Pathogenic variants in the SMN complex gene GEMIN5 cause cerebellar atrophy

AbstractPLA2G6 is the causative gene for a group of autosomal recessive neurodegenerative disorders known as PLA2G6-associated neurodegeneration (PLAN). We present a case with early-onset parkinsonism, ataxia, cognitive decline, cerebellar atrophy, and brain iron accumulation. Sequencing of PLA2G6 coding regions identified only a heterozygous nonsense variant, but mRNA analysis revealed the presence of an aberrant transcript isoform due to a novel deep intronic variant (c.2035-274G > A) leading to activation of an intronic pseudo-exon. These results expand the genotypic spectrum of PLAN, showing the paramount importance of detecting possible pathogenic variants in deep intronic regions in undiagnosed patients.

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Ataxia teleangiectasia. Az idegrendszeri érintettség prototípusa primer immundefektusokban

Orvosi Hetilap ◽

10.1556/650.2018.31271 ◽

2018 ◽

Vol 159 (49) ◽

pp. 2057-2064

Author(s):

Zoltán Liptai

Keyword(s):

Immune Deficiency ◽

Ataxia Telangiectasia ◽

Late Onset ◽

Brain Mri ◽

Cerebellar Atrophy ◽

Biallelic Mutation ◽

Pathogenic Variants ◽

Diagnostic Difficulties ◽

Immune Deficiencies ◽

Atm Gene

Abstract: The number of primary immune deficiencies exceeds 350, approximately a quarter of them having neurological implications. Severe central nervous system infections may occur in an even higher proportion. Beyond listing in a table of all diseases with a neurological impact, the author gives detailed analysis of one typical disorder. Ataxia telangiectasia is caused by biallelic mutation of the ATM gene resulting in genomic instability, increased cancer risk, immune deficiency and a predominantly cerebellar neurodegeneration. The most common classic form is characterized by gait and limb ataxia, oculomotor apraxia, choreoathetosis, disturbance of speech and swallowing, less often by other movement disorders. There is no remarkable cognitive deficit. Telangiectasia of the conjunctivae and skin usually appears after 6 years of age. Frequent, especially severe sino-pulmonary infections may indicate the immune deficiency present in 60 to 80% of patients, who are also prone to malignancies. The clinical course is sometimes atypical or has a late onset which results in diagnostic difficulties. Serum alpha-fetoprotein level is elevated in nearly all patients. Brain MRI shows progressive cerebellar atrophy starting at the age of 7–8 years. DNA testing of the ATM gene is necessary for the diagnosis. The detected biallelic pathogenic variants provide help for family planning and for possible gene therapies in the future. Ataxia telangiectasia has to be differentiated from a number of other disorders, some of which also belong to primary immune deficiencies. The disorder has no causal treatment at present, the patients live until their young adult ages. Orv Hetil. 2018; 159(49): 2057–2064.

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Characterization of a novel variant in the HR1 domain of MFN2 in a patient with ataxia, optic atrophy and sensorineural hearing loss

10.1101/2021.01.11.426268 ◽

2021 ◽

Author(s):

Govinda Sharma ◽

Rasha Saubouny ◽

Matthew M Joel ◽

Kristina Martens ◽

Davide Martino ◽

...

Keyword(s):

Hearing Loss ◽

Cerebellar Ataxia ◽

Optic Atrophy ◽

Cerebellar Atrophy ◽

Lipid Transfer ◽

Motor Weakness ◽

Charcot Marie Tooth Disease ◽

Pathogenic Variants ◽

Novel Variant

AbstractPathogenic variants in MFN2 cause Charcot-Marie-Tooth disease (CMT) type 2A (CMT2A) and are the leading cause of the axonal subtypes of CMT. CMT2A is characterized by predominantly distal motor weakness and muscle atrophy, with highly variable severity and onset age. Notably, some MFN2 variants can also lead to other phenotypes such as optic atrophy, hearing loss and lipodystrophy. Despite the clear link between MFN2 and CMT2A, our mechanistic understanding of how dysfunction of the MFN2 protein causes human disease pathologies remains incomplete. This lack of understanding is due in part to the multiple cellular roles of MFN2. Though initially characterized for its role in mediating mitochondrial fusion, MFN2 also plays important roles in mediating interactions between mitochondria and other organelles, such as the endoplasmic reticulum and lipid droplets. Additionally, MFN2 is also important for mitochondrial transport, mitochondrial autophagy, and has even been implicated in lipid transfer. Though over 100 pathogenic MFN2 variants have been described to date, only a few have been characterized functionally, and even then, often only for one or two functions. Here, we describe a novel homozygous MFN2 variant, D414V, in a patient presenting with cerebellar ataxia, deafness, blindness, and diffuse cerebral and cerebellar atrophy. Characterization of patient fibroblasts reveals phenotypes consistent with impaired MFN2 functions and expands the phenotypic presentation of MFN2 variants to include cerebellar ataxia.

