unusual brain/neuro +/- muscular findings

Vocabulary flashcards covering key genetic syndromes and their characteristic features from the lecture notes.

Angelman Syndrome: Core Definition

severe neurodevelopmental disorder characterized by:

profound developmental delay

Intellectual disability

speech impairment

ataxia

a recognizable behavioral profile (e.g., frequent smiling/laughter, excitability)

often a seizure disorder

Angelman Syndrome: Genetic Basis (UBE3A Gene)

deficiency of the maternally inherited allele of the Ubiquitin Protein Ligase E3A (UBE3A) gene, located on chromosome 15q11-q13.

The UBE3A gene encodes an E3 ubiquitin ligase, an enzyme crucial for protein degradation via the proteasome system, essential for neuronal function and synaptic plasticity.

Approximately 10% of individuals with AS have a point mutation or a small deletion/insertion within the maternal UBE3A gene itself. These mutations lead to a non-functional or absent UBE3A protein.

Angelman Syndrome: Genetic Mechanism

1. Maternal Deletion

The most common genetic etiology for Angelman Syndrome (\approx 70% of cases) is a de novo deletion within the 15q11-q13 region on the maternally inherited chromosome. This deletion removes the intact UBE3A gene, leading to its functional absence.

This deletion is typically detectable by fluorescence in situ hybridization (FISH) or chromosomal microarray analysis.

Angelman Syndrome: Genetic Mechanisms

2. Paternal Uniparental Disomy (UPD)

Paternal uniparental disomy (UPD) of chromosome 15 accounts for approximately 5% of AS cases.

individual inherits both copies of chromosome 15 from the father and no copies from the mother. Since the paternal UBE3A allele is normally imprinted (silenced) in neurons, the absence of a functional maternal allele results in the deficiency of UBE3A protein. This mechanism is detectable by methylation analysis.

Angelman Syndrome: Genetic Mechanisms

4. Imprinting Defects

Imprinting defects account for a smaller percentage (\approx 2%) of AS cases. In these instances, the normal epigenetic mark that silences the paternal UBE3A allele in neurons is aberrantly applied to the maternal allele as well, or there is an abnormal methylation pattern in the imprinting center, effectively silencing both alleles. This is also detected by methylation analysis.

Angelman Syndrome: Neurological Presentation

Neurological features are prominent in Angelman Syndrome:

• Developmental Delay: Profound global developmental delay is universal, with significant impairment in motor and cognitive skills.

• Speech Impairment: Severely compromised or absent expressive language, often limited to non-verbal communication.

• Motor Dysfunction: Characterized by progressive ataxia (impaired coordination and balance), truncal instability, tremulous movements (particularly of the limbs), and a distinctive stiff-legged, wide-based, often "puppet-like" gait.

• Seizures: Present in about 80-90% of cases, often beginning in early childhood. Seizures can be varied (myoclonic, atypical absence, atonic, tonic-clonic) and frequently resistant to conventional anti-epileptic treatment. Characteristic EEG patterns include large-amplitude slow-wave (2-3 \text{ Hz}) discharges, especially observed in the occipital regions.

Angelman Syndrome: Behavioral Phenotype & Other Features

The behavioral phenotype of Angelman Syndrome is highly distinctive:

• Behavior: A remarkably happy demeanor, characterized by frequent paroxysms of laughter (often unprovoked or without clear external stimuli), excitability, easily amused, hypermotoric behavior, and characteristic hand-flapping or mouthing behaviors.

• Craniofacial Features: Microcephaly (small head circumference, becoming more apparent with age) coupled with brachycephaly (flattened head), often a wide mouth, widely spaced teeth, and prognathism.

• Other: Sleep disturbances (decreased need for sleep, irregular sleep patterns), strabismus (ocular misalignment), and feeding difficulties (e.g., suck/swallow discoordination) in infancy are also common.

Prader-Willi Syndrome: Core Definition & Pathophysiology

Prader-Willi Syndrome (PWS) is a complex genetic disorder primarily affecting the hypothalamus, leading to significant challenges in metabolism, growth, and neurodevelopment. It is characterized by two distinct nutritional phases: severe hypotonia and failure to thrive in infancy, followed by insatiable appetite (hyperphagia) leading to morbid obesity in childhood. PWS results from the loss of expression of normally paternally inherited genes in the 15q11.2-q13 region, which are critical for hypothalamic function.

