Organic acidurias (OADs) are inherited neurometabolic diseases largely caused by deficiencies in enzymes involved in amino acid degradation, which result in accumulation of organic acids in the brain and other tissues. Disease presentation usually occurs in infancy, although late-onset variants can emerge during childhood or adulthood. Patients predominantly manifest with acute encephalopathy with life-threatening systemic manifestations (classical OADs) or progressive neurological symptoms (cerebral OADs), leading to permanent cerebral abnormalities. Some OADs are treatable, and early diagnosis and treatment implementation have substantially decreased the mortality and overall morbidity from OADs. However, long-term irreversible cerebral and systemic complications are frequent because the therapeutic options are currently limited. The pathophysiology of brain dysfunction is still unclear in most OADs, and further investigation is needed to enable the development of novel therapeutic strategies. This Review focuses on current knowledge of the OADs, including epidemiology, short-term and long-term neurological and systemic features, diagnosis and prognosis, and recent advances in therapy and pathophysiology. The goal of the article is to alert neurologists and related health professionals to the existence and importance of these neurometabolic diseases and to stimulate research into the damaging factors that contribute to their neurodegenerative sequelae.
Organic acidurias (OADs) make up a large and prevalent group of inherited neurometabolic intoxication disorders caused by deficient enzyme activities, mostly of amino acid catabolism.
Acute or progressive signs of metabolic intoxication — predominantly or exclusively neurological — emerge in infancy (early onset) or during childhood or adulthood (late onset), resulting in high mortality and poor neurological outcome.
A diagnosis is usually reached through detection of characteristic organic acid profiles in the urine.
Current treatment strategies have decreased mortality and overall morbidity but do not prevent long-term systemic and neurological complications.
A better understanding of the precise mechanisms underlying the pathogenesis of OADs should aid the development of new therapies to target CNS injury.
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The author acknowledges all colleagues and researchers who, over the past three decades, have made substantial contributions to the diagnosis and treatment of patients with organic acidurias and to investigations into the pathomechanisms of brain injury in these diseases. Special thanks go to C. M. D. Wannmacher, C. S. Dutra-Filho, A. T. S. Wyse, G. Leipnitz, C. R. Vargas, A. U. Amaral, A. Sitta and D. M. Coelho. The author also thanks the patients and their families for their long-standing confidence and patience while diagnosis was performed and treatment implemented. The author also acknowledges the invaluable technical assistance of C. Cecatto and P. Batista da Rosa.
The author declares no competing interests.
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Wajner, M. Neurological manifestations of organic acidurias. Nat Rev Neurol 15, 253–271 (2019). https://doi.org/10.1038/s41582-019-0161-9
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