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Incidental Finding of MEGDEL Syndrome Based on Neuroimaging: Case Report

Case Reports in Neurology ◽

10.1159/000516319 ◽

2021 ◽

pp. 429-433

Author(s):

Salma A. Alshammari ◽

Fouad A. Alghamdi ◽

Rami Alhazmi ◽

Shaikhah Aldossary

Keyword(s):

Incidental Finding ◽

Molecular Genetic ◽

Cerebellar Atrophy ◽

Failure To Thrive ◽

Autosomal Recessive Disorder ◽

Disease Diagnosis ◽

First Year ◽

Pathogenic Variants ◽

Clinical Presentations ◽

First Year Of Life

MEGDEL 3-methylglutaconic (MG) aciduria, deafness, encephalopathy, Leigh-like syndrome is an autosomal recessive disorder associated with infantile hypoglycemia, progressive psychomotor developmental delay, cerebellar atrophy with lesions in the basal ganglia, spasticity, dystonia, deafness, and transient liver problems, which typically occur in the first year of life. Other clinical presentations include failure to thrive, epilepsy, and optic nerve atrophy. The serine active site-containing 1 (SERAC1) mutation is localized at the mitochondria-associated membranes, which are responsible for encoding a phosphatidylglycerol remodeler essential for both mitochondrial function and intracellular cholesterol trafficking and is thus responsible for the disease. Diagnosis is confirmed by the elevation of and concentrations of 3-MG acid and 3-methylglutaric acid in the urine or by identification of bi-allelic SERAC1 pathogenic variants on molecular genetic testing. Different pathological variants of SERAC1 have been identified in MEGDEL syndrome to date. Here, we report a case of a child with MEGDEL syndrome due to SERAC1 mutation. The child presented with accidental finding by CT showing hypodensity on bilateral symmetric anterior putamen and caudate abnormal. Neurological examination was unremarkable. This report presents a new neuroimaging finding by CT of MEGDEL syndrome.

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Characterization of a novel variant in the HR1 domain of MFN2 in a patient with ataxia, optic atrophy and sensorineural hearing loss

F1000Research ◽

10.12688/f1000research.53230.1 ◽

2021 ◽

Vol 10 ◽

pp. 606

Author(s):

Govinda Sharma ◽

Rasha Sabouny ◽

Matthew Joel ◽

Kristina Martens ◽

Davide Martino ◽

...

Keyword(s):

Hearing Loss ◽

Cerebellar Ataxia ◽

Optic Atrophy ◽

Lipid Droplets ◽

Cerebellar Atrophy ◽

Mitochondrial Fusion ◽

Lipid Transfer ◽

Mtdna Copy Number ◽

Pathogenic Variants ◽

Novel Variant

Background: Pathogenic variants in MFN2 cause Charcot-Marie-Tooth disease (CMT) type 2A (CMT2A) and are the leading cause of the axonal subtypes of CMT. CMT2A is characterized by predominantly distal motor weakness and muscle atrophy, with highly variable severity and onset age. Notably, some MFN2 variants can also lead to other phenotypes such as optic atrophy, hearing loss and lipodystrophy. Despite the clear link between MFN2 and CMT2A, our mechanistic understanding of how dysfunction of the MFN2 protein causes human disease pathologies remains incomplete. This lack of understanding is due in part to the multiple cellular roles of MFN2. Though initially characterized for its role in mediating mitochondrial fusion, MFN2 also plays important roles in mediating interactions between mitochondria and other organelles, such as the endoplasmic reticulum and lipid droplets. Additionally, MFN2 is also important for mitochondrial transport, mitochondrial autophagy, and has even been implicated in lipid transfer. Though over 100 pathogenic MFN2 variants have been described to date, only a few have been characterized functionally, and even then, often only for one or two functions. Method: Several MFN2-mediated functions were characterized in fibroblast cells from a patient presenting with cerebellar ataxia, deafness, blindness, and diffuse cerebral and cerebellar atrophy, who harbours a novel homozygous MFN2 variant, D414V, which is found in a region of the HR1 domain of MFN2 where few pathogenic variants occur. Results: We found evidence for impairment of several MFN2-mediated functions. Consistent with reduced mitochondrial fusion, patient fibroblasts exhibited more fragmented mitochondrial networks and had reduced mtDNA copy number. Additionally, patient fibroblasts had reduced oxygen consumption, fewer mitochondrial-ER contacts, and altered lipid droplets that displayed an unusual perinuclear distribution. Conclusion: Overall, this work characterizes D414V as a novel variant in MFN2 and expands the phenotypic presentation of MFN2 variants to include cerebellar ataxia.

