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Abstract Background Intellectual disability (ID) is a devastating and frequent condition, affecting 2-3% of the population worldwide. Early recognition of treatable underlying conditions drastically improves health outcomes and decreases burdens to patients, families and society. Our systematic literature review identified 81 such inborn errors of metabolism, which present with ID as a prominent feature and are amenable to causal therapy. The WebAPP translates this knowledge of rare diseases into a diagnostic tool and information portal. Methods & results Freely available as a WebAPP via http://www.treatable-id.org and end 2012 via the APP store, this diagnostic tool is designed for all specialists evaluating children with global delay / ID and laboratory scientists. Information on the 81 diseases is presented in different ways with search functions: 15 biochemical categories, neurologic and non-neurologic signs & symptoms, diagnostic investigations (metabolic screening tests in blood and urine identify 65% of all IEM), therapies & effects on primary (IQ/developmental quotient) and secondary outcomes, and available evidence For each rare condition a ‘disease page’ serves as an information portal with online access to specific genetics, biochemistry, phenotype, diagnostic tests and therapeutic options. As new knowledge and evidence is gained from expert input and PubMed searches this tool will be continually updated. The WebAPP is an integral part of a protocol prioritizing treatability in the work-up of every child with global delay / ID. A 3-year funded study will enable an evaluation of its effectiveness. Conclusions For rare diseases, a field for which financial and scientific resources are particularly scarce, knowledge translation challenges are abundant. With this WebAPP technology is capitalized to raise awareness for rare treatable diseases and their common presenting clinical feature of ID, with the potential to improve health outcomes. This innovative digital tool is designed to motivate health care providers to search actively for treatable causes of ID, and support an evidence-based approach to rare metabolic diseases. In our current –omics world with continuous information flow, the effective synthesis of data into accessible, clinical knowledge has become ever more essential to bridge the gap between research and care.

Background: The creatine/creatine-phosphate system is essential for the storage and transmission of phosphate-bound energy in muscle and brain. In infants, inefficiency or failure of this metabolic pathway can impair the development of motor control and mentation.Methods: We studied and treated an infant with extrapyramidal signs who was shown--by assay for urinary creatinine and by analysis of brain metabolites with use of nuclear magnetic resonance spectra--to have depletion of body and brain creatine, due to inborn deficiency of guanidinoacetate methyltransferase (GAMT).Findings: Long-term oral administration of creatine-monohydrate (4-8 g per day) to this index patient resulted in substantial clinical improvement, disappearance of magnetic resonance (MRI) signal abnormalities in the globus pallidus, and normalisation of slow background activity on the electroencephalogram (EEG). During the 25-month treatment period, both brain and total body creatine concentrations became normal.Interpretation: Oral creatine replacement has proved to be effective in one child with an inborn error of GAMT. It may well be effective in the treatment of other disorders of creatine synthesis. [ABSTRACT FROM AUTHOR]

Purpose: The presentation and etiology of cerebral palsy (CP) are heterogeneous. Diagnostic evaluation can be a prolonged and expensive process that might remain inconclusive. This study aimed to determine the diagnostic yield and impact on management of next-generation sequencing (NGS) in 50 individuals with atypical CP (ACP)., Methods: Patient eligibility criteria included impaired motor function with onset at birth or within the first year of life, and one or more of the following: severe intellectual disability, progressive neurological deterioration, other abnormalities on neurological examination, multiorgan disease, congenital anomalies outside of the central nervous system, an abnormal neurotransmitter profile, family history, brain imaging findings not typical for cerebral palsy. Previous assessment by a neurologist and/or clinical geneticist, including biochemical testing, neuroimaging, and chromosomal microarray, did not yield an etiologic diagnosis., Results: A precise molecular diagnosis was established in 65% of the 50 patients. We also identified candidate disease genes without a current OMIM disease designation. Targeted intervention was enabled in eight families (~15%)., Conclusion: NGS enabled a molecular diagnosis in ACP cases, ending the diagnostic odyssey, improving genetic counseling and personalized management, all in all enhancing precision medicine practices.

