Thiamine-responsive: This type of MSUD responds to treatment using high doses of vitamin B1 (thiamine) along with a restricted diet. With treatment, people with thiamine-responsive MSUD have higher tolerance for the three amino acids.
What is thiamine-responsive MSUD?
Thiamine-responsive: This type of MSUD responds to treatment using high doses of vitamin B1 (thiamine) along with a restricted diet. With treatment, people with thiamine-responsive MSUD have higher tolerance for the three amino acids. How common is maple syrup urine disease (MSUD)?
What is thiamine-responsive maple syrup urine disease?
Thiamine-responsive maple syrup urine disease (thiamine-responsive MSUD) is a less severe variant of MSUD (see this term) that manifests with a phenotype similar to intermediate MSUD (see this term) but that responds positively to treatment with thiamine. ORPHA:268184 Classification level: Subtype of disorder Synonym(s):
What are the treatment options for thiamine-responsive multiple sclerosis (MSUD)?
No individuals with thiamine-responsive MSUD have been treated solely with thiamine – most follow a combination of thiamine with a partially-restricted protein diet.
What is MSUD and how is it treated?
The finding that is unique to MSUD is the emergence of a characteristic odor, reminiscent of maple syrup that can most readily be detected in the urine and earwax and may be smelled within a day or two of birth. The disorder can be successfully managed through a specialized diet.
What is Thiamine-responsive MSUD?
Thiamine-responsive maple syrup urine disease (thiamine-responsive MSUD) is a less severe variant of MSUD (see this term) that manifests with a phenotype similar to intermediate MSUD (see this term) but that responds positively to treatment with thiamine.
What vitamin supplement should be given to patient with MSUD?
Thiamine-responsive: This type of MSUD responds to treatment using high doses of vitamin B1 (thiamine) along with a restricted diet. With treatment, people with thiamine-responsive MSUD have higher tolerance for the three amino acids.
What is the treatment for maple syrup urine disease?
How Is Maple Syrup Urine Disease Treated? The main treatment for MSUD is a low-protein diet with low levels of the three amino acids. Babies with MSUD must be on a special formula as soon as possible. Then, they'll follow the special diet for the rest of their lives.
How is MSUD managed in the long term?
The two main approaches to the treatment of maple syrup urine disease (MSUD) include (1) long-term daily dietary management and (2) treatment of episodes of acute metabolic decompensation. The mainstay in the treatment of maple syrup urine disease is dietary restriction of branched-chain amino acids (BCAAs).
Why are branched-chain amino acids important?
Branched-chain amino acids are essential nutrients that help support muscle metabolism and are important for building muscle tissue protein.
What enzyme causes maple syrup urine disease?
Maple syrup urine disease is caused by a deficiency of the branched-chain alpha-keto acid dehydrogenase (BCKD) enzyme complex, which catalyses the decarboxylation of the alpha-keto acids of leucine, isoleucine, and valine to their respective branched-chain acyl-CoAs.
Is there gene therapy for MSUD?
MSUD calves will be treated with human-like doses of AAV gene therapy and fed adult MSUD formula until the AAV gene therapy starts to work. Blood levels of BCAA will be monitored.
Can MSUD be prevented?
Since MSUD is an inherited disease, there is no method for prevention. A genetic counselor can help you determine your risk for having a baby with MSUD. Genetic testing can tell you if you or your partner is a carrier of the disease.
How does maple syrup urine disease disrupt the metabolic pathway?
Maple syrup urine disease (MSUD, MIM #248600) is an autosomal recessive disease characterized by disruption of the normal activity of the branched-chain α-ketoacid dehydrogenase (BCKAD) complex, the second step in the catabolic pathway for the branched-chain amino acids (BCAAs) that include leucine, isoleucine, and ...
What is thiamine-responsive MSUD?
Thiamine-responsive: This type of MSUD responds to treatment using high doses of vitamin B1 (thiamine) along with a restricted diet. With treatment, people with thiamine-responsive MSUD have higher tolerance for the three amino acids.
When can MSUD be diagnosed?
Doctors diagnose classic MSUD with newborn screenings (blood tests) soon after a baby is born. People with intermediate, intermittent, or thiamine-responsive MSUD might not show signs of the disease until their toddler years or early childhood.
What is the most severe type of MSUD?
Classic: Classic maple syrup urine disease is the most severe type of MSUD. It is also the most common. Symptoms usually develop within the first three days of birth. Intermediate: This type of MSUD is less severe than classic MSUD. Symptoms typically appear in children between the ages of 5 months and 7 years.
What is maple syrup urine disease?
