Clinical Presentation
Genetics
Treatment
Conventional Knowledge
Less Conventional Knowledge
100
At what age does SMA type I typically present, and what are two hallmark physical findings?
Presents within the first six months of life; key findings include hypotonia and areflexia.
100
Which gene is most commonly deleted or mutated in patients with SMA type I, and where is its location?
The SMN1 gene, located on chromosome 5q13.
100
What is the primary diagnostic test currently used to confirm SMA type I?
Molecular genetic testing for homozygous deletion or mutation of the SMN1 gene.
100
Define "pectus excavatum."
A chest wall deformity where the ribs sternum curve inward, creating a depression in the chest.
100
What is A.T. Still's date of birth?
August 6, 1828.
200
Create a differential diagnosis for SMA type I for a child under 6 months old.
Pompe disease, Prader-Willi syndrome, Myotonic dystrophy type 1, Sellweger spectrum disorder, Congenital myasthenic syndromes, X-linked infantile spinal muscular atrophy. It is essential to consider congenital myopathies, disorders of metabolism, and disorders of mitochondria.
200
What is the function of SMN1?
The SMN protein, encoded by SMN1, is a critical component of the SMN complex, which is required for the assembly of small nuclear ribonucleoproteins (snRNPs) involved in pre-mRNA splicing. This function is fundamental for the proper processing of mRNA.
200
Why are EMG, NCS, and muscle biopsy no longer routinely used in the diagnosis of SMA type I?
Because SMN1 genetic testing provides a rapid, definitive, and non-invasive diagnosis, making these invasive and less specific tests unnecessary.
200
What is the incidence of SMA?
Incidence has been estimated at 1 in 6000-11000, with a carrier frequency of 2-3%
200
Name this song.
Get Lucky - Daft Punk
300
Explain why infants with SMA type I develop a “bell-shaped chest” and a paradoxical breathing pattern.
Due to weakness of intercostal muscles with relative sparing of diaphragmatic function, causing the abdomen to move outward while the chest moves inward during inspiration.
300
Two infants are both diagnosed with SMA due to homozygous SMN1 deletion. Infant A has two copies of SMN2, and Infant B has four copies. Predict and explain the difference in their clinical outcomes.
Infant A, with two SMN2 copies, will likely present with type I SMA (severe, early onset), while Infant B’s higher SMN2 copy number may yield a less severe phenotype, delayed onset of symptoms, prolonged survival, and later need for respiratory and feeding support in SMA type I.
300
Explain how newborn screening impacts the prognosis of SMA type I and why timing is critical in diagnosis.
Newborn screening enables presymptomatic detection, allowing for the earliest possible initiation of therapy. Because motor neuron loss occurs rapidly, even brief diagnostic delays can lead to irreversible weakness and worse long-term outcomes.
300
Identify support groups for persons/families afflicted with SMA type I.
Cure SMA and the Muscular Dystrophy Association (MDA).
300
What is 294,483/700 (long division only)?
420.69
400
Compare the overall systemic and developmental features of an infant with SMA type I to those of a typically developing infant of the same age.
SMA I infants have profound proximal weakness, hypotonia, poor head control, weak cry, and feeding difficulties; respiratory distress with paradoxical breathing and bell-shaped chest; normal cognition and social responsiveness. In contrast, normal infants show progressive motor milestones, normal tone, symmetric movement, and no respiratory or feeding compromise. Preservation of cognition amid severe motor deficits helps distinguish SMA I and underscores the importance of early screening and treatment before irreversible motor neuron loss.
400
Describe how the cellular functions of the SMN protein explain the motor neuron degeneration seen in SMA type I.
SMN protein is critical in both cytoplasmic mRNA transport/axon maintenance and nuclear snRNP assembly for splicing. Deficiency disrupts mRNA processing and cytoskeletal integrity in motor neurons, leading to axonal dysfunction, synaptic loss, and neuronal death, which manifest clinically as progressive weakness and atrophy.
