Methylmalonic Acidemia (MMA) is a metabolic disorder of branched chain amino acids. The underlying defect in more than half of the cases in MMA is due to defects in or absence of the Methylmalonyl-CoA Mutase (MCM) enzyme. As most other disorders in this category, the signs and symptoms of this condition develop in early infancy. Infants present with vomiting, hypotonia, dehydration, lethargy, seizures, and failure to thrive. Progressive encephalopathy and developmental delays will also be noticed later. If not detected and managed at an early stage, death can result. Even if properly managed, some long term complications may remain, including mental retardation, chronic kidney disease, and pancreatitis.
MMA is suspected in neonates with progressive encephalopathy along with severe metabolic acidosis, ketosis and ketonuria, hyperammonemia, hyperglycinemia, thrombocytopenia, and neutropenia. Mass spectrometric analysis of plasma, CSF, and/or urine samples is the next step towards a definite diagnosis. In the case of affected patients, this should show elevated levels of methylmalonic acid. Management is a life long process. Critically ill patients need to be taken special care of, with elimination of protein intake, and increase in fluid and glucose uptake. Dietary management with a low-protein and high calorie diet is the best method for long-term management. Antibiotics may be required to stem the growth of propionate producing gut flora, and hydroxycobalamine and carnitine may be supplemented in the diet. It is important to avoid fasting and take care to prevent recurrent infections, both of which result in breakdown of stored protein.
Al-Arrayed (Personal communication, Dubai, 2006) indicated that 3-methylglutaric acidemia occurs in Bahrain at an approximate incidence of 6/10,000 births.
In a retrospective analysis of IEMs diagnosed over a 12-year period (1998-2010) in a hospital in Lebanon, Karam et al. (2013) found 23 patients diagnosed with methylmalonic aciduria. Five of these were through newborn screening. Mean age at diagnosis was of 1 year and 5-months.
Joshi et al. (2002) carried out a retrospective analysis of all patients born with inborn errors of metabolism in Oman between June 1998 and December 2000. Among the 82 patients, one was diagnosed with methylmalonic aciduria [CTGA Database Editor's note: Computed annual incidence rate is 0.8/100,000]. Few years later, Joshi and Venugopalan (2007) conducted a study over a seven year period (1998-2005) to evaluate the clinical profiles of 166 neonates at high risk of having inborn errors of metabolism using Tandem Mass Spectrometry (TMS). Out of a total of 38 neonates with positive TMS results, one baby, aged six days, was diagnosed with Methylmalonic Acidemia. He was born to consanguineous parents and presented with acute neonatal encephalopathy.
Al-Riyami et al (2012) reported on the types and patterns of IEMs encountered in a sample of 1100 high-risk neonates referred to SQU Hospital in Oman over a 10-year period (1998-2002). MS/MS was used to analyze blood samples from heel pricks. A total of 119 of these neonates were found to test positive for an IEM. MMA was detected in five neonates (three males, two females), belonging to two families. Four of the patients had a family history of the condition, while three had consanguineous parents.
In 2003, the Hamad Medical Corporation, in partnership with the University Children's Hospital of Heidelberg built a comprehensive newborn screening program. Between December 2003 and July 2006, Lindner et al. (2007) investigated 25,214 neonates born in Qatar for inborn errors of metabolism and endocrine disorders. One neonate was diagnosed with MMA deficiency. The NBS result was available at 8-days of age, and treatment was started immediately.
Brismar and Ozand (1994) reported the results of CT and/or MRI of the brain in 107 patients with different types of organic acidemia. The CSF spaces were wide in more than two-thirds of the patients, in 46 slightly-to-moderately and in 26 markedly-to-severely dilated. Marked widening of the opercula was found in all 5 patients with glutaric acidemia type 1, but open opercula was also found in other organic acidemias. White matter changes were found in about half the patients, in 28 mildly-to-moderately pronounced, in another 28 marked or severe. Basal ganglia or central pathway pathology was seen in a total of 34 patients. These changes in 25 patients involved the caudate and/or lentiform nuclei: in 14 cases the T2 signal was increased and volume loss was present, in 9 cases increased T2 signal with preserved volume was found (in one of these the changes were transient). In 2 patients, both with ethylmalonic aciduria (cause unknown), only small high T2 spots were seen in the caudate heads and the putamina. In 4 patients, all suffering from methylmalonic acidemia, only the globus pallidus was affected.
Worthen et al. (1994) retrospectively analyzed 144 patients who were followed for 1-5 years for the severity and frequency of hypoglycemia. The patients were mainly Saudi; however, 10-25% were from neighboring countries in the Arabian peninsula. Less than 50% of the patients with MSUD older than 8 months, pyruvate carboxylase deficiency, methylmalonic acidemia, or propionic acidemia had hypoglycemia during metabolic crisis.
Moammar et al. (2010) reviewed all patients diagnosed with inborn errors of metabolism (IEM) from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia. During the study period, 165530 Saudi infants were born, of whom a total of 248 newborns were diagnosed with 55 IEM. Affected patients were evaluated based on clinical manifestations or family history of similar illness and/or unexplained neonatal deaths. Almost all patients were born to consanguineous parents. Organic acidopathies (OA) were diagnosed in 48 out of 248 cases (19%), which constituted the second largest group of IEM found in this cohort after lysosomal storage disease. Among OA patients, two cases from two families were found to have methylmalonic acidemia due to mutase deficiency. The estimated incidence of this condition is 1 in 100,000 live births. Methylmalonic acidemia accounts for 27% of all cases of OA found in this cohort. The authors concluded that data obtained from this study underestimate the true figures of various IEM in the region. Therefore, there is an urgent need for centralized newborn screening program that utilizes tandem mass spectrometry, and offers genetic counseling for these families.