Maple syrup urine disease (MSUD) is a life-threatening metabolic disorder. Metabolic disorders are conditions in which your body can’t function normally because it can’t properly convert food to energy to keep your body healthy. Protein is needed by the body to function normally. Proteins are made up of 20 different types of amino acids.
How long does it take for MSUD to show?
Symptoms of classic MSUD appear in newborns within 48 hours of birth. In older children, signs of intermediate, intermittent, and thiamine-responsive MSUD usually develop before age seven. All four types of MSUD have symptoms including: Urine, sweat, or earwax that smells like maple syrup or burnt sugar.
What are the complications of maple syrup?
Complications of maple syrup urine disease include: Brain damage, neurological problems, and developmental delays. Increased risk of attention deficit/hyperactivity disorder (ADHD), anxiety, and depression.
How rare is MSUD?
MSUD is very rare. It occurs in about 1 of every 185,000 births worldwide. It appears more often in populations with a small gene pool or when cousins and other close relatives have children together. About 2,000 people in the United States live with MSUD.
What happens to BCAAs in MSUD?
In the classic, severe form of MSUD, plasma concentrations of the BCAAs begin to rise within a few hours of birth.
What is the most common form of MSUD?
The symptoms and severity of MSUD varies greatly from patient to patient and largely depends upon the amount of residual enzyme activity. Classic maple syrup urine disease is the most common and most severe form of MSUD characterized by little to no enzyme activity.
What is the toxicity of leucine?
The toxicity is the result of damaging effects of leucine on the brain accompanied by severe ketoacidosis caused by accumulation of the three branched-chain ketoacids (BCKAs). The disorder can be successfully managed through a specialized diet in which the three BCAAs are rigorously controlled.
What is maple syrup urine disease?
Maple syrup urine disease (MSUD) is a rare genetic disorder characterized by deficiency of an enzyme complex (branched-chain alpha-keto acid dehydrogenase) that is required to break down (metabolize) the three branched-chain amino acids (BCAAs) leucine, isoleucine and valine, in the body. The result of this metabolic failure is that all three BCAAs, along with a number of their toxic byproducts, (specifically their respective organic acids), all accumulate abnormally. In the classic, severe form of MSUD, plasma concentrations of the BCAAs begin to rise within a few hours of birth. If untreated, symptoms begin to emerge, often within the first 24-48 hours of life.
How long does it take for MSUD to smell?
The only specific finding that is unique to MSUD is the development of a characteristic odor, reminiscent of maple syrup that can most readily be detected in the urine and earwax and may be smelled within a day or two of birth.
How many types of MSUD are there?
There are three or possibly four types of MSUD: the classic type; intermediate type, intermittent type, and possibly a thiamine-responsive type. Each of the various subtypes of MSUD have different levels of residual enzyme activity which account for the variable severity and age of onset.
What is MSUD genetics?
MSUD follows autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms.
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Epidemiology
MSUD has an estimated incidence of 1/150,000 live births. The thiamine-responsive type appears to be very rare.
Clinical description
Thiamine-responsive MSUD is poorly characterized. It appears to usually present after infancy with a phenotype very similar to that seen in intermediate MSUD (see this term). Manifestations include feeding problems, poor growth, maple syrup odor in urine and developmental delay. Older children usually present with learning difficulties.
Etiology
MSUD is due to mutations in the genes encoding 3 of the 4 subunits of branched-chain 2-ketoacid dehydrogenase (BCKAD) complex. The genes are BCKDHA (19q13.1-q13.2), encoding E1a; BCKDHB (6q14.1), encoding E1b; and DBT (1p31), encoding E2 respectively.
Genetic counseling
Inheritance is autosomal recessive and genetic counseling is possible.
What is the cause of MSUD?
MSUD is caused by a deficiency in branched-chain ketoacid dehydrogenase (B CKDH). The BCKDH complex is composed of three subunits: E1, E2, and E3. The decarboxylase (E1 subunit) is in turn composed of an α subunit (encoded by BCKDHA) and a β subunit (encoded by BCKDHB ). The dihydrolipoamide branched-chain transacylase (E2 subunit) is encoded by DBT, while the dihydrolipoamide dehydrogenase (E3 subunit) is encoded by DLD. In addition, phosphorylation of the complex inactivates it, while dephosphorylation by a phosphatase makes it active. Mutations in BCKDHA cause MSUD type 1A, and are responsible for 33% of cases, while mutations in BCKDHB cause MSUD type 1B, responsible for 38% of cases, and mutations in DBT cause MSUD type 2, responsible for 19% of all MSUD cases ( Nellis and Danner, 2001 ). A founder mutation in BCKDHA is present in Old Order Mennonites, where the incidence of the disease reaches 1 in 150 individuals ( Carleton et al., 2010 ). Mutations in DLD cause a different condition, E3 deficiency, sometimes called MSUD type 3. Finally, a mutation in PPM1K, encoding for the BCKDH phosphatase, has been associated with a mild variant of MSUD ( Oyarzabal et al., 2013 ).
