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1.
Genet Med ; : 101144, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38641994

RESUMO

PURPOSE: GM1 gangliosidosis (GM1) a lysosomal disorder caused by pathogenic variants in GLB1, is characterized by relentless neurodegeneration. There are no approved treatments. METHODS: Forty-one individuals with type II (late-infantile and juvenile) GM1 participated in a single-site prospective observational study. RESULTS: Classification of 37 distinct variants using ACMG criteria resulted in the upgrade of six and the submission of four new variants. In contrast to type I infantile disease, children with type II had normal or near normal hearing and did not have cherry red maculae or hepatosplenomegaly. Some older children with juvenile onset disease developed thickened aortic and/or mitral valves. Serial MRIs demonstrated progressive brain atrophy, more pronounced in late infantile patients. MR spectroscopy showed worsening elevation of myo-inositol and deficit of N-acetyl aspartate that were strongly correlated with scores on the Vineland Adaptive Behavior Scale, progressing more rapidly in late infantile than juvenile onset disease. CONCLUSION: Serial phenotyping of type II GM1 patients expands the understanding of disease progression and clarifies common misconceptions about type II patients; these are pivotal steps toward more timely diagnosis and better supportive care. The data amassed through this 10-year effort will serve as a robust comparator for ongoing and future therapeutic trials.

2.
bioRxiv ; 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38352418

RESUMO

Neuronal ceroid lipofuscinosis (NCL), type 6 (CLN6) is a neurodegenerative disorder associated with progressive neurodegeneration leading to dementia, seizures, and retinopathy. CLN6 encodes a resident-ER protein involved in trafficking lysosomal proteins to the Golgi. CLN6p deficiency results in lysosomal dysfunction and deposition of storage material comprised of Nile Red + lipids/proteolipids that include subunit C of the mitochondrial ATP synthase (SUBC). White matter involvement has been recently noted in several CLN6 animal models and several CLN6 subjects had neuroimaging was consistent with leukodystrophy. CLN6 patient-derived induced pluripotent stem cells (IPSCs) were generated from several of these subjects. IPSCs were differentiated into oligodendroglia or neurons using well-established small-molecule protocols. A doxycycline-inducible transgenic system expressing neurogenin-2 (the I3N-system) was also used to generate clonal IPSC-lines (I3N-IPSCs) that could be rapidly differentiated into neurons (I3N-neurons). All CLN6 IPSC-derived neural cell lines developed significant storage material, CLN6-I3N-neuron lines revealed significant Nile Red + and SUBC + storage within three and seven days of neuronal induction, respectively. CLN6-I3N-neurons had decreased tripeptidyl peptidase-1 activity, increased Golgi area, along with increased LAMP1 + in cell bodies and neurites. SUBC + signal co-localized with LAMP1 + signal. Bulk-transcriptomic evaluation of control- and CLN6-I3N-neurons identified >1300 differentially-expressed genes (DEGs) with Gene Ontogeny (GO) Enrichment and Canonical Pathway Analyses having significant changes in lysosomal, axonal, synaptic, and neuronal-apoptotic gene pathways. These findings indicate that CLN6-IPSCs and CLN6-I3N-IPSCs are appropriate cellular models for this disorder. These I3N-neuron models may be particularly valuable for developing therapeutic interventions with high-throughput drug screening assays and/or gene therapy.

3.
medRxiv ; 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38313286

RESUMO

Purpose: GM1 gangliosidosis (GM1) is an ultra-rare lysosomal storage disease caused by pathogenic variants in galactosidase beta 1 (GLB1; NM_000404), primarily characterized by neurodegeneration, often in children. There are no approved treatments for GM1, but clinical trials using gene therapy (NCT03952637, NCT04713475) and small molecule substrate inhibitors (NCT04221451) are ongoing. Understanding the natural history of GM1 is essential for timely diagnosis, facilitating better supportive care, and contextualizing the results of therapeutic trials. Methods: Forty-one individuals with type II GM1 (n=17 late infantile and n=24 juvenile onset) participated in a single-site prospective observational study. Here, we describe the results of extensive multisystem assessment batteries, including clinical labs, neuroimaging, physiological exams, and behavioral assessments. Results: Classification of 37 distinct variants in this cohort was performed according to ACMG criteria and resulted in the upgrade of six and the submission of four new variants to pathogenic or likely pathogenic. In contrast to type I infantile, children with type II disease exhibited normal or near normal hearing and did not have cherry red maculae or significant hepatosplenomegaly. Some older children with juvenile onset developed thickened aortic and/or mitral valves with regurgitation. Serial MRIs demonstrated progressive brain atrophy that were more pronounced in those with late infantile onset. MR spectroscopy showed worsening elevation of myo-inositol and deficit of N-acetyl aspartate that were strongly correlated with scores on the Vineland Adaptive Behavior Scale and progress more rapidly in late infantile than juvenile onset disease. Conclusion: The comprehensive serial phenotyping of type II GM1 patients expands the understanding of disease progression and clarifies some common misconceptions about type II patients. Findings from this 10-year endeavor are a pivotal step toward more timely diagnosis and better supportive care for patients. The wealth of data amassed through this effort will serve as a robust comparator for ongoing and future therapeutic trials.

