• Some single-gene disorders do not follow classic Mendelian inheritance.
• Three important groups:
  • triplet repeat mutations
  • mitochondrial gene mutations
  • abnormalities involving genomic imprinting

Triplet Repeat Mutations

• These disorders result from abnormal expansion of a 3-nucleotide sequence within a gene.
• Increasing repeats → gene dysfunction.
• Examples include:
  • Fragile X syndrome
  • Huntington disease
  • myotonic dystrophy
  • spinocerebellar ataxias
• About 50 diseases are known to result from these mutations, and those identified so far are associated with neurodegenerative abnormalities.

Fragile X Syndrome (FXS)

• Fragile X syndrome is the prototype triplet-repeat disorder.
• It results from expansion of CGG repeats in the FMR1 gene.
• FXS is:
  • the most common genetic cause of intellectual disability in males
  • overall second only to Down syndrome
• Frequency:
  • males → about 1 in 1550
  • females → about 1 in 8000
• FMR1 repeat expansions are also associated with:
  • fragile X–associated tremor/ataxia syndrome
  • fragile X–associated primary ovarian insufficiency
• The name “fragile X” came from the old cytogenetic appearance:
  • cells grown in folate-deficient medium showed a constriction/discontinuity in the long arm of X
  • this method has largely been replaced by DNA analysis of repeat number
• Typical affected males may show:
  • severe intellectual disability
  • long face
  • large mandible
  • large, everted ears
  • macroorchidism
• Other possible features:
  • hyperextensible joints
  • high-arched palate
  • mitral valve prolapse
• These physical findings may be subtle or absent.
• The most consistent distinctive physical finding after puberty is macroorchidism, present in at least 90% of affected males.
• Neurologic and behavioral manifestations include:
  • epilepsy → about 30%
  • aggressive behavior → about 90%
  • autism spectrum disorder
  • anxiety/hyperactivity disorders
• FXS mainly affects males, but its inheritance differs from typical X-linked recessive disorders (Fig. 4.21).
• Carrier males:
  • about 20%–50% of males carrying an FMR1 expansion may lack typical neurologic disease
  • they transmit the altered gene to all daughters
  • affected descendants may appear in later generations
  • these men are called normal transmitting males
• Affected females:
  • about 20% of carrier females may show intellectual disability and other manifestations
  • this is more frequent than in typical X-linked recessive diseases
• Anticipation:
  • disease becomes more severe in successive generations
  • caused by progressive expansion of the triplet repeat
• The unusual inheritance is explained by the dynamic nature of CGG repeat expansion.
• Repeat numbers:
  • normal → average around 29 CGG repeats
  • premutation → 52–200 repeats
  • full mutation → 200–4000 repeats
• Carrier males and females generally carry a premutation.
• During oogenesis, a premutation may expand further: premutation → more CGG repeats → full mutation
• This expansion does not usually occur during spermatogenesis.
• A carrier female can therefore transmit a full mutation to either:
  • sons
  • daughters
• This explains:
  • why some carrier males remain unaffected → premutation
  • why some carrier females can have affected children → premutation expands during oogenesis

KEY CONCEPT

• Fragile X = FMR1 CGG triplet-repeat expansion.
• Normal ≈ 29 repeats → premutation 52–200 → full mutation 200–4000.
• Expansion mainly occurs during oogenesis.
• More repeats across generations → anticipation → more severe disease.
• Major clues:
  intellectual disability + long face + large ears + macroorchidism.

CONCEPTUAL EXAMPLES

• Male carries a premutation → may appear normal → passes it to all daughters → normal transmitting male.
• Daughter inherits premutation → during her oogenesis repeats expand → child receives full mutation → Fragile X syndrome.
• Repeat size increases from one generation to the next → disease becomes more severe → anticipation.

FIG. 4.21 — FRAGILE X PEDIGREE

🧠 Simplest idea

Fragile X shows anticipation: a small FMR1 CGG-repeat expansion (premutation) can become a full mutation when transmitted through a carrier mother → the next generation may develop Fragile X syndrome.

