3-Methylcrotonyl-CoA Carboxylase Deficiency (MCCD) is an organic aciduria caused by the deficiency of an enzyme that plays a role in the metabolism of leucine. Patients with this enzyme defect appear normal at birth, with the first signs and symptoms of the condition appearing in infancy or early childhood. These signs include a poor appetite, a lack of energy, lethargy, extreme sleepiness, irritable mood, hypotonia, nausea, vomiting, feeding difficulties, and behavior changes. If left untreated, the condition can progress to delayed development, breathing problems, seizures, liver failure, and coma, sometimes even leading to death. The severity of the symptoms differs from patient to patient. Some children with the enzyme deficiency remain asymptomatic, and do not require any treatment or management.
Diagnosis is made on the basis of symptoms and metabolic findings. Typically, affected children will show metabolic acidosis, with low levels of blood sugar and carnitine, and increased levels of blood ammonia and urinary ketones. Patients may also show liver problems. Once diagnosed, the patients need to be put on a food plan that is low in leucine. Ideally, the diet in this case should be high in carbohydrates and low in protein. Special leucine-free formulas are available, that can be used for feeding affected children. It might benefit some patients to take L-carnitine and other nutritional supplement. Most children who are diagnosed early and managed with the special diet have an excellent prognosis, and lead normal lives. However, if left untreated, the condition can cause brain damage.
MCCD is inherited in an autosomal recessive manner. Mutations in the MCCC1 gene are associated with MCCD type I (MCC1D).
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 MCC deficiency. Result of newborn screening was available at 10-days of age, while treatment was started at 42-days.
Al-Odaib et al. (2006) described the long-term follow-up of a Saudi patient with Biotin-Resistant MCC Deficiency. The female patient, born to consanguineous parents, presented at 2-months of age with tachypnea, gastro-esophageal reflux, diarrhea and acidosis. Tandem MS identified MCC Deficiency, and she was plaved on MSUD formula with isoleucine and valine. She was normal up to 17-months, when she developed a severe respiratory tract infection, and was found to have thrombocytopenia, which resolved spontaneously after a month. She remained a healthy child with appropriate age neuro-developmental milestones until the time of the report, during which time she was 6.5-years old. Tanden MS analysis of both parents and sibs revealed normal parameters. Enzyme analysis in the patient's fibroblasts revealed an isolated MCC deficiency.
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. The number of cases with organic acidopathies was 48 out of 248 (19%). Among them, three cases with 3-methylcrotonylglycinuria were identified. These cases were diagnosed by skin biopsy. The estimated incidence of this condition is 2 in 100,000 live births. 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.
Elpeleg et al. (1992) found hypotonia as the initial symptom in four sibs, aged 2.5 to 9 years, with isolated 3-MCC deficiency in a non-consanguineous Tunisian-Jewish family. Plasma carnitine was markedly deficient and urinary organic acid analysis demonstrated increased excretion of 3-hydroxyisolvaleric acid and 3-methylcrotonylglycine. 3-MCC enzyme activity was reduced in skin fibroblasts.
Al-Shamsi et al. (2014) undertook a study to calculate the birth prevalence of IEMs among Emiratis in the UAE by taking into consideration all neonates born with an inherited metabolic condition at Tawam Hospital between 1995 and 2012. A total of 37 distinct IEMs were found in Emirati neonates in this study, providing an estimated IEM birth prevalence of 75.24 per 100,000 live births. 3-Methylcrotonyl Glycinuria was found to have a birth prevalence of less than 0.98 per 100,000. Three different mutations in the MCCC1 gene and onemutation in the MCCC2 gene were identified among the affected patients.