Reproductive function in men affected by X-linked adrenoleukodystrophy/adrenomyeloneuropathy.

BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is the most frequent, severely neurodegenerative, clinically heterogeneous peroxisomal disorder, the signs of which are a consequence of myelin, adrenal cortex, and testes impairment. OBJECTIVE: We studied testosterone, LH, and FSH levels in X-ALD/adrenomyeloneuropathy (AMN) patients. We evaluate the ability to procreate of these patients by analysis of pedigree and family screening by detection of very long-chain fatty acid (VLCFA) levels. SUBJECT AND METHODS: Seventeen patients with X-ALD/AMN (16 with AMN and one asymptomatic) aged 24-48 (mean±S.D., 34.7±5.9) years, were identified based on the clinical picture, magnetic resonance imaging, and the presence of increased serum VLCFA levels. Nine X-ALD/AMN patients' daughters, mean ages ±S.D.=7.7±3.8 years, were identified as heterozygote by elevated VLCFA levels. Serum VLCFA levels were determined as ester derivatives by a gas chromatography method. Serum testosterone, LH, and FSH levels in X-ALD/AMN patients were detected by IRMAs. RESULTS: Serum testosterone levels were at the lowest levels of normal range but serum LH and FSH concentrations were increased in 57.1 and in 42.9% of X-ALD/AMN patients respectively. Among the 11 investigated of X-ALD/AMN married adult men, nine had produced offspring, a total of 13 children. All patients' daughters showed elevated serum VLCFA at heterozygote levels. CONCLUSION: In this study, we report that in a group of X-ALD/AMN married adult men, we did not find a significant decrease in fertility compared with the Polish population (18.2 vs 15%).

Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.

Autosomal dominant hypercholesterolemia (ADH) is caused by mutations in the genes coding for the low-density lipoprotein receptor (LDLR), apolipoprotein B-100 (APOB), or proprotein convertase subtilisin/kexin type 9 (PCSK9). In this study, a molecular analysis of LDLR and APOB was performed in a group of 378 unrelated ADH patients, to explore the mutation spectrum that causes hypercholesterolemia in Poland. All patients were clinically diagnosed with ADH according to a uniform protocol and internationally accepted WHO criteria. Mutational analysis included all exons, exon-intron boundaries and the promoter sequence of the LDLR, and a fragment of exon 26 of APOB. Additionally, the MLPA technique was applied to detect rearrangements within LDLR. In total, 100 sequence variations were identified in 234 (62%) patients. Within LDLR, 40 novel and 59 previously described sequence variations were detected. Of the 99 LDLR sequence variations, 71 may be pathogenic mutations. The most frequent LDLR alteration was a point mutation p.G592E detected in 38 (10%) patients, followed by duplication of exons 4-8 found in 16 individuals (4.2%). Twenty-five cases (6.6%) demonstrated the p.R3527Q mutation of APOB. Our findings imply that major rearrangements of the LDLR gene as well as 2 point mutations (p.G592E in LDLR and p.R3527Q in APOB) are frequent causes of ADH in Poland. However, the heterogeneity of LDLR mutations detected in the studied group confirms the requirement for complex molecular studies of Polish ADH patients.

Maternal tetrahydrobiopterin deficiency: the course of two pregnancies and follow-up of two children in a mother with 6-pyruvoyl-tetrahydropterin synthase deficiency.

No reports are available about the course of pregnancies in women with tetrahydrobiopterin (BH(4)) deficiencies or the effects of treatment with BH(4), L-dopa/carbidopa and 5-hydroxytryptophan (5-OHTrp) on fetal development. We present for the first time the case of a mother with late-diagnosed mild form of 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, the course of her two subsequent pregnancies and clinical evaluation with follow-up of two offspring. In both pregnancies neurotransmitter precursors, as well as BH(4) dosages were increased proportionally to the mother's weight gain. To prevent maternal phenylketonuria (MPKU) syndrome, special attention was paid to increasing BH(4) dosages. Both pregnancies were complicated by threatened premature labour, by the mother's nicotinism and additionally, in the first pregnancy, by gestational diabetes mellitus and vaginitis. The first child was born in the 31st week of pregnancy with the symptoms of moderate intrauterine growth retardation (IUGR) and brain malformation in the form of right sided closed-lip schizencephaly with absence of septum pellucidum. Although the girl demonstrates mild left-sided hemiparesis, her psychological development at the age of 8 years is above average. The second child was born in the 37th week of pregnancy without brain anomalies and at the age of 5 years his psychomotor development is appropriate for the age. As the cause of brain malformations resulting in physical impairment in the first child is unknown, more data are essential to verify conclusions about the influence of the mother's BH(4) deficiency and the safety of her treatment for fetal development.

Hypoxanthine-guanine phosphoribosylotransferase deficiency--the spectrum of Polish mutations.

