Diversity of cystathionine beta-synthase haplotypes bearing the most common homocystinuria mutation c.833T>C: a possible role for gene conversion.

Homozygosity or compound heterozygosity for the c.833T>C transition (p.I278 T) in the cystathionine beta-synthase (CBS) gene represents the most common cause of pyridoxine-responsive homocystinuria in Western Eurasians. However, the frequency of the pathogenic c.833C allele, as observed in healthy newborns from several European countries (q(c.833C) approximately equals 3.3 x 10(-3)), is approximately 20-fold higher than expected on the basis of the observed number of symptomatic homocystinuria patients carrying this mutation (q(c.833C) approximately equals 0.18 x 10(-3)), implying clinical underascertainment. Intriguingly, the c.833C mutation is also present in combination with a 68-bp insertion, c.[833C; 844_845ins68], in a substantial proportion of chromosomes from nonhomocystinuric individuals worldwide. We have sought to study the relationship between the pathogenic and nonpathogenic c.833C-bearing chromosomes and to determine whether the pathogenic c.[833C; -] chromosomes are identical-by-descent or instead arose by recurrent mutation. Initial haplotype analysis of 780 randomly selected Czech and sub-Saharan African wild-type chromosomes, employing 12 intragenic markers, revealed 29 distinct CBS haplotypes, of which 10 carried the c.[833C; 844_845ins68] combination; none carried an isolated c.833C or c.844_845ins68 mutation. Subsequent examination of 69 pathogenic c.[833C; -] chromosomes, derived from homocystinuria patients of predominantly European origin, disclosed three unrelated haplotypes that differed from their wild-type counterparts by virtue of the presence of c.833C, thereby indicating that c.833T>C transition has occurred repeatedly and independently in the past. Since c.833T does not reside within an obvious mutational hotspot, we surmise that the three pathogenic and comparatively prevalent c.[833C; -] chromosomes may have originated by recurrent gene conversion employing the common nonpathogenic c.[833C; 844_845ins68] chromosomes as templates.

Genetic diversity within the R408W phenylketonuria mutation lineages in Europe.

The R408W phenylketonuria mutation in Europe has arisen by recurrent mutation in the human phenylalanine hydroxylase (PAH) locus and is associated with two major PAH haplotypes. R408W-2.3 exhibits a west-to-east cline of relative frequency reaching its maximum in the Balto-Slavic region, while R408W-1.8 exhibits an east-to-west cline peaking in Connacht, the most westerly province of Ireland. Spatial autocorrelation analysis has demonstrated that the R408W-2.3 cline, like that of R408W-1.8, is consistent with a pattern likely to have been established by human dispersal. Genetic diversity within wild-type and R408W chromosomes in Europe was assessed through variable number tandem repeat (VNTR) nucleotide sequence variation and tetranucleotide short tandem repeat (STR) allelic associations. Wild-type VNTR-8 chromosomes exhibited two major cassette sequence organizations: (a1)5-b3-b2-c1 and (a1)5-b5-b2-c1. R408W-1.8 was predominantly associated with (a1)5-B5-B2-C1. Both wild-type vntr-3 and r408w-2.3 chromosomes exhibited a single invariant cassette sequence organization, a2-b2-c1. STR allele distributions associated with the cassette variants were consistent with greater diversity in the wild-type VNTR-8 lineage and were suggestive of different levels of diversity between R408W-1.8 and R408W-2.3. The finding of greater genetic diversity within the wild-type VNTR-8 lineage compared to VNTR-3 suggests that VNTR-8 may be older within the European population. However, in the absence of a more extensive STR data-set, no such conclusions are possible for the respective R408W mutant lineages.

The mutation spectrum of hyperphenylalaninaemia in the Republic of Ireland: the population history of the Irish revisited.

Phenylketonuric and hyperphenylalaninaemic patients in the population of the Republic of Ireland were screened for mutations at the human phenylalanine hydroxylase (PAH) locus. A composite data set for the island of Ireland was generated by merging the findings of this study with extant data for Northern Ireland. Analysis of this data on the basis of the four historic provinces (Munster, Leinster, Connacht and Ulster) revealed genetic diversity that is informative in terms of demographic forces that shaped the Irish population. R408W, the predominant Irish PAH mutation associated with haplotype 1.8, reached its highest relative frequency in the most westerly province, Connacht. This suggests that the gradient of R408W-1.8 observed across north-western Europe continues into Ireland and peaks in Connacht. Spatial autocorrelation analysis demonstrated that the gradient is consistent with a localised cline of R408W-1.8 likely to have been established by human migration. This and parallel allele frequency clines may represent the genetic traces of the Palaeolithic colonisation of Europe, a pattern not substantially altered in north-western Europe by subsequent Neolithic migrations. An analysis of mutant allele distributions in Ulster, Scotland and the rest of Ireland confirmed that Ulster has been a zone of considerable admixture between the Irish and Scottish populations, indicating a proportion of Scottish admixture in Ulster approaching 46%. Mutations primarily associated with Scandinavia accounted for 6.1% of mutations overall, illustrating the influence of Viking incursions on Irish population history.