Whole figure in one flow

Carrier male (premutation)
→ gives his abnormal X to ALL daughters
→ daughters become carrier females
→ during formation of their eggs, the repeat may expand
→ full mutation
→ affected sons and variably affected daughters.

🎨 COLOR / SYMBOL GUIDE

• 🔵 Square = male
• 🩷 Circle = female
• 🔵 Long chromosome = X chromosome
• 🟢 Small chromosome = Y chromosome
• 🔴 Segment on X = FMR1 repeat expansion
• ⚫ Family lines = inheritance pathway

1️⃣ TOP — CARRIER MALE + NORMAL FEMALE

👨 Carrier male

He has:

X with premutation + normal Y

The 🔴 marked area on his X represents the expanded FMR1 CGG repeat.

A premutation usually means approximately:

55–200 CGG repeats

It is not yet the classic full Fragile X mutation.

Why can a premutation male look normal?

Because FMR1 is generally still expressed.

So he usually does not have classic Fragile X syndrome.

However, some older male premutation carriers can develop:

FXTAS

= Fragile X–associated tremor/ataxia syndrome.

2️⃣ Why are his SONS normal?

A father gives:

Y chromosome → sons

He does not give his X chromosome to sons.

Therefore:

Carrier father → son gets Y → no paternal FMR1 premutation

✅ Sons shown here are normal.

3️⃣ Why are ALL his DAUGHTERS carriers?

A father gives:

his only X chromosome → every daughter

Since his X carries the premutation:

Carrier father
→ premutation X
→ all daughters receive it

Their mother supplies a normal X.

So daughters become:

Premutation X / normal X

= carrier females

🧠 Key rule:

Father gives X to ALL daughters, Y to ALL sons.

4️⃣ MIDDLE — CARRIER FEMALE

A carrier female has:

one normal X + one premutation X

She may appear normal.

But some premutation females can develop:

Fragile X–associated primary ovarian insufficiency

→ reduced ovarian function / premature ovarian failure.

5️⃣ ⭐ MOST IMPORTANT ARROW — Premutation → Full mutation

During:

OOGENESIS

= formation of eggs in the carrier female

the CGG repeats may become longer.

So:

Premutation
⬇️ repeat expansion

FULL MUTATION

A full mutation generally means:

>200 CGG repeats

This is the key reason disease becomes more severe in later generations.

🧠 This is called:

ANTICIPATION

More repeats in later generation → greater likelihood/severity of disease.6️⃣ BOTTOM LEFT — MALE WITH FULL MUTATION

A son receives:

• Y from father
• abnormal X from carrier mother

If that maternal X has expanded to a full mutation:

Xfull mutation + Y

⬇️

Affected male

Why severe?

A male has only one X chromosome.

There is no second normal FMR1 copy to compensate.

7️⃣ What happens molecularly?

Full mutation:

>200 CGG repeats
→ methylation of the FMR1 promoter
→ FMR1 gene silenced
→ ↓ FMRP
→ abnormal synaptic development/function
→ Fragile X phenotype.

Simple:

Too many CGGs → gene switched OFF → FMRP ↓ → neurologic problems BOTTOM MIDDLE — Female with full mutation

A daughter may receive:

one normal X + one full-mutation X

But females have two X chromosomes.

Because of random:

X-inactivation

some cells use the normal X and some use the abnormal X.

Therefore females are:

variably affected

The figure emphasizes that only about 50% may show clinical manifestations, often milder than affected males.

9️⃣ Why are some children completely normal?

A carrier mother does not pass the abnormal X to every child.

Each child has a chance of receiving:

• normal maternal X
  or
• abnormal maternal X.

Thus some sons and daughters remain normal.

⭐ MOST IMPORTANT INHERITANCE CONCEPT

👨 Carrier father

Premutation X

→ ALL daughters = premutation carriers
→ NO sons inherit his abnormal X

👩 Carrier mother

Premutation may expand during oogenesis

→ full mutation can appear in children
→ males with full mutation = affected
→ females with full mutation = variably affected

🧠 Why does Fragile X show “anticipation”?

