Classic Neurodevelopmental Genetic Disorders

1. A 6-month-old infant presents with infantile spasms. Brain MRI reveals multiple cortical tubers, subependymal nodules, and a cardiac rhabdomyoma was noted on prenatal ultrasound. The first-line antiepileptic drug for this infant's seizures is:

1. A.ACTH (adrenocorticotropic hormone)
2. B.Levetiracetam
3. C.Vigabatrin✓
4. D.Carbamazepine — a sodium channel blocker effective for focal seizures arising from cortical tubers

Vigabatrin is the recommended first-line treatment specifically for TSC-associated infantile spasms, with a response rate of approximately 95% in this etiology — significantly higher than ACTH/prednisolone (~50%). While ACTH is first-line for infantile spasms of other etiologies, TSC-associated spasms have a uniquely preferential response to vigabatrin. The EPISTOP trial further demonstrated that preventive vigabatrin — started when EEG becomes epileptiform but before clinical seizures — can reduce epilepsy incidence and improve neurodevelopmental outcomes. This infant's presentation with cortical tubers, subependymal nodules, and cardiac rhabdomyoma meets clinical criteria for TSC.

2. A 14-year-old boy with moderate intellectual disability has been evaluated with chromosomal microarray (normal) and whole exome sequencing (no pathogenic variants identified). He has a long face, large ears, macroorchidism, anxiety, and poor eye contact. His mother reports that her father (the boy's maternal grandfather) recently developed progressive tremor and balance problems at age 65. What is the most likely missed diagnosis?

1. A.Klinefelter syndrome (47,XXY) — tall stature, hypogonadism, and mild intellectual disability with behavioral features
2. B.Fragile X Syndrome — FMR1 CGG repeats are not detected by CMA or WES; grandfather's tremor/ataxia suggests FXTAS✓
3. C.22q11.2 deletion syndrome — should have been detected by the chromosomal microarray that was already performed
4. D.Angelman syndrome — would present with absent speech, happy affect, and characteristic EEG pattern instead

This is a classic case of Fragile X Syndrome missed because neither CMA nor standard WES detects large CGG repeat expansions. The boy's features (moderate ID, characteristic facies, macroorchidism, anxiety, gaze avoidance) are textbook Fragile X. The maternal grandfather's progressive tremor and ataxia strongly suggest FXTAS (premutation carrier). This scenario emphasizes that FMR1 CGG repeat analysis must be specifically ordered as a dedicated test — it is recommended as first-tier testing in any male with unexplained intellectual disability, regardless of other genetic testing results.

3. A family affected by TSC asks about the difference between TSC1 and TSC2 mutations. Which statement most accurately reflects the genotype-phenotype correlation?

1. A.TSC1 and TSC2 mutations produce identical clinical phenotypes because both proteins function in the same mTOR-inhibiting complex
2. B.TSC2 variants are generally associated with more severe disease — more tubers, earlier seizures, higher ID rates, and larger AMLs✓
3. C.TSC1 variants cause only neurological features, while TSC2 variants cause only renal and cardiac manifestations of the disease
4. D.TSC2 variants are always de novo while TSC1 variants are always inherited from an affected parent in autosomal dominant fashion

While both TSC1 (hamartin) and TSC2 (tuberin) function together in the same mTOR-inhibiting complex, TSC2 pathogenic variants are generally associated with a more severe clinical phenotype than TSC1 variants. Patients with TSC2 mutations tend to have more cortical tubers, earlier seizure onset, higher rates of intellectual disability, and larger renal angiomyolipomas. This genotype-phenotype correlation is important for prognostication and counseling. However, significant phenotypic variability exists within both groups, and individual patients with TSC1 mutations can still have severe disease.

4. A 55-year-old man presents with progressive intention tremor, gait ataxia, executive dysfunction, and peripheral neuropathy. Brain MRI shows bilateral T2/FLAIR hyperintensity in the middle cerebellar peduncles and cerebral white matter changes. His daughter has a son with intellectual disability and autism. The MRI finding most suggestive of the diagnosis is:

1. A.Cortical tubers and subependymal nodules — suggesting tuberous sclerosis complex with mTOR pathway involvement
2. B.Posterior periventricular white matter enhancement — suggesting X-linked adrenoleukodystrophy (ABCD1 mutation)
3. C.Bilateral middle cerebellar peduncle T2 hyperintensity (MCP sign) — the MRI hallmark of FXTAS✓
4. D.Bilateral caudate and putamen T2 hyperintensity — suggesting Leigh syndrome or mitochondrial disease

The MCP sign — bilateral T2/FLAIR hyperintensity in the middle cerebellar peduncles — is the radiological hallmark of Fragile X-associated tremor/ataxia syndrome (FXTAS). This man's clinical presentation (progressive tremor, ataxia, executive dysfunction, neuropathy) and family history (grandson with ID and autism, likely Fragile X full mutation through the daughter who is an obligate premutation carrier) are classic for FXTAS. FXTAS is caused by RNA toxicity from the FMR1 premutation (55-200 CGG repeats) — a fundamentally different mechanism from Fragile X Syndrome (full mutation, gene silencing, FMRP absence).

5. A 10-year-old girl with Rett Syndrome (confirmed MECP2 pathogenic variant) is in the plateau phase (Stage III). Her family asks about trofinetide, which was recently FDA-approved. Which statement best describes this therapy?

1. A.Trofinetide is a gene replacement therapy that restores MECP2 expression to normal physiological levels in neurons
2. B.Trofinetide is an antisense oligonucleotide that corrects the specific MECP2 point mutation at the RNA level
3. C.Trofinetide is an IGF-1 analog (FDA-approved 2023) that targets downstream neuroinflammation rather than MECP2 directly✓
4. D.Trofinetide is an mTOR inhibitor similar to everolimus, repurposed from TSC treatment for use in Rett Syndrome

Trofinetide is a synthetic analog of the amino-terminal tripeptide of insulin-like growth factor 1 (IGF-1). It received FDA approval in 2023 as the first treatment specifically for Rett Syndrome. Rather than directly targeting MECP2 (which is challenging due to dosage sensitivity — both under- and overexpression cause disease), trofinetide addresses downstream pathological consequences including neuroinflammation, oxidative stress, and impaired synaptic function. Direct MECP2 gene replacement remains challenging because the gene is dosage-sensitive: overexpression causes MECP2 duplication syndrome, creating a narrow therapeutic window.

6. A female premutation carrier (FMR1 CGG repeat = 90) is planning pregnancy. She asks about the risk that her child will have Fragile X Syndrome. The most accurate counseling statement is:

1. A.There is no risk of expansion because premutation alleles of this size are stable during maternal meiotic transmission
2. B.Only male offspring are at risk of being clinically affected; female offspring will always be unaffected carriers
3. C.At 90 CGG repeats, expansion to full mutation during maternal meiosis is near-certain; each child has a 50% chance of inheriting it✓
4. D.The risk of expansion depends entirely on the father's FMR1 repeat size, not the mother's premutation length

The risk of maternal premutation expansion to full mutation during meiosis is strongly correlated with the mother's CGG repeat length. At 90 repeats, the risk of expansion to full mutation (>200 repeats) approaches 100%. Each child has a 50% chance of inheriting the expanded allele (versus the normal allele). Males who inherit a full mutation will have Fragile X Syndrome with moderate-to-severe intellectual disability. Females who inherit a full mutation have variable cognitive impairment (~50% have some degree) due to random X-inactivation. Preimplantation genetic testing (PGT) or prenatal testing can be offered. The mother herself is also at risk for FXPOI (premature ovarian insufficiency) which may affect fertility planning.