Glutaric aciduria type 1 and neonatal screening: time to proceed—with caution

The new technology of tandem mass spectrometry is having a significant impact on the diagnostics of inborn metabolic errors. One of the most important aspects of this new technology is the possibility of recognising a whole class of disorders within a single analytical step. Shall this powerful technology be applied to the screening of newborn babies? Careful evaluation of every single disorder that could potentially be identified is needed. In the following, I will present some considerations that concern glutaric aciduria type 1 (MIM 231670; glutaryl-CoA dehydrogenase deficiency

Current themes in molecular pediatrics: molecular medicine and its applications

We focus on themes that are derived from clinical practice and research in the field of genetic diseases of bone and inborn errors of metabolism but may be of more general interest as they indicate some trends in molecular medicine as related to pediatrics. Identifying the disease-causing mechanism brings about efficient therapeutic strategies and discovering the mutant genotype in the near future may become helpful for devising custom-built molecular responses. At the same time, the transition of therapy from the experimental phase to industrial application is difficult as there may be novel roles (and potentially conflicting interests) between physicians, patient organisations, governmental agencies and the pharmaceutical industry. Awareness of these potential conflicts may help in recognizing and dealing with these issues

Undersulfation of proteoglycans synthesized by chondrocytes from a patient with achondrogenesis type 1B homozygous for an L483P substitution in the diastrophic dysplasia sulfate transporter.

Achondrogenesis type 1B is an autosomal recessive, lethal chondrodysplasia caused by mutations in the gene encoding a sulfate/chloride antiporter of the cell membrane (Superti-Furga, A., Hastbacka, J., Wilcox, W. R., Cohn, D. H., van der Harten, J. J., Rossi, A., Blau, N., Rimoin, D. L., Steinmann, B., Lander, E. S., and Gitzelmann, R. (1996) Nat. Genet. 12, 100-102). To ascertain the consequences of the sulfate transport defect on proteoglycan synthesis, we studied the structure and sulfation of proteoglycans in cartilage tissue and in fibroblast and chondrocyte cultures from a fetus with achondrogenesis 1B. Proteoglycans extracted from epiphyseal cartilage and separated on agarose gels migrated more slowly than controls and stained poorly with alcian blue. The patient's cultured cells showed reduced incorporation of [35S]sulfate relative to [3H]glucosamine, impaired uptake of sulfate, and higher resistance to chromate toxicity compared to control cells. Epiphyseal chondrocytes cultured in alginate beads synthesized proteoglycans of normal molecular size as judged by gel filtration chromatography, but undersulfated as judged by ion exchange chromatography and by the amount of nonsulfated disaccharide. High performance liquid chromatography analysis of chondroitinase-digested proteoglycans showed that sulfated disaccharides were present, although in reduced amounts, indicating that at least in vitro, other sources of sulfate can partially compensate for sulfate deficiency. A t1475c transition causing a L483P substitution in the eleventh transmembrane domain of the sulfate/chloride antiporter was present on both alleles in the patient who was the product of a consanguineous marriage. The results indicate that the defect of sulfate transport is expressed in both chondrocytes and fibroblasts and results in the synthesis of proteoglycans bearing glycosaminoglycan chains which are poorly sulfated but of normal length

Familial X-linked cardiomyopathy (Danon disease): diagnostic confirmation by mutation analysis of the LAMP2 gene

A boy presented at age 2.5 years with mild left ventricular hypertrophy and mild myopathy. Hypertrophic cardiomyopathy progressed relentlessly, leading to death at age 16 years shortly before planned heart transplantation. During the course of the disease, his mother developed severe dilated cardiomyopathy and died of its complications at 46 years of age. The combination of myopathy and cardiomyopathy, the biochemical and electron microscopy findings in a muscle biopsy, and the pedigree suggested Danon disease (MIM 300257), an X-linked lysosomal storage disorder caused by deficiency of lysosome-associated membrane protein-2 (LAMP2). The diagnosis was confirmed by the identification of a novel mutation, G138A, in the LAMP2gene, leading to the premature stop codon W46X. Conclusion:Early diagnosis of Danon disease is important for genetic counselling and timely cardiac transplantation, the only effective therapeutic optio