Because:

CGG repeats expand between generations

especially during maternal transmission.

So:

Premutation
→ larger repeat
→ full mutation
→ disease appears/becomes more severe.

🔥 Fastest exam recall

FMR1 gene → X chromosome

Premutation = ~55–200 CGG repeats
Full mutation = >200 repeats

Full mutation → hypermethylation → FMR1 OFF → ↓FMRP

Inheritance:

Carrier father → all daughters carriers, no affected sons from him

Carrier mother → repeat can expand → affected sons + variably affected daughters

⭐ One-line memory

Fragile X = maternal CGG-repeat expansion → FMR1 silencing → anticipation; males are usually more severely affected.

FIG. 4.22 — FMRP FUNCTION IN NEURONS

🧠 Simplest idea

FMRP binds selected mRNAs, carries them to dendrites/axons, and controls when ribosomes translate them into proteins. These local proteins are important for synaptic plasticity, learning, and memory.

Whole figure in one flow

FMRP + mRNA → transport through neuron → reaches dendrite/axon → ribosome → controlled local protein synthesis → normal synaptic function

1️⃣ Yellow cell = Neuron

The large yellow structure is the nerve cell.

• Upper branches = dendrites
• Long lower process = axon
• Purple central area = nucleus

2️⃣ 🔴 FMRP

The red structure = FMRP
FMRP = Fragile X messenger ribonucleoprotein

It is an RNA-binding protein.

Main job:

FMRP binds particular mRNAs and regulates their translation.

🧠 Think:

FMRP = mRNA transporter + translation controller

3️⃣ 🟢🔴 FMRP–mRNA complex

Green + red structure = FMRP bound to mRNA.

Black arrows show:

FMRP binds mRNA
→ forms FMRP–mRNA complex
→ complex moves away from the cell body.

4️⃣ Black arrows = Transport

The complex travels toward:

➡️ Dendrites

and

⬇️ Axon

This allows the neuron to carry the instructions for making proteins close to where those proteins are actually needed.

Easy concept:

Instead of making every protein in the cell body:

Neuron sends mRNA to the destination → makes protein locally.

5️⃣ 🔵 Ribosomes

Blue circles = ribosomes.

When the FMRP–mRNA complex reaches the correct location:

Ribosome reads mRNA
→ translation
→ new protein produced.

6️⃣ RIGHT — Dendritic proteins

At the dendrite:

FMRP-controlled mRNA
→ ribosome
→ 🟠 wavy dendritic proteins

These proteins help modify the synapse.

⬇️

Synaptic plasticity

= ability of synapses to become stronger or weaker with activity.

This is essential for:

Learning + memory

7️⃣ BOTTOM — Axonal proteins

The same idea occurs in the axon:

mRNA transported into axon
→ local ribosomes translate it
→ axonal proteins

These proteins help maintain and modify axonal function.

⭐ Why is FMRP important in Fragile X syndrome?

Normally:

FMRP → keeps local mRNA translation under proper control

In Fragile X syndrome:

FMR1 gene silenced
→ ↓ FMRP
→ excessive/uncontrolled translation of certain synaptic mRNAs
→ abnormal synaptic proteins
→ impaired synaptic plasticity
→ problems with learning and cognition.

🎨 COLOR / ARROW GUIDE

• 🟡 Yellow = neuron
• 🟣 Purple center = nucleus
• 🔴 Red = FMRP
• 🟢 structure around FMRP = bound mRNA complex
• 🔵 Blue circles = ribosomes
• 🟠 Wavy lines = newly made proteins
• ⚫ Black arrows = movement of FMRP–mRNA complexes

🧠 Fastest exam recall

FMRP binds mRNA → transports it to dendrites/axons → controls local translation → normal synaptic plasticity.

🔥 Fragile X:

↓ FMRP → ↑ inappropriate synaptic protein translation → abnormal synaptic function → impaired learning/memory.

