Phenotype and genotype in 101 males with X-linked creatine transporter deficiency.

BACKGROUND: Creatine transporter deficiency is a monogenic cause of X-linked intellectual disability. Since its first description in 2001 several case reports have been published but an overview of phenotype, genotype and phenotype--genotype correlation has been lacking. METHODS: We performed a retrospective study of clinical, biochemical and molecular genetic data of 101 males with X-linked creatine transporter deficiency from 85 families with a pathogenic mutation in the creatine transporter gene (SLC6A8). RESULTS AND CONCLUSIONS: Most patients developed moderate to severe intellectual disability; mild intellectual disability was rare in adult patients. Speech language development was especially delayed but almost a third of the patients were able to speak in sentences. Besides behavioural problems and seizures, mild to moderate motor dysfunction, including extrapyramidal movement abnormalities, and gastrointestinal problems were frequent clinical features. Urinary creatine to creatinine ratio proved to be a reliable screening method besides MR spectroscopy, molecular genetic testing and creatine uptake studies, allowing definition of diagnostic guidelines. A third of patients had a de novo mutation in the SLC6A8 gene. Mothers with an affected son with a de novo mutation should be counselled about a recurrence risk in further pregnancies due to the possibility of low level somatic or germline mosaicism. Missense mutations with residual activity might be associated with a milder phenotype and large deletions extending beyond the 3' end of the SLC6A8 gene with a more severe phenotype. Evaluation of the biochemical phenotype revealed unexpected high creatine levels in cerebrospinal fluid suggesting that the brain is able to synthesise creatine and that the cerebral creatine deficiency is caused by a defect in the reuptake of creatine within the neurones.

A known and a novel mutation in the glycine decarboxylase gene in a newborn with classic nonketotic hyperglycinemia.

A term neonate displayed typical features of nonketotic hyperglycinemia (NKH). Conventional magnetic resonance imaging showed corpus callosum hypoplasia and increased signal intensity of the white matter. Magnetic resonance proton spectroscopy revealed high cerebral glycine levels. The liquor/plasma glycine ratio was increased. Genetic testing detected a known and a novel mutation in the glycine decarboxylase gene, leading to the classic form of glycine encephalopathy. Prenatal genetic testing in the subsequent pregnancy showed that this fetus was not affected. As features of neonatal NKH may not be very specific, recognition of the disease may be difficult. An overview of clinical, electroencephalography, and neuroimaging findings is given in this article.

The 48-hour tetrahydrobiopterin loading test in patients with phenylketonuria: evaluation of protocol and influence of baseline phenylalanine concentration.

BACKGROUND: The 24- and 48-hour tetrahydrobiopterin (BH4) loading test (BLT) performed at a minimum baseline phenylalanine concentration of 400 µmol/l is commonly used to test phenylketonuria patients for BH4 responsiveness. This study aimed to analyze differences between the 24- and 48-hour BLT and the necessity of the 400 µmol/l minimum baseline phenylalanine concentration. METHODS: Data on 186 phenylketonuria patients were collected. Patients were supplemented with phenylalanine if phenylalanine was <400 µmol/l. BH4 20mg/kg was administered at T = 0 and T = 24. Blood samples were taken at T=0, 8, 16, 24 and 48 h. Responsiveness was defined as ≥ 30% reduction in phenylalanine concentration at ≥ 1 time point. RESULTS: Eighty-six (46.2%) patients were responsive. Among responders 84% showed a ≥ 30% response at T = 48. Fifty-three percent had their maximal decrease at T = 48. Fourteen patients had ≥ 30% phenylalanine decrease not before T = 48. A ≥ 30% decrease was also seen in patients with phenylalanine concentrations <400 µmol/l. CONCLUSION: In the 48-hour BLT, T = 48 seems more informative than T = 24. Sampling at T = 32, and T = 40 may have additional value. BH4 responsiveness can also be predicted with baseline blood phenylalanine <400 µmol/l, when the BLT is positive. Therefore, if these results are confirmed by data on long-term BH4 responsiveness, we advise to first perform a BLT without phenylalanine loading and re-test at higher phenylalanine concentrations when no response is seen. Most likely, the 48-hour BLT is a good indicator for BH4 responsiveness, but comparison with long term responsiveness is necessary.

Obesity: a new disaster for haemophilic patients? A nationwide survey.

The prevalence of obesity, an important risk factor for both cardiovascular disease and arthropathy, is strongly increasing in the general population, but data for the haemophilia population are scarce. Obesity may have a more profound effect on arthropathy and on cardiovascular disease in patients with haemophilia. To assess the prevalence of obesity in haemophilia patients and install adequate measures, if necessary. We performed a nationwide postal survey to measure the prevalence of overweight and obesity in Dutch haemophilia patients in 1992 (n = 980) and 2001 (n = 1066). A random sample of the Dutch male population served as the control group. In adult haemophiliacs, the prevalence of overweight (BMI 25-30 kg m(-2)) increased from 27% to 35% (95% CI 31.1-38.0) and the prevalence of obesity (BMI >/=30 kg m(-2)) doubled from 4% to 8% (95% CI 6.0-10.1), which was comparable with the general population. The increased prevalence of obesity in boys with haemophiliacs, which tripled in 10 years, is alarming. The increased prevalence of overweight and obesity in patients with haemophilia may have a profound effect on morbidity and quality of life of haemophilia patients by aggravating pre-existing arthropathy and predisposing aged patients to cardiovascular disease. Measures to prevent overweight in haemophiliacs are therefore urgently needed.

Refinement of the multiple exostoses locus (EXT2) to a 3-cM interval on chromosome 11.

Hereditary multiple exostoses (EXT) is an autosomal dominant skeletal disorder characterized by the formation of multiple exostoses on the long bones. EXT is genetically heterogeneous, with at least three loci involved: one (EXT1) in the Langer-Giedion region on 8q23-q24, a second (EXT2) in the pericentromeric region of chromosome 11, and a third (EXT3) on chromosome 19p. In this study, linkage analysis in seven extended EXT families, all linked to the EXT2 locus, refined the localization of the EXT2 gene to a 3-cM region flanked by D11S1355 and D11S1361/D11S554. This implies that the EXT2 gene is located at the short arm of chromosome 11, in band 11p11-p12. The refined localization of EXT2 excludes a number of putative candidate genes located in the pericentromeric region of chromosome 11 and facilitates the process of isolating the EXT2 gene.