400
Describe the expected electrophysiologic and histologic findings in SMA type I and explain how they reflect the underlying pathophysiology.
EMG shows signs of denervation—fibrillation potentials, positive sharp waves, and large polyphasic motor unit potentials with reduced recruitment. NCS shows reduced CMAP amplitude with normal conduction velocity. Muscle biopsy reveals grouped fiber atrophy and hypertrophic fibers, reflecting chronic denervation and collateral reinnervation from motor neuron loss.
400
What is the most expensive medicinal drug in the world?
Onasemnogene abeparvovec is priced at $2.125 million for a single injection and has been reported to be the most expensive drug in the world. Onasemnogene abeparvovec is currently licensed for use in the USA.
400
Draw a cyclic glucose molecule.
500
Based on the clinical presentation, explain how SMA type I can be differentiated from congenital myopathies and congenital muscular dystrophies in early infancy without genetic testing.
SMA type I presents with profound hypotonia and areflexia but preserved cognition and alertness, paradoxical breathing, and tongue fasciculations—findings more consistent with a lower motor neuron disorder than with myopathies or dystrophies, which often preserve reflexes and have different muscle involvement patterns.
500
If SMN protein is essential in all eukaryotic cells, why does SMA type I predominantly affect motor neurons rather than other cell types, and what does this reveal about selective neuronal vulnerability in genetic diseases?
They express markedly lower levels of full-length SMN mRNA from SMN2 compared to other cell types, resulting in a critical threshold deficit when SMN1 is lost. SMN is required not only for ubiquitous snRNP assembly and pre-mRNA splicing, but also for motor neuron-specific processes such as axonal outgrowth, cytoskeletal maintenance, and neuromuscular junction integrity, which are disproportionately affected by SMN deficiency. This pattern of selective neuronal vulnerability in SMA type I reveals that genetic diseases caused by loss of ubiquitously expressed proteins can manifest as cell type-specific disorders when certain cells have unique molecular dependencies, lower baseline protein levels, or reduced capacity for compensation and adaptation.
500
Compare the mechanisms of action of nusinersen and onasemnogene abeparvovec in the treatment of SMA type I, and explain how each targets the underlying genetic defect differently.
Nusinersen is an intrathecally administered antisense oligonucleotide that modifies SMN2 pre-mRNA splicing by inhibiting ISS-N1, increasing production of full-length functional SMN protein from the SMN2 gene. Onasemnogene abeparvovec is an adeno-associated virus vector-based gene therapy delivered intravenously, which introduces a functional SMN1 gene into motor neurons, allowing cells to produce normal SMN protein directly. Nusinersen boosts output from the backup gene, while onasemnogene replaces the defective primary gene.
500
Name and define the four main subtypes of SMA.
SMA type I (Werdnig-Hoffmann disease): Onset before 6 months of age, characterized by severe, generalized muscle weakness and hypotonia. Infants never achieve the ability to sit independently and typically have a poor prognosis, with death from respiratory failure often occurring within the first two years of life.
SMA type II (Dubowitz disease): Onset between 6 and 18 months. Children can sit independently but cannot stand or walk unaided. Life expectancy is variable, and respiratory complications are common.
SMA type III (Kugelberg-Welander disease): Onset after 18 months, usually in childhood or adolescence. Individuals can stand and walk unaided at some point but may lose ambulation later. Life expectancy is generally normal, though progressive weakness may require wheelchair use.
SMA type IV: Adult-onset, typically after age 20. This form is characterized by mild to moderate proximal muscle weakness, with normal life expectancy and minimal respiratory involvement.
500
What is the arcuate fasciculus and what is its function?
The arcuate fasciculus is a bundle of nerve fibers that connects two key language areas in the brain, Broca's area (for speech production) and Wernicke's area (for language comprehension). Its primary function is to integrate these regions to facilitate language processing, including tasks like repetition, word retrieval, spontaneous speech, and comprehension.