HUT (Hutterite)

Inheritance: autosomal recessive
Genes: MUT

Methylmalonic acidemia
Mut
Mut(0) type
Mut(-) type

Metabolic acidosis
Hyperammonemia
Thrombocytopenia
Hypotonia
Neutropenia
Hyperbilirubinemia
Hypotonicity
Hepatomegaly
Failure to thrive
Renal failure
Respiratory distress

Methylmalonic Aciduria (MUT Type)

Clinical Characteristics

General description (for patients):  

The mutation causing this disease seems to have a wide spectrum of clinical disease.  It can lead to severe metabolic problems and even death in infancy and early childhood, but other children seem to develop almost normally.  The serious symptoms are lethargy, coma, breathing difficulties, floppy muscles, and dehydration.  The liver may be enlarged and kidney failure can occur.  It is important to seek prompt treatment because dietary treatment may be available but obviously is primarily beneficial before the brain is damaged.

Medical description: 

The methylmalonyl acidemias comprise a group of methylmalonate and cobalamin (vit B12) metabolism disorders.  Most are unresponsive to vitamin B12 supplementation.  The clinical spectrum is wide with some patients having a ‘benign’ mutase deficient form with normal development, whereas others developed severe metabolic problems with fatal outcomes in infancy.  Those with the mut(0) mutation have the poorest prognosis.  Signs and symptoms of hepatomegaly, developmental delay, respiratory distress, ketonuria, hyperglycinemia, and hyperammonemia may not be evident until late infancy and early childhood, even without acute metabolic decompensation.

Genetics:

Methylmalonic acidemia or aciduria of the mut type is an autosomal recessive disorder caused by a mutation in the nuclear gene encoding methylmalonyl-CoA mutase (MUT).   The protein product is a mitochondrial enzyme. The gene is located on chromosome 6 (6p21) and hundreds of mutations have been identified.  Compound heterozygosity is common.  Some cause only a partial deficiency of enzymatic activity {mut(-)} whereas others have no activity {mut(0)} but there is only broad correlation between genotype and phenotype.   A substitution (1420C>T) mutation has been identified in a Hutterite population.

Treatment: 

Low protein diets have proven beneficial in some patients but modifications may be necessary depending on the type of mutation.  Vitamin B12 is usually not beneficial, again depending on the specific metabolic defect.

Prognosis:

A few patients do well without treatment but the prognosis for the rest depends upon the timing of the diagnosis and therapy.

Ancillary treatments and support:

Appropriate to the stage of diseases and neurological damage

Specialists and specialty centers:

Pediatrician, neurologist, nutritionist.

References:

Shevell, M.I., Matiaszuk, N., Ledley, F.D., and Rosenblatt, D.S.:  Varying neurological phenotypes among mut-0 and mut- patients with methylmalonyl CoA mutase deficiency.  Am. J. Med. Genet. 45: 619-624, 1993.  PubMed ID: 7681251

Fowlow, S.B., Holmes, T.M., Morgan, K., and Snyder, F.F.:  Screening for methylmalonic aciduria in Alberta: a voluntary program with particular significance for the Hutterite brethren.  Am. J. Med. Genet. 22: 513-519, 1985.  PubMed ID:2865895

Worgan, L., Niles, K., Tirone, J., Hofmann, A., Verner, A., Sammak, A., Kucic, T., Lepage, P., and Rosenblattt, D.:  Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype.  Hum. Mutat. 27: 31-43, 2006.  PubMed ID: 16281286

Resources:

Organic Acidemia Association

Associated Graphics