4.
Orphanet J Rare Dis ; 19(1): 79, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38378692

RESUMO

BACKGROUND: TBL1XR1 encodes a F-box-like/WD40 repeat-containing protein that plays a role in transcription mediated by nuclear receptors and is a known genetic cause of neurodevelopmental disease of childhood (OMIM# 608628). Yet the developmental trajectory and progression of neurologic symptoms over time remains poorly understood. METHODS: We developed and distributed a survey to two closed Facebook groups devoted to families of patients with TBL1XR1-related disorder. The survey consisted of 14 subsections focused upon the developmental trajectories of cognitive, behavioral, motor, and other neurological abnormalities. Data were collected and managed using REDCap electronic data capture tools. RESULTS: Caregivers of 41 patients with a TBL1XR1-related disorder completed the cross-sectional survey. All reported variants affecting a single amino acid, including missense mutations and in-frame deletions, were found in the WD40 repeat regions of Tbl1xr1. These are domains considered important for protein-protein interactions that may plausibly underlie disease pathology. The majority of patients were diagnosed with a neurologic condition before they received their genetic diagnosis. Language appeared most significantly affected with only a minority of the cohort achieving more advanced milestones in this domain. CONCLUSION: TBL1XR1-related disorder encompasses a spectrum of clinical presentations, marked by early developmental delay ranging in severity, with a subset of patients experiencing developmental regression in later childhood.


Assuntos
Transtornos do Neurodesenvolvimento , Humanos , Estudos Transversais , Mutação de Sentido Incorreto/genética , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Repressoras/genética
6.
J Clin Invest ; 134(1)2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-37988172

RESUMO

BACKGROUNDSystemic administration of adeno-associated virus (AAV) can trigger life-threatening inflammatory responses, including thrombotic microangiopathy (TMA), acute kidney injury due to atypical hemolytic uremic syndrome-like complement activation, immune-mediated myocardial inflammation, and hepatic toxicity.METHODSWe describe the kinetics of immune activation following systemic AAV serotype 9 (AAV9) administration in 38 individuals following 2 distinct prophylactic immunomodulation regimens. Group 1 received corticosteroids and Group 2 received rituximab plus sirolimus in addition to steroids to prevent anti-AAV antibody formation.RESULTSGroup 1 participants had a rapid increase in immunoglobulin M (IgM) and IgG. Increase in D-dimer, decline in platelet count, and complement activation are indicative of TMA. All Group 1 participants demonstrated activation of both classical and alternative complement pathways, as indicated by depleted C4 and elevated soluble C5b-9, Ba, and Bb antigens. Group 2 patients did not have a significant change in IgM or IgG and had minimal complement activation.CONCLUSIONSThis study demonstrates that TMA in the setting of AAV gene therapy is antibody dependent (classical pathway) and amplified by the alternative complement pathway. Critical time points and interventions are identified to allow for management of immune-mediated events that impact the safety and efficacy of systemic gene therapy.


