Maple syrup disease

Classification according to ICD-10
E71.0	Maple Syrup (Urinary) Disease
ICD-10 online (WHO version 2019)

Under the maple syrup urine disease ( English Maple syrup urine disease ) or branched chain disease or Leuzinose is an autosomal - recessive inherited disease understood that disturbances in the metabolism of amino acids causes. The disease occurs only rarely (1: 216,000), but it is more common in Georgia (1: 123,000) and among Mennonites in the US state of Pennsylvania (1: 760).

causes

There are currently three known genes whose mutation leads to the disease. Depending on the genetic defect, a distinction is made between type Ia, type Ib and type II. The BCKDHA gene changed in type Ia is on chromosome 19 (19q13.2) in humans , the BCKDHB mutated in type Ib is on chromosome 6 (6q14.1). Type II has a mutation in the DBT gene on chromosome 1 (1p21.2). All three genes code for 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 breakdown of the branched-chain amino acids leucine , isoleucine and valine .

If the third subunit of the alpha-keto acid dehydrogenase complex, dihydrolipoyl dehydrogenase ( EC  1.8.1.4 ), is defective, the more severe type III of the disease is present, which is also known as DLD deficiency (dihydrolipoamide dehydrogenase deficiency, DLDD). Here the defect is on chromosome 7 (7q31). This drastically reduces the breakdown of the branched-chain amino acids leucine (Leu), isoleucine (Ile) and valine (Val) in leukocytes , fibroblasts and in liver tissue . These amino acids and their breakdown products (keto acids and other intermediate products) accumulate in blood and urine by a factor of 10 to 40 . In addition, there is a lack of blood sugar ( hypoglycaemia ), metabolic acidosis (blood pH below 7.36), uric acid disorders - excretion and inhibition of myelination .

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

Clinical symptoms

Already in the first week of life, the sick infant shows refusal to eat, apathy, poor drinking, opisthotonus (backward bending of the head and overstretching of the extremities and trunk), high-pitched screaming, muscle hypotonia (reduced muscle resistance with passive stretching) and stiffness, seizures . Also a coma can occur. Undetected, the classic variant of maple syrup disease leads to severe permanent brain damage after just a few days (around 7th to 15th day of life). If left untreated, the disease will lead to death within a short time.

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

Gradient forms

a) classic: This form is the most common form of the disease. The residual enzyme activity is less than two percent and the clinical symptoms are recognizable within the first days of life.

b) intermediate: the enzyme activity is 5 to 20 percent. The spectrum of damage ranges from developmental delay to severe intellectual disability, especially with increased catabolism or after protein intake of more than 1–1.5 g / kg body weight · d (grams of protein per kilogram of body weight and day) and ketoacidosis.

c) intermittent : 3 to 30 percent of the enzyme activity can be detected. The form does not appear until the age of 12 to 24 months with severe catabolism and (probably) significant protein intake. The following occur: movement coordination disorders ( ataxia ), convulsions, coma. Outside of crisis patients, however, this form is inconspicuous.

d) dependent on thiamine: By increasing the enzyme activity by means of large amounts of thiamine (100–1000 mg / 24 h), there is usually no need to restrict protein intake.

Diagnosis

• Prenatal: Defect detection of the enzyme in amnion cells possible
• Newborn screening : by mass spectrometric methods in plasma and urine, in blood [Leu]> 8 mg / dl in the first 3 days of life
• Orientation: through 2,4-dinitrophenylhydrazine (DNPH) in the urine (deep red reaction to BCAA )
• Breath test with marked ¹³ C isotope : assessment of the leucine requirement
• outside of the crises, the amino acid values ​​are in the normal range in intermittent form

therapy

A liver transplant can create the opportunity to break down the branched amino acids yourself. However, the availability of organs is very limited, especially for small children, which is why conservative therapy by avoiding the ingestion of branched amino acids with food must be resorted to.

