ABSTRACT
Over the past three decades, we studied 184 individuals with 174 different molecular variants of branched-chain α-ketoacid dehydrogenase activity, and here delineate essential clinical and biochemical aspects of the maple syrup urine disease (MSUD) phenotype. We collected data about treatment, survival, hospitalization, metabolic control, and liver transplantation from patients with classic (i.e., severe; n = 176), intermediate (n = 6) and intermittent (n = 2) forms of MSUD. A total of 13,589 amino acid profiles were used to analyze leucine tolerance, amino acid homeostasis, estimated cerebral amino acid uptake, quantitative responses to anabolic therapy, and metabolic control after liver transplantation. Standard instruments were used to measure neuropsychiatric outcomes. Despite advances in clinical care, classic MSUD remains a morbid and potentially fatal disorder. Stringent dietary therapy maintains metabolic variables within acceptable limits but is challenging to implement, fails to restore appropriate concentration relationships among circulating amino acids, and does not fully prevent cognitive and psychiatric disabilities. Liver transplantation eliminates the need for a prescription diet and safeguards patients from life-threatening metabolic crises, but is associated with predictable morbidities and does not reverse pre-existing neurological sequelae. There is a critical unmet need for safe and effective disease-modifying therapies for MSUD which can be implemented early in life. The biochemistry and physiology of MSUD and its response to liver transplantation afford key insights into the design of new therapies based on gene replacement or editing.
Subject(s)
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/genetics , Amino Acids, Branched-Chain/metabolism , Biomarkers/blood , Leucine/blood , Liver Transplantation , Maple Syrup Urine Disease/diet therapy , Maple Syrup Urine Disease/therapy , 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/metabolism , Adolescent , Adult , Child , Child, Preschool , Cognitive Dysfunction/metabolism , Cognitive Dysfunction/physiopathology , Cohort Studies , Diet , Female , Homozygote , Humans , Infant , Leucine/metabolism , Male , Maple Syrup Urine Disease/genetics , Maple Syrup Urine Disease/metabolism , Mental Disorders/metabolism , Mental Disorders/physiopathology , Middle Aged , PhenotypeABSTRACT
We correlate chromosome 5 haplotypes and SMN2 copy number with disease expression in 42 Mennonite and 14 Amish patients with spinal muscular atrophy (SMA). A single haplotype (A1) with 1 copy of SMN2 segregated among all Amish patients. SMN1 deletions segregated on four different Mennonite haplotypes that carried 1 (M1a, M1b, M1c) or 2 (M2) copies of SMN2. DNA microsatellite and microarray data revealed structural similarities among A1, M1a, M1b, and M2. Clinical data were parsed according to both SMN1 genotype and SMN2 copy number (2 copies, n = 44; 3 copies, n = 9; or 4 copies, n = 3). No infant with 2 copies of SMN2 sat unassisted. In contrast, all 9 Mennonites with the M1a/M2 genotype (3 copies of SMN2) sat during infancy at a median age of 7 months, and 5 (56%) walked and dressed independently at median ages of 18 and 36 months, respectively. All are alive at a median age of 11 (range 2-31) years without ventilatory support. Among 13 Amish and 26 Mennonite patients with 2 copies of SMN2 who did not receive feeding or ventilatory support, A1/A1 as compared to M1a/M1a genotype was associated with earlier clinical onset (p = 0.0040) and shorter lifespan (median survival 3.9 versus 5.7 months, p = 0.0314). These phenotypic differences were not explained by variation in SMN1 deletion size or SMN2 coding sequence, which were conserved across haplotypes. Distinctive features of SMA within Plain communities provide a population-specific framework to study variations of disease expression and the impact of disease-modifying therapies administered early in life.
