TABLE 2.
Targeted genetic testing strategy guided by clinical symptoms and key findings from ancillary tests
| Phenotype besides ataxia | Laboratory findings | Neuroimaging patterns | Targeted gene/s |
|---|---|---|---|
| Intention tremor, cognitive decline, behavioral disturbances, parkinsonism, neuropathy, dysautonomia over the age of 50 years | – | Middle cerebellar peduncle sign: hyperintensities in middle cerebellar peduncles (usually in association with corpus callosum splenium, or periventricular white matter hyperintensities) | FMR1 |
| Episodic ataxia, downbeat nystagmus, vestibular dysfunction, diplopia, oscillopsia | – | Superior cerebellar peduncles atrophy and hyperintensity | FGF14 |
| Chronic cough, downbeat nystagmus, vestibular dysfunction, neuropathy, parkinsonism, dysautonomia over the age of 35 years | – | Occasional spinal cord atrophy | RFC1 |
| Dysarthria, absent deep tendon reflexes, impaired proprioception, fixation instability, and variably present features such as scoliosis, pes cavus, optic atrophy, hearing loss, diabetes mellitus, and cardiomyopathy | – | Spinal cord atrophy without cerebellar atrophy Spinal cord hyperintense signaling of dorsal part on inversion recovery images | FXN |
| Friedreich ataxia-like,a pigmentary retinopathy | Vitamin E (↓ levels) | Spinal cord hyperintense signaling of dorsal part on inversion recovery images | TTPA |
| Friedreich ataxia-like,a chronic diarrhea, pigmentary retinopathy, liver disease | Vitamin E, cholesterol, apolipoprotein B (↓ levels), ↑ liver transaminases, anemia, acanthocytosis | – | MTTP |
| Conjunctival telangiectasias, dystonia, immune deficiency, predisposition to malignancy | α-Fetoprotein (↑ levels: ≈ 200 μg/L) | Spinal cord atrophy | ATM |
| Friedreich ataxia-like,a oculomotor apraxia, neuropathy, dystonia, chorea | α-Fetoprotein (↑ levels: 5–20 μg/L), cholesterol (↑ levels), albumin (↓ levels) | – | APTX |
| Friedreich ataxia-like,a oculomotor apraxia, strabismus, hypogonadism, neuropathy, dystonia, chorea | α-Fetoprotein (↑ levels: 15–65 μg/L), gonadotrophin (↓ levels) | – | SETX |
| Friedreich ataxia-like,a prominent myelinated fibers radiating from the edges of the optic disc, spastic gait, neuropathy | – | Superior cerebellar vermis atrophy; posterior mid-body corpus callosum thinning; bilateral hypointense pontine striations; hyperintense peri thalamic rims, enlarged pons | SACS |
| Juvenile cataracts, tendon xanthomas, xanthelasmata, chronic diarrhea, prominent early psychosis or bipolar affective disorder-like symptoms, dystonia, parkinsonism, seizures, neuropathy | Cholestanol and urinary hydroxylated bile alcohols (↑ levels), cholesterol: (↓ levels) | Bilateral heterogeneous hyperintensities of the dentate nuclei with a central hypointensity in the deep cerebellar nuclei related to deposition of hemosiderin and focal calcifications | CYP27A1 |
| Liver disease, Kayser-Fleischer rings, dystonia, parkinsonism, early psychosis or bipolar affective disorder-like symptom | 24-hr cupruria (↑ levels); ceruloplasmin (↓ levels); hemolytic anemia; liver transaminases (↑ levels) | Bilateral hyperintensities in the putamen, caudate nuclei, thalamus, internal and external capsules, midbrain, middle cerebellar peduncles, and cerebellum; hypointensities in globus pallidus; T1-hyperintensity of the globus pallidus; cerebral, cerebellar, putamen and pons atrophy; central pontine myelinolysis; ‘face of the giant panda’; ‘double panda sign’; ‘face of the miniature panda’ | ATP7B |
| Vertical supranuclear gaze palsy, intellectual disability, dystonia, gelastic cataplexy, seizures, prominent treatment-resistant psychiatric syndromes (depression, psychosis, bipolar disorders), liver diseaseb | Oxysterols (↑ levels), Filipin staining test | – | NPC1 |
| Liver disease, diabetes mellitus, pigmentary retinopathy, dystonia | Copper and ceruloplasmin (↓ levels), anemia with ferritin (↑ levels), glycemia (↑ levels) | Hypointensities in dentate nucleus and basal ganglia, spinal cord hyperintense signaling of dorsal part on inversion recovery images | CP |
| Abnormal dentition, hypogonadotropic hypogonadism, intellectual disability, tremor | Gonadotrophin (↓ levels) | Bilateral hyperintensity along the superior cerebellar peduncles ranging from the dentate nucleus up to the midbrain just below the red nucleus | POLR3A |
| Episodic ataxia, dystonia, seizures, spasticity, microcephaly with facial dysmorphism, occasional intellectual disability | Lactate and pyruvate in serum and CSF (↑ levels) | Leigh syndrome-like pattern: bilateral pallidal, caudate, and putaminal hyperintensities with (occasional) cavitations. Corpus callosum agenesis (complete or partial) or dysgenesis | PDHA1 |
| Developmental delay, intellectual disability, dystonia, seizures | L-2-hydroxyglutaric acid in urine, serum, and CSF (↑ levels) | Leigh syndrome-like pattern; bilateral hyperintensities of dentate nuclei commonly combined with mild cerebellar atrophy; hypointensities in dentate nucleus, and basal ganglia | L2HGDH |
| Developmental delay, macrocephaly, spasticity, epilepsy | – | Megalencephaly with large frontotemporal subcortical cavitations and leukoencephalopathy | MLC1 |
| Pigmentary retinopathy, cataracts, hearing impairment, peripheral neuropathy, skin manifestations, cardiac disease | Phytanic acid (↑ levels) | Hypointensities in the dentate nucleus and basal ganglia | PHYH |
| Stroke-like episodes, exercise intolerance, muscle weakness, seizures, tremor, dystonia, cataracts, optic atrophy, hearing impairment, diabetes mellitus | Creatine kinase and lactate (↑ levels) | Stroke-like hyperintensities | ADCK3 |
| Myoclonus, seizures, areflexia, scoliosis | Creatine kinase (↑ levels) | – | GOSR2 |
| Intellectual disability, exercise intolerance, muscle weakness, peripheral neuropathy, seizures, hearing impairment, optic atrophy, gaze palsy, hypergonadotropic hypogonadism | Gonadotrophin (↑ levels) | Stroke-like hyperintensities; spinal cord atrophy | TWNK |
| Neuropathy, myopathy, seizures, pigmentary retinopathy, gaze palsy, ptosis, hearing impairment, stroke-like episodes, short stature, diabetes, cardiomyopathy | Lactate in serum, and CSF (↑ levels) | Stroke-like hyperintensities | mtDNA |
| Erythrokeratodermia | – | ‘Hot cross bun’ sign (rare) | ELOVL4 |
Note: In bold: genes related to repeat expansion disorders; underlined: treatable ataxias with mechanism-directed treatments. All tests are serum biomarkers unless otherwise indicated. The genes listed here are intended to serve as a guide and other targeted approaches can be applied depending on clinical suspicion.
Abbreviation: CSF, cerebrospinal fluid.
a
‘Friedreich ataxia-like’ phenotype indicates a patient exhibits clinical manifestations that resemble Friedreich ataxia.
b
Phenotype of the childhood late-onset NPC1.