Methylmalonic and propionic acidemia (MMA/PA) are inborn errors of metabolism characterized by accumulation of propionic acid and/or methylmalonic acid due to deficiency of methylmalonyl-CoA mutase (MUT) or propionyl-CoA carboxylase (PCC). MMA has an estimated incidence of~1: 50,000 and PA of~1:100’000 -150,000. Patients present either shortly after birth with acute deterioration, metabolic acidosis and hyperammonemia or later at any age with a more heterogeneous clinical picture, leading to early death or to severe neurological handicap in many survivors. Mental outcome tends to be worse in PA and late complications include chronic kidney disease almost exclusively in MMA and cardiomyopathy mainly in PA. Except for vitamin B12 responsive forms of MMA the outcome remains poor despite the existence of apparently effective therapy with a low protein diet and carnitine. This may be related to under recognition and delayed diagnosis due to nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim to provide a trans-European consensus to guide practitioners, set standards of care and to help to raise awareness. To achieve these goals, the guidelines were developed using the SIGN methodology by having professionals on MMA/PA across twelve European countries and the U.S. gather all the existing evidence, score it according to the SIGN evidence level system and make a series of conclusive statements supported by an associated level of evidence. Although the degree of evidence rarely exceeds level C (evidence from non-analytical studies like case reports and series), the guideline should provide a firm and critical basis to guide practice on both acute and chronic presentations, and to address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Furthermore, these guidelines highlight gaps in knowledge that must be filled by future research. We consider that these guidelines will help to harmonize practice, set common standards and spread good practices, with a positive impact on the outcomes of MMA/PA patients.

/pdf/proposed-guidelines-for-the-diagnosis-and-management-of-1ke10xqzrz.pdf

Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia

Branched-chain organic acidurias.

Methylmalonic and propionic aciduria (PA) are the most frequent forms of branched-chain organic acidurias. These autosomal recessive disorders result from deficient activity of methylmalonyl-CoA mutase and propionyl-CoA carboxylase, respectively. Clinically, acute or chronic neurologic signs are caused by the accumulation of toxic compounds proximal to the metabolic block. Phenotype varies from severe neonatal-onset forms with high mortality and poor outcome to milder forms with a later onset. In both cases the clinical course is dominated by the risk of relapses of life-threatening episodes of metabolic decompensation and of severe organ failure. Despite improvement of treatment, the overall outcome remains disappointing with no major differences between the two diseases. The diagnosis is based on the presence of characteristic compounds in body fluids as detected by organic acid analysis in urine and acylcarnitine profile in blood. Therapy is based on low-protein high-energy diet, carnitine supplementation, and metronidazole. Some patients with methylmalonic aciduria (MMA) respond to pharmacological doses of vitamin B12. Given the poor long-term prognosis, liver transplantation has been recently attempted as an alternative therapy to conventional medical treatment to cure the underlying metabolic defect. Nevertheless, the overall experience to date does not clearly demonstrate its effectiveness in preventing further deterioration or improving survival and quality of life. The recent implementation of neonatal screening by electrospray tandem mass spectrometry has decreased early mortality and improved the short-term outcome, without changing the detection rate of both diseases in the screening population compared to clinically detected cases. However, the limited number of patients and the short duration of their follow-up do not yet permit drawing final conclusions on its effect on the long-term outcome of methylmalonic and propionic acidemia. © 2006 Wiley-Liss, Inc.

Methylmalonic and propionic aciduria.

Background
The clinical presentation of patients with organic acidurias (OAD) and urea cycle disorders (UCD) is variable; symptoms are often non-specific.

/pdf/the-phenotypic-spectrum-of-organic-acidurias-and-urea-cycle-6wap76uh4z.pdf

The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation

Purpose of review Recent clinical studies and management guidelines for the treatment of the organic acidopathies methylmalonic acidemia (MMA) and propionic acidemia address the scope of interventions to maximize health and quality of life. Unfortunately, these disorders continue to cause significant morbidity and mortality due to acute and chronic systemic and end-organ injury. Recent findings Dietary management with medical foods has been a mainstay of therapy for decades, yet well controlled patients can manifest growth, development, cardiac, ophthalmological, renal, and neurological complications. Patients with organic acidopathies suffer metabolic brain injury that targets specific regions of the basal ganglia in a distinctive pattern, and these injuries may occur even with optimal management during metabolic stress. Liver transplantation has improved quality of life and metabolic stability, yet transplantation in this population does not entirely prevent brain injury or the development of optic neuropathy and cardiac disease. Summary Management guidelines should identify necessary screening for patients with methylmalonic acidemia and propionic acidemia, and improve anticipatory management of progressive end-organ disease. Liver transplantation improves overall metabolic control, but injury to nonregenerative tissues may not be mitigated. Continued use of medical foods in these patients requires prospective studies to demonstrate evidence of benefit in a controlled manner.

/pdf/methylmalonic-and-propionic-acidemias-clinical-management-57pc69hf4y.pdf

Methylmalonic and propionic acidemias: clinical management update.

A retrospective study was performed on the clinical outcome and long-term treatment of 17 patients with propionic acidaemia diagnosed during the last 20 years in our hospital. The study group consisted of 12 patients with early onset type of disease and 5 patients with late onset. Seven (41%) patients died, five with early onset and two with late onset. The deceased early onset patients had a median survival of 0.4 years while the deceased late onset patients died at the age of 2.8 and 4 years respectively. Median age of the living early onset patients was 5.2 (1–9.25) years, the late onset patients were 4,7 and 23 years old. Patients were all treated with natural protein restriction and in most cases carnitine and metronidazole were added. The early onset patients were almost all treated with daily home tube feeding. The mean natural protein intake of early onset patients (6.3±1.5 g/day) was significantly lower than the natural protein intake of late onset patients (17.6±5.3 g/day). Supplemental protein intake was higher in early onset patients. The general neurological outcome of our study group was satisfactory with a better outcome for early onset patients. As to growth, many patients showed a failure to thrive, this was particularly for height. The strong protein restriction during the first years of life probably contributed to this.

Clinical outcome and long-term management of 17 patients with propionic acidaemia.

Management and Long Term Follow-up of Organic Acidemias : Criteria for Therapeutic Decisions

Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia.

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Clinical outcome and long-term management of 17 patients with propionic acidaemia.

Management and Long Term Follow-up of Organic Acidemias : Criteria for Therapeutic Decisions

Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia.