Maple syrup disease: what is it, causes, symptoms, treatment, prognosis

What is Maple Syrup Disease?

Maple syrup disease (leucinosis, branched chain ketonuria, maple syrup-smelling urine disease) Is a rare genetic disease characterized by a deficiency of an enzyme complex (branched-chain alpha-keto acid dehydrogenase), which is necessary for the breakdown (metabolism) of leucine, isoleucine and valine of the three branched-chain amino acids (BCAAs) in the body. The result of this metabolic deficiency is that all three BCAAs, as well as a number of their toxic byproducts (especially their corresponding organic acids), become excessively accumulated. In the classic severe form of the disease, plasma BCAA concentrations begin to rise within hours of birth. If untreated, symptoms begin to appear, often within the first 24 to 48 hours of life.

Manifestations begin with nonspecific symptoms of increased neurological dysfunction and include lethargy, irritability, and poor nutrition. soon followed by focal neurological signs such as abnormal movements, increased spasticity, and shortly thereafter, epilepsy and coma. If untreated, progressive brain damage is inevitable, and death usually occurs within weeks or months. The only specific feature that is unique to the disease is the development of a characteristic odor resembling maple syrup, which is most readily found in urine and earwax, and can smell within a day or two after a baby is born. The toxicity results from the damaging effects of leucine on the brain, accompanied by severe ketoacidosis caused by the accumulation of three branched-chain keto acids (BCKA).

The disorder can be successfully treated with a special diet in which the three BCAAs are tightly controlled. However, even with treatment, patients of all ages with maple syrup disease remain at high risk of developing acute metabolic decompensation (metabolic crises), often caused by infection, trauma, refusal to eat (fasting), or even psychological stress. During these episodes, there is a rapid, sudden rise in amino acid levels that require immediate medical attention.

There are three or possibly four types of this disease: the classic type; an intermediate type, an intermittent type, and possibly a thiamine-responsive type. Each of the different subtypes of maple syrup disease has different levels of residual enzyme activity, which give rise to varying degrees of severity and age of onset. All forms are inherited in an autosomal recessive manner.

Signs and symptoms

Symptoms and severity of maple syrup disease vary greatly from patient to patient and are highly dependent on the amount of residual enzyme activity.

Classic form the disease is the most common and most severe form of the disease, characterized by a lack of enzyme activity. In most children with the classic disease, subtle, nonspecific symptoms; these include poor bottle or breastfeeding and increased lethargy and irritability. As feeding decreases, the infant's condition continues to regress, focal neurological signs, including abnormal movements, as well as increased hypertension and spasticity, progressing to epilepsy and coma.

There may be temporary episodes of extreme hypotension. Ultimately, central neurological function is impaired, with respiratory failure and death occurring. By the time early symptoms appear, the characteristic smell of maple syrup may be detected in serum, sweat, and urine. It comes from one of the organic BCKA acids derived from the corresponding BCAAs that build up when the disorder gets out of control. Odor usually cannot be detected during periods of metabolic stability.

After treatment and stabilization of the disorder, there is a lifelong threat of sudden or gradual relapse. metabolic decompensation, which results in the return of all symptoms typical of untreated cases disease. Food intake of BCAAs should be strictly controlled. But even without any changes in the diet, metabolic crises can occur, caused by an imbalance between inherent residual enzyme activity and increased release of BCAA protein from tissues due to increased degradation (catabolism). An increase in the rate of catabolism can occur imperceptibly or develop rapidly during any metabolic stress, including infection, even if very mild, psychological or physical stress, injury or starvation. These episodes are characterized by the onset of symptoms that are typical in untreated cases and are due to elevated BCAAs, especially leucine and the three associated BCKA. Each episode can turn into a metabolic crisis and should be treated as vigorously as any episode in a newborn. People with the classic type of illness may exhibit a degree of intellectual disability and exhibit a variety of behavioral problems, including attention deficit hyperactivity disorder (ADHD), impulsivity, anxiety, and / or depression and epilepsy.

Additional complications of the classic disorder include generalized bone loss (osteoporosis), which can predispose to fractures, and inflammation pancreas (pancreatitis). Some people may develop increased pressure in the skull (intracranial hypertension), which causes headaches that are sometimes associated with nausea and vomiting.

Intermediate form the disorder is characterized by higher levels of residual enzyme activity than in the classical form. The onset and symptoms of intermediate wedge syrup disease may be neonatal, but most children are diagnosed with the disease between 5 months and 7 years of age. Symptoms, when they occur, are similar to those of the classic form and may include:

• lethargy;
• nutritional problems;
• poor growth;
• ataxia;
• acute metabolic crises that lead to seizures, coma, brain damage and, in rare cases, life-threatening neurological complications.

It should be noted that patients with an intermediate form are prone to the same degree of neurological complications and extreme acidosisas patients with the classic type of the disease. Earwax, sweat and urine have the characteristic smell of maple syrup. Some affected children may remain asymptomatic until later in life.

Intermittent type the disease is usually characterized by normal growth and mental development, and sick people can often tolerate normal protein levels in their diets. Symptoms are triggered by the same stressors as in the classic type. Thiamine-responsive disease form responds to thiamine (vitamin B1) treatment. Thiamine plays a role in the BCAA enzyme complex. The symptoms and clinical course of thiamine responsive disorder resemble an intermediate type of disease and are rarely present during the neonatal period. Affected children respond to high doses of thiamine, which increases the residual enzyme activity. No thiamine sensitive person has been treated with thiamine alone - most stick to a combination of thiamine with a partially restricted protein diet.

Causes

The disorder is caused by changes (mutations) in one of three different genes: BCKDHA, BCKDHB and DBT. Mutations in these genes result in the absence or decrease in the activity of the branched-chain complex alpha-keto acid dehydrogenase enzymes (BCKAD) in humans. These enzymes are responsible for the breakdown of the branched-chain amino acids leucine, isoleucine and valine, which are found in all proteins. The accumulation of these amino acids and their toxic byproducts (keto acids) leads to serious health problems associated with maple syrup disease. The toxicity of these amino acids is limited to leucine; in fact, valine and isoleucine are often prescribed during treatment. The accumulation of the corresponding keto acids leads to metabolic acidosis.

The disorder follows an autosomal recessive inheritance. Recessive genetic disorders occur when a person inherits a non-working gene from each parent. If a person receives one working gene and one non-working gene for a disease, then the person will be a carrier of the disease, but usually asymptomatic. The risk of both carrier parents passing on a non-working gene and therefore having a sick child is 25% in every pregnancy. The risk of having a carrier child, like the parents, is 50% with each pregnancy. The probability for a child to receive working genes from both parents is 25%. The risk is the same for men and women.

Affected populations

The estimated incidence in the general population is 1 in 185,000 live births. Parents who are close relatives (blood siblings) are more likely than unrelated parents parents who have the same abnormal gene, which increases the risk of having children with recessive genetic disorder.

Symptomatic disorders

Symptoms of the following disorders may be similar to those of maple syrup disease. Comparisons can be useful for differential diagnosis.

• Urea cycle disorders are a group of rare disorders that affect the urea cycle, a series of biochemical processes in which nitrogen is converted to urea and excreted through urine. Symptoms of all disorders of the urea cycle vary in severity and are the result of excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, epilepsy and / or to whom. With the disorder, the liver may enlarge (hepatomegaly), life-threatening complications can occur. Urea cycle disorders include ornithine transcarbamylase deficiency: carbamoyl phosphate synthetase deficiency; deficiency of argininosuccinate synthetase (citrullinemia); deficiency of argininosuccinate lyase; arginase deficiency (argininemia); and N-acetylglutamate synthetase deficiency.
• Propionic Acidemia is a rare autosomal recessively inherited metabolic disorder caused by a deficiency the enzyme propionyl-CoA carboxylase, one of the enzymes needed to break down certain amino acids. Symptoms most often appear during the first weeks of life and may include hypotension, poor nutrition, vomiting, dehydration and seizures, accompanied by worsening metabolic acidosis and often with hyperammonemia. Dangerous complications and coma occur without proper treatment. In milder cases, the disease may only appear later in infancy and may be associated with less severe symptoms and signs.
• Methylmalonic Acidemia (MMA) is a rare congenital metabolic error in which people have problems metabolizing certain proteins and fats in food. Symptoms usually begin in early childhood, but may remain latent until adulthood. During the course of the illness, patients may develop mental retardation, chronic kidney disease, pancreatitis and nutritional problems. Mutations in several different genes can cause MMA, and therefore each type requires different treatments. The mainstay of treatment is a carefully balanced dietary restriction of certain amino acids; namely methionine, threonine, isoleucine and valine. Some require specific forms of cobalamin (vitamin B12). All MMAs are autosomal recessive genetic disorders and can be caused by mutations in five different genes: MMAA, MMAB, MMADHC, MCEE and MUT.
• Glycine encephalopathy is a congenital metabolic error characterized by the accumulation of large amounts of the amino acid glycine in the blood and, especially, in the cerebrospinal fluid (CSF). The metabolic block occurs when glycine is converted into smaller molecules. There are four forms of this disorder: the relatively common neonatal form, the infantile form, the mild episodic form, and the late-onset form. Common symptoms of the disease include hypotension, seizures, unexplained coma, and developmental delay in neonates and infants. Metabolic acidosis is not a feature of this disorder.