Ocular axial length in homocystinuria patients with and without ocular changes: effects of early treatment and biochemical control.

PURPOSE: To establish whether myopia in homocystinuria could be due to increased ocular axial length. METHODS: Measurement of ocular axial length by A-scan ultrasound in eyes of homocystinuria patients. RESULTS: Patients were divided into three groups. Group I, with no ocular pathology (28 eyes), had mean refractive error of -0.25 D (spherical equivalent) and mean axial length of 23.4 mm +/- 0.9 (+/-1 standard deviation) mm. Group II, with phacodonesis or lens subluxation (12 eyes), had mean refractive error of -10.7 D and mean axial length of 23.8 mm +/-1.9 mm. Patients with phacodonesis had simple myopia whereas those with lens subluxation had marked myopic astigmatism. Group III included patients with complete lens dislocation in at least one eye (12 eyes) and were optically aphakic with a mean refractive error of +12.9 D and mean axial length of 24.9 mm +/- 0.9 mm. All Group I patients had good long-term metabolic control while those in Groups II and III did not. Group III eyes had significantly longer mean axial length than Group I (P =.0018) or normal eyes (P =.0163). There was no statistical difference in mean axial length between Group I and normal eyes. CONCLUSIONS: Ocular axial length is significantly increased in individuals with homocystinuria and lens dislocation. Increased axial length is a complication that has not been previously described in homocystinuria and may be preventable with early treatment and good biochemical control.

Neuroimaging findings in glutaric aciduria type 1.

OBJECTIVE: To review the imaging features of glutaric aciduria type 1 (GA-1) in a group of 20 patients, the largest published series to date. To document the findings not previously reported and compare our findings with the imaging characteristics of GA-1 previously reported in the literature. MATERIALS AND METHODS: For 14 patients the original scans were examined and in the remaining 6, where the imaging was unavailable, the radiology reports were consulted. Nine patients had serial cranial US examinations, 13 had 18 CT scans performed and 14 patients had 39 MRI scans. RESULTS: Widening of the sylvian fissures and of the fluid spaces anterior to the temporal lobes was seen in 93% of cases. The mesencephalic cistern was also widened in 86%. Abnormal high-signal intensity on T2-weighted (T2-W) images was seen in the basal ganglia and periventricular white matter in 64% of children. Subdural collections were found in 3 patients, all of which resolved spontaneously. Four neonates followed with serial cranial US showed bilateral multiple caudothalamic cysts. Abnormal high signal on T2-W images was seen in the dentate nucleus, substantia nigra and the pontine medial lemniscus in 79, 43 and 64%, respectively. CONCLUSIONS: Widening of the sylvian fissure, mesencephalic cistern and expansion of CSF spaces anterior to the temporal lobes are cardinal signs of GA-1. If combined with abnormalities of the basal ganglia and white matter, GA-1 should be strongly suspected.

Identification of sequence variation in the galactose-1-phosphate uridyl transferase gene by dHPLC.

Transferase-deficient galactosaemia is an inherited disorder of carbohydrate metabolism, caused by mutation at the galactose-1-phosphate uridyl transferase (GALT) locus. A denaturing high performance liquid chromatography (dHPLC) method was developed for variant scanning of the GALT gene. The method unequivocally identified the Duarte D1, D2, Q188R, and K285N GALT alleles and associated polymorphisms. Length polymorphism in an intronic Alu repeat was characterised and a novel Single Nucleotide Polymorphism (IVS10nt-322g-->t) associated with the D1 allele was identified.

Frequency distribution of the Los Angeles and Duarte galactose-1-phosphate uridyltransferase variant alleles in the Irish population.

Anonymous population screening was carried out to detect the N314D, Los Angeles (D1), and Duarte (D2) alleles of the galactose-1-phosphate uridyltransferase gene in Ireland using 743 blood samples, covering the Traveller (n = 243) and non-Traveller (n = 500) population groups. The frequency of the N314D substitution was found to be 0.099 overall. D1 allele frequencies were found to be 0.031 and 0.023 in the Traveller and non-Traveller groups, respectively, while D2 allele frequencies were 0.058 and 0.076, respectively. No significant differences in allele frequency were detected between the Traveller and non-Traveller groups, or between the Irish population groups and the literature values for Northern and Western Europe.