scholarly journals Tripeptidyl Peptidase 1 (TPP1) Deficiency in a 36-Year-Old Patient with Cerebellar-Extrapyramidal Syndrome and Dilated Cardiomyopathy

Life ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 3
Author(s):  
Agnieszka Ługowska ◽  
Joanna K. Purzycka-Olewiecka ◽  
Rafał Płoski ◽  
Grażyna Truszkowska ◽  
Maciej Pronicki ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Clinical Symptoms ◽  
Brain Mri ◽  
Severe Heart Failure ◽  
Cerebellar Atrophy ◽  
Unknown Origin ◽  
Spinocerebellar Ataxia Type ◽  
Extrapyramidal Syndrome ◽  
Spinocerebellar Ataxia Type 7 ◽  
Tripeptidyl Peptidase

We report on a 36-year-old man with cerebellar-extrapyramidal syndrome and severe heart failure because of dilated cardiomyopathy of unknown origin. Dysarthria and cardiac arrhythmia began at early childhood (4 years of age). Brain MRI (28 years of age) demonstrated severe cerebellar atrophy. At the age 32, he presented with dysarthria, ataxia, dystonia, and tremor of the right hand, bilateral slowed neural conduction in the visual pathways, and decreased mental acuity. At the age of 33 years, the patient underwent cardiac transplantation because of severe dilated cardiomyopathy. In the TPP1 gene, biallelic variants were identified: previously reported p.(Leu13Pro) and novel p.(Tyr508Cys) variant. Additionally, hemizygous novel missense variant in the ABCD1 gene was inherited from the mother p.(Arg17His). Normal very-long-chain fatty acids (VLCFA) levels both in patient and his mother excluded ABCD1 mutation as the pathogenic one. Tripeptidyl peptidase 1 (TPP1) activity was reduced (8,8 U/mg protein/h; reference range: 47.4 ± 10.7). In light microscopy the biopsy specimens obtained from explanted heart showed severe myocyte hypertrophy with perinuclear vacuolization with inclusions. Electron microscopy revealed absence of lipofuscin accumulation, no ultrastructural curvilinear profiles, fingerprint bodies, or granular osmiophilic deposits (GRODs) in lysosomes. As described here, the patient presents clinical symptoms observed in benign forms of ceroid lipofuscinosis type 2 (CLN2) and simultaneously some features of autosomal recessive spinocerebellar ataxia type 7 (SCAR7), which is also caused by mutations in the TPP1 gene.

scholarly journals Progression of Cerebellar Atrophy in Spinocerebellar Ataxia Type 2 Gene Carriers: A Longitudinal MRI Study in Preclinical and Early Disease Stages

2020 ◽  
Vol 11 ◽  
Author(s):  
Anna Nigri ◽  
Lidia Sarro ◽  
Alessia Mongelli ◽  
Chiara Pinardi ◽  
Luca Porcu ◽  
...  
Keyword(s):  
Structural Changes ◽  
Time Window ◽  
Brain Mri ◽  
Disease Onset ◽  
Clinical Signs ◽  
Cerebellar Atrophy ◽  
Spinocerebellar Ataxia Type ◽  
Volume Loss ◽  
Early Disease

Spinocerebellar ataxias type 2 (SCA2) is an autosomal dominant inherited disease caused by expanded trinucleotide repeats (≥32 CAG) within the coding region of ATXN2 gene. Age of disease onset primarily depends on the length of the expanded region. The majority of subjects carrying the mutation remain free of clinical signs for few decades (“pre-symptomatic” stage), but in proximity of disease onset subtle neurophysiological, cognitive, and structural brain imaging changes may occur. Aims of the present study are to determine the time-window in which early clinical and neurodegenerative MRI changes may be identified, and to evaluate the rate of the disease progression in both preclinical and early disease phases. We performed a 1-year longitudinal study in 42 subjects: 14 SCA2 patients (mean age 39 years, disease duration 7 years, SARA score 9 points), 13 presymptomatic SCA2 subjects (preSCA2, mean age 39 years, expected time to disease onset 16 years), and 15 gene-negative healthy controls (mean age 33 years). All participants underwent genetic test, neurological examination, cognitive tests, and brain MRI. Evaluations were repeated at 1-year interval. Baseline MRI evaluations in SCA2 patients showed significant atrophy in cerebellum, brainstem, basal ganglia and cortex compared to controls, while preSCA2 subjects had isolated volume loss in the pons, and cortical thinning in specific frontal and parietal areas, namely rostral-middle-frontal and precuneus. One-year longitudinal follow-up demonstrated, in SCA2 patients, volume reduction in cerebellum, pons, superior cerebellar peduncles, and midbrain, and only in the cerebellum in preSCA2 subjects. No progression in clinical or cognitive measures was observed in preSCA2 subjects. The rate of volume loss in the cerebellum and subcortical regions greatly differed between patients and preSCA2. In conclusion, our pilot study demonstrated that MRI measures are highly sensitive to identify longitudinal structural changes in SCA2 patients, and in preSCA2 up to a decade before expected disease onset. These findings may contribute in the understanding of early neurodegenerative processes and may be useful in future therapeutical trials.