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Defining the phenotypical spectrum associated with variants in TUBB2A

Journal of Medical Genetics ◽

10.1136/jmedgenet-2019-106740 ◽

2020 ◽

Vol 58 (1) ◽

pp. 33-40

Author(s):

Stefanie Brock ◽

Tim Vanderhasselt ◽

Sietske Vermaning ◽

Kathelijn Keymolen ◽

Luc Régal ◽

...

Keyword(s):

Amino Acids ◽

Cerebral Cortex ◽

Early Life ◽

Cerebellar Atrophy ◽

Imaging Features ◽

Pathogenic Variants ◽

Brain Malformations ◽

Severe Motor ◽

Normal Cortex

BackgroundVariants in genes belonging to the tubulin superfamily account for a heterogeneous spectrum of brain malformations referred to as tubulinopathies. Variants in TUBB2A have been reported in 10 patients with a broad spectrum of brain imaging features, ranging from a normal cortex to polymicrogyria, while one patient has been reported with progressive atrophy of the cerebellar vermis.MethodsIn order to further refine the phenotypical spectrum associated with TUBB2A, clinical and imaging features of 12 patients with pathogenic TUBB2A variants, recruited via the international network of the authors, were reviewed.ResultsWe report 12 patients with eight novel and one recurrent variants spread throughout the TUBB2A gene but encoding for amino acids clustering at the protein surface. Eleven patients (91.7%) developed seizures in early life. All patients suffered from intellectual disability, and 11 patients had severe motor developmental delay, with 4 patients (36.4 %) being non-ambulatory. The cerebral cortex was normal in five individuals and showed dysgyria of variable severity in seven patients. Associated brain malformations were less frequent in TUBB2A patients compared with other tubulinopathies. None of the patients had progressive cerebellar atrophy.ConclusionThe imaging phenotype associated with pathogenic variants in TUBB2A is highly variable, ranging from a normal cortex to extensive dysgyria with associated brain malformations. For recurrent variants, no clear genotype–phenotype correlations could be established, suggesting the role of additional modifiers.

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B.06 Whole exome sequencing in genetic ataxias associated with cerebellar atrophy: the Canadian experience

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2019.95 ◽

2019 ◽

Vol 46 (s1) ◽

pp. S11

Author(s):

L Gauquelin ◽

T Hartley ◽

M Tarnopolsky ◽

DA Dyment ◽

B Brais ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Diagnostic Yield ◽

Genetic Diseases ◽

Genetic Diagnosis ◽

Cerebellar Atrophy ◽

Clinical Findings ◽

Disease Genes ◽

Pathogenic Variants ◽

Whole Exome

Background: Cerebellar atrophy is characterized by loss of cerebellar tissue, with evidence on brain imaging of enlarged interfolial spaces compared to the foliae. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. We investigated the prevalence in Canada and the diagnostic yield of whole exome sequencing (WES) for this group of conditions. Methods: Between 2011 and 2017, WES was performed in 91 participants with cerebellar atrophy as part of one of two national research programs, Finding of Rare Genetic Disease Genes (FORGE) or Enhanced Care for Rare Genetic Diseases in Canada (Care4Rare). Results: A genetic diagnosis was established in 58% of cases (53/91). Pathogenic variants were found in 24 known genes, providing a diagnosis for 46/53 participants (87%), and in four novel genes, accounting for 7/53 cases (13%). 38/91 cases (42%) remained unsolved. The most common diagnoses were channelopathies in 12/53 patients (23%) and mitochondrial disorders in 9/53 (17%). Inheritance was autosomal recessive in the majority of cases. Additional clinical findings provided useful clues to some of the diagnoses. Conclusions: This is the first report on the prevalence of genetic ataxias associated with cerebellar atrophy in Canada, and the utility of WES for this group of conditions.

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Simultaneous Identification of Both MFSD8 and RDH12 Pathogenic Variants in a Chinese Family Affected With Retinitis Pigmentosa

Frontiers in Genetics ◽

10.3389/fgene.2021.715100 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yihui Wang ◽

Yanling Teng ◽

Desheng Liang ◽

Zhuo Li ◽

Lingqian Wu

Keyword(s):

Retinitis Pigmentosa ◽

Molecular Genetic ◽

Cerebellar Atrophy ◽

Compound Heterozygous Mutation ◽

Chinese Family ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Homozygous Mutation ◽