Fragile X–Associated Tremor/Ataxia Syndrome and Fragile X–Associated Primary Ovarian Failure

• FMR1 CGG premutations can cause disorders different from classic fragile X syndrome.
• These disorders result from a toxic gain of function, rather than loss of FMRP.
• Two important disorders are:
  • Fragile X–associated primary ovarian failure
  • Fragile X–associated tremor/ataxia syndrome
• Fragile X–associated primary ovarian failure:
  • occurs in about 20% of females carrying an FMR1 premutation
  • ovarian failure develops before age 40
  • causes:
    • menstrual irregularities
    • decreased fertility
• Fragile X–associated tremor/ataxia syndrome:
  • occurs in about 50% of premutation-carrying males
  • usually begins in the sixth decade of life
  • is a progressive neurodegenerative disorder
  • major manifestations:
    • intention tremor
    • cerebellar ataxia
  • may later progress to parkinsonism

KEY CONCEPT

• FMR1 full mutation → fragile X syndrome → loss of FMRP function.
• FMR1 premutation → toxic gain of function → ovarian failure in females or tremor/ataxia syndrome in older males.
• Female premutation carrier → premature ovarian failure + reduced fertility.
• Male premutation carrier → late-onset tremor + ataxia ± parkinsonism.

CONCEPTUAL EXAMPLES

• Woman carrying an FMR1 premutation develops irregular periods before age 40 → fragile X–associated primary ovarian failure.
• Older man carrying an FMR1 premutation develops intention tremor followed by gait incoordination → fragile X–associated tremor/ataxia syndrome.

Pathogenesis

• In some FMR1 premutation carriers, the gene is not methylated or silenced.
• Instead: FMR1 remains active → excess CGG-containing FMR1 mRNA is produced
• This abnormal mRNA becomes toxic.
• Toxic FMR1 mRNA:
  • binds RNA-binding proteins
  • traps/sequesters them
  • prevents them from performing their normal functions
• In affected males: expanded FMR1 mRNA + trapped RNA-binding proteins → nuclear aggregates → intranuclear inclusions
• These inclusions occur in both:
  • central nervous system
  • peripheral nervous system
• This toxic RNA mechanism contributes to fragile X–associated tremor/ataxia syndrome.
• The mechanism of fragile X–associated primary ovarian insufficiency is less clear.
• FMR1 mRNA aggregates have been found in:
  • granulosa cells
  • ovarian stromal cells
• These aggregates may cause: ovarian follicle injury/death → premature ovarian failure
• General principles of trinucleotide repeat diseases:
  • Repeat expansion alters gene function.
  • The number of repeats needed to change a premutation → full mutation differs between diseases.
• Site of repeat expansion also differs:
  • Fragile X syndrome → expansion mainly during oogenesis
  • Huntington disease → expansion may occur during spermatogenesis
• Repeat expansions may occur in:
  • untranslated/noncoding regions
  • coding regions (Fig. 4.23)
• Expansion in a noncoding region usually causes: gene silencing → ↓ protein production → loss of function Example: Fragile X → ↓ FMRP
• Expansion in a coding region usually produces: abnormal protein → misfolding → toxic gain of function Example: Huntington disease
• Many toxic coding-region mutations involve CAG repeats.
• CAG codes for glutamine → expanded CAG repeats produce long polyglutamine tracts.
• These disorders are therefore called polyglutamine diseases.
• Misfolded proteins commonly accumulate as cytoplasmic aggregates, especially in nervous tissue.

KEY CONCEPT

• FMR1 premutation → gene remains active → toxic CGG-containing mRNA → traps RNA-binding proteins → cell dysfunction.
• Fragile X full mutation → methylation + gene silencing → loss of FMRP.
• Noncoding repeat expansion → usually loss of function.
• Coding CAG expansion → polyglutamine misfolded protein → toxic gain of function.

CONCEPTUAL EXAMPLES

• Premutation FMR1 mRNA traps important proteins in neurons → nuclear inclusions → tremor/ataxia.
• FMR1 RNA aggregates in ovarian cells → possible follicle loss → premature ovarian insufficiency.
• CAG expansion in a coding region → long polyglutamine protein → misfolding + toxic protein aggregates.