Assuntos
Dependovirus , Microangiopatias Trombóticas , Humanos , Dependovirus/genética , Microangiopatias Trombóticas/terapia , Imunoglobulina M , Imunoglobulina G
7.
Mol Genet Metab Rep ; 37: 101014, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38053937

RESUMO

Late-onset forms of GM2 gangliosidosis-mainly, Tay-Sachs disease and Sandhoff disease-are under-recognized in clinical practice. In these rare lysosomal storage disorders, deficiency of ß-hexosaminidase A results in excessive accumulation of GM2 ganglioside primarily within neurons, leading to cell death and progressive neurodegenerative symptoms, including ataxia, dysarthria, muscle weakness, tremors, atrophy, and psychosis. Presentation is variable and often mimics more common neurodegenerative disorders. We conducted semi-structured interviews on GM2 gangliosidoses diagnosis and treatment with five experts, 30 neurologists, and 28 patients and caregivers. Symptom onset occurred during adolescence/early adulthood in 92% of patients (median age: 14 years). Patients first visited a healthcare provider at a median age of 20 years and received a GM2 diagnosis at a median age of 26 years. Nearly all patients reported problems with their legs and balance starting from symptom onset. Problems with memory, attention span, speech and fatigue were reported more after diagnosis. Patients visited an average of eight healthcare providers before receiving a diagnosis; 64% were diagnosed by a neurologist. Four neurologists (13%) in our sample were aware that there are late-onset forms of GM2 gangliosidosis. The path to diagnosis is long for this late-onset form of a classically fatal infantile disease.

8.
Mol Genet Metab ; 140(3): 107707, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37883914

RESUMO

PURPOSE: The NIH Undiagnosed Diseases Program (UDP) aims to provide diagnoses to patients who have previously received exhaustive evaluations yet remain undiagnosed. Patients undergo procedural anesthesia for deep phenotyping for analysis with genomic testing. METHODS: A retrospective chart review was performed to determine the safety and benefit of procedural anesthesia in pediatric patients in the UDP. Adverse perioperative events were classified as anesthesia-related complications or peri-procedural complications. The contribution of procedures performed under anesthesia to arriving at a diagnosis was also determined. RESULTS: From 2008 to 2020, 249 pediatric patients in the UDP underwent anesthesia for diagnostic procedures. The majority had a severe systemic disease (American Society for Anesthesiology status III, 79%) and/or a neurologic condition (91%). Perioperative events occurred in 45 patients; six of these were attributed to anesthesia. All patients recovered fully without sequelae. Nearly half of the 249 patients (49%) received a diagnosis, and almost all these diagnoses (88%) took advantage of information gleaned from procedures performed under anesthesia. CONCLUSIONS: The benefits of anesthesia involving multiple diagnostic procedures in a well-coordinated, multidisciplinary, research setting, such as in the pediatric UDP, outweigh the risks.


Assuntos
Anestesia , Anestesiologia , Doenças não Diagnosticadas , Criança , Humanos , Estados Unidos/epidemiologia , Doenças não Diagnosticadas/etiologia , Estudos Retrospectivos , Anestesia/efeitos adversos , Medição de Risco , Difosfato de Uridina
9.
J Lipid Res ; 64(12): 100463, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37871851

RESUMO

GM1 gangliosidosis is a neurodegenerative disorder caused by mutations in the GLB1 gene, which encodes lysosomal ß-galactosidase. The enzyme deficiency blocks GM1 ganglioside catabolism, leading to accumulation of GM1 ganglioside and asialo-GM1 ganglioside (GA1 glycolipid) in brain. This disease can present in varying degrees of severity, with the level of residual ß-galactosidase activity primarily determining the clinical course. Glb1 null mouse models, which completely lack ß-galactosidase expression, exhibit a less severe form of the disease than expected from the comparable deficiency in humans, suggesting a potential species difference in the GM1 ganglioside degradation pathway. We hypothesized this difference may involve the sialidase NEU3, which acts on GM1 ganglioside to produce GA1 glycolipid. To test this hypothesis, we generated Glb1/Neu3 double KO (DKO) mice. These mice had a significantly shorter lifespan, increased neurodegeneration, and more severe ataxia than Glb1 KO mice. Glb1/Neu3 DKO mouse brains exhibited an increased GM1 ganglioside to GA1 glycolipid ratio compared with Glb1 KO mice, indicating that NEU3 mediated GM1 ganglioside to GA1 glycolipid conversion in Glb1 KO mice. The expression of genes associated with neuroinflammation and glial responses were enhanced in Glb1/Neu3 DKO mice compared with Glb1 KO mice. Mouse NEU3 more efficiently converted GM1 ganglioside to GA1 glycolipid than human NEU3 did. Our findings highlight NEU3's role in ameliorating the consequences of Glb1 deletion in mice, provide insights into NEU3's differential effects between mice and humans in GM1 gangliosidosis, and offer a potential therapeutic approach for reducing toxic GM1 ganglioside accumulation in GM1 gangliosidosis patients.


