No abstract

Unlike some other childhood neurodevelopmental disorders, no diagnostic biochemical marker has been identified in all individuals with an autism spectrum disorder (ASD). This deficit likely results from genetic heterogeneity among the population. Therefore, we evaluated a subset of individuals with ASDs, specifically, individuals with or without macrocephaly in the presence or absence of PTEN mutations. We sought to determine if amino or organic acid markers could be used to identify individuals with ASDs with or without macrocephaly in the presence or absence of PTEN mutations, and to establish the degree of macrocephaly in individuals with ASDs and PTEN mutation. Urine, blood and occipital-frontal circumference (OFC) measurements were collected from 69 individuals meeting DSM-IV-TR criteria. Urine and plasma samples were subjected to amino and organic acid analyses. PTEN was Sanger-sequenced from germline genomic DNA. Germline PTEN mutations were identified in 27% (6/22) of the macrocephalic ASD population. All six PTEN mutation-positive individuals were macrocephalic with average OFC þ 4.35 standard deviations (SDs) above the mean. No common biochemical abnormalities were identified in macrocephalic ASD individuals with or without PTEN mutations. In contrast, among the collective ASD population, elevation of urine aspartic acid (87%; 54/62), plasma taurine (69%; 46/67) and reduction of plasma cystine (72%; 46/64) were observed. PTEN sequencing should be carried out for all individuals with ASDs and macrocephaly with OFC Z2SDs above the mean. A proportion of individuals with ASDs may have an underlying disorder in sulfur amino acid metabolism.

Historically, many different therapies have been assessed for their ability to alter disease progression of the Neuronal Ceroid Lipofuscinoses (NCLs). While some treatments have lead to minor improvements, none have been able to arrest disease progression or improve the quality or duration of life. Presently, many new therapeutic strategies, such as chaperone therapy, enzyme replacement therapy, gene therapy, and stem cell therapy, are being investigated for their ability to alter the disease course of the NCLs. This review summarizes previous studied therapies, discusses those currently being evaluated and examines possibilities for future therapies for the treatment of patients with NCL.

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) results from a deficiency of CLN3, a protein recently identified within detergent-resistant membranes (DRMs). To study the function of CLN3 within these domains we isolated DRMs from control and JNCL-brain and noted that JNCL-derived DRMs are less buoyant than control. Analysis of DRM phospholipids derived from JNCL-brain revealed a reduction of bis(monoacylglycerol)phosphate. Metabolic labeling of JNCL-fibroblasts demonstrated a reduction in the synthesis of bis(monoacylglycerol)phosphate which was restored following complementation with wild-type-CLN3, substantiating our initial observation in brain. Metabolic labeling of cell lines overexpressing wild-type-CLN3 resulted in increased bis (monoacylglycerol)phosphate synthesis, while overexpression of mutant CLN3-L170P decreased bis(monoacylglycerol)phosphate synthesis. These data illustrate a new finding, a strong correlation between CLN3 protein expression and synthesis of bis(monoacylglycerol)phosphate.

Purpose Cowden Syndrome (CS) results from germline mutations in phosphatase and tensin homologue deleted on chromosome ten (PTEN) and from variants in succinate dehydrogenase (SDH) B and D subunits. We hypothesized that succinate accumulation may be common among individuals with SDH variants/mutations and those with PTEN mutations. Methods Urine and blood were collected from individuals meeting full or partial CS diagnostic criteria, those with paraganglioma or a known susceptibility PGL-associated gene mutation and succinate was measured. PTEN, SDHB, SDHC, and SDHD-genes were sequenced from genomic DNA. Results Elevated plasma succinate was observed in 13/21 (62%) individuals with germline PTEN, SDHB or SDHD mutations compared to 5/32 (16%) controls (p<0.001); 10/15 (67%) individuals with pathogenic PTEN mutations, but in <20% of mutation negative individuals meeting identical criteria; and among individuals with mutations in SDHB (1/1, 100%) and SDHD (2/5, 40%). Conclusions Our data suggest that mutations in PTEN, SDHB and SDHD reduce catalytic activity of SDH and result in succinate accumulation and identify a common biochemical alteration between these two patient populations. Plasma organic acid analysis may provide an effective and inexpensive screening method to determine when more expensive gene sequencing of PTEN and SDH-genes is warranted.