Late-onset cobalamin C disease (cblC disease; combined methylmalonic aciduria and homocystinuria, cblC type; MMACHC deficiency)

Page most recently updated 7 September 2026

This page focuses on the reported psychiatric associations, which may be the initial presenting manifestation, and on other clinical features that may assist the psychiatrist or primary care physician in identifying the underlying diagnosis, considered through the lenses of the diagnostic lenses framework.

Late-onset cobalamin C disease (cblC disease; combined methylmalonic aciduria and homocystinuria, cblC type; MMACHC deficiency) is a genetic neurometabolic disorder that can affect mental health, neurological function, and multiple organ systems. It occurs as an inherited autosomal recessive genetic condition; absence of a relevant family history does not exclude the diagnosis because the parents of an affected individual are typically unaffected carriers. A distinctive presentation may include the combination of neuropsychiatric features, myelopathy or peripheral neuropathy, and thromboembolic or renal disease.

It can present with psychiatric features such as depression, anxiety, mania, behavioural or personality change, and, less commonly, psychosis. These manifestations can have a late onset in adolescence or adulthood and may be the presenting features of the disease.

Other characteristic features include progressive cognitive impairment or dementia; cerebellar ataxia and dysarthria; peripheral neuropathy; myelopathy, including subacute combined degeneration of the spinal cord; seizures; and, less commonly, movement abnormalities. Thromboembolic complications are an important feature, particularly in adult-onset disease.

From a multisystemic lens perspective, clinical features in other body systems include (but are not limited to):

  • Cardiovascular: thromboembolic disease, including arterial or venous thrombosis; pulmonary hypertension and, in some cases, pulmonary thrombotic disease and associated right-sided cardiac complications.

  • Respiratory: pulmonary hypertension and pulmonary thromboembolic complications.

  • Renal/electrolytes: renal thrombotic microangiopathy, hemolytic uremic syndrome, glomerular disease, proteinuria, and renal impairment, including progressive renal dysfunction in adult-onset disease.

  • Hematologic: macrocytic or megaloblastic anemia and other cytopenias may occur, although hematologic abnormalities are less consistently prominent in late-onset disease.

Early diagnosis is important to reduce the risk of potentially serious and irreversible neurological, renal, vascular, and other systemic complications; to facilitate prompt disease-specific metabolic treatment; and to improve long-term prognosis, functional outcomes, and quality of life. Earlier treatment, before irreversible organ damage develops, is associated with better outcomes.

Selected references and further reading — Multisystemic lens

Cardinal RN, Bullmore ET. The diagnosis of psychosis. Cambridge: Cambridge University Press; 2011.

Sachdev PS, Keshavan MS, editors. Secondary schizophrenia. Cambridge: Cambridge University Press; 2010.

Levenson JL, editor. The American Psychiatric Association Publishing textbook of psychosomatic medicine and consultation-liaison psychiatry. 3rd ed. Washington (DC): American Psychiatric Association Publishing; 2019.

Stern TA, Beach SR, Smith FA, Freudenreich O, Vranceau AM, Fava M, editors. Massachusetts General Hospital handbook of general hospital psychiatry. 8th ed. Philadelphia: Elsevier; 2025.

Arciniegas DB, Yudofsky SC, Hales RE, editors. The American Psychiatric Association Publishing textbook of neuropsychiatry and clinical neurosciences. 6th ed. Washington (DC): American Psychiatric Association Publishing; 2018.

Agrawal N, Faruqui R, Bodani M, editors. Oxford textbook of neuropsychiatry. Oxford: Oxford University Press; 2020.

Boland R, Verduin M, editors. Kaplan and Sadock's comprehensive textbook of psychiatry. 11th ed. Philadelphia: Wolters Kluwer; 2024.

Loscalzo J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, editors. Harrison's principles of internal medicine. 22nd ed. New York: McGraw Hill; 2025.