The clinical foundation for understanding the phenotype of methylmalonic acidemia derives from a series of reports published in the late 1960s [1
]. Oberholtzer et al. described two unrelated patients with methylmalonic acidemia [1
]. The first affected individual was initially suspected to have a renal tubular dysfunction syndrome. This patient had frequent attacks of dehydration and acidosis, and perished during a decompensation at age 2 years. On postmortem examination, a fungal pneumonia was noted and a peculiar histopathological appearance of the kidneys was documented. Specifically, the kidneys were shrunken; the tubules were diminutive and had increased interstitial tissue with a lymphocytic infiltration. The second child, a 6 year-old female, displayed a similar phenotype with respect to acid-base instability. Classical analytic chemical methods, such as paper chromatography, melting point analysis, and reactivity with diazotized p-nitroaniline, were used to demonstrate that she produced large amounts of methylmalonic acid in her urine, blood and cerebral spinal fluid (CSF). Of note, she had a CSF: plasma methylmalonic acid (MMA) gradient, with concentrations of MMA equal to 1.55 mM in her plasma and 1.575 mM in her CSF. The authors also recognized that the metabolic acidosis was only partly explained by the plasma MMA levels. A propensity toward ketosis was demonstrated, with an exquisite sensitivity to oral propionic acid. The child had problems with growth and motor skills in the early years, but when assessed at age 5 years, had a normal IQ.
The same year Stokke et al. studied the third child born to a family that had two infants perish in the newborn period with overwhelming acidosis and coma [2
]. Using a newer method of GC/MS, they demonstrated that the patient produced MMA in enormous amounts. Whole body metabolism was studied in the index case with C14
-valine and H3
-MMA. The patient did not respond to parenteral cobalamin but did demonstrate a clinical improvement when treated with a simple hyperalimentation consisting of elemental amino acids and glucose given IV, and fats and carbohydrates administered by nasogastric feeding, prior to perishing from an intercurrent infection. In the next year, a patient with a similar phenotype of intermittent ketoacidosis and severe methylmalonic aciduria was proven to respond to vitamin B12, firmly establishing a role for the vitamin in human intermediary metabolism [3
]. The early studies on patients with methylmalonic acidemia generated theories to explain the metabolic perturbations seen in these individuals, demonstrated fundamental precursor relationships, described a renal lesion seen in the patients, demonstrated that MMA is likely produced de novo
or concentrated in the nervous system, showed that the disorder could be treated with precursor restriction and possibly hyperalimentation, proved that the block was located at the methylmalonyl-CoA mutase (MCM, EC 220.127.116.11) step and was co-factor responsive in some patients. These papers provided the foundation of current therapies for methylmalonic acidemia.
Scientific studies of methylmalonic acidemia have provided a paradigm for the importance of human genetics and the investigation of rare disorders as a means to elucidate fundamental aspects of metabolism. Over the past three decades, great progress has been made in understanding and treating this group of disorders. However, the challenges faced by physicians caring for the early patients, such as the propensity toward metabolic decompensation, growth and feeding problems, renal disease and premature death, still exist [5
]. The use of model systems to study methylmalonic acidemia may help guide the development and testing of newer therapies for this devastating disorder. In this review, we will update the reader on the molecular genetics of isolated methylmalonic acidemia and highlight the use of model systems to study MMAemia and cobalamin metabolic disorders.