Prader-Willi Syndrome: Genetic Locus & Imprinting

The critical region for Prader-Willi Syndrome is located on chromosome 15q11.2-q13. This region contains several paternally expressed genes (e.g., SNRPN, NDN, MAGEL2) that are normally inactivated (imprinted) on the maternally inherited chromosome. The functional absence of these paternally expressed genes in this region, due to various genetic mechanisms, underlies the syndrome.

Prader-Willi Syndrome: Genetic Mechanism

1. Paternal Deletion

Approximately 70% of PWS cases are caused by a de novo deletion within the 15q11.2-q13 region on the paternally inherited chromosome. This deletion removes the critical cluster of paternally expressed genes. This is typically detectable by FISH or chromosomal microarray analysis.

Prader-Willi Syndrome: Genetic Mechanisms

2. Maternal Uniparental Disomy (UPD)

Maternal uniparental disomy (UPD) of chromosome 15 accounts for 25-30% of PWS cases. In this situation, an individual inherits both copies of chromosome 15 from the mother and no copies from the father. Since the paternally expressed genes in the 15q11.2-q13 region are imprinted (silenced) on the maternal chromosomes, the individual lacks any functional copies of these critical genes. This diagnosis is confirmed by methylation analysis.

Prader-Willi Syndrome: Genetic Mechanisms

3. Imprinting Defects

A smaller percentage (\text{< 5\%}) of PWS cases result from a mutation or epigenetic alteration in the imprinting control region (ICR) within 15q11-q13. This defect leads to the silencing of the paternal genes, mimicking the maternal imprinting pattern. Such defects are identified through methylation analysis.

Prader-Willi Syndrome: Infantile Phase Presentation

The infantile phase of Prader-Willi Syndrome (birth to 1-6 years) is characterized by:

• Severe Neonatal Hypotonia: Profound muscle weakness ('floppy infant') is a hallmark, often noticeable prenatally with decreased fetal movements. This can lead to a weak cry and poor reflexes.
• Feeding Difficulties: Due to hypotonia affecting oral-motor coordination and a poor suck reflex, infants typically experience significant feeding problems and failure to thrive, often requiring gavage (tube) feeding.
• Sleepiness: Infants may exhibit excessive somnolence.
• Dysmorphic Features: Subtle facial features (e.g., almond-shaped eyes, narrow nasal bridge) may be present.

Prader-Willi Syndrome: Childhood/Adolescence & Metabolic Phase

The transition from infancy marks the onset of critical metabolic and behavioral challenges, typically between 1 and 6 years of age:

• Hyperphagia: Development of an insatiable appetite, coupled with a diminished sense of satiety and a lower-than-normal caloric requirement. This drives chronic, excessive eating.
• Morbid Obesity: Without strict food control, hyperphagia inevitably leads to rapid weight gain and severe, morbid obesity, which is the leading cause of morbidity and mortality in PWS. This is linked to hypothalamic dysfunction affecting appetite regulation and energy homeostasis.

Prader-Willi Syndrome: Endocrine & Growth Dysfunctions

Endocrine dysfunction is a central feature of PWS, reflecting hypothalamic involvement:

• Hypogonadism: Universal feature, characterized by incomplete pubertal development (e.g., cryptorchidism in males, hypoplastic labia in females) and reduced fertility.
• Growth Hormone Deficiency (GHD): Highly prevalent, contributing to short stature (if untreated) and reduced lean body mass. Growth hormone therapy is a standard treatment.
• Central Adrenal Insufficiency: A significant number of individuals with PWS are at risk for central adrenal insufficiency, requiring careful monitoring, especially during periods of stress.
• Thyroid Dysfunction: Hypothyroidism is more common than in the general population.
• Diabetes Mellitus: Early-onset Type 2 Diabetes is frequent, compounded by obesity and insulin resistance.

Prader-Willi Syndrome: Neurodevelopmental & Behavioral Aspects

PWS is associated with characteristic neurodevelopmental and behavioral traits:

• Intellectual Disability: Mild to moderate intellectual disability and global developmental delays are common, with specific learning disabilities.
• Behavioral Problems: Highly characteristic behavioral issues include temper tantrums, stubbornness, obsessive-compulsive traits (e.g., skin picking, repetitive behaviors), anxiety, and difficulty with transitions.
• Speech/Language: Significant speech and language impairments are common, including dysarthria and apraxia of speech.
• Motor Skills: Despite improved muscle tone post-infancy, individuals often exhibit deficits in fine and gross motor skills.

Myotonic Dystrophy (DM): Core Definition & Inheritance

Myotonic Dystrophy (DM) represents a group of highly variable, autosomal dominant, multisystemic disorders. It is the most common form of adult-onset muscular dystrophy. DM is primarily characterized by myotonia (difficulty relaxing muscles) and progressive muscle weakness and atrophy, alongside involvement of cardiac, ocular, endocrine, and central nervous systems. Inheritance follows an autosomal dominant pattern, with a high degree of phenotypic variability.

Myotonic Dystrophy Type 1 (DM1): Genetic Basis & Repeats

Myotonic Dystrophy Type 1 (DM1), also known as Steinert's disease, is caused by an unstable CTG trinucleotide repeat expansion in the 3'-untranslated region (UTR) of the DMPK gene on chromosome 19q13.3. The severity and age of onset are inversely correlated with the number of CTG repeats:

• Normal: 5-37 repeats
• Permutation/Pre-mutation: 38-49 repeats (asymptomatic, but prone to expansion)
• Mild DM1: 50-100 repeats (later onset, milder symptoms)
• Classic DM1: 100-1000 repeats (childhood/adult onset, typical features)
• Congenital DM1: >1000 repeats (severe neonatal onset)

This genetic instability leads to the anticipation phenomenon.

Myotonic Dystrophy Type 1 (DM1): Pathophysiology (Toxic RNA)

DM1 arises from a 'toxic RNA gain-of-function' mechanism. The expanded CUG repeat within the DMPK mRNA causes the aberrant transcript to accumulate in the cell nucleus, forming characteristic nuclear RNA foci. These RNA foci act as sponges, sequestering important RNA-binding proteins, particularly Muscleblind-like Splicing Regulator 1 (MBNL1). This sequestration prevents MBNL1 from performing its normal functions in regulating alternative pre-mRNA splicing. The resulting widespread mis-splicing of numerous target messenger RNAs (e.g., chloride channel CLC-1, insulin receptor, cardiac troponin T) across various tissues underlies the diverse multisystemic clinical manifestations of DM1.

Myotonic Dystrophy Type 1 (DM1): Musculoskeletal & Cardiac Features

Key clinical features of Classic DM1:

• Myotonia: The hallmark symptom, defined as delayed relaxation of muscles after voluntary contraction (e.g., difficulty releasing a handshake, stiffness after eye closure), often exacerbated by cold and fatigue.
• Muscle Weakness & Atrophy: Progressive, insidious weakness and wasting, predominantly affecting distal muscles (e.g., facial muscles resulting in ptosis and a 'tent-shaped' mouth, neck flexors, forearms leading to wrist drop, intrinsic hand muscles, and lower leg muscles causing foot drop). Atrophy of temporal and sternocleidomastoid muscles is also characteristic.
• Cardiac Involvement: A major cause of morbidity and mortality. Includes conduction defects (e.g., PR prolongation, first-degree AV block, bundle branch blocks) leading to a high risk of sudden cardiac death due to arrhythmias. Cardiomyopathy can also occur.

Myotonic Dystrophy Type 1 (DM1): Ocular, Endocrine & CNS Features

Multisystemic involvement beyond muscles and heart:

• Ocular: Early-onset, bilateral, iridescent posterior subcapsular cataracts are highly prevalent and often an early sign.
• Endocrine/Metabolic: Commonly includes hypogonadism (testicular atrophy in males, menstrual irregularities in females), insulin resistance and type 2 diabetes, and primary hypothyroidism.
• Central Nervous System (CNS): Cognitive impairment (frontal lobe dysfunction, executive deficits, visuospatial difficulties), excessive daytime sleepiness (hypersomnia), apathy, and personality changes are frequent.