Background: The urea cycle defect argininosuccinate lyase (ASL) deficiency has a large spectrum of presentations from highly severe to asymptomatic. Enzyme activity assays in red blood cells or fibroblasts, although diagnostic of the deficiency, fail to discriminate between severe, mild or asymptomatic cases. Mutation/phenotype correlation studies are needed to characterize the effects of individual mutations on the activity of the enzyme., Methods: Bacterial in-vitro expression studies allowed the enzyme analysis of purified mutant ASL proteins p.I100T (c.299 T > C), p.V178M (c.532 G > A), p.E189G (c.566A > G), p.Q286R (c.857A > G), p.K315E (c.943A > G), p.R379C (c.1135 C > T) and p.R385C (c.1153 C > T) in comparison to the wildtype protein., Results: In the bacterial in-vitro expression system, ASL wild-type protein was successfully expressed. The known classical p.Q286R, the novel classical p.K315E and the known mutations p.I100T, p.E189G and p.R385C, which all have been linked to a mild phenotype, showed no significant residual activity. There was some enzyme activity detected with the p.V178M (5 % of wild-type) and p.R379C (10 % of wild-type) mutations in which K(m) values for argininosuccinic acid differed significantly from the wild-type ASL protein., Conclusion: The bacterially expressed enzymes proved that the mutations found in patients and studied here indeed are detrimental. However, as in the case of red cell ASL activity assays, some mutations found in genetically homozygous patients with mild presentations resulted in virtual loss of enzyme activity in the bacterial system, suggesting a more protective environment for the mutant enzyme in the liver than in the heterologous expression system and/or in the highly dilute assays utilized here.

Vitamin B6 is an abundant cofactor in aminoacid- and neurotransmitter metabolism. Physiologic availability depends on dietary supply, intact absorption and conversion of pyridoxamine and pyridoxine into the only active cofactor, pyridoxal-5'-phosphate (PLP) in liver. By now we know of four genetic epilepsies with vitamin B6 dependent seizures. Two are caused by reduced synthesis/availability of PLP (Pyridox(am)in-phosphate oxidase (PNPO) deficiency and infantile hypophosphatasia) and two by increased utilization/inactivation (pyridoxine-dependent epilepsy and hyperprolinemia type II). Aside from hyperprolinemia type II these disorders usually present with therapyresistant (myoclonic) seizures in the neonatal period. The EEG findings may range from burst suppression pattern to unspecific slowing or may even be normal. All four disorders can be diagnosed by reliable biomarkers and be confirmed by molecular analysis of the respective genes. While PLP would benefit all four entities, PNPO patients are typically resistant to pyridoxine and need PLP substitution. Especially in neonatal, therapyresistant seizures, these disorders have to be considered early, to prevent irreversible neurologic damage.

In an infant with progressive, severe extrapyramidal movement disorder and extremely. low urinary creatinine excretion, in vivo proton magnetic resonance spectroscopy of the brain showed a depletion of creatine and an accumulation of guanidinoacetate, the immediate precursor of creatine. The suggested defect in creatine biosynthesis at the level of guanidinoacetate methyltransferase was confirmed by the demonstration of defective activity of this enzyme in liver tissue and by identification of the underlying genetic defect. Creatine substitution by means of oral creatine monohydrate at high dosage (4-8 g per day) resulted in a striking improvement of the extrapyramidal movement disorder, normalisation of abnormal slow background activity in the EEG, and disappearance of bilateral abnormal signal intensities in the globus pallidus. The low urinary creatine excretion normalized and brain creatine and creatine phosphate, as measured by in vivo magnetic resonance spectroscopy, increased significantly. Guanidinoacetate methyltransferase deficiency is a new, treatable inborn error of metabolism. Screening methods and non-invasive diagnosis of the enzyme defect are needed for the early detection and treatment of patients with this effect.

Recently, the gene for the most common peroxisomal disorder, X-linked adrenoleukodystrophy (X-ALD), has been described encoding a peroxisomal membrane transporter protein. We analyzed the entire protein-coding sequence of this gene by reverse-transcription PCR, SSCP, and DNA sequencing in five patients with different clinical expression of X-ALD and in their female relatives; these clinical expressions were cerebral childhood ALD, adrenomyeloneuropathy (AMN), and "Addison disease only" (ADO) phenotype. In the three patients exhibiting the classical picture of severe childhood ALD we identified in the 5' portion of the X-ALD gene a 38-bp deletion that causes a frameshift mutation, a 3-bp deletion leading to a deletion of an amino acid in the ATP-binding domain of the ALD protein, and a missense mutation. In the patient with the clinical phenotype of AMN, a nonsense mutation in codon 212, along with a second site mutation at codon 178, was observed. Analysis of the patient with the ADO phenotype revealed a further missense mutation at a highly conserved position in the ALDP/PMP70 comparison. The disruptive nature of two mutations (i.e., the frameshift and the nonsense mutation) in patients with biochemically proved childhood ALD and AMN further strongly supports the hypothesis that alterations in this gene play a crucial role in the pathogenesis of X-ALD. Since the current biochemical techniques for X-ALD carrier detection in affected families lack sufficient reliability, our procedure described for systematic mutation scanning is also capable of improving genetic counseling and prenatal diagnosis.

