Neurogenetic
The anchor question: is there a treatable diagnosis hiding in a progressive neurologic picture? For adult SMA, Friedreich ataxia and a short list of vitamin-responsive mitochondrial disorders, the answer changed in the last decade, and the treatment window is measured in motor neurons that don't come back.
Who this cohort covers
Adults with progressive weakness, ataxia, neuropathy, myopathy, or multisystem disease with a neurologic core: exercise intolerance, hearing loss, diabetes, cardiomyopathy, ophthalmoplegia, stroke-like episodes. Many have a long diagnostic odyssey behind them. Some carry a diagnosis of exclusion made before sequencing improved, and it's worth revisiting.
Looking again has yield. In 353 families with suspected Mendelian disease and prior inconclusive testing, genome sequencing found a diagnosis in 15.3%. More than half of those were in regions earlier tests never interrogated, and a quarter could have been found by reanalyzing the existing exome.5
The vitamin-responsive group is why you screen every mitochondrial patient for a treatable cause. CoQ10 deficiency, biotin-thiamine-responsive basal ganglia disease (SLC19A3) and riboflavin transporter deficiency (SLC52A3) all produce devastating, often Leigh-like or motor-neuron-like disease that responds substantially to an inexpensive vitamin. Don't wait for confirmation to start it. TK2 deficiency now responds to nucleoside supplementation.
Friedreich ataxia. GAA repeat sizing finds about 96% of cases. The other 4% are compound heterozygous for an expansion plus a point variant, which sequencing alone would find and repeat testing alone would miss. Hypertrophic cardiomyopathy drives prognosis. Omaveloxolone is the first disease-modifying therapy.
Adapted from the Atlas at allaboutgenetics.com, entries dz39, cpe031 and rpt04.
Care map
| Role | Year 1, Establish | Year 2, Treat | Year 3, Sustain |
|---|---|---|---|
| Anchor | Full neurologic and family history, including maternal lineage. Functional baseline with a validated scale. Problem list by organ system. | Coordinate therapy start and monitoring. Manage comorbidities. Advance care planning conversation. | Annual functional review. Reprioritize. Revisit the diagnosis if progression doesn't fit it. |
| Genetics | Genome sequencing with mitochondrial DNA, not a panel, when the phenotype is broad.1 5 Biochemical screen: lactate, acylcarnitines, plasma amino acids, urine organic acids. Repeat sizing for suspected Friedreich ataxia, plus sequencing for the compound heterozygotes. SMN1 dosage with SMN2 copy number for suspected SMA. Muscle biopsy only if sequencing is uninformative.1 | Cascade testing. Confirm therapy eligibility by genotype and, for SMA, SMN2 copy number. | Reanalysis at 24 to 36 months. New therapies screened against the diagnosis each year. |
| Specialists | Neurology or neuromuscular medicine. Cardiology baseline. Ophthalmology and audiology when mitochondrial disease is suspected.2 | Treating specialist for disease-modifying therapy: omaveloxolone in Friedreich ataxia,3 4 nusinersen or risdiplam in adult SMA.6 Pulmonology for respiratory involvement. Endocrinology for diabetes or thyroid disease in mitochondrial disease.2 | Follow-up per organ involvement. |
| Diagnostics | EMG and nerve conduction. Brain and spine MRI, with spectroscopy where indicated. Echocardiogram and ECG. Pulmonary function with respiratory muscle testing.2 | Cardiac MRI if cardiomyopathy. Exercise testing for mitochondrial function where it will change management. | Repeat echocardiogram, ECG and PFTs on a set interval; annual in Friedreich ataxia.2 |
| Therapies | Physical and occupational therapy baseline. Assistive device assessment. | Ongoing PT. Speech therapy for dysphagia or dysarthria. | Maintenance program. Equipment review. |
| Behavioral health and nutrition | Screen for depression and caregiver strain. | Dietitian for a metabolic diet or for dysphagia. Counseling. | As needed. |
| Community | Patient organization introduction. Trial and registry enrollment where no approved therapy exists. | Clinical trial referral. |
Visit one
The map is the evidence. This is the patient in the room. Every line comes from the Year 1 column and carries its citations.
| Ask | Onset, course and tempo of every neurologic symptom. Exercise intolerance, hearing, vision, diabetes, cardiomyopathy, seizures, short stature, early deaths across the family, with the maternal lineage drawn out separately. |
| Examine | Full neurologic examination with a functional baseline on a validated scale. Cardiac, ophthalmologic and hearing screen when mitochondrial disease is on the list. |
| Order | Biochemical screen: lactate, acylcarnitines, plasma amino acids, urine organic acids. ECG and echocardiogram. Genome sequencing with mitochondrial DNA when the phenotype is broad, rather than a panel;1 5 repeat-expansion testing for suspected Friedreich ataxia; SMN1 dosage with SMN2 copy number for suspected SMA. Muscle biopsy only if sequencing is uninformative.1 |
| Refer | Neurology or neuromuscular medicine for the examination and electrodiagnostics. Brain and spine MRI with spectroscopy where indicated, with the protocol requested in writing. Physical and occupational therapy baseline. Where: the imaging and specialist rosters. |
| Tell the patient | Why sequencing rather than a panel; that a treatable diagnosis is the thing being looked for; what the biochemical screen can and cannot show; how long results take. |
| Document | The functional baseline, the maternal pedigree, every test ordered with the protocol requested, and the date for reanalysis if sequencing is negative. |
Roster for this cohort
Neurology or neuromuscular medicine, cardiology with a cardiomyopathy interest, pulmonology, endocrinology, EMG, brain and cardiac MRI, physical and speech therapy. Forming; propose entries in the cohort channel.
Readings
- GeneReviews: Friedreich Ataxia (revised 2025), Spinal Muscular Atrophy (revised 2026), Primary Mitochondrial Disorders Overview (2021). University of Washington.
- The Atlas at allaboutgenetics.com: Friedreich ataxia, SMA and the SMN2 modifier, coenzyme Q10 deficiency and vitamin-responsive mitochondrial disease, mitochondrial DNA depletion and deletion syndromes.
- The Mitochondrial Medicine Society consensus statements below: still the standard of care for diagnosis and routine management.
References
- Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015;17(9):689-701. doi:10.1038/gim.2014.177
- Parikh S, Goldstein A, Karaa A, et al. Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2017;19(12). doi:10.1038/gim.2017.107
- Lynch DR, Chin MP, Delatycki MB, et al. Safety and efficacy of omaveloxolone in Friedreich ataxia (MOXIe study). Ann Neurol. 2021;89(2):212-225. doi:10.1002/ana.25934
- Lynch DR, Chin MP, Boesch S, et al. Efficacy of omaveloxolone in Friedreich's ataxia: delayed-start analysis of the MOXIe extension. Mov Disord. 2023;38(2):313-320. doi:10.1002/mds.29286
- Pitsava G, Hawley M, Auriga L, et al. Genome sequencing reveals the impact of pseudoexons in rare genetic disease. Genet Med. 2025;27(11):101574. doi:10.1016/j.gim.2025.101574
- Toro Jimenez W, Yang M, Song W, et al. Real-world treatment patterns in patients with spinal muscular atrophy receiving multiple disease-modifying therapies. Adv Ther. 2026. doi:10.1007/s12325-026-03710-4
References retrieved from PubMed on 2026-10-30. Care maps are peer-authored clinical frameworks for network members, not individualized medical advice, and are reviewed at each yearly cycle.