Parkinson’s puzzle

2012 ◽  
Vol 153 (52) ◽  
pp. 2060-2069 ◽  
Author(s):  
András Guseo
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Symptoms ◽  
Critical Factor ◽  
Unknown Origin ◽  
Symptomatic Improvement ◽  
Blue Green Algae ◽  
Clinical Observations ◽  
Degenerative Disorders ◽  
Local Cell

Parkinson’s disease is one of the most frequent progressive degenerative disorders with unknown origin of the nervous system. The commutation of the disease on Guam led to the discovery of a neurotoxin which was also found in other continents. This neurotoxin was identified in the common cyanobacteria (blue-green algae). Early clinical observations suggested some loose correlations with gastric and duodenal ulcer and Parkinson’s disease, while recent studies revealed a toxin, almost identical to that found in cyanobacteria in one strain of Helicobacter pylori, which proved to cause Parkinson like symptoms in animals. Therefore, it cannot be ruled out that there is a slowly progressive poisoning in Parkinson’s disease. The disease specific alpha-sinuclein inclusions can be found in nerve cells of the intestinal mucosa far before the appearance of clinical symptoms indicating that the disease may start in the intestines. These results are strengthened by the results of Borody’s fecal transplants, after which in Parkinson patients showed a symptomatic improvement. Based on these observations the Parkinson puzzle is getting complete. Although these observations are not evidence based, they may indicate a new way for basic clinical research, as well as a new way of thinking for clinicians. These new observations in psycho-neuro-immunology strengthen the fact that immunological factors may also play a critical factor facilitating local cell necrosis which may be influenced easily. Orv. Hetil., 2012, 153, 2060–2069.

scholarly journals A Clinical-Based Diagnostic Approach to Cerebellar Atrophy in Children

2021 ◽  
Vol 11 (5) ◽  
pp. 2333
Author(s):  
Claudia Ciaccio ◽  
Chiara Pantaleoni ◽  
Franco Taroni ◽  
Daniela Di Bella ◽  
Stefania Magri ◽  
...  
Keyword(s):  
Muscle Biopsy ◽  
Single Gene ◽  
Brain Mri ◽  
Genetic Defect ◽  
Cerebellar Atrophy ◽  
Chain Complex ◽  
Clinical Findings ◽  
Diagnostic Workup ◽  
Diagnostic Approach ◽  
Disease Definition

Background: Cerebellar atrophy is a neuroradiological definition that categorizes conditions heterogeneous for clinical findings, disease course, and genetic defect. Most of the papers proposing a diagnostic workup for pediatric ataxias are based on neuroradiology or on the literature and experimental knowledge, with a poor participation of clinics in the process of disease definition. Our study aims to offer a different perspective on the way we approach cerebellar atrophy in developmental age, building a clinical-based diagnostic workup to guide molecular diagnosis. Methods: we recruited 52 patients with pediatric-onset cerebellar atrophy and definite disease categorization. Children underwent brain MRI, neurophysiological exams, metabolic investigations, and muscle biopsy with respiratory chain complex study. Single-gene sequencing, next-generation sequencing NGS panels, whole-exome sequencing (WES), and disease-specific techniques have been used to reach genetic confirmation. Results: Brain MRI is the main method of diagnosis, followed by tests on muscle biopsy and peripheral nervous system study. Other exams (e.g., metabolic investigations or evoked potentials) may be useful to narrow the list of diagnostic possibilities. Conclusions: We propose a diagnostic approach to cerebellar atrophy in children based on clinical findings, and support the evidence that a precise phenotypic definition may lead to the formulation of a definite diagnosis or otherwise guide the back phenotyping process derived from large molecular data.