In order to prevent severe disabilities , which under certain circumstances can also lead to death, the supply of proteins must be cut off in the first days of life if there is the slightest suspicion of the disease. In addition:

• acute detoxification by peritoneal dialysis (free of nitrogen sources ), plasmapheresis , continuous arteriovenous hemofiltration to bring the leucine level below 0.5  mmol / l
• the balance of acidosis and treatment of hypoglycemia with high glucose doses (insulin 0.2 IU / kg / h i. v. , Glu 1 g / kg / h i. v.)
• the application of a fat-carbohydrate-electrolyte mixture via a nasogastric tube

Initial therapy in the newborn (neonatal) period:

• BCAA -free protein and energy from dextrose, lipids and at least 20 percent of the enzyme activity 1.5 g protein / kg body weight / day
• 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 (e.g. MSUD 1 and 2 from Milupa and ILV-AM from Maizena) with lifelong monitoring of blood levels
• Indirect control of the leucine level by measuring the ketone level in the urine (keto sticks)

Since strict adherence to the diet is associated with a reduction in quality of life , better treatment methods are being sought. A new study showed that fat cell injection was effective in mice. Fat cells are not just energy reserves, they also contain enzymes - including those that can break down branched amino acids. However, the disadvantage here is that the cells have to come from a donor, which is why the recipient must of course also be immunosuppressed for life .

Nutrition design

In infancy

• use only vegetable sources of protein
• Avoid longer periods of fasting at night, keep a late meal between 10 p.m. and midnight until the end of the first year of life
• at the age of one year: drinks containing carbohydrates in the morning and in the evening
• Fruits and vegetables with a low [Leu] <50 mg / 100 g allowed:

Fruit : apples, apricots, cherries, grapes, grapefruit, mandarins, oranges, peaches, pineapples, plums, strawberries, raspberries

Vegetables : cooked asparagus, artichokes, eggplant, beans, beetroot, white cabbage, carrots, cucumber, lettuce, onions, peppers, tomatoes

Small children and school children

• Emergency program for minor infections: Great reduction and possibly substitution of the supply of BCAA and increase of the protein substitute preparation, if possible avoid the consumption of leucine-containing foods

forecast

The time lag between the appearance of the first symptoms and the start of therapy is usually decisive for the prognosis. Adjusted correctly, patients with maple syrup disease have an overall good prognosis. If the therapy is inadequate, a. Damage to the cerebrum and mental retardation occur.

swell

• B. Koletzko: Pediatrics and Adolescent Medicine. 12th edition. Springer, Berlin 2004, ISBN 3-540-44365-7 .
• ME Shils, JA Olson, M. Shike, AC Ross (Eds.): Modern nutrition in health and disease. 9th edition. Williams & Wilkins, Baltimore 1999.
• FC Sitzmann: Pediatrics. 3. Edition. Thieme, Stuttgart 2006, ISBN 3-13-125333-9 .
• J. Stein, KW Jauch: Practical manual for clinical nutrition and infusion therapy . Springer, Berlin 2003, ISBN 3-540-41925-X .
• http://www.stoffwechselzentrum-muenchen.de/ Krank/ahornsir.htm (November 1, 2005)

Individual evidence

1. ↑ ^{a b} Classic maple syrup disease.  In: Online Mendelian Inheritance in Man . (English)
2. ↑ Maple Syrup Disease.  In: Online Mendelian Inheritance in Man . (English).
3. ↑ Maple Syrup Disease. In: Orphanet (Rare Disease Database).
4. ↑ F. Podebrad, M. Heil, S. Reichert, A. Mosandl, AC Sewell, H. Bohles: 4,5-dimethyl-3-hydroxy-2 [5H] -furanone (sotolone) - the odor of maple syrup urine disease. In: J. Inherit. Metab. Dis. Volume 22, No. 2, April 1999, pp. 107-714. PMID 10234605 .
5. ↑ Heather A. Zimmerman, Kristine C. Olson, Gang Chen, Christopher J. Lynch: Adipose transplant for inborn errors of branched chain amino acid metabolism in mice. In: Molecular Genetics and Metabolism. Volume 109, 2013, pp. 345-353, doi: 10.1016 / j.ymgme.2013.05.010 .

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !