Objectives: To describe a case of spinocerebellar ataxia presenting with progressive apraxia of speech (AOS).
Methods: A 54-year-old man with progressive speech changes was seen clinically and referred to our observational research program on degenerative speech and language disorders. He underwent detailed speech-language and neurologic assessments and multimodal neuroimaging studies.
Noonan syndrome (NS) is a predominantly autosomal dominant condition with various cardiac and extra-cardiac manifestations. Although it has been linked with atrial arrhythmias, ventricular arrhythmias are extremely rare in the absence of underlying structural cardiac abnormalities. We report an instance of aborted sudden cardiac arrest in a 7-year-old male with a confirmed SOS1 variant and a lack of evidence to support a structural cardiac, metabolic, or infectious etiology.
View Article and Find Full Text PDFMult Scler Relat Disord
October 2024
Background: Differences in the MS course between White and Black populations is well accepted. The existence of a large Somali immigrant population in Minnesota facilitates a study of MS characteristics in this immigrant native African population. The objective of this study was to compare Somali American (SA), African American (AA), and White American (WA) persons with MS (pwMS) regarding clinical features and disease modifying therapy (DMT) use.
View Article and Find Full Text PDFIntracellular trafficking involves an intricate machinery of motor complexes including the dynein complex to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains as well as cytoplasmic light and intermediate chains have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons.
View Article and Find Full Text PDFPurpose: To document the association of -related disorder (EIEE-50) with cortical visual impairment.
Observations: An 8-month-old Caucasian boy with whole genome sequencing confirming 2 variants in the gene , who presented with severe seizures, microcephaly, hyperreflexia, hypotonia, anemia, and severe cortical visual impairment. Magnetic resonance imaging (MRI) of the brain noted thickened cortical gray matter along the right calcarine fissure as well as changes suggesting malformation of cortical development.
Most rare disease patients (75-50%) undergoing genomic sequencing remain unsolved, often due to lack of information about variants identified. Data review over time can leverage novel information regarding disease-causing variants and genes, increasing this diagnostic yield. However, time and resource constraints have limited reanalysis of genetic data in clinical laboratories setting.
View Article and Find Full Text PDFMitochondrial myopathies are frequently recognized in childhood as part of a broader multisystem disorder and often overlooked in adulthood. Herein, we describe the phenotypic and genotypic spectrum and long-term outcomes of mitochondrial myopathies diagnosed in adulthood, focusing on neuromuscular features, electrodiagnostic and myopathological findings and survival. We performed a retrospective chart review of adult patients diagnosed with mitochondrial myopathy at Mayo Clinic (2005-21).
View Article and Find Full Text PDFA 19-year-old man presented with 3 years of gradually progressive, painless vision loss in both eyes. The ophthalmic examination showed bilateral diminished visual acuity, dyschromatopsia, and temporal optic nerve pallor. The neurological examination was consistent with a mild myelopathy with decreased pin-prick sensation starting at T6-T7 and descending through the lower extremities.
View Article and Find Full Text PDFObjective: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a severe multisystemic disease, although some have a milder phenotype. We aimed to evaluate the clinical spectrum of this disease from MELAS patients to asymptomatic carriers and identify predictors of severity.
Methods: We reviewed 81 patients, who had MELAS or had positive genetics without meeting clinical criteria.
Genetic mutations causative of frontotemporal lobar degeneration (FTLD) are highly predictive of a specific proteinopathy, but there exists substantial inter-individual variability in their patterns of network degeneration and clinical manifestations. We collected clinical and Fluorodeoxyglucose-positron emission tomography (FDG-PET) data from 39 patients with genetic FTLD, including 11 carrying the C9orf72 hexanucleotide expansion, 16 carrying a MAPT mutation and 12 carrying a GRN mutation. We performed a spectral covariance decomposition analysis between FDG-PET images to yield unbiased latent patterns reflective of whole brain patterns of metabolism ("eigenbrains" or EBs).
View Article and Find Full Text PDFIntroduction: Fanconi anemia (FA) is an inherited condition associated with genetic mutations that affect DNA repair proteins. More than 20 genes involved in the FA/BRCA pathway have been implicated in FA, including BRIP1 . Tumefactive brain lesions are rare in FA.
View Article and Find Full Text PDFJ Med Genet
January 2024
Background: Pathogenic variants in the zinc finger protein coding genes are rare causes of intellectual disability and congenital malformations. Mutations in the gene causing GDACCF syndrome (global developmental delay, absent or hypoplastic corpus callosum, dysmorphic facies; MIM #617260) have been reported in five individuals so far.
Methods: As a result of an international collaboration using GeneMatcher Phenome Central Repository and personal communications, here we describe the clinical and molecular genetic characteristics of 22 previously unreported individuals.
Adult-onset leukodystrophies though individually rare are not uncommon. This group includes several disorders with isolated adult presentations, as well as several childhood leukodystrophies with attenuated phenotypes that present at a later age. Misdiagnoses often occur due to the clinical and radiological overlap with common acquired disorders such as infectious, immune, inflammatory, vascular, metabolic, and toxic etiologies.
View Article and Find Full Text PDFThe Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy.
View Article and Find Full Text PDFUnlike familial Alzheimer's disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls.
View Article and Find Full Text PDFBackground And Objectives: Changes in social behavior are common symptoms of frontotemporal lobar degeneration (FTLD) and Alzheimer disease syndromes. For early identification of individual patients and differential diagnosis, sensitive clinical measures are required that are able to assess patterns of behaviors and detect syndromic differences in both asymptomatic and symptomatic stages. We investigated whether the examiner-based Social Behavior Observer Checklist (SBOCL) is sensitive to early behavior changes and reflects disease severity within and between neurodegenerative syndromes.
View Article and Find Full Text PDFPurpose: This is a functional characterization of a novel CYBA variant associated with normal DHR flow cytometry. Chronic granulomatous disease (CGD) is an inborn error of immunity characterized by recurrent bacterial and fungal infections and dysregulated inflammatory responses due to defective phagocytic cell function leading to the formation of granulomas. CGD patients have pathogenic variants in any of the five components of the phagocytic NADPH oxidase, which transfers electrons through the phagosomal membrane and produces superoxide upon bacterial uptake.
View Article and Find Full Text PDFIdentification of an underlying mitochondrial disorder can be challenging due to the significant phenotypic variability between and within specific disorders. Epilepsy can be a presenting symptom with several mitochondrial disorders. In this study, we evaluated clinical, electrophysiologic, and imaging features in patients with epilepsy and mitochondrial disorders to identify common features, which could aid in earlier identification of a mitochondrial etiology.
View Article and Find Full Text PDFBackground: Biallelic pathogenic variants in HTRA1 cause CARASIL. More recently, monoallelic variants have been associated with the autosomal dominant disorder CADASIL2 but not all carriers develop disease manifestations. We describe the clinicoradiologic and mutation spectrum of four new CADASIL2 individuals.
View Article and Find Full Text PDFBackground: Dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures. Heterozygous variants in lysine methyltransferase 2B (KMT2B), encoding a histone H3 methyltransferase, have been associated with a childhood-onset, progressive and complex form of dystonia (dystonia 28, DYT28). Since 2016, more than one hundred rare KMT2B variants have been reported, including frameshift, nonsense, splice site, missense and other in-frame changes, many having an uncertain clinical impact.
View Article and Find Full Text PDF