Maple syrup urine disease

Under the maple syrup urine disease (english Maple syrup urine disease) or branched- chain disease or Leuzinose is an autosomal recessive disorder understood that causes disturbances in the metabolism of amino acids. The disease rarely occurs ( 1:216.000 ), but there are clusters in Georgia ( 1:123.000 ) and Mennonites in the U.S. state of Pennsylvania ( 1:760 ).

Causes

Currently three genes are known, the mutation of which leads to the disease. Depending on the genetic defect is distinguished type Ia, type Ib and type II. The changes in type Ia BCKDHA gene is located on human chromosome 19 ( 19q13.2 ), the mutated in type Ib BCKDHB on chromosome 6 ( 6q14.1 ). In type II, there is a mutation in the gene DBT on chromosome 1 ( 1p21.2 ). All three genes encode two enzymatically active subunits of the alpha -keto acid dehydrogenase complex (branched -chain alpha -keto acid dehydrogenase complex, BCKDC ). This enzyme complex is required for the degradation of the branched chain amino acids leucine, isoleucine and valine.

If the third subunit of the alpha -keto acid dehydrogenase complex defective, the Dihydrolipoyl dehydrogenase (EC 1.8.1.4 ), there is the more serious type III disease, the ( dihydrolipoamide dehydrogenase deficiency, DLDD ) is also known as DLD deficiency. Here, the defect is located on chromosome 7 ( 7q31 ). Thus, the degradation of the branched chain amino acids leucine ( Leu), isoleucine ( Ile) and valine (Val) is drastically reduced in leukocytes, fibroblasts, and in the liver tissue. These amino acids and their degradation products ( keto acids and other intermediates ) are enriched by a factor of 10 to 40 in blood and urine at. In addition, there is hypoglycemia (hypoglycemia ), metabolic acidosis (blood pH below 7.36 ), disorders of uric acid excretion and inhibition of myelination.

The mutation of a regulatory gene on the PPM1K chromosome 4 ( 4q22.1 ) leads to a milder variation of the disease.

Clinical symptoms

Already in the first week of life shows the ill infant food refusal, indifference ( apathy ), poor feeding, opisthotonus (backward bending of the head and hyperextension of the limbs and trunk ), high-pitched crying, hypotonia (reduced muscle resistance to passive stretching ) and stiffness, seizures. A coma can occur. Incognito performs the classic variant of maple syrup urine disease after a few days (about 7 to 15 days of age ) serious permanent brain damage. If the disease remains untreated, it leads to death within a short time.

The urine odor is described as spicy- sweet after maple syrup, Maggi, curry or burnt sugar and goes back to the formed in Leucinintermediärstoffwechsel sotolon.

Progressive forms

A) classical: This form is the most common form of the disease. The residual enzyme activity is less than two percent, and clinical signs are seen in the first days of life.

B) intermediate: The enzyme activity is from 5 to 20 percent. The damage range is of developmental delay up to severe mental disabilities, particularly with increased catabolism or protein intake of more than 1-1.5 g / kg · d ( grams of protein per kilogram of body weight per day ) and ketoacidosis.

C) intermittently: 3 to 30 percent of the enzyme activity can be detected. The form occurs before the age of 12 to 24 months in strong catabolism and (probably ) significant protein intake. There occur: ataxia (ataxia), convulsions, coma. However, outside of the crises patients this form is unremarkable.

D) thiaminabhängig: By increasing the enzyme activity by large Thiaminmengen (100-1000 mg/24 h) generally is not a restriction of protein intake necessary.

Diagnostics

  • Prenatally: Defect detection of the enzyme possible in amniotic
  • Newborn screening: by mass spectrometric methods in plasma and urine, in blood [ Leu ]> 8 mg / dl in the first 3 days of life
  • Orienting: with 2.4 - dinitrophenylhydrazine ( DNPH ) in urine ( deep red response to BCAA )
  • Breath test with 13C -labeled isotope: needs assessment of leucine
  • Outside the crises are the amino acid levels in intermittent form in the normal range

Therapy

Due to the possibility of a liver transplant can be created to be able to break down the branched chain amino acids themselves again. But the availability of organs is very limited, especially for small children, so have to rely on a conservative therapy waiver of recording branched amino acids in the diet.

To prevent severe disabilities, which may also lead to death under certain circumstances, the supply of proteins must be prevented at the slightest indication of the disease in the first days of life. Moreover done:

  • Acute detoxification by peritoneal dialysis ( free of nitrogen sources), plasmapheresis, continuous arteriovenous hemofiltration, to bring the Leucinwert below 0.5 mmol / l
  • The compensation of acidosis and treatment of hypoglycemia with high doses of glucose (insulin 0.2 IU / kg / h i v., Glu 1 g / kg body weight / h i v.)
  • The application of a fat - carbohydrate - electrolyte mixture through a naso-gastric tube

Initial therapy in the newborn ( neonatal ) period:

  • BCAA - free protein and energy doses of dextrose, lipids and at least 20 percent of the enzyme activity of 1.5 g protein / kg bw / d
  • Normalization: isoleucine within two to three days, leucine within eight to ten days
  • Long-term treatment: natural foods in combination with amino acid mixtures without branched-chain amino acids ( about MSUD 1 and 2 of Milupa and ILV -AM of cornflour ) with lifetime monitoring the blood levels
  • Indirect control ability of leucine by measuring the Ketonspiegels in the urine ( keto- sticks)

Since the precise adherence to diet but is accompanied by a reduction of the quality of life, the search for better treatments. A recent study demonstrated by the injection of fat cells a good efficacy in mice. Fat cells are not only energy reserves, but also contain enzymes - including those that can degrade branched amino acids. Disadvantage here is that the cells must come from a donor, so of course must also be a life-long immunosuppression of the recipient.

Food design

In infancy

  • Use only vegetable protein sources
  • Avoid prolonged nocturnal fasting periods, maintained a late night snack 22-24 clock until the end of the first year
  • At the age of one year: morning and evening carbohydrate-containing drinks
  • Fruits and vegetables with lower [ Leu ] < 50 mg/100 g allowed:

Infants and school children

  • For mild infections emergency program: Strong reducing and possibly substituting the intake of BCAA and increase the protein substitute preparation, avoid using food supply leucinhaltiger

Forecast

The decisive factor for the prognosis is usually the time interval between the onset of symptoms and the start of therapy. Correctly adjusted, patients have an overall good prognosis with maple syrup urine disease. In case of inadequate therapy can, inter alia, Damage to the cerebrum and mental retardation may occur.

Swell

  • Koletzko B.: Pediatrics and Adolescent Medicine. 12th edition, Springer, Berlin, 2004. ISBN 3-540-44365-7
  • Shils ME, Olson JA, Shike M, Ross AC ( eds ): Modern nutrition in health and disease. 9th edition, Williams & Wilkins, Baltimore 1999
  • Sitzmann FC:. Pediatrics. 3rd edition, Thieme, Stuttgart, 2006. ISBN 3-13-125333-9
  • Stone J, Jauch KW:. Practical manual of clinical nutrition and infusion therapy. Springer, Berlin, 2003. ISBN 3-540-41925- X
  • Http://www.stoffwechselzentrum-muenchen.de/erkrank/ahornsir.htm (1 November 2005)
Recessive trait Protein subunit Spasm Specific developmental disorder Thiamine Amnion Blood plasma 2,4-Dinitrophenylhydrazine Digital Object Identifier
36031
de