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Difficulty: HardGenetic and Molecular Mechanisms

A 68-year-old man comes to the clinic due to a 1-year history of worsening intention tremor and unsteadiness while walking. He also reports recent difficulties with short-term memory and executive function, such as managing his finances. His medical history is notable for hypertension. His family history is significant; his daughter is healthy, but his 8-year-old maternal grandson has been diagnosed with intellectual disability, a long face, prominent ears, and macroorchidism. On physical examination, the patient exhibits a bilateral intention tremor, broad-based ataxic gait, and symmetrical parkinsonian features including mild rigidity. Magnetic resonance imaging (MRI) of the brain reveals generalized cerebral atrophy and symmetrically increased T2-weighted signal in the middle cerebellar peduncles. Which of the following best describes the underlying molecular mechanism responsible for this patient's current neurologic symptoms?

  1. Accumulation of toxic messenger RNAAnswer
  2. B
    Hypermethylation of a promoter region
  3. C
    Expansion of a polyglutamine tract
  4. D
    Microvascular ischemic white matter injury
  5. E
    Heteroplasmic mitochondrial DNA mutations

Answer

Accumulation of toxic messenger RNA
The correct answer is accumulation of toxic messenger RNA. The patient's clinical presentation (intention tremor, ataxia, parkinsonism, cognitive decline) combined with a characteristic MRI finding (increased T2 signal in the middle cerebellar peduncles) and a family history of a grandson with fragile X syndrome is highly specific for fragile X-associated tremor/ataxia syndrome (FXTAS). Fragile X syndrome is caused by a trinucleotide (CGG) repeat expansion in the FMR1 gene. The grandson has the full mutation (>200>200 repeats), which leads to hypermethylation of the FMR1 promoter and subsequent gene silencing. The patient (grandfather), however, is a carrier of the premutation (5555 to 200200 repeats). In contrast to the full mutation, the premutation results in an overexpression of FMR1 mRNA. The excess messenger RNA accumulates in the nucleus, forming toxic intranuclear inclusions in neurons and astrocytes, which eventually leads to the neurodegeneration seen in FXTAS.

Step-by-Step Solution

1
Analyze the family history to establish the genetic context.
The grandson has intellectual disability, prominent ears, and macroorchidism, classic for fragile X syndrome (FXS). The patient's daughter is an obligate carrier.
Identifying the grandson's condition is essential to recognize the X-linked inheritance pattern and the specific gene involved (FMR1).
2
Correlate the patient's symptoms and imaging with the genetic context.
The patient is an older male with intention tremor, ataxia, memory loss, and MRI evidence of middle cerebellar peduncle (MCP) hyperintensity. This establishes a diagnosis of fragile X-associated tremor/ataxia syndrome (FXTAS).
The grandfather is a premutation carrier who passed the allele to his daughter. The premutation expanded to a full mutation during the daughter's oogenesis, resulting in the grandson's FXS.
3
Determine the precise molecular mechanism for the patient's condition (premutation).
FXTAS is caused by an expansion of 5555 to 200200 CGG repeats in the FMR1 gene. Unlike the full mutation, this premutation leads to increased transcription, causing accumulation of toxic FMR1 messenger RNA.
Differentiating the molecular mechanism of the premutation (RNA toxicity) from the full mutation (gene silencing via methylation) is required to answer the question.

Key Concept

Pathophysiology and molecular mechanisms of fragile X-associated tremor/ataxia syndrome (FXTAS) compared to fragile X syndrome.
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Topics

Genetic and Molecular Mechanisms

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