(4.4) NEUROGENETICS AND STRUCTURAL ABNORMALITIES

Additional Inheritance and Human Pedigrees Questions

• Autosomal dominant inheritance: Possible parent genotypes depend on the specific gene and if the parents are affected or not.
• Autosomal recessive inheritance: Possible parent genotypes depend on the specific gene and if the parents are affected or not.
• Pedigree drawing instructions: A pedigree chart should include individual details, including gender, if they are affected, their siblings (affected or not), and their maternal and paternal grandparents (affected or not). Information should also include presence or absence of affected relatives on both maternal and paternal sides. One additional unaffected child must be added to the chart.

Gene Regulation Questions

• Operon expression: Operons are turned on as needed.
• Translational regulation: Some operon examples also include significant translational regulation, which affects the level of translation and/or (specific) processes.
• mRNA regulation: mRNA higher order structures play a role in regulation.
• Lac operon activity: High glucose and high lactose levels means low lac operon activity.

Proteins and Protein Aggregation Questions

• Protein folding: A protein unable to be folded using usual processes will not correctly adopt its expected structural levels.
• Protein variants: Structurally abnormal proteins that alter the structure of normal proteins are considered a form of pathogenicity potentially creating altered structures.
• Phosphorylation change: Changes in the genetic sequence (phosphorylation site alteration) leading to replacing serine with threonine cause changes in the protein and its function.

Neurogenetics and Structural Abnormalities

• Objectives: Define neurogenetics, polygenic, congenital, phenotypic spectrum, syndactyly and myopathy. Explain role of genomic sequencing in modern neurogenetics and structural anomalies. Connect genes to normal function and activity, including variations. Identify diseases, phenotypic manifestations, and clinical expectations for a given pathogenic variant. Assess likely gene, clinical symptoms, and disease/syndrome. Compare/contrast congenital myopathies by focusing on their discriminating features, genes, expected inheritance, and influencing mutations. Evaluate somatic changes in the mTOR pathway and their role in corresponding disease development. This topic likely covers neurobiology, molecular biology, and genetics.

Introduction to Neurogenetics

• Field: Study of genetic underpinnings of neurological conditions.
• Categorization examples: Neurometabolic, channelopathies, disorders of gene regulation (sequence repeats), and peripheral inherited neuropathies. These topics likely cover neurobiology, molecular biology, and genetics.

Neurogenetics and Phenotypic Spectrums

• Genetic interactions: Not all genetic changes in genes are equivalent or produce identical outcomes; correlation between disease severity and type of change with complex genetic interactions.
• Congenital changes: Changes that are present at birth, most commonly referred to in terms of structural anomalies.

Genetics of Neurologic Diseases

• Genome-wide studies: Valuable in identifying genetic alterations related to disease phenotypes.
• DNA sequencing: Enables identification of rare genetic mutations correlated with neurologic conditions and improvements in testing. Examples include Huntington's disease and certain inborn errors of metabolism.
• Note: Most common neurologic diseases are polygenic and complex

Alzheimer's Disease

• Genetic insights: Genetic studies provide insight into Alzheimer's disease.
• Inheritance: Autosomal dominant inheritance is common.
• Associated mutations: Mutations in Amyloid precursor protein (APP), Presenilin 1 (PSEN1), and Presenilin 2 (PSEN2).
• Monogenic vs. polygenic: Monogenic variations may be specific factors influencing the disease while polygenic variations may alter disease prognosis or cause. Apolipoprotein E (APOE) is a major cholesterol carrier. Variations may alter the disease (worse with early onset).

Wolfram Syndrome 1

• Disease characteristics: A rare neurogenetic disorder characterized by a specific constellation of features (DIDMOAD): diabetes insipidus, diabetes mellitus, optic atrophy, and deafness.
• Inheritance: Generally inherited autosomal recessively due to mutations in the WFS1 gene. 
• Variable inheritance: Some WFS1 mutations may exhibit dominant inheritance patterns but do not typically follow all aspects of disease, such as DIDMOAD.

Huntington's Disease

• Inheritance pattern: Trinucleotide repeat expansion (CAG) results in disease phenotype. Fewer than 27 repeats is normal. 27-35 is unlikely to exhibit clinical symptoms. However, more than 36 repeats leads to disease.
• Phenotype correlations: Number of copies of the expanded gene and the number of repeats in the gene influence the disease phenotype. Younger onset and more severe phenotype is observed in homozygous and larger expansions

Structural Abnormalities due to Genetic Mutation

• Classification: Major structural anomalies or congenital anomalies.
• Examples: Open neural tube defects (Spina Bifida and Myelomeningocele), syndactyly, and congenital myopathies.

