Natural history of children and adults with maple syrup urine disease in the NBS-MSUD Connect registry

Abstract

Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder (OMIM #248600) in which affected individuals cannot metabolize branched-chain amino acids (BCAA) (leucine, isoleucine, and valine) due to pathogenic variations in one of three genes: BCKDHA, BCKDHB, and DBT encoding the E1α, E1β, and E2 subunits of the branched-chain α-ketoacid dehydrogenase (BCKDH) enzyme complex [1]. Consequently, these amino acids and their corresponding α-ketoacids accumulate in the body. In the United States of America (USA), the incidence of MSUD is approximately 1:198,000 [2], although it is considerably higher in some populations such as Old Order Mennonite (1:358) [3] and Ashkenazi Jewish populations (1:26,000) [4]. Without treatment, MSUD can lead to feeding difficulties, lethargy, seizures, urine and cerumen that smell like maple syrup, vomiting, coma, and death [5]. Early diagnosis and treatment can optimize outcomes, although treated individuals have an increased rate of anxiety, depression, attention deficit hyperactivity disorder (ADHD), movement disorders, and small reductions in intelligence and global function [5]. Treatment consists of a protein-restrictive diet that limits the amount of branched-chain amino acids consumed, along with synthetic formula consisting of the other amino acids and various micronutrients [6]. The goal of treatment is to maintain plasma leucine concentrations, with frequent monitoring, between 75 and 200 μmol/L for infants and children age five years and younger, and between 75 and 300 μmol/L for individuals older than five years of age [7]. Even with dietary treatment, metabolic decompensation can occur during times of stress (e.g., infection) and must be treated promptly [5]. Liver transplants may allow for relaxation of the diet, and can help prevent further brain damage but cannot reverse existing damage [8], [9]. Because treatment must be initiated as soon as possible after birth, screening for MSUD was first included in newborn screening (NBS) programs in the USA in 1964 [10]. In 1999, MSUD was included on the American College of Medical Genetics list of recommended diseases for inclusion in tandem mass spectrometry-based NBS panels [11], and is currently screened for in all states in the USA [2]. In order to add to the literature on outcomes of this rare condition, we report the characteristics of a group of respondents with MSUD from NBS-MSUD Connect, the first self-reported patient registry for metabolic NBS disorders. NBS Connect was launched in 2012 with NBS-PKU Connect for phenylketonuria (PKU) as the pilot registry, and NBS-MSUD Connect was added in 2013 [12]. The purpose of this report is to provide a snapshot of respondents with MSUD, including management techniques employed, clinical symptoms, and factors potentially associated with metabolic control of plasma leucine levels.