Maple syrup urine disease MSUD and Homocystinuria

Maple Syrup Urine Disease

HomocystinuriaUNIVERSITY of KALMOONUNTRITION DEPARTMENT

DR. LOUAY LABBAN

HOMOCYSTINURIA

• This metabolic disorder is characterized by an increased blood and urine concentration of homocysteine - a sulfur containing amino acid.

DEFININTION

• Homocystinuria, also known as Cystathionine beta synthase deficiency

• is an inherited disorder of the metabolism of the amino acid methionine,

• It is an inherited autosomal recessive trait, which means a child needs to inherit the defective gene from both parents to be affected.

• Homocystinuria represents a group of hereditary metabolic disorders characterized by an accumulation of homocysteine in the serum and an increased excretion of homocysteine in the urine.

• Infants appear to be normal and early symptoms, if any are present, are vague

• Due to lack of certain enzymes, the body is unable to process certain amino acids

PREVELANCE

• Homocystinuria caused by cystathionine beta-synthase deficiency affects at least

• 1 in 200,000 to 335,000 people worldwide.

• The disorder appears to be more common in some countries, such as

• Ireland (1 in 65,000), • Germany (1 in 17,800), • Norway (1 in 6,400),

• and Qatar (1 in 3,000). Other forms of homocystinuria are much rarer, with a small number of cases reported in the scientific literature

INHERITANCE OF HOMOCYSTINURIA

SYMPTOMS

• Skeletal features: Marfanoid habitus with normal to tall stature (occasionally failure to thrive in infancy)

• Fine, brittle hair, hypopigmentation, high arched palate, crowded teeth, limited joint mobility, pectus excavatum

• Eyes: dislocation of lens usually downward and medially (Ectopia lentis, myopiaحسر, glaucoma

• CNS: Mental retardation (Average IQ = 80; 30% have normal IQ), seizures, psychiatric disorders

Marfanoid habitus

• Pectus excavatum is a condition in which the "breast bone" (sternum) appears sunken and the chest concave. It is sometimes called "funnel chest".

• The majority of these cases are not associated with any other condition (isolated findings). However, some syndromes include pectus excavatum

Pectus excavatum

SPINE DEFORMITY

SCOLIOSIS

SIGNS OF SCOLIOSIS

HOMOCYSTINURIA FEATURES

SYMPTOMS

• This defect leads to a multisystemic disorder of the

• connective tissue, • muscles, • CNS, • and cardiovascular system

• Signs and symptoms• A family history of homocystinuria • Nearsightedness • Flush across the cheeks • Tall, thin build • Long limbs • High-arched feet (pes cavus) • arteries problems

Pes Cavus

• Knock-knees (genu valgum) روحاء ركبة• Pectus excavatum • Mental retardation • Psychiatric disease • Eye anomalies: • 90% have ectopia lentis

Knock knee

Knock Knee

• Myopia نظر حسر• Glaucoma زرق• Optic atrophy • Seizure • extensive atheroma عصيدة formation at

young age which affects many arteries but not the coronary

TREATMENT

• Low-protein food is recommended for this disorder, which requires food products low in particular types of amino-acid (i.e. methionine

TREATMENT

• Effective treatment requires early diagnosis and initiation of therapy

• Try pyridoxine in all - increases CBS activity • Methionine restricted, cystine supplemented

diet for those who do not respond to pyridoxine

• Methionine restriction has been shown to prevent mental retardation and reduce the rate of lens dislocation and seizure activity

• Pyridoxine supplementation for responders (usually 50% of affected patients)

• Pyridoxine treatment of those who are detected late reduces the rate of thromboembolic events

• Avoid folate deficiency

• Consider primary prevention of cardiovascular disease e.g. aspirin, statin

• Referral to specialists as indicated by clinical picture e.g. ophthalmologist, psychiatrist

• There is no cure for homocystinuria. However, many people respond to high doses of vitamin B6 (also known as pyridoxine).

• Slightly less than half of patients respond to this treatment.

• Those who do respond will need to take supplemental vitamin B6 for the rest of their lives.

• Those who do not respond require a low methionine diet. Most will need treatment with trimethylglycine (a medication also known as betaine).

• Neither a low-methionine diet nor medication will improve existing mental retardation. Medication and diet should be closely supervised by a physician with experience treating homocystinuria.

Vitamins and homocystinuria

• A normal dose folic acid supplement and added cysteine (an amino acid) in the diet is helpful

MAPLE SYRUP URINE DISEASE

Maple Syrup Urine Disease is derived from Canadian tree called maple tree where they obtained a sweet syrup from it to be used for pancakes.

