By four days of age, neurologic abnormalities include alternating lethargy and irritability, dystonia, apnea, seizures, and signs of cerebral edema. Newborns typically develop ketonuria within 48 hours of birth and present with neonatal encephalopathy, which is characterized by irritability, poor feeding, vomiting, lethargy, and dystonia. It results from pathogenic variants in the genes for E1-alpha, E1-beta, and E2, leading to less than 3 percent residual enzyme activity. All affected patients have elevated plasma levels of branched-chain amino acids (BCAAs leucine, isoleucine, and valine), including alloisoleucine and urine levels of branched-chain ketoacids, lactate, and pyruvate.Ĭlassic MSUD - Classic MSUD is the most common form of the disorder. Response to oral thiamine treatment may help distinguish the clinical phenotype in patients who present at a later age, but clinicians should keep in mind that response may be incomplete. However, they can be distinguished based upon age of onset and severity of clinical symptoms. Classic and E3-deficient MSUD present during the neonatal period and/or early infancy, while the other forms may present at any age during childhood, typically during a catabolic episode such as an intercurrent illness. In most cases, they do not correlate with specific variants or residual enzyme activity. Ĭlinical phenotypes - There are five distinct clinical phenotypes of MSUD: classic, intermittent, intermediate, thiamine responsive, and E3 deficient ( table 1). Elevated levels of BCAA interfere with normal function of the immune system, skeletal muscle, and central nervous system, exerting direct and indirect neurotoxic effects through tissue swelling, impaired glutamate homeostasis, and relative deficiency of large neutral amino acids, resulting in reduced neurotransmitter synthesis including dopamine and serotonin. A metabolite of isoleucine causes the urine to smell like maple syrup. Decreased activity of BCKDC results in elevation of plasma concentrations of the BCAAs (leucine, isoleucine, and valine) and their corresponding keto acids. Pathogenic variants in the gene encoding the BCKDC kinase have not been identified.īCKDC plays a key role in the metabolism of BCAAs for energy production and synthesis of fatty acids and cholesterol through gluconeogenesis ( figure 1). There are case reports of a mild form of MSUD due to homozygous variants in the protein phosphatase, Mg 2+/Mn 2+ dependent 1K ( PPM1K) gene encoding the BCKDC phosphatase and variable increases of branched-chain amino acids (BCAAs) due to deficiency of one of the two branched-chain aminotransferase (BCAT) enzymes. Founder variants are identified in populations with a particularly high prevalence of MSUD (eg, Mennonites, Amish). No strict genotype-phenotype correlation exists in patients with MSUD. Homozygous or compound heterozygous variants in any of these genes can cause any of the forms of MSUD. The sequences of all genes are fully characterized, including regulatory elements. The mode of inheritance is autosomal recessive. These genes map to human chromosomes 19q13.1-q13.2 (BCKDHA), 6p22-p21 ( BCKDHB), 1p31 (dihydrolipoamide branched-chain transacylase E2 ), and 7q31-q32 (dihydrolipoamide dehydrogenase ), respectively. PATHOGENESIS - MSUD is caused by pathogenic variants of genes that encode branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) components E1-alpha, E1-beta, E2, and E3. The MSUD incidence is up to 1:200 live births in certain Mennonite populations in Pennsylvania and elsewhere due to a founder variant (c.1312T>A) in the branched-chain ketoacid dehydrogenase complex gene ( BCKDHA). (See "Inborn errors of metabolism: Classification".)ĮPIDEMIOLOGY - MSUD occurs in approximately 1 in 86,800 to 185,000 live births. A general discussion of amino acid disorders is presented separately. It is characterized by psychomotor delay, feeding problems, and a maple syrup odor of the urine. It is caused by a deficiency of branched-chain alpha-ketoacid dehydrogenase complex (BCKDC), the second enzyme of the metabolic pathway of the three BCAAs, leucine, isoleucine, and valine. INTRODUCTION - Maple syrup urine disease (MSUD MIM #248600) also known as branched-chain ketoaciduria, is a disorder affecting the aliphatic or branched-chain amino acids (BCAAs).
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