Inherited metabolic disease

Patient cohortTreatable monogenic diseaseSeeking a lead#cohort-inherited-metabolic PDF (members)

The anchor question: which adult in this practice has a treatable inborn error that nobody has named yet? The eight disorders here reach internists and family physicians as abnormal liver tests, emphysema, a clot in a young patient, attacks of abdominal pain, a psychiatric change, or an adult with PKU who is off treatment. Each has a first test primary care can order and a treatment that changes the outcome.

Who this cohort covers

Adults with any of the eight disorders below, diagnosed or suspected, and the women with PKU who are planning a pregnancy. The table is the short version: how each shows up in adults, what to order first, and the treatment that matters.

Disorder	Shows up in adults as	Order first	Treatment that changes outcome
PKU (PAH deficiency)	Treated from birth: modest deficits in executive function and attention, more anxiety and depression, neurologic problems that can improve as Phe falls. In pregnancy, high maternal Phe causes maternal PKU syndrome in the child.¹	Plasma amino acids; PAH sequencing.¹	Lifelong treatment to a blood Phe of 120 to 360 µmol/L.² Diet and medical foods; sapropterin, sepiapterin or pegvaliase in selected patients.¹ On pegvaliase, 60.7% of adults reached Phe ≤360 µmol/L within 24 months.³ Before conception, Phe under 360 µmol/L for three months; 120 to 360 through pregnancy.¹
Urea cycle disorders	Hyperammonemic episodes with neurologic, gastrointestinal and psychiatric symptoms;⁴ triggered by catabolic stress, pregnancy and delivery, steroids or valproate; often nonspecific symptoms such as headache and protein avoidance.⁵ Women with OTC deficiency can be symptomatic.⁴	Plasma ammonia; urine orotic acid; molecular testing, because in OTC deficiency, the commonest adult form, the amino acid profile is often unrevealing.^{4 5}	Low-protein diet with essential amino acids, arginine or citrulline, and nitrogen scavengers; hemodialysis when that fails.⁵
Homocystinuria (CBS deficiency)	Ectopia lentis or severe myopia, long limbs, osteoporosis, thromboembolism; a previously well adult can present with a thrombosis alone, often cerebrovascular.⁶ Mild disease usually presents in adults and responds to pyridoxine.⁷	Plasma total homocysteine;⁷ CBS sequencing.⁶	Pyridoxine in responders; methionine-restricted diet, betaine, folate and B12; total homocysteine kept under 100 µmol/L.^{6 7}
Cerebrotendinous xanthomatosis	Chronic diarrhea from infancy, childhood cataracts, tendon xanthomas, the Achilles among them, in the second or third decade, then progressive neurologic and psychiatric decline, with normal to low cholesterol.⁸	Plasma cholestanol; CYP27A1 sequencing.⁸	Chenodeoxycholic acid, which normalizes cholestanol and improves neurophysiologic findings.⁸
Acute hepatic porphyria	Attacks of severe, usually abdominal pain without peritoneal signs or imaging findings, mainly in women 15 to 50; hyponatremia, hypertension and tachycardia in the attack; later neuropathy, CKD and hepatocellular carcinoma.⁹	Random urine PBG and ALA with creatinine; genetic testing to confirm.⁹	Stop porphyrinogenic drugs; IV hemin for attacks needing admission; consider givosiran or prophylactic hemin for four or more attacks a year.⁹ Givosiran cut the attack rate 74% in acute intermittent porphyria.¹⁰
Wilson disease	Any pattern of liver disease, from self-limited hepatitis to acute liver failure; dysarthria, tremor, dystonia; depression, mood disorder or psychosis; from age 3 to past 70.¹¹	Serum ceruloplasmin, serum copper, 24-hour urine copper; an eye exam for Kayser-Fleischer rings; ATP7B sequencing.¹¹	Lifelong chelation with penicillamine or trientine, or zinc after decoppering, continued through pregnancy; transplant for fulminant failure.¹¹
Alpha-1 antitrypsin deficiency	COPD or emphysema, typically after 30; liver disease without a childhood history; panniculitis; c-ANCA vasculitis.¹² Asthma that never fully reverses, and unexplained bronchiectasis.¹³	Serum AAT level with PI typing or SERPINA1 genotyping.¹² Test every adult with symptomatic fixed airflow obstruction.¹³	No smoking; standard COPD care; IV augmentation for emphysema with severe deficiency,¹² which slowed CT lung density loss at total lung capacity over two years.¹⁴
HFE hemochromatosis	Fatigue, arthralgia, abdominal pain, weight loss, diabetes; cirrhosis risk climbs once ferritin passes 1,000 µg/L.¹⁵ Elevated aminotransferases and second and third MCP arthropathy.¹⁶	Transferrin saturation and ferritin, then HFE p.Cys282Tyr.¹⁵ Ferritin under 1,000 at diagnosis marks low risk of advanced fibrosis.¹⁷	Phlebotomy to ferritin 50 to 100 µg/L, then below 300 (men) or 200 (women).¹⁵