MAPLE LEAF

SYRUP COLLECTION

COLLECTION OF SYRUP IN BAGS

BOILING OF THE SYRUP

SYRUP IS THE FINAL PRODUCT

MAPLE SYRUP ON PANCAKE

MSUD• Maple syrup urine disease (MSUD) is an

aminoacidopathy secondary to an enzyme defect in the catabolic pathway of the branched-chain amino acids leucine, isoleucine, and valine..

• Accumulation of these 3 amino acids and their corresponding keto acids leads to encephalopathy and progressive neurodegeneration in untreated infants

• Early diagnosis and dietary intervention prevent complications and may allow for normal intellectual development.

• Consequently, MSUD has been added to many newborn screening programs, and preliminary results indicate that asymptomatic newborns with MSUD have a better outcome compared with infants who are diagnosed after they become symptomatic

MSUD

• Maple syrup urine disease (MSUD) results from a deficient enzyme (branched-chain alpha-keto acid dehydrogenase, BCKD) necessary for the breakdown of the amino acids leucine, isoleucine, and valine.

• Without the BCKD enzyme, these amino acids build up to toxic levels in the body. If left untreated, this leads to brain damage and progressive nervous system degeneration

DEVELOPMENT OF MSUD

PREVELANCE

• Maple syrup urine disease occurs in about 1 per 180,000 live births and affects both males and females.

• MSUD affects people of all ethnic backgrounds, but higher rates of the disorder occur in populations in which there is a lot of intermarriage, such as the Mennonite (Amish) community in Pennsylvania (U.S.).

Amish

Amish

SYMPTOMS

• There are several types of maple syrup urine disease. The most common (classic) form typically will produce symptoms in newborn infants aged 4-7 days. These symptoms may include:

Child with MSUD

• Poor feeding • Vomiting • Poor weight gain • Increasing lethargy (difficult to wake up) • Characteristic burned sugar smell to urine • Changes in muscle tone, muscle spasms, and

seizures

• If left untreated, these infants will die with the first months of life.

• Individuals with intermittent MSUD, the second most common form of the disorder, develop normally but when ill show the signs of classic MSUD.

• Intermediate MSUD is a more rare form. Individuals with this type have 3-30% of the normal level of Branched Chain Alpha-Keto Dehydrogenase (BCKD) enzyme, so symptoms may begin at any age.

• In thiamine-responsive MSUD, individuals show some improvement when given thiamine supplements

• A very rare form of the disorder is E3-deficient MSUD, in which individuals have additional deficient metabolic enzymes

DIAGNOSIS

• DiagnosisIf maple syrup urine disease is suspected based on the physical symptoms, especially the characteristic urine odor, a blood test for amino acids can be done.

BABY WITH MSUD

• If alloisoleucine is detected, the diagnosis is confirmed. Several U.S. states screen newborns at birth for MSUD.

• The main treatment for maple syrup urine disease is restriction of dietary forms of the three amino acids

• leucine, • isoleucine, and • valine.

• These restrictions must be lifelong. There are several commercial formulas and foods for individuals with MSUD.

• One concern for treatment of MSUD is that when an affected individual is sick, injured, or has surgery, the disorder is exacerbated. Most individuals will require hospitalization during these times for medical management to prevent serious complications.

• Fortunately, with adherence to the dietary restrictions and regular medical checkups individuals with maple syrup urine disease can live long and relatively healthy lives.

• The goal of dietary therapy is normalization of branched-chain amino acids (particularly of leucine) by restricting intake of branched-chain amino acids without impairing growth and intellectual development..

• Dietary therapy must be lifelong. Several commercially available formulas and foods are available without branched-chain amino acids or with reduced levels of branched-chain amino acids

• Products are available for juveniles and adults, such as MSUD Express. The intake of leucine is calculated on an individual basis following the measurement of plasma branched-chain amino acids.

FORMULA FOR MSUD

• Measure plasma amino acid levels on a regular basis at appropriate intervals for the first 6-12 months of life. In addition to dietary therapy, administer thiamine (10-20 mg/d) for 4 weeks to determine thiamine responsiveness

• Thiamine (Thiamilate)• An essential coenzyme in carbohydrate and

amino acid metabolism. Combines with ATP to form thiamine pyrophosphate.

• During periods of illness, fasting and infection, aggressive treatment is initiated to prevent the body breaking down its own proteins. This comprises giving additional fluids, carbohydrates and fats plus, in some cases, dialysis to reduce amino acids levels in the blood.