Clinical Reasoning
Repeat Expansions
Move from the patient’s pattern to the affected system, the test that narrows the mechanism, and the repeat expansion that explains the disease.
Do not start with the repeat. Start with the tissue and function that are failing.
Why this teaches clinical reasoning +
The disease label stays hidden until you can connect the patient’s presentation to a localization, a discriminating test, and the mechanism upstream. This helps distinguish coding, noncoding, intronic, and regulatory repeat expansions by their consequences rather than by memorized lists.
Retrieval mode +−
HPI / chief complaint → system / organ / tissue issue → targeted test → outcome of testing → reverse pathophysiology → treatment direction → disease / process.
Begin with the patient’s function. Predict the affected system and the question a test must answer, then work backward from the observed failure to the repeat mechanism before revealing the diagnosis.
How to use the table +
Tap once to revealDouble-tap to blurSelect revealed text to highlightTap a highlight to remove itUse each reasoning note to check why one idea logically follows the next as you move across a row, then shuffle to retrieve the chain out of order.
| Patient presentation HPI / chief complaint | System / organ / tissue issue Where might the problem be? | Testing What question does it answer? | Outcome of testing What does it mean? | Reverse pathophysiology Failure → cause | Treatment direction What follows safely? | Disease / process Reveal this last |
|---|---|---|---|---|---|---|
| An adult develops gradually progressive involuntary, dance-like movements, worsening judgment or personality change, depression or irritability, and later cognitive decline. A parent or multiple relatives may have developed a similar progressive illness in adulthood. | The movement pattern points to basal-ganglia circuit dysfunction. Behavioral and cognitive change adds frontal-cortical network involvement. A slowly progressive family-pattern neurologic syndrome is more coherent than an acute stroke, isolated psychiatric illness, or peripheral neuromuscular disorder. | First assess reversible or acquired causes of chorea and cognitive or behavioral change. If the progressive basal-ganglia/cortical pattern and family history remain compelling, offer pretest counseling and a targeted repeat-length assay. | Neuroimaging may show caudate or striatal atrophy. A pathogenic expanded CAG repeat in HTT establishes the inherited toxic-protein disorder; repeat length helps explain, but does not perfectly predict, age at onset. | Chorea and executive or behavioral decline → degeneration of striatal and cortical neuronal networks → expanded CAG tract in HTT → elongated polyglutamine-containing huntingtin with toxic misfolding and impaired neuronal function → autosomal-dominant transmission with anticipation. | Address safety, mood and psychiatric symptoms, involuntary movements, functional support, and family-centered genetic counseling. Predictive testing requires careful consent and psychosocial support. | Huntington disease |
| An adolescent or adult has difficulty releasing a hand grip, distal weakness or foot drop, early cataracts, excessive daytime sleepiness, and may have palpitations, conduction abnormalities, endocrine or reproductive issues, or a family history of progressively earlier and more severe disease. | Delayed relaxation after contraction localizes to skeletal-muscle membrane excitability and muscle-function regulation. Cataracts, cardiac conduction symptoms, sleep, and endocrine findings show a multisystem process rather than isolated injury or one peripheral nerve lesion. | Use examination and EMG to ask whether the muscle has myotonic electrical discharges, and obtain ECG or rhythm evaluation when cardiac symptoms or conduction risk are present. If the phenotype supports inherited multisystem myotonia, use a targeted repeat-length assay after counseling. | EMG with myotonic discharges establishes abnormal muscle electrical behavior; ECG may show conduction disease. A pathogenic CTG expansion in the 3′ untranslated region of DMPK establishes a toxic-RNA repeat disorder. | Delayed relaxation, distal weakness, and multisystem dysfunction → abnormal RNA-splicing regulation in muscle, heart, lens, and endocrine tissues → expanded CTG repeat in DMPK transcript → toxic RNA sequestration of splicing factors → mis-splicing of multiple tissue-specific transcripts and anticipation. | Screen for and manage cardiac conduction disease, respiratory or sleep complications, cataracts, mobility and function, and endocrine or reproductive concerns; provide genetic counseling. | Myotonic dystrophy type 1 |
| A child or adolescent develops progressive gait and limb ataxia, dysarthria, loss of vibration or proprioception, absent reflexes, and may have scoliosis or pes cavus. Some patients also develop hypertrophic cardiomyopathy or diabetes. | Ataxia plus loss of proprioception points to cerebellar or spinocerebellar and dorsal-column sensory pathways; absent reflexes adds peripheral sensory-motor involvement. Cardiomyopathy and diabetes show a systemic energy-vulnerability pattern. | Perform a detailed neurologic examination and evaluate cardiac structure, rhythm, and glucose metabolism when indicated. In a progressive childhood-onset multisystem ataxia, a targeted repeat-length assay is appropriate after genetic counseling. | Neurologic testing supports combined sensory-pathway and peripheral involvement; echocardiography may show hypertrophic cardiomyopathy. A pathogenic intronic GAA expansion in FXN establishes reduced frataxin expression. | Progressive sensory and cerebellar dysfunction with myocardial and pancreatic involvement → mitochondrial iron accumulation, oxidative injury, and energy failure → impaired iron-sulfur-cluster handling and oxidative metabolism → reduced frataxin → intronic GAA expansion in FXN. | Coordinate neurologic rehabilitation, mobility and fall prevention, cardiology surveillance, diabetes screening or management, and genetic counseling. | Friedreich ataxia |
| A boy or young man has developmental delay or intellectual disability, autism features, anxiety or attention difficulties, characteristic long face or large ears, and may develop macroorchidism after puberty. Family history may show related males with neurodevelopmental differences or women with reproductive or neurologic manifestations. | The core localization is CNS neurodevelopment and synaptic function, with characteristic growth or connective-tissue and pubertal findings. The pedigree may suggest an inherited mechanism with variable expression across sexes. | Assess developmental, behavioral, sensory, and educational needs and consider other causes of global delay. When the phenotype and family pattern support this syndrome, order a targeted repeat-length assay with methylation assessment rather than relying only on a routine coding-sequence panel. | A full CGG expansion with abnormal methylation of FMR1 establishes transcriptional silencing and reduced FMRP. Premutation and full-expansion results have distinct clinical and reproductive implications. | Neurodevelopmental and synaptic dysfunction → reduced FMRP-dependent regulation of local neuronal translation and synapse maturation → CGG expansion in the 5′ untranslated region of FMR1 → hypermethylation and transcriptional silencing in full mutation → anticipation, typically through maternal transmission. | Use developmental, behavioral, educational, and family-genetic support; counsel families about reproductive implications and distinct premutation-associated conditions. | Fragile X syndrome |
Study order
Priority order
Use this only after working through the cases yourself. The sequence is intentionally hidden so recognition does not replace reasoning.
Huntington disease → Myotonic dystrophy type 1 → Friedreich ataxia → Fragile X syndrome
For educational use only. This is a study and reasoning tool, not medical advice or a substitute for clinical supervision, diagnosis, or treatment.