Amino acid synthesis deficiencies

In recent years the number of disorders known to affect amino acid synthesis has grown rapidly. Nor is it just the number of disorders that has increased: the associated clinical phenotypes have also expanded spectacularly, primarily due to the advances of next generation sequencing diagnostics. In contrast to the "classical" inborn errors of metabolism in catabolic pathways, in which elevated levels of metabolites are easily detected in body fluids, synthesis defects present with low values of metabolites or, confusingly, even completely normal levels of amino acids. This makes the biochemical diagnosis of this relatively new group of metabolic diseases challenging. Defects in the synthesis pathways of serine metabolism, glutamine, proline and, recently, asparagine have all been reported. Although these amino acid synthesis defects are in unrelated metabolic pathways, they do share many clinical features. In children the central nervous system is primarily affected, giving rise to (congenital) microcephaly, early onset seizures and varying degrees of mental disability. The brain abnormalities are accompanied by skin disorders such as cutis laxa in defects of proline synthesis, collodion-like skin and ichthyosis in serine deficiency, and necrolytic erythema in glutamine deficiency. Hypomyelination with accompanying loss of brain volume and gyration defects can be observed on brain MRI in all synthesis disorders. In adults with defects in serine or proline synthesis, spastic paraplegia and several forms of polyneuropathy with or without intellectual disability appear to be the major symptoms in these late-presenting forms of amino acid disorders. This review provides a comprehensive overview of the disorders in amino acid synthesis

MtDNA-maintenance defects: syndromes and genes

A large group of mitochondrial disorders, ranging from early-onset pediatric encephalopathic syndromes to late-onset myopathy with chronic progressive external ophthalmoplegia (CPEOs), are inherited as Mendelian disorders characterized by disturbed mitochondrial DNA (mtDNA) maintenance. These errors of nuclear-mitochondrial intergenomic signaling may lead to mtDNA depletion, accumulation of mtDNA multiple deletions, or both, in critical tissues. The genes involved encode proteins belonging to at least three pathways: mtDNA replication and maintenance, nucleotide supply and balance, and mitochondrial dynamics and quality control. In most cases, allelic mutations in these genes may lead to profoundly different phenotypes associated with either mtDNA depletion or multiple deletions. Communicated by: Shamima Rahman Presented at the Annual Symposium of the Society for the Study of Inborn Errors of Metabolism, Rome, Italy, September 6–9, 2016This work was supported by: ERC FP7-322424 grant (to MZ), CoEN grant 3038 (to MZ and CV) and the MRC core grant to the Mitochondrial Biology Unit