These are not paper diseases in adults. In a French cohort of 71 patients whose urea cycle disorder was diagnosed after age 16, the median age at diagnosis was 33 and 68% were women; 89% of those diagnosed during a decompensation needed intensive care, and 10% of the cohort died.⁴ Among C282Y homozygotes followed for an average of 12 years in Melbourne, 28.4% of men and 1.2% of women had documented iron-overload-related disease.¹⁶

Care map

Role	Year 1, Establish	Year 2, Treat	Year 3, Sustain
Anchor	Keep the eight on the list where they live: ammonia in unexplained encephalopathy or psychiatric change;⁵ homocysteine in a young thrombosis or a dislocated lens;⁷ urine PBG in a woman 15 to 50 with recurrent unexplained abdominal pain;⁹ copper studies in unexplained liver disease, a movement disorder or new psychiatric illness;¹¹ an AAT level in every symptomatic adult with fixed airflow obstruction;¹³ iron studies with raised aminotransferases, arthropathy or diabetes.^{15 16} Every adult with PKU back in care, women of childbearing age first.¹ Three-generation pedigree with consanguinity asked.	Hold the drug-avoidance list: porphyrinogenic drugs and alcohol in AHP;⁹ valproate and steroids in UCD;⁵ oral contraceptives and nitrous oxide in homocystinuria;⁶ medicinal iron and excess vitamin C in hemochromatosis;¹⁵ aspartame in PKU.¹ Coordinate the infusion, injection or phlebotomy calendar.	Annual review against each disorder's surveillance list. Revisit the diagnosis if the course doesn't fit it.
Genetics	Biochemistry first, then the gene that confirms it (table above). For UCDs, molecular testing is often the only way to a diagnosis.⁵	Cascade testing: at-risk siblings of a Wilson, CTX or homocystinuria proband, before symptoms;^{6 8 11} first-degree relatives in AATD;¹³ adult siblings in HFE;¹⁵ female relatives in OTC deficiency, who can be symptomatic.⁴	Reproductive planning: maternal PKU targets set months ahead;¹ pregnancy and delivery as a UCD trigger;⁵ low-molecular-weight heparin in the third trimester and postpartum in homocystinuria.⁶
Specialists	Biochemical genetics or a metabolic clinic, with a metabolic dietitian, for PKU, UCD, homocystinuria and CTX.^{1 6} Hepatology or a Wilson disease center for Wilson;¹¹ hepatology for HFE with ferritin over 1,000;¹⁷ pulmonology for AATD lung disease.¹²	Start the treatment that changes outcome, from the table above, through the treating specialist.	Continuous adult metabolic follow-up, including for patients who left pediatric care.¹
Diagnostics	The first test in the table for each suspected disorder. Liver tests, ultrasound and elastography where liver disease is possible;¹² MRI T2* rather than biopsy to quantify liver iron in HFE.¹⁷ Spirometry with bronchodilator and DLCO in AATD.¹² Ophthalmology for lens position in homocystinuria and Kayser-Fleischer rings in Wilson.^{6 11} Brain MRI in CTX.⁸	Treat to target: blood Phe 120 to 360 µmol/L;² total homocysteine under 100 µmol/L;⁷ cholestanol yearly;⁸ ferritin 50 to 100 µg/L during depletion;¹⁵ serum copper, ceruloplasmin and 24-hour urine copper in Wilson;¹¹ aminotransferases and creatinine on givosiran.¹⁰	AHP: liver tests yearly, creatinine yearly on treatment, and liver ultrasound every six months from age 50 for HCC.⁹ AATD: lung function and liver assessment every 6 to 12 months.¹² HFE: ferritin every three to four months once depleted.¹⁵ Wilson: labs at least twice a year and 24-hour urine copper yearly.¹¹
Therapies	Speech, physical and occupational therapy for neurologic Wilson disease.¹¹	Cataract surgery in CTX; physiotherapy and joint care for HFE arthropathy.^{8 15}	Maintenance program.
Behavioral health and nutrition	Metabolic dietitian from the first visit for PKU, UCD and homocystinuria.^{1 5 6} Screen for anxiety and depression in adults with PKU.¹ New psychiatric symptoms get a metabolic look in Wilson and UCD.^{4 11}	Smoking cessation in AATD.¹² High-copper foods limited early in Wilson treatment.¹¹ Alcohol counseling in AHP, HFE and AATD.^{9 12 15}	As needed.
Community	Disease-specific patient organizations and registries.	Trial referral where approved therapy does not fit.