scholarly journals Nanoscopic quantification of sub-mitochondrial morphology, mitophagy and mitochondrial dynamics in living cells derived from patients with mitochondrial diseases

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Weiwei Zou ◽  
Qixin Chen ◽  
Jesse Slone ◽  
Li Yang ◽  
Xiaoting Lou ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Optic Atrophy ◽  
Respiratory Function ◽  
Clinical Symptoms ◽  
Mitochondrial Dynamics ◽  
Cerebellar Atrophy ◽  
Mitochondrial Diseases ◽  
Living Cells ◽  
Mitochondrial Morphology ◽  
Mitochondrial Oxidative Phosphorylation

AbstractSLC25A46 mutations have been found to lead to mitochondrial hyper-fusion and reduced mitochondrial respiratory function, which results in optic atrophy, cerebellar atrophy, and other clinical symptoms of mitochondrial disease. However, it is generally believed that mitochondrial fusion is attributable to increased mitochondrial oxidative phosphorylation (OXPHOS), which is inconsistent with the decreased OXPHOS of highly-fused mitochondria observed in previous studies. In this paper, we have used the live-cell nanoscope to observe and quantify the structure of mitochondrial cristae, and the behavior of mitochondria and lysosomes in patient-derived SLC25A46 mutant fibroblasts. The results show that the cristae have been markedly damaged in the mutant fibroblasts, but there is no corresponding increase in mitophagy. This study suggests that severely damaged mitochondrial cristae might be the predominant cause of reduced OXPHOS in SLC25A46 mutant fibroblasts. This study demonstrates the utility of nanoscope-based imaging for realizing the sub-mitochondrial morphology, mitophagy and mitochondrial dynamics in living cells, which may be particularly valuable for the quick evaluation of pathogenesis of mitochondrial morphological abnormalities.

scholarly journals In vivo assessment of neurodegeneration in Spinocerebellar Ataxia type 7

2021 ◽  
Vol 29 ◽  
pp. 102561
Author(s):  
Jacob A. Parker ◽  
Shabbir H. Merchant ◽  
Sanaz Attaripour-Isfahani ◽  
Hyun Joo Cho ◽  
Patrick McGurrin ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 7 ◽  
In Vivo Assessment

Abstract 12621: Gender Differences Among Implantable Cardioverter Defibrillators Recipients in the Setting of Primary Prevention

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Eloi Marijon ◽  
Rui Providencia ◽  
Pascal Defaye ◽  
Didier Klug ◽  
Daniel Gras ◽  
...  
Keyword(s):  
Primary Prevention ◽  
Dilated Cardiomyopathy ◽  
Specific Interaction ◽  
Severe Heart Failure ◽  
Real Life ◽  
Functional Class ◽  
Cardiac Resynchronization ◽  
Implantable Cardioverter Defibrillators ◽  
Icd Implantation ◽  
Cardioverter Defibrillators

Background: Data regarding sex specificities in the use, benefits and complications of implantable cardioverter-defibrillators (ICDs) in primary prevention in the real-world European setting are sparse. Methods: Using a large multicentric cohort of consecutive patients referred for ICD implantation for primary prevention (2002-2012), in the setting of coronary artery disease or dilated cardiomyopathy, we examined potential sex differences in subjects’ characteristics and outcomes. Results: Of 5,539 patients, only 837 (15.1%) were women and 53.8% received cardiac resynchronization therapy (CRT-D). Compared to men, women presented a significantly higher proportion of dilated cardiomyopathy (60.2% vs. 36.2%, P120ms: 74.6% vs. 68.5%, P=0.003), higher New York Heart Association functional class (2.5±0.7 vs. 2.4±0.7, P=0.003) and lower prevalence of atrial fibrillation (18.7% vs. 24.9%, P<0.001). During a 16,786 patient-years follow-up, overall, fewer appropriate therapies were observed in women (HR = 0.59, CI95% 0.45-0.76; P<0.001). By contrast, no sex-specific interaction was observed for inappropriate shocks (OR for women = 1.00, 95%CI 0.74-1.35, P=0.997) and mortality (HR = 0.87; 95%CI 0.66-1.15, P=0.324), with similar patterns of cause of deaths. Conclusion: In our real life registry, women account for the minority of ICD recipients. While female ICD recipients present with features of more severe heart failure in the setting of primary prevention of sudden cardiac death, we observed they have a 40% lower incidence of appropriate therapies.