What is MSUD in biology?
MSUD is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in one of three genes encoding the aforementioned subunits of the BCKDH complex, also known as BCKDC.
What is MSUD in genetics?
MSUD is a pan-ethnic, autosomal-recessive condition that can be caused by mutations in any of the components of the mitochondrial branched-chain α-ketoacid dehydrogenase complex. In a study of 63 individuals, E1β subunit mutations were most common (38%), followed by E1α (33%), and E2 (19%) mutations. Branched-chain α-ketoacid dehydrogenase phosphatase or kinase mutations are also thought to cause MSUD. The overall incidence is approximately 1 case per 150,000 people in the general population, but MSUD is more common in Old Order Mennonites in southeastern Pennsylvania (1 in 176 births). A novel founder mutation in the E1β subunit has been reported in the Ashkenazi Jewish population.
What is MSUD type IA?
MSUD is an autosomal recessive disorder resulting from homozygous or compound heterozygous mutations in one of three genes encoding the aforementioned subunits of the BCKDH complex, also known as BCKDC. MSUD type IA results from mutations in BCKDHA (chromosome 19q13.2), which encodes the E1α subunit; MSUD type IB results from mutations in BCKDHB (chromosome 6q14.1), which encodes the E1β subunit; and MSUD type II DBT on chromosome 1p21.1, which encodes the E2 subunit. Mutations in the gene encoding the E3 subunit, DLD (chromosome 7q31.1), causes a broader disorder called dihydrolipoamide dehydrogenase deficiency, or DLDD, sometimes referred to as MSUD type III. 146 All of these various mutations result in accumulation of both the branched-chain amino acids as well as alloisoleucine and organic acids. The disorder derives its name from the distinctive sweet odor of affected individuals’ urine. One analysis found that 33% of MSUD was due to BCKDHA mutations, 38% due to BCKDHB mutations, and 19% due to DBT mutations (10% of cases were not found to have mutations in any of the above). 147 The incidence of MSUD worldwide is ∼1/185,000 live births, 148 with a higher frequency noted in certain populations – 1/290,000 live births in New Englanders of mostly Caucasian descent, 149 and in old-order Mennonites in Pennsylvania, as high as 1/176 live births, 150 likely due to a founder effect. BCKHB mutations are more common in Ashkenazi Jews, with a carrier frequency of 1/113; most of these individuals carried the same mutation, R183P. 151
What is the main source of nitrogen for glutamate?
In brain, BCAAs are the major source of nitrogen for formation of glutamate as a neural transmitter. The reason relates to the rapid access BCAAs have in crossing the blood–brain barrier. Likewise, the transaminated BCKA in turn serves as the nitrogen acceptor in glutamate conversion back to α -ketoglutarate.
What is maple syrup urine disease?
Maple syrup urine disease (MSUD) is an autosomal-recessive inherited metabolic disorder involving the branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Defects in the mitochondrial branched-chain α-ketoacid dehydrogenase complex result in markedly elevated levels of leucine, and, particularly, isoleucine and valine. Early appearance of an acute encephalopathy in the newborn period marked by lethargy, hypertonia, poor feeding, and ketoacidosis requires rapid management to reduce the possibility of permanent neural damage or even death. Effective dietary control of the BCAAs can be associated with normal development, but acute decompensation secondary to acute dietary protein loads, catabolic protein insults related to other chronic diseases, infection, exercise, injury, and physiological stress must be constantly monitored. The consequences of children born to mothers with MSUD require that dietary control during pregnancy be followed closely. Liver transplantation has been effective.
Is MSUD heterogeneous or heterogeneous?
MSUD is genetically heterogeneous since the BCKDC is encoded by six different genetic loci. Using the tools of molecular biology, many mutations in all of these loci have been identified. A tight association of genetic lesions in the E2 locus with the thiamine-responsive MSUD phenotype was demonstrated.
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- Treatment The treatment of classic, intermediate, intermittent, and thiamine-responsive MSUD has two chief components: lifelong therapy to maintain acceptable amino acid levels in the body and immediate medical intervention for metabolic crises. Some physicians recommend a trial of thiamine therapy to determine whether an affected individual is thi...
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