Visit one

The map above is the evidence. This is what to do with the patient in the room. Each line comes from the Year 1 column and carries the same citations.

Ask	Episodes of confusion, headache or psychiatric change after illness, heavy exercise or childbirth; protein avoidance.⁵ Recurrent severe abdominal pain with no explanation after a workup.⁹ Clots, especially young or cerebrovascular; lens dislocation.⁶ Childhood diarrhea, early cataracts.⁸ Tremor, slurred speech, mood change, past hepatitis.¹¹ Breathlessness, smoking, asthma that never fully clears.¹³ Hand joint pain, diabetes, fatigue.¹⁵ In women with PKU, pregnancy plans.¹ Family: consanguinity; relatives with liver disease, emphysema or iron overload.
Examine	Mental status, tremor and dystonia;¹¹ lens position and body habitus;⁶ Achilles and extensor tendon xanthomas;⁸ liver size; skin pigmentation and second and third MCP joints.^{15 16}
Order	By suspicion: plasma ammonia and urine orotic acid;⁵ plasma total homocysteine;⁷ plasma cholestanol;⁸ random urine PBG and ALA with creatinine;⁹ ceruloplasmin, serum copper and 24-hour urine copper;¹¹ serum AAT with PI typing or genotype;¹² transferrin saturation and ferritin, then HFE genotype;¹⁵ plasma amino acids for PKU.¹ Liver tests in all of them.
Refer	Biochemical genetics for PKU, UCD, homocystinuria and CTX;^{1 6} hepatology for Wilson and for HFE with ferritin over 1,000;^{11 17} pulmonology for AATD lung disease.¹² Where: the esoteric assays, clinical expertise, specialist and resource rosters.
Tell the patient	That each of these is treatable; for PKU, that treatment is lifelong and a pregnancy needs planning months ahead;¹ for AHP, which drugs and exposures to avoid;⁹ that a confirmed result matters for siblings.
Document	Which disorders were considered and why, the first-line results, the drug-avoidance list, and the referral question.

Roster for this cohort

Drawn from the esoteric assays roster (plasma amino acids, urine orotic acid, total homocysteine, cholestanol, porphyrin precursors, copper studies, AAT phenotyping), the clinical expertise roster (biochemical genetics consults), the specialist roster (hepatology, pulmonology, neurology, hematology), the empiric therapies roster (hemin, givosiran, augmentation therapy, pegvaliase through infusion centers and specialty pharmacy), the advanced imaging roster (liver MRI T2*, brain MRI), the procedural studies roster (pulmonary function, elastography), and the resource roster (metabolic dietitians). The roster is forming; members propose and vet entries in the cohort's Slack channel.

