Treatable monogenic disease

Domain 2 of 5Patients: care maps

A diagnosis here changes treatment, not just understanding. Every cohort in this domain is a group of single-gene diseases with an approved or imminent disease-modifying therapy, and every one of them has adults walking around undiagnosed, or diagnosed late, because the early picture looked like something common.

Why this is a domain

The treatable rare disease is the strongest argument for genetics in primary care. The therapies exist: enzyme replacement for the lysosomal storage disorders and for hypophosphatasia,¹ stabilizers and silencers for transthyretin amyloidosis,² dietary and pharmacologic control for the inherited metabolic diseases, gene-targeted therapy for spinal muscular atrophy, and a first disease-modifying agent for Friedreich ataxia. What is missing is recognition. Adult patients with these conditions reach a diagnosis years after first symptoms, through cardiology, neurology, orthopedics or gastroenterology, each seeing one organ.^{3 4}

The cohorts are organized by therapy pathway rather than by organ, because the pathway is what the anchor physician has to navigate: who confirms the diagnosis, who prescribes, where the infusion happens, and how the family is tested.

The five cohorts

How the care maps differ here

The Establish year has a recognizable shape in every cohort: a screening test that primary care can order (an enzyme assay, a dried blood spot, an alkaline phosphatase, a scintigraphy study, a biochemical panel), a confirmatory genetic test, and a documented decision about therapy eligibility. The genetics role includes cascade testing from the first visit, because these are inherited conditions with treatable relatives.

The Treat year is where this domain earns its name: starting therapy, arranging infusion or specialty pharmacy, measuring response against a defined endpoint, and handling the payer or cash-price conversation. The Sustain year is maintenance, monitoring for antibody or adverse effects, screening new therapies against the diagnosis each year, and the family.

The anchor role is unusually important. These therapies are prescribed by specialists but lived with in primary care, and the anchor physician is often the only clinician who sees the patient between infusions.

What the domain needs from the provider rosters

Esoteric assays (biochemical genetics, enzyme activity, biomarkers), clinical expertise in metabolic and biochemical genetics, empiric therapies (infusion centers and specialty pharmacies willing to work with an independent practice), and specialists in cardiology, neurology, hepatology and endocrinology.

Starting references

1. Whyte MP, Greenberg CR, Salman NJ, et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. N Engl J Med. 2012;366(10):904-913. doi:10.1056/NEJMoa1106173
2. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016. doi:10.1056/NEJMoa1805689
3. Grabowski GA, Kishnani PS, Alcalay RN, et al. Challenges in Gaucher disease: perspectives from an expert panel. Mol Genet Metab. 2025;145(1):109074. doi:10.1016/j.ymgme.2025.109074
4. Geberhiwot T, Wasserstein M, Wanninayake S, et al. Consensus clinical management guidelines for acid sphingomyelinase deficiency (Niemann-Pick disease types A, B and A/B). Orphanet J Rare Dis. 2023;18(1):85. doi:10.1186/s13023-023-02686-6
5. 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

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