Methylmalonic Acidemia: Can Treatment be Improved?

Methylmalonic acidemia (MMA) is a severe metabolic disorder, particularly with complete deficiency of methylmalonyl-CoA mutase. Dietary restriction has led to overt signs of deficiencies including skin rashes, hair loss, and poor growth. More liberal intake of the restricted amino acids has resulted in better growth and less frequent episodes of illness

Molecular Genetics and Metabolism 86 (2005) S17-S21 Minireview Response of patients with phenylketonuria in the US to tetrahydrobiopterin

Abstract Tetrahydrobiopterin (BH 4 ) responsive forms of phenylketonuria (PKU) have been recognized since 1999. Subsequent studies have shown that patients with PKU, especially those with mild mutations, respond with lower blood phenylalanine (Phe) concentrations following oral administration of 6-R-L-erythro-5, 6, 7, 8-tetrahydrobiopterin (BH 4 ). To determine the incidence of BH 4 responding PKU patients in the United States and characterize their phenylalanine hydroxylase (PAH) mutations, a study was undertaken at UTMB in Galveston and the Children's Hospital of Los Angeles on 38 patients with PKU. Patients were screened by a single oral dose of BH 4 , 10 mg/kg and blood Phe and tyrosine were determined at 0, 4, 8, and 24 h. Twenty-two individuals (58%) responded with marked decrease in blood Phe (>30%) at 24 h. Some of the patients that responded favourably were clinically described as having Classical PKU. Blood tyrosine concentrations did not change signiWcantly. Twenty subjects with PKU, responsive and nonresponsive to BH 4 , were enrolled in a second study to evaluate blood Phe response to ascending single doses of BH 4 with 10, 20, and 40 mg/kg and to evaluate multiple daily doses, for 7 days each, with 10 and 20 mg/kg BH 4 . The 7-day trial showed a sustained decrease in blood Phe in 14 of 20 patients taking 20 mg/kg BH 4 (70%). Of these 14 patients, 10 (71%) responded with a signiWcant decrease in blood Phe following 10 mg/kg BH 4 daily. To understand the mechanism of response to BH 4 , the kinetics and stability of mutant PAH were studied. We found that mutant PAH responds with increase in the residual enzyme activity following BH 4 administration. The increase in activity is multi-factorial caused by increased stability, chaperone eVect, and correction of the mutant Km. These studies indicate that BH 4 can be of help to patients with PKU, including some considered to have Classical PKU. The PKU population in US is heterogeneous and mutations can be varied so mutations need to be characterized and response to BH 4 tested. It is more likely that mutations with residual activity should respond to BH 4 , therefore the clinical deWnition of "Classical PKU" should be reconciled with the residual activity of PAH mutations

Phenylketonuria Scientific Review Conference:State of the science and future research needs

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 Rtnol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 [tmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.</p