Myotonic Dystrophy
Congenital DM1 (CDM) & Anticipation

Two important concepts in DM1:

• Anticipation: The phenomenon where the disease onset occurs earlier and its severity increases in successive generations. This is due to further expansion of the CTG trinucleotide repeat length during meiosis, particularly through maternal transmission, leading to larger repeat sizes in offspring.
• Congenital Myotonic Dystrophy (CDM): The most severe form of DM1, typically occurring when very large CTG repeat expansions (>1000 repeats) are maternally inherited. Presents at birth with profound generalized hypotonia, severe respiratory insufficiency often requiring mechanical ventilation, significant feeding difficulties, talipes equinovarus (clubfoot), and severe cognitive impairment. Neonatal mortality is high, predominantly due to respiratory failure.

Myotonic Dystrophy Type 2 (DM2)

Myotonic Dystrophy Type 2 (DM2), also known as Proximal Myotonic Myopathy (PROMM), is less common than DM1. It is caused by a CCTG tetranucleotide repeat expansion in the first intron of the CNBP (Cellular Nucleic Acid Binding Protein) gene on chromosome 3q21. While sharing features with DM1 (myotonia, cataracts, cardiac issues), DM2 typically presents with more prominent proximal muscle weakness, milder myotonia, and generally a less severe, later-onset course than classic DM1, without a distinct congenital form.

Robin Sequence: Core Definition & 'Sequence' Concept

Robin Sequence (formerly Pierre Robin Syndrome) is a congenital anomaly complex characterized by a triad of micrognathia (small mandible), glossoptosis (posterior displacement of the tongue), and upper airway obstruction. It is termed a 'sequence' rather than a 'syndrome' because its distinct features are not inherited as a single genetic disorder but rather result from a cascade of developmental events initiated by a single primary malformation.

Robin Sequence: Primary Malformation (Mandibular Hypoplasia)

The initiating event in Robin Sequence is mandibular hypoplasia (underdevelopment or smallness of the lower jaw). This primary malformation occurs early in fetal development, typically between 7 and 11 weeks of gestation, when the mandible fails to grow sufficiently. The small or recessed jaw creates insufficient space within the oral cavity.

Robin Sequence: Pathophysiological Cascade - Glossoptosis

As a direct consequence of the primary mandibular hypoplasia, the developing tongue (glossus) cannot descend normally into the oral cavity. Instead, it remains positioned high and posteriorly within the pharyngeal space. This backward and upward displacement of the tongue is termed glossoptosis.

Robin Sequence: Pathophysiological Cascade - Cleft Palate Formation

The persistently high and posteriorly displaced tongue mechanically interferes with the normal fusion of the lateral palatal shelves, which typically occurs around 9-12 weeks of gestation. This mechanical obstruction prevents the palatal shelves from migrating horizontally and fusing in the midline, resulting in a characteristic U-shaped cleft soft palate in approximately \text{80\%} of cases. It is important to note that the cleft palate is a secondary consequence, not a primary malformation.

Robin Sequence: Critical Clinical Challenge (Airway Obstruction)

The most critical clinical challenge in Robin Sequence is recurrent and potentially life-threatening upper airway obstruction. This is primarily caused by the posterior displacement of the tongue falling back into the pharynx, which can block the laryngeal inlet. Clinical signs include inspiratory stridor (noisy breathing), intercostal and substernal retractions, dyspnea (difficulty breathing), cyanosis, and severe apneic episodes, particularly when the infant is in a supine position. Airway management is the immediate priority for affected neonates.

Robin Sequence: Feeding Difficulties & Management

Infants with Robin Sequence frequently experience significant feeding difficulties due to multifactorial issues:

• Poor Oral Seal: Resulting from micrognathia and/or the cleft palate, making it difficult to create suction.
• Dysphagia: Difficulty coordinating suck-swallow-breathe mechanics.
• Airway Compromise during feeding: Risk of aspiration. These challenges often lead to poor weight gain and require specialized feeding strategies, such as prone feeding, specialized bottles, or even nasogastric/orogastric tube feeding to ensure adequate nutrition.

Robin Sequence: Associated Syndromes & Management Strategies

While Robin Sequence can occur in isolation (isolated PRS), it is frequently associated with other genetic syndromes, chromosomal anomalies, or teratogenic exposures in \text{20\% - 40\%} of cases (e.g., Stickler syndrome, velocardiofacial syndrome/22q11.2 deletion syndrome, Treacher Collins syndrome). Therefore, a comprehensive genetic evaluation is often warranted. Management strategies focus on:

• Airway Management: Prone positioning, nasopharyngeal airway insertion, glossopexy (suturing the tongue forward), mandibular distraction