Diagnostics

Diagnosis of maple syrup disease is based on an analysis of the pedigree, an assessment of the history data, clinical manifestations, the results of an analysis of the level of amino acids leucine, isoleucine, valine in the blood with calculation of the leucine / alanine ratio, determination of renal excretion of organic acids - 2-ketoisocaproic, 2-keto-3-methylvaleric, 2- ketoisocaproic acids. The main methods for confirming the diagnosis are biochemical methods: tandem mass spectrometry (MS / MS), amino acid analysis, gas chromatography-mass spectrometry.

To confirm the diagnosis and medical genetic counseling, a molecular genetic study is carried out.

The following groups of children are subject to examination for the disorder:

• children of any age from families with patients with this disease (first of all, the brothers and sisters of the patient);
• children of the first days and weeks / months of life, who, after a certain period (sometimes very short, within 1-2 days), have a satisfactory condition refusal to eat, vomiting, irritability or lethargy, hypotension / dystonia, convulsions, ataxia, coma, metabolic acidosis, ketonuria, peculiar the smell of urine;
• children of any age in a state of ketoacidotic crisis;
• children who are lagging behind in psychomotor development, with epilepsy, impaired muscle tone.

To establish a diagnosis of the disease in patients with clinical symptoms of the disease, specific diagnostic tests should be considered (strength A on the Oxford scale):

• quantitative determination of leucine, isoleucine, valine, alloisoleucine, alanine in the blood;
• quantitative determination of 2-keto-isocaproic, 2-keto-3-methylvaleric, 2-keto-isovaleric, 2-hydroxy-isovaleric, 2-hydroxy-isocaproic, 2-hydroxy-3-methylvaleric acid in urine;
• identification of mutations in the BCKDHA or BCKDHB or DBT genes.

Standard treatments

The treatment of classic, intermediate, intermittent and thiamine-responsive maple syrup disease consists of three main components:

1. Lifelong therapy to maintain an acceptable diet;
2. Maintenance of normal metabolic conditions throughout life, including the levels of BCAA in the body;
3. Immediate medical intervention for metabolic crises.

People with the disorder should eat a protein-restricted diet that limits the amount of branched-chain amino acids. Protein restriction should begin as soon as possible after birth to promote proper growth and development of the baby. Artificial (synthetic) formulas are available that provide all the nutrients needed for proper growth and development, but are free of leucine, isoleucine and valine. Diet is a constant balance between providing enough food, protein and BCAAs to support normal growth and development on the one hand and an attempt to ensure that the patient's condition and biochemistry remain in the therapeutic range, with another. It is especially important to limit the amount of leucine in the diet. Three amino acids are essential nutrients. They are added to the diet separately in small amounts depending on their plasma levels. The amount of leucine, isoleucine and valine that a child can tolerate depends on the residual enzyme activity. Affected children should be monitored regularly to ensure that their diet is adequate and that amino acid levels remain within acceptable normal ranges.

Some doctors recommend trial thiamine therapy to determine if the patient is responding to thiamine. However, no person with the disease was treated exclusively with thiamine.

Even if patients strictly follow a special diet, the risk of metabolic crisis always remains. Episodes of metabolic crisis require immediate medical attention to lower the levels of BCAAs, especially leucine, in the blood. Various methods are used to lower the level of leucine in blood plasma, including dialysis or a process, when in which blood is removed from the body and passed through a filter before being returned to the body (hemofiltration).

The goal of aggressive therapy for metabolic crises is to try to reduce and then reverse the increase in protein catabolism, which is the main cause of such episodes. This means that ANY method of increasing calories, decreasing protein catabolism (for energy needs) can be beneficial. This includes a high intake of glucose with intravenous glucose, if necessary with the addition of "glucose-insulin", since insulin is known to enhance endogenous protein synthesis. Intravenous fat is another important source of calories. In addition, it is important to provide all other amino acids in sufficient quantities to synthesize new protein. This is accomplished by judicious use of IV parenteral nutrition using leucine-free solutions. Many hospitals can use general parenteral nutrition solutions that lack the branched chain amino acid. In addition, insulin can be used to stimulate a metabolic process known as anabolism. During anabolism, amino acids and other compounds are synthesized to form new muscle and other proteins, as well as a huge variety of other compounds.

Other treatments are symptomatic and supportive.

Forecast

The prognosis of the state and level of mental development of patients depends on many factors: the form of the disease and the associated severity of the enzyme defect; timing of initiation and adequacy of specialized treatment; the effectiveness of intensive therapy of ketoacidotic crises leading to cerebral edema and deep damage to the central nervous system. The prognosis of the disease is relatively favorable with early diagnosis and careful metabolic control.