| Phenotype | HPO term suggestion(s) | Typical onset | Course | Frequency/notes with numeric estimates | Key evidence citation IDs |
|---|---|---|---|---|---|
| Intention/action tremor | HP:0002080 Tremor; HP:0002068 Action tremor; HP:0002345 Intention tremor | Usually adult-onset after age 50; mean onset ~60.2 years in males | Progressive; often first major motor symptom | Core feature of FXTAS; male premutation-carrier penetrance rises with age: 17% (50–59), 38% (60–69), 47% (70–79), 75% (80+); overall ~40% of male carriers >50 affected; female risk lower (~16–20%) (pqac-00000001, pqac-00000004, pqac-00000005, pqac-00000006) | (pqac-00000001, pqac-00000004, pqac-00000005, pqac-00000006) |
| Gait ataxia | HP:0002066 Ataxia; HP:0001288 Gait disturbance; HP:0002317 Unsteady gait | Usually begins after tremor in later adulthood; often around the 60s | Progressive; balance impairment worsens, leading to falls and walking-aid dependence | Major clinical sign in diagnostic criteria; family-based natural history reported median delay from tremor to ataxia of 2 years and to falls of 6 years; progression to walking-aid dependence around 15 years after onset (pqac-00000003, pqac-00000006) | (pqac-00000003, pqac-00000006) |
| Parkinsonism | HP:0001300 Parkinsonism; HP:0001336 Bradykinesia; HP:0000736 Rigidity | Later adult onset, usually after tremor/ataxia emerge | Progressive, variable severity | Approximately 30% of FXTAS patients have parkinsonian symptoms; considered a minor clinical criterion and relevant differential with Parkinson disease/MSA-C (pqac-00000003, pqac-00000013) | (pqac-00000003, pqac-00000013) |
| Peripheral neuropathy | HP:0009830 Peripheral neuropathy; HP:0003443 Decreased vibratory sense; HP:0002528 Areflexia | Adult onset, often after or alongside motor syndrome | Progressive sensory and reflex abnormalities | Frequent associated finding; includes distal sensory loss, decreased reflexes, impaired vibration sense; lower-extremity neuropathy is a minor clinical diagnostic criterion (pqac-00000003, pqac-00000008) | (pqac-00000003, pqac-00000008) |
| Cognitive/executive dysfunction / dementia | HP:0002185 Neurocognitive decline; HP:0000734 Executive dysfunction; HP:0001268 Dementia; HP:0002354 Memory impairment | Usually later than motor onset, often in the 60s–70s | Progressive fronto-subcortical pattern; may advance to major neurocognitive disorder | Executive dysfunction and short-term memory deficiency are minor diagnostic criteria; ~50% of males with FXTAS may develop frontal-subcortical dementia/MNCD; cognitive impairment correlates with MCP sign and disease progression (pqac-00000002, pqac-00000003, pqac-00000008, pqac-00000013) | (pqac-00000002, pqac-00000003, pqac-00000008, pqac-00000013) |
| Psychiatric symptoms (depression/anxiety/apathy) | HP:0000716 Depression; HP:0000739 Anxiety; HP:0000741 Apathy | Can precede or accompany motor symptoms; often prominent in females/preFXTAS | Chronic/progressive with disease burden; may worsen with cognitive decline | Common comorbidities include depression, anxiety, irritability, and apathy; female premutation carriers may show earlier neuropsychiatric manifestations than overt motor syndrome (pqac-00000002, pqac-00000004, pqac-00000015) | (pqac-00000002, pqac-00000004, pqac-00000015) |
| Autonomic dysfunction | HP:0001284 Orthostatic hypotension; HP:0000011 Neurogenic bladder; HP:0000047 Urinary incontinence; HP:0004383 Erectile dysfunction | Adult onset, usually after established neurologic disease | Progressive, contributes to disability and complications | Frequent associated finding; reported manifestations include orthostatic hypotension, impotence, and progressive bowel/bladder dysfunction (pqac-00000001, pqac-00000008) | (pqac-00000001, pqac-00000008) |
| White matter lesions / MCP sign (imaging phenotype) | HP:0012707 Abnormality of cerebral white matter; HP:0002500 Abnormal cerebral MRI white matter signal intensity; HP:0025437 Middle cerebellar peduncle hyperintensity | Usually detected in symptomatic adults; may occasionally precede overt tremor/ataxia | Progressive radiologic white matter disease and atrophy | Major radiologic hallmark; MCP sign = increased T2/FLAIR signal in middle cerebellar peduncles. Observed only in premutation carriers in one cohort and present in 52% of carriers aged ≥45 vs 0% controls; recent review notes MCP hyperintensities in ~60% of male FXTAS patients; asymptomatic carriers with MCP sign have been reported (pqac-00000003, pqac-00000006, pqac-00000013, pqac-00000017) | (pqac-00000003, pqac-00000006, pqac-00000013, pqac-00000017) |


*Table: This table summarizes the main clinical and imaging phenotypes of fragile X-associated tremor/ataxia syndrome, with suggested HPO mappings, typical onset and progression, and key numeric estimates useful for knowledge-base curation.*