From congenital microcephaly to adult onset cerebellar ataxia: Distinct and overlapping phenotypes in patients with PNKP gene mutations

2019 ◽  
Vol 179 (11) ◽  
pp. 2277-2283 ◽  
Author(s):  
Marta Gatti ◽  
Stefania Magri ◽  
Lorenzo Nanetti ◽  
Elisa Sarto ◽  
Daniela Di Bella ◽  
...  
Keyword(s):  
Cerebellar Ataxia ◽  
Gene Mutations ◽  
Adult Onset ◽  
Congenital Microcephaly

Absence of PAX6 Gene Mutations in Gillespie Syndrome (Partial Aniridia, Cerebellar Ataxia, and Mental Retardation)

Genomics ◽  
1994 ◽  
Vol 19 (1) ◽  
pp. 145-148 ◽  
Author(s):  
Tom Glaser ◽  
Carl C.T. Ton ◽  
Robert Mueller ◽  
Maria Luiza Petzl-Erler ◽  
Christina Oliver ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Cerebellar Ataxia ◽  
Gene Mutations ◽  
Pax6 Gene

scholarly journals Genetic Rhabdomyolysis within the Spectrum of the Spinocerebellar Ataxia Type 2 Responsive to Pregabalin

2021 ◽  
Author(s):  
Fabian Rossi ◽  
Joe Ma ◽  
Nina Tsakadze ◽  
Lourdes Benes-Lima ◽  
Julio Araque Gonzalez ◽  
...  
Keyword(s):  
Cerebellar Ataxia ◽  
Spinocerebellar Ataxia ◽  
Clinical Presentation ◽  
Spinocerebellar Ataxia Type ◽  
Adult Onset ◽  
Spinocerebellar Ataxia Type 2 ◽  
First Report ◽  
Recurrent Rhabdomyolysis

Abstract BackgroundSpinocerebellar Ataxia type 2 is a slowly progressive adult onset ataxia with a broad clinical presentation. Case presentationWe describe a man with Spinocerebellar Ataxia type 2 with chronic, severe, and recurrent rhabdomyolysis, as part of the cerebellar ataxia genetic spectrum. Initially rhabdomyolysis was refractory to multiple medications, but entirely resolved and remained in chronic remission with pregabalin. ConclusionThis is the first report of Spinocerebellar Ataxia type 2 associated with chronic, severe, recurrent rhabdomyolysis as part of its genetic phenotype responsive to pregabalin.

scholarly journals Hemophagocytic Lymphohistiocytosis Gene Mutations in Adult Patients Presenting With CLIPPERS-Like Syndrome

2021 ◽  
Vol 8 (3) ◽  
pp. e970
Author(s):  
Guillaume Taieb ◽  
Elsa Kaphan ◽  
Claire Duflos ◽  
Christine Lebrun-Frénay ◽  
Valérie Rigau ◽  
...  
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Brain Mri ◽  
Gene Mutations ◽  
Adult Onset ◽  
Cytotoxic Lymphocyte ◽  
Familial Hemophagocytic Lymphohistiocytosis ◽  
Non Hodgkin Lymphoma ◽  
Treatable Condition ◽  
Perforin Expression

ObjectiveTo determine whether adult cases of Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) may be related to familial hemophagocytic lymphohistiocytosis (HLH) causes, we have screened patients with adult-onset CLIPPERS for mutations in primary HLH-associated genes.MethodsIn our cohort of 36 patients fulfilling the criteria for probable or definite CLIPPERS according to the CLIPPERS-2017 criteria, we conducted a first study on 12 patients who consented to genetic testing. In these 12 patients, systemic HLH criteria were searched, and genetic analysis of 8 genes involved in primary HLH was performed.ResultsFour definite and 8 probable CLIPPERS were enrolled (n = 12). Mutations involved in HLH were identified in 2 definite and 2 probable CLIPPERS (4/12). Three of them had biallelic PRF1 mutations with reduced perforin expression in natural killer cells. The remaining patient had biallelic UNC13D mutations with cytotoxic lymphocyte impaired degranulation. None of the mutated patients reached the criteria for systemic HLH. During follow-up, 3 of them displayed atypical findings for CLIPPERS, including emergence of systemic non-Hodgkin lymphoma (1/3) and confluent gadolinium-enhancing lesions on brain MRI (3/3).ConclusionsIn our patients presenting with adult-onset CLIPPERS, one-third have HLH gene mutations. This genetic treatable condition should be searched in patients with CLIPPERS, especially in those presenting with atypical findings.