Assuntos
Gangliosidose GM1 , Animais , Humanos , Camundongos , beta-Galactosidase/genética , beta-Galactosidase/metabolismo , beta-Galactosidase/uso terapêutico , Gangliosídeo G(M1)/metabolismo , Gangliosídeo G(M1)/uso terapêutico , Gangliosidose GM1/genética , Glicolipídeos , Neuraminidase/genética , Neuraminidase/uso terapêutico
10.
EBioMedicine ; 92: 104627, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37267847

RESUMO

BACKGROUND: GM1 gangliosidosis is a rare, fatal, neurodegenerative disease caused by mutations in the GLB1 gene and deficiency in ß-galactosidase. Delay of symptom onset and increase in lifespan in a GM1 gangliosidosis cat model after adeno-associated viral (AAV) gene therapy treatment provide the basis for AAV gene therapy trials. The availability of validated biomarkers would greatly improve assessment of therapeutic efficacy. METHODS: The liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to screen oligosaccharides as potential biomarkers for GM1 gangliosidosis. The structures of pentasaccharide biomarkers were determined with mass spectrometry, as well as chemical and enzymatic degradations. Comparison of LC-MS/MS data of endogenous and synthetic compounds confirmed the identification. The study samples were analyzed with fully validated LC-MS/MS methods. FINDINGS: We identified two pentasaccharide biomarkers, H3N2a and H3N2b, that were elevated more than 18-fold in patient plasma, cerebrospinal fluid (CSF), and urine. Only H3N2b was detectable in the cat model, and it was negatively correlated with ß-galactosidase activity. Following intravenous (IV) AAV9 gene therapy treatment, reduction of H3N2b was observed in central nervous system, urine, plasma, and CSF samples from the cat model and in urine, plasma, and CSF samples from a patient. Reduction of H3N2b accurately reflected normalization of neuropathology in the cat model and improvement of clinical outcomes in the patient. INTERPRETATIONS: These results demonstrate that H3N2b is a useful pharmacodynamic biomarker to evaluate the efficacy of gene therapy for GM1 gangliosidosis. H3N2b will facilitate the translation of gene therapy from animal models to patients. FUNDING: This work was supported by grants U01NS114156, R01HD060576, ZIAHG200409, and P30 DK020579 from the National Institutes of Health (NIH) and a grant from National Tay-Sachs and Allied Diseases Association Inc.


Assuntos
Gangliosidose GM1 , Doenças Neurodegenerativas , Animais , Gangliosidose GM1/genética , Gangliosidose GM1/terapia , Gangliosidose GM1/patologia , Doenças Neurodegenerativas/terapia , Cromatografia Líquida , Espectrometria de Massas em Tandem , beta-Galactosidase/genética , beta-Galactosidase/química , beta-Galactosidase/uso terapêutico , Biomarcadores/líquido cefalorraquidiano , Terapia Genética
11.
Genet Med ; 25(6): 100833, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37013900

RESUMO

PURPOSE: Myocardin-related transcription factor B (MRTFB) is an important transcriptional regulator, which promotes the activity of an estimated 300 genes but is not known to underlie a Mendelian disorder. METHODS: Probands were identified through the efforts of the Undiagnosed Disease Network. Because the MRTFB protein is highly conserved between vertebrate and invertebrate model organisms, we generated a humanized Drosophila model expressing the human MRTFB protein in the same spatial and temporal pattern as the fly gene. Actin binding assays were used to validate the effect of the variants on MRTFB. RESULTS: Here, we report 2 pediatric probands with de novo variants in MRTFB (p.R104G and p.A91P) and mild dysmorphic features, intellectual disability, global developmental delays, speech apraxia, and impulse control issues. Expression of the variants within wing tissues of a fruit fly model resulted in changes in wing morphology. The MRTFBR104G and MRTFBA91P variants also display a decreased level of actin binding within critical RPEL domains, resulting in increased transcriptional activity and changes in the organization of the actin cytoskeleton. CONCLUSION: The MRTFBR104G and MRTFBA91P variants affect the regulation of the protein and underlie a novel neurodevelopmental disorder. Overall, our data suggest that these variants act as a gain of function.


Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Animais , Criança , Humanos , Drosophila/genética , Actinas/genética , Mutação com Ganho de Função , Fatores de Transcrição/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Fenótipo
12.
Am J Hum Genet ; 110(4): 663-680, 2023 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-36965478

RESUMO

The vast majority of human genes encode multiple isoforms through alternative splicing, and the temporal and spatial regulation of those isoforms is critical for organismal development and function. The spliceosome, which regulates and executes splicing reactions, is primarily composed of small nuclear ribonucleoproteins (snRNPs) that consist of small nuclear RNAs (snRNAs) and protein subunits. snRNA gene transcription is initiated by the snRNA-activating protein complex (SNAPc). Here, we report ten individuals, from eight families, with bi-allelic, deleterious SNAPC4 variants. SNAPC4 encoded one of the five SNAPc subunits that is critical for DNA binding. Most affected individuals presented with delayed motor development and developmental regression after the first year of life, followed by progressive spasticity that led to gait alterations, paraparesis, and oromotor dysfunction. Most individuals had cerebral, cerebellar, or basal ganglia volume loss by brain MRI. In the available cells from affected individuals, SNAPC4 abundance was decreased compared to unaffected controls, suggesting that the bi-allelic variants affect SNAPC4 accumulation. The depletion of SNAPC4 levels in HeLa cell lines via genomic editing led to decreased snRNA expression and global dysregulation of alternative splicing. Analysis of available fibroblasts from affected individuals showed decreased snRNA expression and global dysregulation of alternative splicing compared to unaffected cells. Altogether, these data suggest that these bi-allelic SNAPC4 variants result in loss of function and underlie the neuroregression and progressive spasticity in these affected individuals.


Assuntos
Processamento Alternativo , Proteínas de Ligação a DNA , Paraparesia Espástica , Fatores de Transcrição , Paraparesia Espástica/genética , Humanos , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Células HeLa , Isoformas de Proteínas/genética , RNA-Seq , Masculino , Feminino , Linhagem , Alelos , Lactente , Pré-Escolar , Criança , Adolescente , Estrutura Secundária de Proteína , RNA Nuclear Pequeno/genética
13.
Sci Adv ; 9(10): eade1463, 2023 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-36897941

RESUMO

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.


Assuntos
Megalencefalia , Transtornos do Neurodesenvolvimento , Animais , Humanos , Camundongos , Haploinsuficiência , Metiltransferases/genética , Camundongos Knockout , Transtornos do Neurodesenvolvimento/genética , Fenótipo
14.
NPJ Genom Med ; 8(1): 4, 2023 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-36765070

RESUMO

Autophagy regulates the degradation of damaged organelles and protein aggregates, and is critical for neuronal development, homeostasis, and maintenance, yet few neurodevelopmental disorders have been associated with pathogenic variants in genes encoding autophagy-related proteins. We report three individuals from two unrelated families with a neurodevelopmental disorder characterized by speech and motor impairment, and similar facial characteristics. Rare, conserved, bi-allelic variants were identified in ATG4D, encoding one of four ATG4 cysteine proteases important for autophagosome biogenesis, a hallmark of autophagy. Autophagosome biogenesis and induction of autophagy were intact in cells from affected individuals. However, studies evaluating the predominant substrate of ATG4D, GABARAPL1, demonstrated that three of the four ATG4D patient variants functionally impair ATG4D activity. GABARAPL1 is cleaved or "primed" by ATG4D and an in vitro GABARAPL1 priming assay revealed decreased priming activity for three of the four ATG4D variants. Furthermore, a rescue experiment performed in an ATG4 tetra knockout cell line, in which all four ATG4 isoforms were knocked out by gene editing, showed decreased GABARAPL1 priming activity for the two ATG4D missense variants located in the cysteine protease domain required for priming, suggesting that these variants impair the function of ATG4D. The clinical, bioinformatic, and functional data suggest that bi-allelic loss-of-function variants in ATG4D contribute to the pathogenesis of this syndromic neurodevelopmental disorder.

