TSC is an autosomal dominant multi-system disorder caused by loss-of-function variants in TSC1 (hamartin, 9q34) or TSC2 (tuberin, 16p13.3). These proteins form a complex that inhibits the mTOR pathway — loss of either releases constitutive mTOR activation, driving hamartoma formation across organs. ~2/3 of cases are de novo.

Neurological features

• Cortical tubers — disorganized cortical tissue, highly epileptogenic
• Subependymal nodules (SENs) — calcified periventricular nodules
• SEGAs — growing tumors near the foramen of Monro; risk of obstructive hydrocephalus
• Epilepsy in ~85% (often infantile spasms in the first year)
• ASD in 40–50%; intellectual disability in ~50%

Systemic features

• Cardiac rhabdomyomas — often the earliest sign (prenatal/neonatal); typically regress
• Renal angiomyolipomas — lifelong hemorrhage risk
• LAM (lymphangioleiomyomatosis) — cystic lung disease, predominantly adult females
• Facial angiofibromas — appear in childhood, pathognomonic

Diagnosis: 2012 criteria use major and minor features (2 major or 1 major + ≥2 minor = definite diagnosis). A pathogenic TSC1/TSC2 variant is independently sufficient. The old Vogt triad is present in only a minority.

TSC is a paradigm for targeted therapy in neurogenetics — because the mechanism is constitutive mTOR activation, mTOR inhibitors directly address the molecular defect.

Everolimus (mTOR inhibitor) — FDA-approved for:

• TSC-associated SEGA (reduces tumor volume, can avoid surgery)
• Renal angiomyolipomas (reduces size, decreases hemorrhage risk)
• Adjunctive therapy for TSC-associated refractory focal seizures

Vigabatrin — first-line for TSC-associated infantile spasms (~95% response rate vs. ~50% for ACTH). The EPISTOP trial (2021) showed that preventive vigabatrin — started when EEG becomes epileptiform but before clinical seizures — reduced epilepsy incidence, drug-resistant epilepsy, and improved neurodevelopmental outcomes at 24 months.

Surveillance: regular brain MRI (SEGA monitoring to age 25), renal imaging (AML), echocardiography (infancy), CT chest (LAM screening in adult females), dermatology, ophthalmology, and serial EEG in infants.

Fragile X is the most common inherited cause of intellectual disability and most common single-gene cause of ASD. It results from a CGG repeat expansion in the 5'UTR of FMR1 (Xq27.3).

Repeat ranges: normal <45; intermediate 45–54; premutation 55–200; full mutation >200. Full mutation triggers promoter hypermethylation → FMR1 silencing → absent FMRP (an RNA-binding protein critical for synaptic plasticity and translational regulation).

Clinical features in affected males: moderate-to-severe ID, long face, prominent ears/jaw, macroorchidism (post-pubertal), anxiety, ADHD, hand flapping, gaze avoidance, joint hypermobility.

Females with full mutation: ~50% have some cognitive impairment (severity depends on X-inactivation ratio).

Anticipation: premutation alleles are unstable during maternal meiosis — risk of expansion to full mutation increases with repeat length (>90 repeats → near-100% expansion risk). Paternal transmission of premutations is generally stable.

Testing: FMR1 CGG repeat analysis (Southern blot/triplet-repeat PCR) — standard WES does NOT detect this. Must be specifically ordered.

The FMR1 premutation (55–200 repeats) is not clinically silent. Unlike the full mutation (gene silenced, no FMRP), the premutation produces elevated FMR1 mRNA (2–8× normal) with expanded CGG repeats. This excess mRNA is directly toxic — it sequesters RNA-binding proteins and forms intranuclear inclusions, causing progressive neurodegeneration. This is an RNA gain-of-function mechanism, fundamentally different from the FMRP-loss mechanism in Fragile X Syndrome.

FXTAS (Fragile X-associated tremor/ataxia syndrome):

• Late-onset (>50 years), predominantly males
• Progressive intention tremor, cerebellar gait ataxia, executive dysfunction, neuropathy
• MRI hallmark: bilateral T2/FLAIR hyperintensity in the middle cerebellar peduncles (MCP sign)

FXPOI (primary ovarian insufficiency):

• Affects ~20–25% of female premutation carriers
• Premature menopause (<40 years), menstrual irregularity, infertility

Counseling: premutation females risk FXPOI + expansion to full mutation in offspring; premutation males risk FXTAS and transmit premutation (not full mutation) to all daughters. Cascade testing is critical.

Rett Syndrome is X-linked dominant, caused by de novo loss-of-function variants in MECP2 (Xq28). It affects almost exclusively females (hemizygous males typically die in infancy). >95% of variants are de novo. MECP2 binds methylated CpG sites genome-wide and recruits chromatin remodeling complexes — its loss causes widespread transcriptional dysregulation in mature neurons. See the Epigenetics module for more on methylation mechanisms.

Classic presentation: apparently normal development to 6 months, then stagnation and regression (6–18 months) with loss of hand skills and speech, emergence of hand stereotypies (wringing, washing), and gait abnormalities.

Four stages: I — early stagnation (6–18 mo, subtle slowing, head growth deceleration); II — rapid regression (1–4 yr, hand/speech loss, stereotypies, breathing irregularities); III — plateau (2–10 yr, some social improvement, seizures peak, scoliosis); IV — late motor deterioration (>10 yr, rigidity, loss of ambulation).

Additional features: seizures (60–80%), acquired microcephaly, breathing irregularities (hyperventilation/apnea), prolonged QTc (cardiac monitoring needed), severe scoliosis.

Atypical variants: CDKL5 disorder (early seizures before regression — now a distinct entity); FOXG1 (congenital variant with severe impairment from birth).

Therapy: MECP2 is dosage-sensitive — underexpression = Rett, overexpression = MECP2 duplication syndrome. This narrow window makes gene replacement extremely challenging. Trofinetide (IGF-1 analog, FDA-approved 2023) is the first approved Rett treatment, targeting downstream neuroinflammation rather than MECP2 directly.

Each disorder requires a distinct testing approach. The key pitfall: assuming WES/WGS detects everything.

TSC: TSC1/TSC2 sequencing detects variants in ~85% of clinical TSC; ~15% are mutation-negative by standard sequencing (may harbor deep intronic, mosaic, or structural variants needing MLPA/long-read). Genetic confirmation alone is sufficient for diagnosis.

Fragile X: FMR1 CGG repeat analysis (Southern blot/triplet-repeat PCR) is the gold standard. Standard WES does NOT detect this — must be specifically ordered. ACMG recommends FMR1 testing as first-tier in any male with unexplained ID.

Rett: MECP2 sequencing + del/dup analysis detects >95% of classic Rett. If negative with Rett-like phenotype, test CDKL5 and FOXG1.

Counseling highlights

• TSC: AD, 2/3 de novo; recurrence ~1–2% for apparently de novo (germline mosaicism)
• Fragile X: X-linked with maternal anticipation; counsel premutation carriers about FXTAS/FXPOI
• Rett: >95% de novo; low but non-zero recurrence (~1% germline mosaicism)