Methylmalonic acidemia: Neurodevelopment and neuroimaging

Chen, Tao; Gao, Yian; Zhang, Shengdong; Wang, Yuanyuan; Sui, Chaofan; Yang, Linfeng

doi:10.3389/fnins.2023.1110942

Cited by 20 publications

(8 citation statements)

References 55 publications

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“…Examples of genes for which we found converging evidence in neuroticism for transcript and protein level associations with neuroticism include low density lipoprotein receptor-related protein 4 ( LRP4), syntaxin 4 ( STX4 ), and metabolism of cobalamin associated B ( MMAB ) (Supplementary Sheet 8). LRP4 has diverse roles in neuromuscular junction and in disorders of the nervous system including Alzheimer’s disease and amyotrophic lateral sclerosis [46], STX4 is implicated in synaptic growth and plasticity [47], and MMAB , which catalyzes the final step in the conversion of cobalamin (Vitamin B12) into adenosylcobalamin (biologically active coenzyme B12), all of which have broad implications for brain function including those in relation to methylmalonic acidemia [48]. Low levels of plasma vitamin B12 have been found to be associated with higher depression cases in multiple studies [49].…”

Section: Discussionmentioning

confidence: 99%

A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology

Gupta,

Galimberti,

Liu

et al. 2024

Preprint

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Personality is influenced by both genetic and environmental factors and is associated with other psychiatric traits such as anxiety and depression. The “Big Five” personality traits, which include neuroticism, extraversion, agreeableness, conscientiousness, and openness, are a widely accepted and influential framework for understanding and describing human personality. Of the big five personality traits, neuroticism has most often been the focus of genetic studies and is linked to various mental illnesses including depression, anxiety, and schizophrenia. Our knowledge of the genetic architecture of the other four personality traits is more limited. Utilizing the Million Veteran Program (MVP) cohort we conducted a genome-wide association study (GWAS) in individuals of European and African ancestry. Adding other published data, we performed GWAS meta-analysis for each of the five personality traits with sample sizes ranging from 237,390 to 682,688. We identified 158, 14, 3, 2, and 7 independent genome-wide significant (GWS) loci associated with neuroticism, extraversion, agreeableness, conscientiousness, and openness, respectively. These findings represent 55 novel loci for neuroticism, as well as the first GWS loci discovered for extraversion and agreeableness. Gene-based association testing revealed 254 genes showing significant association with at least one of the five personality traits. Transcriptome-wide and proteome-wide analysis identified altered expression of genes and proteins such asCRHR1, SLC12A5, MAPT, andSTX4. Pathway enrichment and drug perturbation analyses identified complex biology underlying human personality traits. We also studied the inter-relationship of personality traits with 1,437 other traits in a phenome-wide genetic correlation analysis, identifying new associations. Mendelian randomization showed positive bidirectional effects between neuroticism and depression and anxiety while a negative bidirectional effect was observed for agreeableness and these psychiatric traits. This study improves our comprehensive understanding of the genetic architecture underlying personality traits and their relationship to other complex human traits.

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Section: Discussionmentioning

confidence: 99%

A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology

Gupta,

Galimberti,

Liu

et al. 2024

Preprint

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“…Diffuse white matter swelling, severe leukoaraiosis of varying degrees, hydrocephalus, corpus callosum atrophy, and symmetric bilateral lesions of the basal ganglia are frequent and distinctive imaging findings in early-onset cblC disease. However, late-onset cases often exhibit cerebral atrophy and patchy lesions in the deep white matter (17)(18)(19). Cerebellar involvement is uncommon in cblC disease, and literature review reveals only seven reported cases with cerebellar symptoms or imaging changes (12,16,18,(20)(21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

Late-onset cobalamin C deficiency type in adult with cognitive and behavioral disturbances and significant cortical atrophy and cerebellar damage in the MRI: a case report

Sun,

Dai

2023

Front. Neurol.

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BackgroundLate-onset cobalamin C (cblC) deficiency is associated with a wide range of neurological and psychiatric symptoms, hematological manifestations, anorexia, renal failure, ocular abnormalities, dermatitis, and pancreatitis. However, the neuroimaging characteristics of late-onset cblC deficiency remain insufficiently documented. Common findings include diffuse white matter swelling, varying degrees of severe leukoaraiosis, hydrocephalus, corpus callosum atrophy, and symmetric bilateral basal ganglia lesions. In this report, we present a case of late-onset cblC deficiency in adults presenting with cerebellar ataxia as the primary symptom. The MRI findings revealed bilateral lateral cerebellar hemispheres exhibiting symmetric hyperintensity, primarily observed in diffusion-weighted imaging (DWI), which is a rarely reported imaging change in this context.Case presentationOur patient was a male who experienced symptoms starting at the age of 30 years, including unsteady walking, apparent cerebellar ataxia, and cognitive impairment upon nervous system examination. Brain magnetic resonance imaging (MRI) exhibited symmetric hyperintensity in the bilateral lateral cerebellar hemispheres, predominantly manifested in DWI, without any enhancement. Subsequently, significantly elevated blood total homocysteine and urinary methylmalonic acid levels were observed. Genetic analysis confirmed the presence of MMACHC compound heterozygous mutants c.482G > A and c.609G > A, thus confirming the diagnosis of cblC deficiency. These variants were classified as likely pathogenic following the guidelines of the American College of Medical Genetics and Genomics (ACMG) and were verified using Sanger sequencing. Following treatment, the patient experienced improvements in walking ability and cognition, a significant decrease in blood total homocysteine levels, and reversal of the imaging lesions.In conclusionLate-onset cblC deficiency presents with diverse clinical and imaging manifestations. Early diagnosis and treatment are crucial in achieving a favorable prognosis. This case serves as a reminder to clinicians not to overlook genetic metabolic disorders, particularly those causing multisite damage, in adult patients with undiagnosed neurological disorders, especially those affecting the cerebellum. Notably, methylmalonic acidemia should be considered within the spectrum of bilateral cerebellar lesions.

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“…93 The outcome is guarded. 94 However, many cases with cobalamin-responsive subtypes may have better prognosis. 9,85 1C.…”

Section: Future Studiesmentioning

confidence: 99%

Organic Acidemias: Clinical Presentation in Neonates

Motta,

Rahman,

Athalye-Jape

et al. 2024

Newborn

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Organic acidemias (OAs) are heritable genomic abnormalities characterized by the absence or defects in critical enzyme(s), which result in the accumulation of abnormal and toxic organic acid metabolites. These metabolites can be detected in blood and/or urine in high levels. Organic acidemias can have severe clinical manifestations, where most patients become symptomatic within the neonatal period or early infancy. Mildly affected cases may present later during adolescence or adulthood following decompensation during illness, following surgery, or with prolonged fasting. Acute clinical presentations include liver failure, lethargy, altered sensorium (encephalopathy), and/or seizures in the acute phase; subacute/delayed manifestations may include failure to thrive, developmental delay, and/or cardiomyopathy. In neonates, differential diagnoses include sepsis, metabolic disturbances, and intracranial bleeding. A high index of suspicion is essential for early, timely diagnosis. This article seeks to provide consolidated information on OAs, including pathogenesis, clinical presentation, diagnosis, and contemporary management.

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Methylmalonic acidemia: Neurodevelopment and neuroimaging

Cited by 20 publications

References 55 publications

A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology

A genome-wide investigation into the underlying genetic architecture of personality traits and overlap with psychopathology

Late-onset cobalamin C deficiency type in adult with cognitive and behavioral disturbances and significant cortical atrophy and cerebellar damage in the MRI: a case report

Organic Acidemias: Clinical Presentation in Neonates

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