Symmetric hypoplasia of the temporal cerebral lobes was demonstrated by magnetic resonance imaging of the brain in a macrocephalic male patient with glutaric aciduria type II within the first week of life. Psychomotor development was normal until the age of 11 months, when the patient died of sudden cardiac arrest. Autopsy revealed symmetric hypoplasia of the temporal cerebral lobes with loss of axons and hypomyelination in the temporal medullary layers.

A 28-year-old asymptomatic woman was diagnosed to be heterozygous for adrenoleukodystrophy (ALD) by elevated very long-chain fatty acids in serum and fibroblasts after ADL had been diagnosed in her son. A year later she had transient unilateral blurred vision. Evoked potentials and brain magnetic resonance imaging showed further separate cerebral white matter lesions suggesting multiple sclerosis (MS). MS-like syndromes in women heterozygous for ALD may be more frequent than previously recognized.

An eleven month-old boy presented clinically with craniofacial dysmorphia, severe psychomotor retardation, neurological deterioration, no response to visual and acoustic stimuli, failure to thrive, hepatomegaly and adrenal insufficiency. Specific biochemical markers for a peroxisomal deficiency disorder (Zellweger's syndrome, neonatal adrenoleukodystrophy, infantile Refsum's disease) revealed pathological results for very long chain fatty acids, phytanic acid, pristanic acid, plasmalogen biosynthesis and catalase, thus confirming the clinical diagnosis. Comparison of clinical and biochemical findings in the patient with the characteristics of the three peroxisomal deficiency disorders showed overlapping with each of these disorders, which corresponds to the current view that these three peroxisomal disorders differ only with respect to onset and severity of the clinical manifestations, but not with regard to the biochemical defects.

Lysosomal diseases are a group of about 30 genetic defects with a total incidence of 3 to 4 cases/10,000 newborns. Their clinical appearance is very heterogeneous and comprises infantile, as well as juvenile or adult forms. Our concept for their diagnosis has now been in use for eight years and entails the following strategy: The three main symptom groups coarse facial features, visceromegaly and/or psychomotor retardation should be examined for their typical expression and for the occurrence of specific "key symptoms". Thereafter, biochemical analysis of urine for oligosaccharides, mucopolysaccharides and in some cases, of sphingolipids or direct enzyme assays in serum, peripheral leucocytes or skin fibroblasts are performed. The selection of appropriate methods is usually the domain of the biochemist and greatly depends on the available samples and the quality of clinical information. The diagnostic value and the limitations of methods and samples are discussed in detail. Finally, evidence of defects in the expression of relevant gene products, such as enzymes, activator proteins or transport proteins can be obtained and used for genetic counselling and/or for prenatal diagnosis in chorionic villi or cultured amniotic fluid cells. Our results confirm the data on the high incidence of mucopolysaccharidoses I and III A. In addition, a comparatively high number of otherwise rare diseases, such as fucosidosis or sialic acid storage disease was found. Among the group of sphingolipidoses, special attention should be paid to juvenile or adult forms.

Peroxisomal disorders are genetic metabolic diseases with generalized, multiple, or single functional disturbances of the peroxisome. According to the extent of the functional disturbances 3 groups of diseases can be differentiated: disorders with generalized loss of peroxisomal functions (Zellweger syndrome, ZS; neonatal adrenoleukodystrophy, NALD; infantile Refsum's disease), disorders with multiple enzymatic defects (e.g. rhizomelic chondrodysplasia punctata), and disorders with a single enzymatic defect in the peroxisome, the most important being adrenoleukodystrophy/adrenomyeloneuropathy (ALD/AMN). Adult Refsum's disease, a genetic neurological disorder with phytanic acid accumulation, is due to a mitochondrial enzyme deficiency, but is often considered together with peroxisomal diseases because of phytanic acid (PHYT) accumulation in most peroxisomal diseases. The main clinical and pathological criteria of the major disorders and the biochemical parameters of their differentiation are presented. Elevated levels of very long chain fatty acids (VLCFA) and/or PHYT are the primary diagnostic markers for all peroxisomal disorders and adult Refsum's disease, respectively. Our investigations disclosed 30 ALD/AMN hemizygotes, 16 ALD/AMN heterozygotes, 8 cases of ZS/NALD and 7 patients with adult Refsum's disease. In addition, 15 cases of peroxisomal disorders were confirmed by biochemical investigations in autopsy material. With regard to peroxisomal disorders, therapeutic concepts exist only for ALD/AMN: corticosteroid substitution for adrenal insufficiency, dietary treatment, and bone marrow transplantation (BMT). Adult Refsum's disease can be treated successfully by dietary therapy. In case of dietary treatment and BMT, assay of VLCFA and/or PHYT is important for the biochemical evaluation of these therapies.