Pathogenic Variants ◽

Reproductive Counseling

Retinitis pigmentosa (RP) is characterized by tremendous genetic and phenotypic heterogeneity. Here, we investigate the pathogeny of RP in a family to provide evidence for genetic and reproductive counseling for families. Although this pregnant woman of 8+3 weeks presented with RP, her first baby was born with RP, epilepsy, and cerebellar atrophy. The research identified a compound heterozygous mutation (c.998+3_998+6del/deletion) in the MFSD8 gene of the first born, explaining the cause of the proband’s disease, which cannot explain the mother’s. Then, a homozygous mutation c.343+1G > A in RDH12 of the mother was found. RT-PCR is employed to find that there is a skipping of exon 10 in MFSD8 and a 15-nucleotide retention of intron5 in RDH12. The coexistence of two independent instances of RP caused by distinct genes in one pedigree is demonstrated. Based on the diagnosis, a prenatal diagnosis performed on the fetus found that the fetus’s MFSD8 is affected by the same mutation as the proband. The research underscoring the complexity of RP and the need for the combination of extensive molecular genetic testing and clinical characterization in addition expands the spectrum of MFSD8 mutations. Finally, it is expected that the family members would be prevented from reproducing children with the similar disease.

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Heterozygous STUB1 missense variants cause ataxia, cognitive decline, and STUB1 mislocalization

Neurology Genetics ◽

10.1212/nxg.0000000000000397 ◽

2020 ◽

Vol 6 (2) ◽

pp. e397 ◽

Cited By ~ 1

Author(s):

Dong-Hui Chen ◽

Caitlin Latimer ◽

Mayumi Yagi ◽

Mesaki Kenneth Ndugga-Kabuye ◽

Elyana Heigham ◽

...

Keyword(s):

Cognitive Decline ◽

Autosomal Dominant ◽

Cerebellar Atrophy ◽

Dominant Inheritance ◽

Missense Variants ◽

Pathogenic Variants ◽

Behavioral Abnormalities ◽

Significant Pathology ◽

Autosomal Dominant Ataxia ◽

Dominant Ataxia

ObjectiveTo identify the genetic cause of autosomal dominant ataxia complicated by behavioral abnormalities, cognitive decline, and autism in 2 families and to characterize brain neuropathologic signatures of dominant STUB1-related ataxia and investigate the effects of pathogenic variants on STUB1 localization.MethodsClinical and research-based exome sequencing was used to identify the causative variants for autosomal dominant ataxia in 2 families. Gross and microscopic neuropathologic evaluations were performed on the brains of 4 affected individuals in these families.ResultsMutations in STUB1 have been primarily associated with childhood-onset autosomal recessive ataxia, but here we report heterozygous missense variants in STUB1 (p.Ile53Thr and p.The37Leu) confirming the recent reports of autosomal dominant inheritance. Cerebellar atrophy on imaging and cognitive deficits often preceded ataxia. Unique neuropathologic examination of the 4 brains showed the marked loss of Purkinje cells (PCs) without microscopic evidence of significant pathology outside the cerebellum. The normal pattern of polarized somatodendritic STUB1 protein expression in PCs was lost, resulting in aberrant STUB1 localization in the distal PC dendritic arbors.ConclusionsThis study confirms a dominant inheritance pattern in STUB1-ataxia in addition to a recessive one and documents its association with cognitive and behavioral disability, including autism. In the most extensive analysis of cerebellar pathology in this disease, we demonstrate disruption of STUB1 protein in PCs as part of the underlying pathogenesis.

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Heterozygous deletion in exon 6 of STEX gene causing ataxia with oculomotor apraxia type 2 (AOA-2) with ovarian failure

BMJ Case Reports ◽

10.1136/bcr-2021-241767 ◽

2021 ◽

Vol 14 (6) ◽

pp. e241767

Author(s):

Jiwan Shriram Kinkar ◽

Patel Zeeshan Jameel ◽

Banshi Lal Kumawat ◽

Priyanka Kalbhor

Keyword(s):

Premature Ovarian Failure ◽

Neurodegenerative Disorder ◽

Elevated Serum ◽

Cerebellar Atrophy ◽

Ovarian Failure ◽

Heterozygous Deletion ◽

Pathogenic Variants ◽

Oculomotor Apraxia ◽

Ataxia With Oculomotor Apraxia

Ataxia with oculomotor apraxia type 2 (AOA2), recently renamed as ATX-SETX, is an autosomal recessive, progressive neurodegenerative disorder belonging to inherited cerebellar ataxias. The pathogenic variants of the SETX gene have been implicated in ATX-SETX. We report the case of a 21-year-old woman presenting with ataxia, oculomotor apraxia and dystonia. She had elevated serum α-fetoprotein (AFP), follicle stimulating hormone (FSH) and luteinising hormone (LH) levels and moderate cerebellar atrophy. On further evaluation, she was found to have premature ovarian failure as well. Multiplex ligation-dependent probe amplification detected a heterozygous deletion in exon 6 of the SETX gene. A combination of cerebellar ataxia, oculomotor apraxia with elevated AFP and cerebellar atrophy are highly suggestive of ATX-SETX. In rare instances, it may be associated with premature ovarian failure with elevated FSH and LH levels, necessitating hormonal survey and fertility evaluation in all patients with ATX-SETX.

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