Readings

GeneReviews: Phenylalanine Hydroxylase Deficiency, Homocystinuria due to Cystathionine Beta-Synthase Deficiency, Cerebrotendinous Xanthomatosis, Wilson Disease, Alpha-1 Antitrypsin Deficiency, HFE-Related Hemochromatosis, and the Urea Cycle Disorders Overview. University of Washington.
ACMG: Vockley J, et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014.
Morris AAM, et al. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis. 2017.
AGA: Wang B, et al. Clinical practice update on diagnosis and management of acute hepatic porphyrias. Gastroenterology. 2023.
Alpha-1 Foundation: Sandhaus RA, et al. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Chronic Obstr Pulm Dis. 2016.
ACG: Kowdley KV, et al. ACG clinical guideline: hereditary hemochromatosis. Am J Gastroenterol. 2019.

References

Arnold G, Vockley J. Phenylalanine hydroxylase deficiency. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. NBK1504
Vockley J, Andersson HC, Antshel KM, et al. Phenylalanine hydroxylase deficiency: diagnosis and management guideline. Genet Med. 2014;16(2):188-200. doi:10.1038/gim.2013.157
Thomas J, Levy H, Amato S, et al. Pegvaliase for the treatment of phenylketonuria: results of a long-term phase 3 clinical trial program (PRISM). Mol Genet Metab. 2018;124(1):27-38. doi:10.1016/j.ymgme.2018.03.006
Toquet S, Spodenkiewicz M, Douillard C, et al. Adult-onset diagnosis of urea cycle disorders: results of a French cohort of 71 patients. J Inherit Metab Dis. 2021;44(5):1199-1214. doi:10.1002/jimd.12403
Das AM. Urea cycle defects in adulthood: clinical presentation, diagnosis and treatment in genetically encoded hepatic metabolic disorders with a potential for encephalopathy. Metab Brain Dis. 2025;40(5):192. doi:10.1007/s11011-025-01619-5
Sacharow SJ, Levy HL. Homocystinuria due to cystathionine beta-synthase deficiency. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. NBK1524
Morris AAM, Kožich V, Santra S, et al. Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. J Inherit Metab Dis. 2017;40(1):49-74. doi:10.1007/s10545-016-9979-0
Federico A, Gallus GN. Cerebrotendinous xanthomatosis. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. NBK1409
Wang B, Bonkovsky HL, Lim JK, Balwani M. AGA clinical practice update on diagnosis and management of acute hepatic porphyrias: expert review. Gastroenterology. 2023;164(3):484-491. doi:10.1053/j.gastro.2022.11.034
Balwani M, Sardh E, Ventura P, et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N Engl J Med. 2020;382(24):2289-2301. doi:10.1056/NEJMoa1913147
Weiss KH, Schilsky M. Wilson disease. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. NBK1512
Stoller JK, Hupertz V, Aboussouan LS. Alpha-1 antitrypsin deficiency. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. NBK1519
Sandhaus RA, Turino G, Brantly ML, et al. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Chronic Obstr Pulm Dis. 2016;3(3):668-682. doi:10.15326/jcopdf.3.3.2015.0182
Chapman KR, Burdon JG, Piitulainen E, et al. Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9991):360-368. doi:10.1016/S0140-6736(15)60860-1
Barton JC, Parker CJ. HFE-related hemochromatosis. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. NBK1440
Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 2008;358(3):221-230. doi:10.1056/NEJMoa073286
Kowdley KV, Brown KE, Ahn J, Sundaram V. ACG clinical guideline: hereditary hemochromatosis. Am J Gastroenterol. 2019;114(8):1202-1218. doi:10.14309/ajg.0000000000000315

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.

Discuss this cohort in Slack

Colorado Care Network. Inherited metabolic disease. Version 2026-10-30.