Hypomorphic mutations of TRIP11 cause odontochondrodysplasia

Odontochondrodysplasia (ODCD) is an unresolved genetic disorder of skeletal and dental development. Here, we show that ODCD is caused by hypomorphic TRIP11 mutations, and we identify ODCD as the nonlethal counterpart to achondrogenesis 1A (ACG1A), the known null phenotype in humans. TRIP11 encodes Golgi-associated microtubule-binding protein 210 (GMAP-210), an essential tether protein of the Golgi apparatus that physically interacts with intraflagellar transport 20 (IFT20), a component of the ciliary intraflagellar transport complex B. This association and extraskeletal disease manifestations in ODCD point to a cilium-dependent pathogenesis. However, our functional studies in patient-derived primary cells clearly support a Golgi-based disease mechanism. In spite of reduced abundance, residual GMAP variants maintain partial Golgi integrity, normal global protein secretion, and subcellular distribution of IFT20 in ODCD. These functions are lost when GMAP-210 is completely abrogated in ACG1A. However, a similar defect in chondrocyte maturation is observed in both disorders, which produces a cellular achondrogenesis phenotype of different severity, ensuing from aberrant glycan processing and impaired extracellular matrix proteoglycan secretion by the Golgi apparatus

Mucolipidosis II presenting as severe neonatal hyperparathyroidism

Mucolipidosis II (ML II or I-cell disease ) (OMIM 252500) is an autosomal recessive lysosomal enzyme targeting disorder that usually presents between 6 and 12 months of age with a clinical phenotype resembling Hurler syndrome and a radiological picture of dysostosis multiplex. When ML II is severe enough to be detected in the newborn period, the radiological changes have been described as similar to hyperparathyroidism or rickets. The biological basis of these findings has not been explored and few biochemical measurements have been recorded. We describe three unrelated infants with ML II who had radiological features of intrauterine hyperparathyroidism and biochemical findings consistent with severe secondary neonatal hyperparathyroidism (marked elevation of serum parathyroid hormone and alkaline phosphatase levels). The vitamin D metabolites were not substantially different from normal and repeatedly normal calcium concentrations excluded vitamin D deficiency rickets and neonatal severe hyperparathyroidism secondary to calcium-sensing receptor gene mutations (OMIM 239200). The pathogenesis of severe hyperparathyroidism in the fetus and newborn with ML II is unexplained. We hypothesize that the enzyme targeting defect of ML II interferes with transplacental calcium transport leading to a calcium starved fetus and activation of the parathyroid response to maintain extracellular calcium concentrations within the normal range. Conclusion: Newborns with mucolipidosis II can present with radiological and biochemical signs of hyperparathyroidism. Awareness of this phenomenon may help in avoiding diagnostic pitfalls and establishing a proper diagnosis and therap

Sudden unexpected death in an infant with L-2-hydroxyglutaric aciduria

Inherited metabolic disorders are the cause of a small but significant number of sudden unexpected deaths in infancy. We report a girl who suddenly died at 11months of age, during an intercurrent illness. Autopsy showed spongiform lesions in the subcortical white matter, in the basal ganglia, and in the dentate nuclei. Investigations in an older sister with developmental delay, ataxia, and tremor revealed l-2-hydroxyglutaric aciduria and subcortical white matter changes with hyperintensity of the basal ganglia and dentate nuclei at brain magnetic resonance imaging. Both children were homozygous for a splice site mutation in the L2HGDH gene. Sudden death has not been reported in association with l-2-hydroxyglutaric aciduria so far, but since this inborn error of metabolism is potentially treatable, early diagnosis may be importan