Cervical Spinal Cord Degeneration in Spinocerebellar Ataxia Type 7

2021 ◽  
Author(s):  
C.R. Hernandez-Castillo ◽  
R. Diaz ◽  
T.J.R. Rezende ◽  
I. Adanyeguh ◽  
I.H. Harding ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinocerebellar Ataxia ◽  
Cervical Spinal Cord ◽  
Spinocerebellar Ataxia Type ◽  
Spinocerebellar Ataxia Type 7

scholarly journals Antisense oligonucleotides targeting mutant Ataxin-7 restore visual function in a mouse model of spinocerebellar ataxia type 7

2018 ◽  
Vol 10 (465) ◽  
pp. eaap8677 ◽  
Author(s):  
Chenchen Niu ◽  
Thazah P. Prakash ◽  
Aneeza Kim ◽  
John L. Quach ◽  
Laryssa A. Huryn ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Spinocerebellar Ataxia ◽  
Visual Function ◽  
Antisense Oligonucleotides ◽  
Neurodegenerative Disorder ◽  
Retinal Disease ◽  
Fundus Photography ◽  
Spinocerebellar Ataxia Type ◽  
Autofluorescence Imaging ◽  
Spinocerebellar Ataxia Type 7

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by cerebellar and retinal degeneration, and is caused by a CAG-polyglutamine repeat expansion in the ATAXIN-7 gene. Patients with SCA7 develop progressive cone-rod dystrophy, typically resulting in blindness. Antisense oligonucleotides (ASOs) are single-stranded chemically modified nucleic acids designed to mediate the destruction, prevent the translation, or modify the processing of targeted RNAs. Here, we evaluated ASOs as treatments for SCA7 retinal degeneration in representative mouse models of the disease after injection into the vitreous humor of the eye. Using Ataxin-7 aggregation, visual function, retinal histopathology, gene expression, and epigenetic dysregulation as outcome measures, we found that ASO-mediated Ataxin-7 knockdown yielded improvements in treated SCA7 mice. In SCA7 mice with retinal disease, intravitreal injection of Ataxin-7 ASOs also improved visual function despite initiating treatment after symptom onset. Using color fundus photography and autofluorescence imaging, we also determined the nature of retinal degeneration in human SCA7 patients. We observed variable disease severity and cataloged rapidly progressive retinal degeneration. Given the accessibility of neural retina, availability of objective, quantitative readouts for monitoring therapeutic response, and the rapid disease progression in SCA7, ASOs targeting ATAXIN-7 might represent a viable treatment for SCA7 retinal degeneration.

scholarly journals Long-term follow-up until early adulthood in autosomal dominant, complex SPG30 with a novel KIF1A variant: a case report

2019 ◽  
Vol 45 (1) ◽  
Author(s):  
Carlotta Spagnoli ◽  
Susanna Rizzi ◽  
Grazia Gabriella Salerno ◽  
Daniele Frattini ◽  
Carlo Fusco
Keyword(s):  
Autosomal Dominant ◽  
De Novo ◽  
Current Knowledge ◽  
Brain Mri ◽  
Early Adulthood ◽  
Cerebellar Atrophy ◽  
Mild Intellectual Disability ◽  
Long Term Follow Up

Abstract Background Pathogenic variants in KIF1A (kinesin family member 1A) gene have been associated with hereditary spastic paraplegia (HSP) type 30 (SPG30), encopassing autosomal dominant and recessive, pure and complicated forms. Case presentation We report the long-term follow-up of a 19 years-old boy first evaluated at 18 months of age because of toe walking and unstable gait with frequent falls. He developed speech delay, mild intellectual disability, a slowly progressive pyramidal syndrome, microcephaly, bilateral optic subatrophy and a sensory axonal polyneuropathy. Brain MRI showed cerebellar atrophy, stable along serial evaluations (last performed at 18 years of age). Targeted NGS sequencing disclosed the de novo c.914C > T missense, likely pathogenic variant on KIF1A gene. Conclusions We report on a previously unpublished de novo heterozygous likely pathogenic KIF1A variant associated with slowly progressive complicated SPG30 and stable cerebellar atrophy on long-term follow-up, adding to current knowledge on this HSP subtype.

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