Kristi Bentler

Siblings With Mitochondrial Acetoacetyl-CoA Thiolase Deficiency Not Identified by Newborn Screening

Screened for by all state newborn screening (NBS) programs in the United States, mitochondrial acetoacetyl-coenzyme A thiolase (T2), or β-ketothiolase, deficiency is a rare autosomal recessive disorder that causes ketoacidosis and hypoglycemia/hyperglycemia. Outcomes vary from normal development to severe cognitive impairment or even death after an acute episode of ketoacidosis. The classical biochemical profile of T2 deficiency is a result of null mutations in both alleles of the ACAT1 gene and consists of persistently increased urinary excretion of ketones, characteristic organic acids, and tiglylglycine as well as abnormal blood or plasma acylcarnitine profiles in acute and stable conditions. Early diagnosis and aggressive management can prevent further episodes of ketoacidosis and lead to normal development. We report the cases of 3 children, all subsequently found to have mutations predicted to be associated with no residual T2 enzymatic activity, but only 1 was identified by NBS in Minnesota since 2001. To our knowledge, this is the first description of compound heterozygotes for null mutations associated with no enzymatic activity exhibiting normal urinary organic acid, blood, and plasma acylcarnitine profiles when clinically well, thereby explaining the false-negative NBS results. We suggest that T2 deficiency may be underrecognized, because the incidence of T2 deficiency in Minnesota, on the basis of these 3 cases, is 1 in 232 000, higher than the reported <1 in 1 million incidence. Our cases emphasize that T2 deficiency must be considered in patients who present with ketoacidosis disproportionately severe to the triggering illness despite normal NBS results or nonspecific biochemical findings in blood and urine during asymptomatic periods.

Recessive mutations in PCBD1 cause a new type of early-onset diabetes

Mutations in several genes cause nonautoimmune diabetes, but numerous patients still have unclear genetic defects, hampering our understanding of the development of the disease and preventing pathogenesis-oriented treatment. We used whole-genome sequencing with linkage analysis to study a consanguineous family with early-onset antibody-negative diabetes and identified a novel deletion in PCBD1 (pterin-4 α-carbinolamine dehydratase/dimerization cofactor of hepatocyte nuclear factor 1 α), a gene that was recently proposed as a likely cause of diabetes. A subsequent reevaluation of patients with mild neonatal hyperphenylalaninemia due to mutations in PCBD1 from the BIODEF database identified three additional patients who had developed HNF1A-like diabetes in puberty, indicating early β-cell failure. We found that Pcbd1 is expressed in the developing pancreas of both mouse and Xenopus embryos from early specification onward showing colocalization with insulin. Importantly, a morpholino-mediated knockdown in Xenopus revealed that pcbd1 activity is required for the proper establishment of early pancreatic fate within the endoderm. We provide the first genetic evidence that PCBD1 mutations can cause early-onset nonautoimmune diabetes with features similar to dominantly inherited HNF1A-diabetes. This condition responds to and can be treated with oral drugs instead of insulin, which is important clinical information for these patients. Finally, patients at risk can be detected through a newborn screening for phenylketonuria.

The inborn errors of metabolism information system: A project of the Region 4 Genetics Collaborative Priority 2 Workgroup.

The Region 4 Genetics Collaborative has brought together metabolic clinicians and follow-up specialists from state departments of health in the region (Illinois, Indiana, Kentucky, Michigan, Minnesota, Ohio, and Wisconsin) in a workgroup to create a dynamic registry, the Inborn Errors of Metabolism Information System, to facilitate gathering information about long-term follow-up for individuals identified by newborn blood spot screening. With the concept that by developing a core series of agreed-on data elements and general treatment strategies, differences in treatment plans could yield evidence about optimal treatment choices, data elements for initial intake, and interval follow-up were selected based on a paradigm condition, medium-chain acyl-CoA dehydrogenase deficiency. Demographic elements that will be used as a common data set for all conditions were identified along with condition-specific elements and general information to be obtained at intervals. Subjects were enrolled after obtaining prospective informed consent; data entry began in January 2007. Additional conditions have had data sets defined and data entry initiated; 21 disorders as of July 2009. Web-based data entry has been employed using DocSite® as the platform for data entry. With continued collaboration among members of the workgroup, we hope to extend the intellectual questions that can be explored using this data, expand the spectrum of the registry and number of patients engaged, and integrate the registry into additional domains.

Cardiac conduction improvement in two heterozygotes for primary carnitine deficiency on L-carnitine supplementation

Sarafoglou K, Tridgell AHC, Bentler K, Redlinger‐Grosse K, Berry SA, Schimmenti LA. Cardiac conduction improvement in two heterozygotes for primary carnitine deficiency on l‐carnitine supplementation.