Chromosome 22, particularly band 22q11.2, is predisposed to rearrangements due to misalignments of low-copy repeats (LCRs). DiGeorge/velocardiofacial syndrome (DG/VCFS) is a common disorder resulting from microdeletion within the same band. Although both deletion and duplication are expected to occur in equal proportions as reciprocal events caused by LCR-mediated rearrangements, very few microduplications have been identified. We have identified 13 cases of microduplication 22q11.2, primarily by interphase fluorescence in situ hybridization (FISH). The size of the duplications, determined by FISH probes from bacterial artificial chromosomes and P(1) artificial chromosomes, range from 3-4 Mb to 6 Mb, and the exchange points seem to involve an LCR. Molecular analysis based on 15 short tandem repeats confirmed the size of the duplications and indicated that at least 1 of 15 loci has three alleles present. The patients' phenotypes ranged from mild to severe, sharing a tendency for velopharyngeal insufficiency with DG/VCFS but having other distinctive characteristics, as well. Although the present series of patients was ascertained because of some overlapping features with DG/VCF syndromes, the microduplication of 22q11.2 appears to be a new syndrome.

Follow-up of neonatally diagnosed patients with GA-I in Germany clearly demonstrates that the inclusion of this rare disease in the NBS disease panel has significantly improved the neurological outcome of affected individuals. The establishment of and adherence to evidence-based treatment recommendations, and supervision by experienced metabolic centers helps to minimize the number of patients who do not benefit from NBS.

NBS is a beneficial, disease-changing intervention for GA1. However, improved neurologic outcome critically depends on adherence to recommended therapy, whereas kidney dysfunction does not appear to be impacted by recommended therapy. Ann Neurol 2018;83:970-979.

BackgroundPropionic acidemia is an inherited disorder caused by deficiency of propionyl-CoA carboxylase. Although it is one of the most frequent organic acidurias, information on the outcome of affected individuals is still limited.Study design/methodsClinical and outcome data of 55 patients with propionic acidemia from 16 European metabolic centers were evaluated retrospectively. 35 patients were diagnosed by selective metabolic screening while 20 patients were identified by newborn screening. Endocrine parameters and bone age were evaluated. In addition, IQ testing was performed and the patients’ and their families’ quality of life was assessed.ResultsThe vast majority of patients (>85%) presented with metabolic decompensation in the neonatal period. Asymptomatic individuals were the exception. About three quarters of the study population was mentally retarded, median IQ was 55. Apart from neurologic symptoms, complications comprised hematologic abnormalities, cardiac diseases, feeding problems and impaired growth. Most patients considered their quality of life high. However, according to the parents’ point of view psychic problems were four times more common in propionic acidemia patients than in healthy controls.ConclusionOur data show that the outcome of propionic acidemia is still unfavourable, in spite of improved clinical management. Many patients develop long-term complications affecting different organ systems. Impairment of neurocognitive development is of special concern. Nevertheless, self-assessment of quality of life of the patients and their parents yielded rather positive results.

Isovaleric acidemia (IVA) is an autosomal recessive inborn error of leucine metabolism caused by a deficiency of the mitochondrial enzyme isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of derivatives of isovaleryl-CoA. It was the first organic acidemia recognized in humans and can cause significant morbidity and mortality. Early diagnosis and treatment with a protein restricted diet and supplementation with carnitine and glycine are effective in promoting normal development in severely affected individuals. Both intra-and inter-familial variability have been recognized. Initially, two phenotypes with either an acute neonatal or a chronic intermittent presentation were described. More recently, a third group of individuals with mild biochemical abnormalities who can be asymptomatic have been identified through newborn screening of blood spots by tandem mass spectrometry. IVD is a flavoenzyme that catalyzes the conversion of isovaleryl-CoA to 3-methylcrotonyl-CoA and transfers electrons to the electron transfer flavoprotein. Human IVD has been purified from tissue and recombinant sources and its biochemical and physical properties have been extensively studied. Molecular analysis of the IVD gene from patients with IVA has allowed characterization of different types of mutations in this gene. One missense mutation, 932C>T (A282V), is particularly common in patients identified through newborn screening with mild metabolite elevations and who have remained asymptomatic to date. This mutation leads to a partially active enzyme with altered catalytic properties; however, its effects on clinical outcome and the necessity of therapy are still unknown. A better understanding of the heterogeneity of this disease and the relevance of genotype/phenotype correlations to clinical management of patients are among the challenges remaining in the study of this disorder in the coming years.

Isovaleric acidemia (IVA) is an inborn error of leucine metabolism that can cause significant morbidity and mortality. Since the implementation, in many states and countries, of newborn screening (NBS) by tandem mass spectrometry, IVA can now be diagnosed presymptomatically. Molecular genetic analysis of the IVD gene for 19 subjects whose condition was detected through NBS led to the identification of one recurring mutation, 932C-->T (A282V), in 47% of mutant alleles. Surprisingly, family studies identified six healthy older siblings with identical genotype and biochemical evidence of IVA. Our findings indicate the frequent occurrence of a novel mild and potentially asymptomatic phenotype of IVA. This has significant consequences for patient management and counseling.

The question of which factors drive human eating and nutrition is a key issue in many branches of science. We describe the creation, evaluation, and updating of an interdisciplinary, interactive, and evolving “framework 2.0” of Determinants Of Nutrition and Eating (DONE). The DONE framework was created by an interdisciplinary workgroup in a multiphase, multimethod process. Modifiability, relationship strength, and population-level effect of the determinants were rated to identify areas of priority for research and interventions. External experts positively evaluated the usefulness, comprehensiveness, and quality of the DONE framework. An approach to continue updating the framework with the help of experts was piloted. The DONE framework can be freely accessed (http://uni-konstanz.de/DONE) and used in a highly flexible manner: determinants can be sorted, filtered and visualized for both very specific research questions as well as more general queries. The dynamic nature of the framework allows it to evolve as experts can continually add new determinants and ratings. We anticipate this framework will be useful for research prioritization and intervention development.

Guanidinoactetate methyltransferase deficiency should be considered in patients with unexplained intellectual disability, and urinary guanidinoacetate should be determined as an initial diagnostic approach.