What is an example of an autosomal dominant disorder diagnosed later in life?

Huntington Disease: The Prototypical Late-Onset Autosomal Dominant Disorder

Huntington disease (HD) is the classic example of an autosomal dominant disorder diagnosed later in life, with typical symptom onset between ages 35-45 years. 1

Genetic Inheritance Pattern

• HD demonstrates autosomal dominant inheritance with complete penetrance, meaning each child of an affected parent has a 50% chance of inheriting the disease-causing mutation 1
• The genetic basis involves an abnormally expanded CAG trinucleotide repeat (>38 repeats) in the huntingtin gene on chromosome 4p16.3 1, 2
• Normal individuals have 6-39 CAG repeats, while HD patients have 36-180 repeats 2
• The mutation exhibits anticipation—progressive increase in repeat length across generations, resulting in earlier symptom onset in successive generations 1

Clinical Presentation and Timing

• Average age of onset is 35-45 years, making this a quintessential late-onset genetic disorder 1
• The disease progresses relentlessly over 15-20 years from symptom onset until death 1, 3, 4
• The classic triad includes: progressive choreoathetosis (involuntary flowing movements), cognitive dysfunction/dementia, and psychiatric/behavioral symptoms 1, 3

A critical pitfall: The late onset means affected individuals typically have children before knowing they carry the mutation, inevitably transmitting the disease to the next generation before symptoms develop 5

Pathophysiology and Diagnosis

• The expanded polyglutamine stretch in mutant huntingtin protein leads to abnormal protein aggregation and selective loss of GABAergic medium spiny neurons, particularly in the striatum (caudate nucleus and putamen) 1, 2
• Genetic testing measuring CAG repeat number is the diagnostic test of choice and is commercially available 1
• Patients with suspected HD should undergo genetic counseling and testing in concert with initial brain imaging 1
• MRI may be normal early in the disease course, with progressive caudate and putamen atrophy becoming apparent only later 1

Epidemiology

• HD affects approximately 1 in 10,000 individuals (incidence ~10/100,000) 1, 2
• It represents the most common monogenic neurodegenerative disease and the most common genetic cause of dementia in the developed world 4

Management Considerations

• No disease-modifying treatments currently exist; management focuses on symptomatic control of motor, psychiatric, and cognitive symptoms 3, 4
• Presymptomatic genetic testing is available for at-risk family members but requires comprehensive genetic counseling given the devastating implications 3, 6
• A multidisciplinary approach including neurology, psychiatry, physical/occupational therapy, and social work support is essential for optimizing quality of life 3

Important caveat: While HD typically presents in mid-life, juvenile-onset HD can occur (often with paternal transmission and longer CAG repeats), and late-onset cases after age 60 also exist, though these are less common 4