15.
Mol Genet Metab ; 138(2): 107508, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36709532

RESUMO

GM1 gangliosidosis is a rare lysosomal storage disorder affecting multiple organ systems, primarily the central nervous system, and is caused by functional deficiency of ß-galactosidase (GLB1). Using CRISPR/Cas9 genome editing, we generated a mouse model to evaluate characteristics of the disease in comparison to GM1 gangliosidosis patients. Our Glb1-/- mice contain small deletions in exons 2 and 6, producing a null allele. Longevity is approximately 50 weeks and studies demonstrated that female Glb1-/- mice die six weeks earlier than male Glb1-/- mice. Gait analyses showed progressive abnormalities including abnormal foot placement, decreased stride length and increased stance width, comparable with what is observed in type II GM1 gangliosidosis patients. Furthermore, Glb1-/- mice show loss of motor skills by 20 weeks assessed by adhesive dot, hanging wire, and inverted grid tests, and deterioration of motor coordination by 32 weeks of age when evaluated by rotarod testing. Brain MRI showed progressive cerebellar atrophy in Glb1-/- mice as seen in some patients. In addition, Glb1-/- mice also show significantly increased levels of a novel pentasaccharide biomarker in urine and plasma which we also observed in GM1 gangliosidosis patients. Glb1-/- mice also exhibit accumulation of glycosphingolipids in the brain with increases in GM1 and GA1 beginning by 8 weeks. Surprisingly, despite being a null variant, this Glb1-/- mouse most closely models the less severe type II disease and will guide the development of new therapies for patients with the disorder.


Assuntos
Gangliosidose GM1 , Doenças por Armazenamento dos Lisossomos , Masculino , Feminino , Animais , Camundongos , Gangliosidose GM1/genética , Camundongos Knockout , beta-Galactosidase/genética , Doenças por Armazenamento dos Lisossomos/genética , Éxons
16.
J Inherit Metab Dis ; 46(4): 687-694, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36700853

RESUMO

Treatment of monogenic disorders has historically relied on symptomatic management with limited ability to target primary molecular deficits. However, recent advances in gene therapy and related technologies aim to correct these underlying deficiencies, raising the possibility of disease management or even prevention for diseases that can be treated pre-symptomatically. Tay-Sachs disease (TSD) would be one such candidate, however very little is known about the presymptomatic stage of TSD. To better understand the effects of TSD on brain development, we evaluated the transcriptomes of human fetal brain samples with biallelic pathogenic variants in HEXA. We identified dramatic changes in the transcriptome, suggesting a perturbation of normal development. We also observed a shift in the expression of the sphingolipid metabolic pathway away from production of the HEXA substrate, GM2 ganglioside, presumptively to compensate for dysfunction of the enzyme. However, we do not observe transcriptomic signatures of end-stage disease, suggesting that developmental perturbations precede neurodegeneration. To our knowledge, this is the first report of the relationship between fetal disease pathology in juvenile onset TSD and the analysis of gene expression in fetal TSD tissues. This study highlights the need to better understand the "pre-symptomatic" stage of disease to set realistic expectations for patients receiving early therapeutic intervention.


Assuntos
Gangliosidoses GM2 , Doença de Tay-Sachs , Humanos , Doença de Tay-Sachs/genética , Doença de Tay-Sachs/metabolismo , Doença de Tay-Sachs/patologia , Gangliosidoses GM2/genética , Gangliosidoses GM2/metabolismo , Encéfalo/patologia , Expressão Gênica
17.
Am J Med Genet A ; 191(3): 711-717, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36461157

RESUMO

Natural history studies of pediatric rare neurometabolic diseases are important to understand disease pathophysiology and to inform clinical trial outcome measures. Some data collections require sedation given participants' age and neurocognitive impairment. To evaluate the safety of sedation for research procedures, we reviewed medical records between April 2017 and October 2019 from a natural history study for CLN3 (NCT03307304) and one for GM1 gangliosidosis (NCT00029965). Twenty-two CLN3 individuals underwent 28 anesthetic events (age median 11.0, IQR 8.4-15.3 years). Fifteen GM1 individuals had 19 anesthetic events (9.8, 7.1-14.7). All participants had the American Society of Anesthesiology classification of II (8/47) or III (39/47). Mean sedation durations were 186 (SD = 54; CLN3) and 291 (SD = 33; GM1) min. Individuals with GM1 (6/19, 31%) were more frequently prospectively intubated for sedation (CLN3 3/28, 11%). Minor adverse events associated with sedation occurred in 8/28 (28%, CLN3) and 6/19 (32%, GM1) individuals, frequencies within previously reported ranges. No major adverse clinical outcomes occurred in 47 anesthetic events in pediatric participants with either CLN3 or GM1 gangliosidosis undergoing research procedures. Sedation of pediatric individuals with rare neurometabolic diseases for research procedures is safe and allows for the collection of data integral to furthering their understanding and treatment.


