APA (Old Order Amish; Eastern Pennsylvania)

MEN (General Swiss-German Mennonite)

Inheritance: autosomal recessive
Genes: MCCC2

3-alpha-methylcrotonyl-CoA carboxylase 2 deficiency
3-alpha-methylcrotonylglycinuria II
Methylcrotonylglycinuria Type II

Epilepsy
Hypotonia
Lactic acidemia
Metabolic acidosis
Developmental delay
Seizures
Myopathy

MCCC2 Deficiency

Clinical Characteristics

General description (for patients):   

This disorder of metabolism has highly variable features.  Some individuals, even adults, have no symptoms.  Infants may be diagnosed via blood spots in the absence of any symptoms whereas others become seriously ill in the first year of life or during early childhood.  Switching to a high protein diet or having a serious infection may precipitate symptoms.  Acute episodes may manifest as seizures, floppiness and weakness, vomiting, coma, and rapid breathing. Development may be normal or delayed.

Medical description: 

This metabolic disorder has a highly variable clinical presentation.  It often presents as an acute, early childhood illness of hypoglycemia, hypotonia, (seizures rarely), metabolic acidosis, and lactic acidemia.  Episodes can be triggered by changes to a high protein diet, or by acute infectious illnesses.  However, asymptomatic adults have also been identified, sometimes following the birth of an affected child.  Adults can be hypotonic with signs of myopathy such as weakness and fatigue.   Psychomotor retardation and mental deficiencies can occur but not in everyone.  Abnormal acylcarnitine profiles in blood spots can lead to the diagnosis as can excretion of large amounts of 3-methylcrotonylglycine and 3-hydroxyisovaleric acid.

Genetics: 

A mutation encoding the beta subunit of 3-methylcrotonyl-CoA carboxylase, a biotin-dependent mitochondrial enzyme, is responsible for the metabolic imbalances in this disorder.  The gene (MCCC2) is located on chromosome 5 (5q12-q13).  This is an autosomal recessive disorder.  It has been reported in the Amish/Mennonite community of Pennsylvania.   A homozygous 295G>C substitution in this gene has been found in a mildly affected Amish woman in Lancaster County, PA.  A heterozygous 517insT frameshift mutation has been found in a Mennonite woman from the same area.  The latter has also been identified in a patient from Switzerland where the Amish originated.

Treatment:

Metabolic acidosis needs urgent treatment.  Protein restriction can be helpful in the longer term.  This disorder is resistant to biotin treatment.

Prognosis:

Too highly variable to predict.  Some normal functioning adults with the metabolic profile complain of little beyond malaise and tiredness, whereas some children have acute episodes, with mild to moderate psychomotor and developmental delays.  A few children have died.

Ancillary treatments and support:

Many if not most require only metabolic surveillance.

Specialists and specialty centers:

Pediatrician, neurologist, nutritionist.

References:

Gibson, K.M., Bennett, M.J., Naylor, E.W., and Morton, D.H.:  3-methylcrotonyl-coenzyme A carboxylase deficiency in Amish/Mennonte adults identified by detection of increased acylcarnitines in blood spots of their children.  J. Pediat.132: 519-523, 1998.  PubMed ID: 9544913

Gallardo, M.E., Desviat, L.R., Rodriguez, J.M., Esparza-Gordillo, J., Perez-Cerda, C., Perez, B., Rodriguez-Pombo, P., Criado, O., Sanz, R., Morton, D.H., Gibson, K.M., Le, T.P., Ribes, A., Rodriguez de Cordoba, S., Ugarte, M., and Penalva, M.A.:  The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine catabolism.  Am.  J.  Hum. Genet. 68: 334-346, 2001.  PubMed ID: 11170888

Baumgartner, M.R., Almashanu, S., Suormala, T., Obie, C., Cole, R.N., Packman, S., Baumgartner, E.R., and Valle, D.:  The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency.  J. Clin. Invest. 107: 495-504, 2001.  PubMed ID: 11181649

Resources:

Organic Acidemia Association
Genetics Home Reference

Associated Graphics