Adult onset cerebellar ataxia due to novel mutations in BRAT1

2021 ◽  
Vol 429 ◽  
pp. 118261
Author(s):  
Grazia Maria Igea Falcone ◽  
Alessandra Tessa ◽  
Filippo Maria Santorelli ◽  
Graziana Tavilla ◽  
Antonio Toscano ◽  
...  
Keyword(s):  
Cerebellar Ataxia ◽  
Adult Onset ◽  
Novel Mutations

Heterozygous Missense Pathogenic Variants Within the Second Spectrin Repeat of SPTBN2 Lead to Infantile-Onset Cerebellar Ataxia

2019 ◽  
Vol 35 (2) ◽  
pp. 106-110 ◽  
Author(s):  
Andrea Accogli ◽  
Judith St-Onge ◽  
Nassima Addour-Boudrahem ◽  
Joël Lafond-Lapalme ◽  
Alexandre Dionne Laporte ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cerebellar Ataxia ◽  
De Novo ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Adult Onset ◽  
Spinocerebellar Ataxias ◽  
Spectrin Repeat ◽  
Missense Variants ◽  
Pathogenic Variants

The term spinocerebellar ataxia encompasses a heterogeneous group of neurodegenerative disorders due to pathogenic variants in more than 100 genes, underlying 2 major groups of ataxia: autosomal dominant cerebellar ataxias (ADCA, also known as spinocerebellar ataxias [SCAs]) due to heterozygous variants or polyglutamine triplet expansions leading to adult-onset ataxia, and autosomal recessive spinocerebellar ataxias (ARCAs, also known as SCARs) due to biallelic variants, usually resulting in more severe and earlier-onset cerebellar ataxia. Certain ataxia genes, including SPTBN2 which encodes β-III spectrin, are responsible for both SCA and SCAR, depending on whether the pathogenic variant occurs in a monoallelic or biallelic state, respectively. Accordingly, 2 major phenotypes have been linked to SPTBN2: pathogenic heterozygous in-frame deletions and missense variants result in an adult-onset, slowly progressive ADCA (SCA5) through a dominant negative effect, whereas biallelic loss-of-function variants cause SCAR14, an allelic disorder characterized by infantile-onset cerebellar ataxia and cognitive impairment. Of note, 2 heterozygous missense variants (c.1438C>T, p.R480 W; c.1309C>G, p.R437G), both lying in the second spectrin repeat of SPTBN2, have been linked to infantile-onset cerebellar ataxia, similar to SCAR14. Here, we report a novel de novo heterozygous pathogenic missense variant (c.1310G>A) in SPTBN2 in a child with infantile-onset cerebellar ataxia and mild cognitive impairment. This variant affects the same R437 residue of the second spectrin repeat but results in a different amino acid change (p.R437Q). We review previously reported cases and discuss possible pathomechanisms responsible for the early-onset cerebellar phenotype due to disease-causing variants in the second spectrin repeat.

The association of TNFRSF1A gene and MEFV gene mutations with adult onset Still’s disease

2012 ◽  
Vol 33 (7) ◽  
pp. 1675-1680 ◽  
Author(s):  
Fulya Cosan ◽  
Zeliha Emrence ◽  
Gokhan Erbag ◽  
Hulya Azakli ◽  
Baris Yilmazer ◽  
...  
Keyword(s):  
Mefv Gene ◽  
Gene Mutations ◽  
Adult Onset Still’S Disease ◽  
Adult Onset ◽  
Still’S Disease ◽  
Still's Disease ◽  
Tnfrsf1a Gene ◽  
Adult Onset Still's Disease

scholarly journals Reviewing the Clinical Spectrum Related to Kmt2b Gene Mutations: Unusual Clinical Presentation and a Possible New Pathogenic Mutation

2021 ◽  
Author(s):  
Cristina del Toro ◽  
Jesús Olivares Romero
Keyword(s):  
Gene Mutations ◽  
Index Patient ◽  
Pathogenic Mutation ◽  
Focal Dystonia ◽  
Clinical Spectrum ◽  
Its Sequencing ◽  
Adult Onset ◽  
Childhood Onset ◽  
Variant Of Uncertain Significance ◽  
Generalized Dystonia

Abstract Introduction KMT2B related dystonia is a childhood onset generalized dystonia. Since its first description in 2016, different phenotypic spectrum have been reported. The aim of the case report is to provide data that may help to understand the spectrum of KMT2B-related disorders. We present two members of a family with a possible non-previously described pathogenic mutation and an unusual KMT2B related dystonia presentation: an adult onset and focal dystonia.Case Presentation The index patient is a 32 year-old woman with a generalized dystonia. Her maternal uncle presented a focal dystonia. Next-generation sequencing revealed a heterozygous missense mutation in KMT2B gene (19q13.12), described as a variant of uncertain significance (VUS). Although characteristic phenotype of KMT2B dystonia is a childhood onset generalized dystonia, different phenotypes have been related according to the kinds of mutations in this gene, also varying the age of symptom onset and the penetrance of the mutation. Asymptomatic or sub-clinical carriers and adult onset has been described. Due to the low prevalence of this variant in the general population and the low penetrance and high intrafamilial variability of this entity, we suggest that this mutation might be a pathogenic variant.ConclusionsKMT2B related dystonia is an emerging and prevalent monogenic dystonia whose incidence, genetic variability and clinical spectrum remain unknown. Despite the study of this gene is indicated in childhood onset dystonia, description of cases such as ours shows that its sequencing in patients with an adult-onset dystonia with family history can be useful for the diagnosis.