Development of the Spinal Cord

• Neural tube formation: A detailed explanation of the developmental stages of a neural tube.
• Neuroprogenitor differentiation: How neuroprogenitor cells transform into neuroblasts.
• Alar plate and dorsal root ganglion: The importance of the role of the alar plate, and the formation of dorsal root ganglia.
• Basal plates and ventral horn: Role of basal plates and formation of ventral homs.
• Central canal: Formation and importance of the central canal.

Development of the Dermatomes and Myotomes

• Somite formation: Process of dermatomes and myotome formation.
• Axon migration: How axons travel to different parts of the body during development in order to create segmental distribution of dermatomes and myotomes.

Spina Bifida and Myelomeningocele

• Complicated inheritance pattern: Involves multiple genes and the combination of variants at multiple loci.
• Environmental factors: Environmental factors may also contribute to the development of these conditions. For example folic acid intake is important to consider for neural tube development.
• Associated genes: Specific genes with autosomal dominant inheritance are related to this.

Development of the Limbs

• Limb bud growth: Limb growth along three axes: proximal–distal, anterior–posterior, and dorsoventral.
• Apical ectodermal ridge (AER): Important to limb growth and limb mesenchyme.
• Zone of polarizing activity (ZPA): Determines anterior-posterior patterning.
• Future limb development: Development of flexors and extensors and future bone models.

Development of the Limbs (detailed/week-by-week)

• Limb bud and plate formation details (weeks 5–7).
• Digital ray development during weeks 6-7.
• Limb rotation at the end of week 7.

Syndactyly

• Definition: Soft tissue fusion of adjacent digits.
• Causes/results: Failure in apoptosis separating mesenchymal tissue or failure of notch formation in apical ectodermal ridge (AER).
• Classification: Syndactyly can be classified as simple, complex or complicated. 
• Inheritance: Autosomal dominant inheritance with incomplete penetrance potentially associated with genetic syndromes. HOXD13 is involved.

Congenital Myopathies

• Definition: A group of rare hereditary muscle diseases characterized by architectural abnormalities.
• Subgroups: Five main subgroups: core myopathies, nemaline myopathies, centronuclear myopathies, congenital fiber-type disproportion myopathy, and myosin storage myopathy.
• Diagnostic tools: Muscle biopsy, muscle imaging, and genetic analysis.

Excitation-Contraction Coupling

• Overview diagram and description of excitation-contraction coupling.
• Step-by-step explanation of the process: Mechanism, including the role of action potential, T tubules, calcium release, and repolarization.

Differentiating Features (Muscle Disorders)

• Core myopathies: Presence of cores/minicores, lack of oxidative enzyme activity within the muscle fibers. 
• Nemaline myopathy: Presence of nemaline bodies/rods in muscle fibers. 
• Centronuclear myopathies: Centralized nuclei, larger than normal with a vesicular appearance.

Differentiating Features (Myosin Storage Myopathy)

• Myosin storage myopathy: Presences of hyaline bodies. Common mutations are in MYH7.

Clinical Features and Key Genes (Muscle Disorders)

• Correlation between clinical features and key related genes/mutations.
• Specific features: Such as eye involvement, cardiac involvement, marked congenital hypotonia, respiratory involvement severity, facial dysmorphism, and other potential clinical presentations as related to gene specificities.

Inheritance Patterns (Congenital Myopathies)

• Inheritance patterns vary depending on the gene mutation.
• Criticality and role of gene sequencing: Gene sequencing is necessary for an accurate diagnosis and to determine the inheritance patterns of various congenital myopathies based on the specific gene mutations.

Inheritance Patterns (detailed table)

• Summary table of inheritance patterns relating to the most common genes that cause the disorders.
• Descriptions of most common changes and additional information pertinent to each muscle and myopathy condition.

Somatic Changes and Neurogenetics

• mTOR pathway: The role of somatic variations and mutations in mTOR pathways in the brain's generation of focal malformations and development of conditions including FCD, HMEG, and DMEG.
• Neurodevelopmental disorders: Pathogenic variants in the mTOR pathways causing brain overgrowth, cellular abnormalities, intellectual disability, intractable epilepsy, and spectrum autism disorder.

Questions (regarding RYR1 and inheritance patterns)

• RYR1 inheritance patterns: What condition is RYR1 linked with, and what inheritance pattern (if the condition is due to biallelic mutations, what is the expected inheritance pattern), and what additional clinical features are possible/associated?

Explore the concepts of inheritance patterns and gene regulation through this quiz. Topics include autosomal dominant and recessive inheritance, pedigree charting, operon expression, and mRNA regulation. Test your knowledge of genetic principles and their implications.