In conclusion, patients with PNPLA6 variants present a variable age of onset spanning from infancy to adulthood, and each clinical symptom has an age-dependent manifestation thus requiring a multi-systemic diagnostic approach. The description of patients presenting very late-onset cerebellar ataxia suggests that PNPLA6 genetic screening should also be considered in the diagnostic workout of adult cerebellar ataxia. [ABSTRACT FROM AUTHOR]

Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause a relatively pure, slowly progressive cerebellar recessive ataxia mostly identified in Quebec, Canada. Combining next-generation sequencing techniques and deep-phenotyping (clinics, magnetic resonance imaging, positron emission tomography, muscle histology), we here established the frequency, phenotypic spectrum and genetic spectrum of SYNE1 in a screening of 434 non-Canadian index patients from seven centres across Europe. Patients were screened by whole-exome sequencing or targeted panel sequencing, yielding 23 unrelated families with recessive truncating SYNE1 mutations (23/434 = 5.3%). In these families, 35 different mutations were identified, 34 of them not previously linked to human disease. While only 5/26 patients (19%) showed the classical SYNE1 phenotype of mildly progressive pure cerebellar ataxia, 21/26 (81%) exhibited additional complicating features, including motor neuron features in 15/26 (58%). In three patients, respiratory dysfunction was part of an early-onset multisystemic neuromuscular phenotype with mental retardation, leading to premature death at age 36 years in one of them. Positron emission tomography imaging confirmed hypometabolism in extra-cerebellar regions such as the brainstem. Muscle biopsy reliably showed severely reduced or absent SYNE1 staining, indicating its potential use as a non-genetic indicator for underlying SYNE1 mutations. Our findings, which present the largest systematic series of SYNE1 patients and mutations outside Canada, revise the view that SYNE1 ataxia causes mainly a relatively pure cerebellar recessive ataxia and that it is largely limited to Quebec. Instead, complex phenotypes with a wide range of extra-cerebellar neurological and non-neurological dysfunctions are frequent, including in particular motor neuron and brainstem dysfunction. The disease course in this multisystemic neurodegenerative disease can be fatal, including premature death due to respiratory dysfunction. With a relative frequency of ∼5%, SYNE1 is one of the more common recessive ataxias worldwide. [ABSTRACT FROM AUTHOR]