Near miss events or apparent life threatening events (ALTE) are considered preliminary stages of sudden infant death syndrome (SIDS). The current definition of near miss SIDS postulates that such an event happens unexpectedly and that no life threatening cause of disease can be detected. However in 32 of 34 observations of ALTE pathological changes actually could be identified by through investigations: 11 central nervous diseases, 10 respiratory tract disturbances, 5 metabolic abnormalities, 5 disturbances of the digestive tract and 1 cardiac disease. There were 22 morphologically manifested causes as opposed to 10 functional failures mainly respiratory control and oesophageal disturbances. Irrespective of the main diagnosis sleep apnea syndrome (SAS) could be detected in 17 of 28 infants combined with bradycardia in 5 cases, and oesophageal disturbances in 16 of 17 infants. Four babies later died, two of them suffered from carnitine deficiency and one from organic acidopathy. It is our conclusion that numerous, even banal causes of disease are able to trigger ALTE if there is a coincidence with phases of increased instability of vital regulatory mechanisms of autonomous centres in infants.

We report on a mature male newborn who presented clinically on the 2nd day of live with poor feeding and acidotic breathing. Laboratory findings like severe metabolic acidosis, hyperammonemia, hyperglycinemia, ketonuria and elevated urinary excretion of lactate and propionate suggested the presence of organoacidopathia. Propionic acidemia, however could be diagnosed definitively only when the characteristic urinary and blood metabolites were found during the state of a hyperammonemic coma provoked by a fully oral protein regimen. The diagnosis was affirmed by reduced propionate fixation and by reduced propionyl-CoA-carboxylase shown in the patient's skin fibroblasts.

In two patients suffering from infantile and juvenile types of alpha-1,4 glucosidase deficiency (Pompe's disease, glycogen storage disease types 2a and 2b) with typical lysosomal glycogen storage, widespread dry "ichthyosiform" scaling skin was observed. The clinical and microscopical findings resembled those of ichthyosis vulgaris. Even in the cytoplasm of keratinocytes vacuolar glycogen accumulation was demonstrated, suggesting a correlation between this pathological storage process and the symptom of "scaling". Therefore, ichthyosiform scaling conditions should be investigated not only for disorders of lipid metabolism but also for a possible disturbance of the carbohydrate-digesting enzymes.

The sequence of reactions involved in plasmalogen biosynthesis has been evaluated in cultured fibroblasts of patients with the cerebrohepatorenal syndrome. A double-label, double-substrate incubation using [1-14C] hexadecanol and 1-0-[9', 10'-3H]hexadecylglycerol was performed to monitor the relative rates of peroxisomal and microsomal biosynthesic steps. [14C] radioactivity associated with 1'-alkenyl groups of plasmalogens was found to be drastically reduced in fibroblasts of affected patients whereas [3H] incorporation was apparently normal. This finding is specific for cerebrohepatorenal syndrome fibroblasts since cell lines of patients with childhood adrenoleukodystrophy and neuronal ceroidlipofuscinosis utilized the lipid precursors of plasmalogen biosynthesis at normal rates. The results show that the defect in plasmalogen synthesis in the cerebro-hepato-renal syndrome is restricted to the peroxisomal steps. The finding of normal microsomal biosynthetic steps was exploited to devise a novel diagnostic assay in fibroblasts and amniocytes based on the comparison of [3H/14C] isotope ratios within aldehydes released from plasmalogens by acid hydrolysis. The procedure can be completed with a minimal amount of cells since it renders quantitative analyses unnecessary. Therefore, this technique appears ideally suited for the sensitive and safe prenatal diagnosis of the cerebro-hepato-renal syndrome.