scholarly journals A Novel Coq8a Mutation in a Case with Juvenile Onset Coq10d4: Case Report and Literature Review

2022 ◽  
Author(s):  
Özge Dedeoglu ◽  
Ajlan Tükün ◽  
Yahya Laleli
Keyword(s):  
Cerebellar Ataxia ◽  
Clinical Laboratory ◽  
Cerebellar Atrophy ◽  
Gene Mutations ◽  
Autosomal Recessive Disorder ◽  
Mitochondrial Respiratory Chain ◽  
Clinical Findings ◽  
Exercise Intolerance ◽  
Juvenile Onset ◽  
Progressive Cerebellar Ataxia

Abstract Primary coenzyme Q10 deficiency-4 (COQ10D4) is an autosomal recessive disorder characterized by childhood-onset of cerebellar ataxia and exercise intolerance. Molecular pathology responsible for clinical findings is mitochondrial respiratory chain dysfunction. The main clinical manifestation involves early onset exercise intolerance, progressive cerebellar ataxia and movement disorders. Some affected individuals develop seizures and have mild mental impairment, indicating variable severity. COQ8A gene mutations are responsible for this disease. Here we present a patient with tremor and cerebellar atrophy in which we detected a new mutation in the COQ8A gene. The patient's clinical findings were compatible with juvenile onset COQ10D4. Therefore, we reviewed the clinical, laboratory and genetic findings of 11 juvenile-onset COQ10D4 patients reported to date, as well as the patient's presentation.

scholarly journals Adult-Onset Spinal Muscular Atrophy due to Mutations in the VRK1 Gene

2021 ◽  
Vol 7 (4) ◽  
pp. e599
Author(s):  
Angela Sung ◽  
Paolo Moretti ◽  
Aziz Shaibani
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Gene Mutations ◽  
Molecular Data ◽  
Clinical Syndrome ◽  
Compound Heterozygous ◽  
Adult Onset ◽  
Pathogenic Variants ◽  
Neurologic Disorders ◽  
Progressive Weakness

ObjectiveTo expand our knowledge of the range of clinical phenotypes associated with vaccinia-related kinase 1 (VRK1) gene mutations.MethodsWe present clinical and molecular data of 2 individuals with slowly progressive weakness and a clinical syndrome consistent with adult-onset spinal muscular atrophy without pontocerebellar atrophy.ResultsGenetic testing revealed likely pathogenic variants in the VRK1 gene in both subjects. One individual carried homozygous p.R321C (c.961 C>T), likely pathogenic variants. The other carried compound heterozygous p.V236M (c.706 G>A) and p.R321C (c.961 C>T), likely pathogenic variants. Notably, both patients were of Hispanic descent.ConclusionsWe report 2 cases with VRK1 mutations presenting as adult-onset spinal muscular atrophy without pontocerebellar hypoplasia and review the current literature of similar cases. Our report expands the clinical spectrum of neurologic disorders associated with VRK1 mutations.

Three adult-onset autosomal recessive ataxias

2020 ◽  
pp. 10.1212/CPJ.0000000000000947
Author(s):  
Jordan A. Paulus ◽  
Melinda S. Burnett
Keyword(s):  
Cerebellar Ataxia ◽  
Autosomal Recessive ◽  
Late Onset ◽  
Clinical Signs ◽  
Allelic Frequency ◽  
Adult Onset ◽  
Recessive Mutations ◽  
Autosomal Recessive Cerebellar Ataxia ◽  
Tay Sachs Disease ◽  
Cerebellar Ataxias

Purpose of reviewThis review will increase vigilance for 3 autosomal recessive ataxias that look different clinically when presenting in adulthood rather than childhood.Recent findingsA study found a high allelic frequency for repeat expansions in the RFC1 gene, a cause of Cerebellar Ataxia, Neuropathy, Vestibular Areflexia syndrome, which presents exclusively in adults. This implies that autosomal recessive etiologies of adult-onset cerebellar ataxias may be more common than previously thought.SummaryAdult-onset cerebellar ataxias are commonly caused by mutations inherited in either an autosomal dominant or X-linked pattern, as most autosomal recessive mutations cause disease at earlier ages. However, some autosomal recessive etiologies such as Late-onset Tay Sachs disease, Very Late-Onset Friedreich's Ataxia, and ARSACS emerge in adulthood, with age at presentation influencing the progression and clinical signs of the disease. This review will cover the genetics, clinical presentation, and necessary diagnostic steps required to identify 3 causes of Autosomal Recessive Cerebellar Ataxia that manifest differently in adults vs children.

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