Assuntos
Anestesia , Anestesiologia , Gangliosidose GM1 , Adolescente , Criança , Humanos , beta-Galactosidase , Gangliosídeo G(M1) , Gangliosidose GM1/genética , Lisossomos , Glicoproteínas de Membrana/genética , Chaperonas Moleculares/genética , Doenças Raras , Estudos Retrospectivos
18.
Mol Genet Genomic Med ; 10(9): e2013, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35848209

RESUMO

OBJECTIVES: To review the referral and clinical characteristics of adult patients diagnosed with lysosomal storage diseases (LSD) through the Undiagnosed Diseases Network (UDN). METHODS: Retrospective review of both application and evaluation records for adults admitted to the UDN with a final diagnosis of a lysosomal storage disease. RESULTS: Ten patients were identified. Final diagnoses included late onset Tay Sachs, attenuated MPS I, MPS IIIA, MPS IIIB, and MPS IIIC. Most patients presented with neurocognitive changes. Prior to referral, all patients had been evaluated by neurology, four patients underwent phenotype specific panel testing that did not include the causative gene, and four patients had non-diagnostic clinical exome sequencing. CONCLUSIONS: LSDs figure highly in the differential diagnosis of neurometabolic disorders in pediatric onset progressive diseases. In adults, their subtle initial presentations overlap with symptoms of more common disorders and less practitioner awareness may lead to prolonged diagnostic challenges.


Assuntos
Doenças por Armazenamento dos Lisossomos , Mucopolissacaridose III , Doenças não Diagnosticadas , Humanos , Doenças por Armazenamento dos Lisossomos/diagnóstico , Doenças por Armazenamento dos Lisossomos/genética , Mucopolissacaridose III/genética , Fenótipo
19.
Clin Neurophysiol Pract ; 7: 169-173, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35800887

RESUMO

Objective: Sialidosis is an inborn error of metabolism. There is evidence that the myoclonic movements observed in this disorder have a cortical origin, but this mechanism does not fully explain the bilaterally synchronous myoclonus activity frequently observed in many patients. We present evidence of a subcortical basis for synchronous myoclonic phenomena. Methods: Electromyographic investigations were undertaken in two molecularly and biochemically confirmed patients with sialidosis type-1. Results: The EMG recordings showed clear episodes of bilaterally synchronous myoclonic activity in contralateral homologous muscles. We also observed a high muscular-muscular coherence with near-zero time-lag between these muscles. Conclusion: The absence of coherence phase lag between the right-and-left homologous muscles during synchronous events indicates that a unilateral cortical source cannot fully explain the myoclonic activity. There must exist a subcortical mechanism for bilateral synchronization accounting for this phenomenon. Significance: Understanding this mechanism may illuminate cortical-subcortical relationships in myoclonus.

20.
Sci Rep ; 12(1): 9186, 2022 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-35655070

RESUMO

P/Q-type Ca2+ currents mediated by CaV2.1 channels are essential for active neurotransmitter release at neuromuscular junctions and many central synapses. Mutations in CACNA1A, the gene encoding the principal CaV2.1 α1A subunit, cause a broad spectrum of neurological disorders. Typically, gain-of-function (GOF) mutations are associated with migraine and epilepsy while loss-of-function (LOF) mutations are causative for episodic and congenital ataxias. However, a cluster of severe CaV2.1 channelopathies have overlapping presentations which suggests that channel dysfunction in these disorders cannot always be defined bimodally as GOF or LOF. In particular, the R1667P mutation causes focal seizures, generalized hypotonia, dysarthria, congenital ataxia and, in one case, cerebral edema leading ultimately to death. Here, we demonstrate that the R1667P mutation causes both channel GOF (hyperpolarizing voltage-dependence of activation, slowed deactivation) and LOF (slowed activation kinetics) when expressed heterologously in tsA-201 cells. We also observed a substantial reduction in Ca2+ current density in this heterologous system. These changes in channel gating and availability/expression manifested in diminished Ca2+ flux during action potential-like stimuli. However, the integrated Ca2+ fluxes were no different when normalized to tail current amplitude measured upon repolarization from the reversal potential. In summary, our findings indicate a complex functional effect of R1667P and support the idea that pathological missense mutations in CaV2.1 may not represent exclusively GOF or LOF.


Assuntos
Canalopatias , Transtornos do Neurodesenvolvimento , Ataxia , Canais de Cálcio/genética , Canais de Cálcio Tipo N , Canalopatias/genética , Humanos , Hipotonia Muscular
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