Hypoxanthine-guanine phosphoribosyltransferase (HPRT; EC 2.4.2.8) deficiency (OMIM 308000) is an inborn error of purine metabolism. The defect causes three overlapping clinical syndromes: Lesch-Nyhan disease (LND; OMIM 300322), HPRT-related hyperuricaemia with neurologic dysfunction (HRND) and hyperuricaemia alone (HRH; OMIM 300322). During the period 1977-2007, 18 patients belonging to 12 Polish families and one Latvian family with HPRT deficiency have been identified. The majority of patients had a typical LND phenotype, three patients were classified as HRH and one patient as an intermediate phenotype (HRND). Genetic analysis revealed 12 different HPRT1 mutations, five of them being unique. In two typical Lesch-Nyhan families a novel single-base substitution, c.220T>G (p.Phe74Val), and a deletion of seven nucleotides, c.395_401del7 (p.Ile132LysfsX3), were found. Another novel single-base substitution, c.295T>G (p.Phe99Val), was identified in a patient with severe partial deficiency of HPRT with neurological dysfunction. In patients belonging to the HRH group, two transitions were detected: c.481G>A (p.Ala161Thr) and c.526C>T (p.Pro176Ser). Other mutations identified in Polish patients, c.131A>G (p.Asp44Gly), c.222C>A (p.Phe74Leu), c.385-1G>A (p.Asn129_Glu134del), c.482C>A (p.Ala161Glu), c.508C>T (p.Arg170Ter) and c.569G>A (p.Gly190Glu), have been reported previously in unrelated patients and are located within one of the clusters of hot spots of the HPRT1 gene (exons 3, 7 and 8). Patients with partial phenotypes presented mutations predicted to permit some degree of residual enzyme function (single-base substitutions). All mutations, except c.508C>T (p.Arg170Ter), were found in single families only, indicating the lack of any common mutation causing HPRT deficiency in Poland.

LDL-R and Apo-B-100 gene mutations in Polish familial hypercholesterolemias.

A group of 30 Polish families with clinical signs of familial hypercholesterolemia was studied for the presence of germ-line mutations in the LDL-R and ApoB-100 genes. Screening of the LDL-R gene was performed at the genomic DNA level by single-strand conformation polymorphism analysis of all 18 exons and extended by sequencing of polymerase chain reaction (PCR) products showing abnormalities. The occurrence of large LDL-R gene alterations was evaluated by analysis of restriction enzyme patterns on Southern blots and using the long-PCR technique. The ApoB-100 gene was studied by combined allele-specific and asymmetric PCR for the occurrence of the common B-3500 missense mutation G to A at nucleotide position 10,708. Germ-line mutations were found in 17 families. In 12 of them LDL-R gene mutations were detected. Three of 11 different mutations had previously been described in other populations (3-bp deletion of codon 197; Ser156Leu; Gly571Glu). Of the mutations not previously recognized and identified in Polish families, there were three small deletions (2-bp deletion AG at codon 291; 4-bp deletion CCCT at codons 661-662; 1-bp deletion A at codon 830), and four point mutations (Arg239Stop, Cys331Stop, Asn543Ser, Gln665Stop). Additionally, one large (approximately 1-kb) LDL-R gene deletion between exons 6 and 9 was identified. In five families, the B-3500 mutation within the ApoB-100 gene was revealed.

[Arterial hypertension as a complication of homocystinuria in a 14-year old boy]. / Nadcisnienie tetnicze jako powiklanie homocystynurii u 14-letniego chlopca.

A boy with homocystinuria diagnosed at the age of fourteen during arterial hypertension diagnostic procedures performed because of severe arterial hypertension. Hypertension was caused by thromboembolic changes within segmental branch of renal artery.

[Ocular problems in children with homocystinuria]. / Problemy okulistyczne u dzieci z homocystynuria.

Homocystinuria was diagnosed in 12 patients, aged 3-12 years. Myopia, ranged from -5.0 D to -20.0 D, and bilateral subluxation of lens were found in all children. In 8 eyes during follow-up luxation of lens was observed in 8 eyes, in 5 complicated by acute glaucoma. Surgical treatment, mostly pars plana lensectomia, was applied in 20 eyes. Normalisation of the intraocular pressure was achieved after surgery in 4 cases and improvement of visual acuity in 16 eyes. In 1 case of a boy after cerebral vessels infarct the intraocular pressure remained elevated and optic nerve atrophy developed. In 3 cases anterior scleral staphyloma was found.

[Metabolic cataract among the children from the Children's Health Center]. / Zacmy metaboliczne w materiale Centrum Zdrowia Dziecka.

The investigations concerned 385 children with a congenital cataract. It was not possible to establish the causes of the condition in 46.5 p.c. of examined children. The set of examinations which was used was sufficient for an explicit determination of the cause of the metabolic part of congenital cataracts. In galactosaemia opacification of the lens appeared in 64 p.c. of cases, in hypofunction of the parathyroids in 17.8 p.c., in hypoglycaemia in 6.6 p.c., in Lowe's syndrome in 100 p.c. of cases.

Disturbances in histidine metabolism in children with speech abnormalities.

Catabolism of histidine was investigated in 24 patients with different speech and language disorders and with significantly low histidase activity in stratum corneum. No classical histidinemia was found. Biochemical investigation of these patients after loading with L-histidine led to the conclusions that low histidase activity in stratum corneum was connected with: disturbances in folic acid metabolism (2 cases); "atypical histidinemia" (1 case); heterozygotes of histidinemia (2 cases); normal liver histidine metabolism but abnormal in other tissues (18 cases); previously unknown error of histidine metabolism (1 case).

9p-syndrome: two new observations.

Our patients with 9p-syndrome show typical stigmata when compared with the 28 know cases described in the literature . In Table 1 we compared our 4 cases with those previously described. Only A.K. lacks two features present in all the others: flat occiput and micrognathia.

Prenatal diagnosis of Sanfilippo disease type B.

The prenatal diagnosis of a fetus affected with Sanfilippo disease type B is described. The deficiency of alpha-N-acetylglucosaminidase in the cultured amniotic fluid cells was shown by a microassay enabling early prenatal diagnosis. In addition an increased level of heparan sulphate was demonstrated in the amniotic fluid by two-dimensional electrophoresis of glycosaminoglycans. The latter result confirmed the value of this test as an adjunctive method in the prenatal diagnosis. The pregnancy was terminated and the prenatal diagnosis was confirmed by enzyme analysis of cultured fetal fibroblasts and fetal liver.