MEN (General Swiss-German Mennonite)

Inheritance: autosomal recessive
Genes: BCKDHA
BCKDHB
DBT
DLD

MSUD
Branched-chain ketoaciduria
Branched-chain alpha-ketoacid dehydrogenase
Ketoacid decarboxylase deficiency
BCKD deficiency

Ketonuria
Maple syrup urine
Inborn error of metabolism
Mental retardation
Physical retardation
Seizures
Failure to thrive

Maple Syrup Urine Disease

Clinical Characteristics

General description (for patients): 

Newborns are listless, have feeding difficulties, seizures, periods of interrupted breathing, global developmental delay, and growth deficiency.  The urine has a maple syrup odor.  General muscle tone may be poor.  Symptoms in acute episodes Include: seizures, abdominal pain, muscle weakness, unsteadiness, a dull affect, and sometimes hallucinations.  Left untreated, progressive neurodegeneration can lead to coma and death within the first months of life.  Early and prompt treatment can prevent many of the neurological damage.

Medical description:  

Multiple types have been described. The most common and most severe form of the disease is the classic type, which appears soon after birth. The diagnosis is made from elevated blood leucine levels.  There are several other types: intermediate MSUD, intermittent MSUD, thiamine-responsive MSUD, and E3-deficient MSUD with lactic acidosis (type III).  These appear later in infancy or childhood and are typically milder.  The most severe classic form of MSUD can damage the brain early and require prompt diagnosis and treatment to prevent neurologic damage.  This form has been identified in several Anabaptist communities but the largest number of patients reported has been in the Old Order Mennonites in Eastern Pennsylvania.  The Clinic for Special Children in Lancaster has successfully treated these using a strict dietary protocol.

Genetics:

This genetic disorder can be caused by a mutation in one of at least four genes; BCKDHA (19q13.1-q13.2), BCKDHB (6p22-p21, or 6q14), DBT (1p31), or DLD (7q31-q32).  These genes are responsible for encoding component proteins of the branched-chain α-keto acid dehydrogenase complex (BCKD) which catalyses the breakdown of branched -chain amino acids, leucine, isoleucine, and valine.  Mutations in any of these genes decrease or eliminate the activity of the enzyme complex, preventing the normal breakdown of these amino acids.  High levels in the blood are toxic to the brain and other organs and when present in urine are responsible for the distinct smell.  The mutation (1312T>A) in Mennonites is located in the BCKDHA gene.

Treatment:

Currently treatment consists of restricting the dietary intake of branched-chain amino acids to the absolute minimum that is needed for growth. These include dietary leucine restriction, high-calorie BCAA-free formulas and frequent monitoring of plasma amino acid concentrations and fetal growth may be necessary to avoid essential amino acid deficiencies especially during pregnancy.  However, studies have shown that it is possible to transfer subunits of the BCKDH enzyme into cells using a retrovirus.

Prognosis:

This disease can be life threatening if untreated.  Even with dietary treatment, stressful situations and febrile illnesses can lead to high levels of certain amino acids.  Death may occur during these episodes. With strict and early dietary treatment, children have grown into healthy adulthood.

Ancillary treatments and support:

Strict dietary monitoring.

Specialists and specialty centers:

Neurologists, nutritionists, pediatricians.

References:

Zneimer, S.M., Lau, K.S., Eddy,R.L., Shows, T.B., Chuang, J.L., Chuang, D.T., and Cox,R.P.: Regional assignment of two genes of the human branched-chain alpha-keto acid dehydrogenase complex: the E1 beta gene (BCKDHB) to chromosome 6p21-22 and the E2 gene (DBT) to chromosome 1p31. Genomics. 10(3):740-747, 1991. PubMed ID: 1889817

Chuang, D.T., Chuang, J.L., and Wynn, R.M.:  Lessons from genetic disorders of branched-chain amino acid metabolism.  J. Nutr. 136 (Suppl): 243S-249S, 2006.  PubMed ID: 16365091

Chuang D.T.:  Maple syrup urine disease: it has come a long way.  Pediat. 132: S17-23, 1998.  PubMed ID: 9546032

Morton, D.H., Strauss, K.A., Robinson, D.L., Puffenberger, E.G., and Kelley, R.I.:  Diagnosis and treatment of maple syrup disease: a study of 36 patients. Pediatrics 109: 999-1008, 2002.  PubMed ID: 12042535

Resources:

Clinic for Special Children
Genetics Home Reference
MSUD Family Support Group

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