Isolated Deficiency of 3-Methylcrotonyl CoA Carboxylase (3-MCC)

Collated and co-written by Rachael Sharman, parent (3-MCC) and Vice President MDDA.
Co-written and edited by Dr Jim McGill, Director Metabolic Medicine, Royal Children's Hospital, Brisbane, Queensland, Australia.

Once considered extremely rare, this condition is featuring strongly since the introduction of Tandem Mass Spectroscopy (TMS) newborn screening. It would appear to have a range of disease presentations from seemingly "asymptomatic" to rapidly fatal.

The disorder involves a deficiency of the enzyme 3 Methylcrotonyl CoA carboxylase (3-MCC) involved in the breakdown of leucine. Leucine is an amino acid in all food-based protein. Treatment largely involves restricting protein intake to prevent the build up of 3-hydroxyisovaleric acid and 3 methylcoronlglycine. Recommended protein intake is usually at the level considered necessary for "normal" growth (1-2g per kilo bodyweight per day). Therefore, non-leucine protein supplements may not be considered necessary for individuals progressing normally with growth and development. A secondary consideration in this disorder is the risk of sudden hypoglycemia if the individual is anorexic or depleted of nutrition (eg due to a vomiting virus).

Many 3-MCC individuals also require supplements of carnitine. Carnitine is a naturally occurring substance that is important in transporting toxic compounds out of cells. The carnitine combines with the toxic compound and carries it out of the body into the urine. As more and more toxin is removed, more and more carnitine is lost from the body into the urine so that eventually the body stores of carnitine are diminished. This is called a secondary carnitine deficiency. (A primary deficiency results when there is a problem making or transporting the carnitine). Carnitine deficiency can cause major problems and opinions about the effects of this supplement specifically for 3-MCC individuals vary. However, some parents/carers of 3-MCC children, as well as their metabolic physicians, have noted a positive effect of carnitine on general well being, sleep patterns and temperament.

The most common clinical presentation of the disease before the introduction of TMS, involved children aged 1 - 3 yrs becoming suddenly and critically ill following a period of poor nutrition or gastroenteritis. Similar presentations have been reported from early infancy into late childhood. "Lazy" milestones and failure to thrive have also been reported. A common feature for many sufferers is the presence of a strong odour in the urine, similar to cats urine. Very severe nappy rash (presumably as a result of the substances in the urine) has also been noted by some carers.

The recent introduction of TMS screening and subsequent sibling and family screening has also identified individuals with the disease who are well into adolescence or adulthood and who display few or mild symptoms to apparently none at all. This has lead to some debate amongst physicians on how, if at all, apparently asymptomatic cases should be treated. It is important to remember that most cases of 3-MCC appear clinically asymptomatic until the individual's first hypoglycaemic episode and it's usual successor, metabolic "stroke". Despite the absence of known clinical indicators, some parents have reported that subtle symptoms (eg behavioural, sleeping trouble, skin irritations) have resolved after diet and treatment is commenced. I shall leave the last word on this issue to Scriver - the accepted guru of metabolic medicine: "The lack of symptoms should not lull the clinician into a false sense of security, as in other organic acidemia's, acute decomposition and death have occurred with the first severe catabolic episode in the second decade of life." (Scriver et al, 2001, p 2136).

The main issue for individuals and families is early detection. 3-MCC is a generally a disorder that responds extremely well to diet and treatment. Severe brain damage and subsequent problems have usually been a direct result of the hypoglycaemic coma trigged by a sudden deprivation of nutrition, and subsequent metabolic stroke caused by the build up of harmful metabolites. Early detection is standard for newborns in areas that have TMS screening, others must take their chances during hypoglycemia or stroke. Common complications resulting from severe hypoglycemia/metabolic stroke largely revolve around permanent intellectual disability. The sudden onset of coma/stroke of a 3-MCC infant may also lead to death, the event closely representing "cot death" or Sudden Infant Death Syndrome.

As with all IEproteinM, maintaining diet is also a challenge, although the diet in this disorder is usually adequate for normal growth and may not need additional protein supplementation. The diet is generally non-dairy and mostly vegetarian. Specialised low-protein foods such as breads, pastas and milks may also be necessary. The possibility of a sudden episode of hypoglycemia must also be monitored when children are unwell, as younger 3-MCC children may slip suddenly into coma in response to illness, with little warning. This risk tends to lessen as the child grows in age and mass, having more physical resources to cope with loss of nutrition for longer periods. Access and supply of the supplement carnitine may be an issue, particularly for individuals who are especially "carnitine sensitive". Carnitine in it's pure and recommended form is extremely expensive and in Australia it is provided by the State Government free of significant expense. If this were to change, individuals who need carnitine could face medication expenses in the range of several hundreds of dollars per month.