Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness.

Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy of large neurons. Mutations in PNPLA6 also cause human spastic paraplegia characterized by motor neuron degeneration. Here we identify PNPLA6 mutations in childhood blindness in seven families with retinal degeneration, including Leber congenital amaurosis and Oliver McFarlane syndrome. PNPLA6 localizes mostly at the inner segment plasma membrane in photoreceptors and mutations in Drosophila PNPLA6 lead to photoreceptor cell death. We also report that lysophosphatidylcholine and lysophosphatidic acid levels are elevated in mutant Drosophila. These findings show a role for PNPLA6 in photoreceptor survival and identify phospholipid metabolism as a potential therapeutic target for some forms of blindness.

[Prenatal diagnosis of skeletal dysplasia in first trimester of pregnancy X-linked dominant chondrodysplasia punctata]. / Prenatální diagnóza skeletální dysplazie v prvním trimestru tehotenství X-vázaná dominantní chondrodysplasia punctata.

Case report describes successful prenatal diagnosis of skeletal dysplasia in the first trimester of pregnancy in a female patient affected with X-linked dominat chondrodysplasia punctata (CDPX2). Her first pregnancy was terminated in the second trimester due to skeletal dysplasia of the foetus. The diagnosis in the following pregnancy was finished in the first trimester - before the end of the 13th gestational week. The diagnosis was established on the basis of ultrasonographic (US) examination and mutation analysis of the EBP gene in the material of chorionic villus sampling (CVS).

SHOX gene defects and selected dysmorphic signs in patients of idiopathic short stature and Léri-Weill dyschondrosteosis.

The aim of the study was to analyze frequency of SHOX gene defects and selected dysmorphic signs in patients of both idiopathic short stature (ISS) and Léri-Weill dyschondrosteosis (LWD), all derived from the Czech population. Overall, 98 subjects were analyzed in the study. Inclusion criteria were the presence of short stature (-2.0 SD), in combination with at least one of the selected dysmorphic signs for the ISS+ group; and the presence of Madelung deformity, without positive karyotyping for the LWD+ group. Each proband was analyzed by use of P018 MLPA kit, which covers SHOX and its regulatory sequences. Additionally, mutational analysis was done of the coding portions of the SHOX. Both extent and breakpoint localizations in the deletions/duplications found were quite variable. Some PAR1 rearrangements were detected, without obvious phenotypic association. In the ISS+ group, MLPA analysis detected four PAR1 deletions associated with a SHOX gene defect, PAR1 duplication with an ambiguous effect, and two SHOX mutations (13.7%). In the LWD+ group, MLPA analysis detected nine deletions in PAR1 region, with a deleterious effect on SHOX, first reported case of isolated SHOX enhancer duplication, and SHOX mutation (68.8%). In both ISS+ and LWD+ groups were positivity associated with a disproportionately short stature; in the ISS+ group, in combination with muscular hypertrophy. It seems that small PAR1 rearrangements might be quite frequent in the population. Our study suggests disproportionateness, especially in combination with muscular hypertrophy, as relevant indicators of ISS to be the effect of SHOX defect.

[Comparison of prenatal ultrasound examination, post-mortem magnetic resonance imaging and autopsy (a case report--schizencephaly)]. / Komparace prenatáního ultrazvukového vysetrení, post mortem magnetické rezonance a patologicko-anatomické pitvy (kazuistika--schizencefalie).

OBJECTIVE: To improve prenatal diagnostic with a feedback of autopsy, complemented by post mortem magnetic resonance imaging (MRI). MRI is important for malformations of CNS, where autopsy can be insufficient. SUBJECT: Case report. SETTING: MR unit of the Department of radiology, Department of obstetrics and gynaecology and Department of pathology, 1st medical school, Charles University in Prague, General Teaching Hospital. SUBJECT AND METHOD: To compare prenatal ultrasound, post mortem MRI and autopsy. CONCLUSION: Case report documented complementarity of all three method; full agreement in brain malformation type was found.

Meningocerebral angiodysplasia: post-mortem magnetic resonance imaging and autopsy. A case report.

This case report describes a finding of vascular malformation of an aborted foetus of gestational age of the 22nd week. This concerns meningocerebral angiodysplasia, located in the posterior fossa and around the thalami. This disease is rare and is often accompanied by renal agenesis. The finding was complicated by hydrocephalus. Our report compares all three diagnostic methods (prenatal ultrasonography, post-mortem MR and autopsy). Prenatal ultrasonography described only hydrocephalus and reduction of cerebral parenchyma. MR displayed the extent of the malformation, the exact diagnosis was however determined by histological examination. MR described agenesis of structures of midbrain, which was confirmed by autopsy.

[Antley-Bixler syndrome or POR deficiency?]. / Antley-Bixleruv syndrom nebo POR deficience?

Antley-Bixler syndrome (ABS) is a rare congenital disorder characterized by numerous craniofacial, skeletal and, in some cases, urogenital abnormalities resulting from disordered steroidogenesis. Known genetic causes in sporadic cases of ABS include dominant mutations in the fibroblast growth factor 2 receptor gene (FGFR2). Recent research shows surprisingly that symptoms of Antley-Bixler syndrome, combined with disordered steroidogenesis and urogenital anomalies, are caused by mutations in the POR gene that encodes NADPH-cytochrome P450 oxidoreductase (CYPOR). CYPOR is a four domain-containing monomeric flavoprotein that contains two flavins, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), a binding site for NADPH, and the N-terminal sequence of 25 amino acids which determines the microsomal localization of the protein. CYPOR is the electron donor to microsomally localized cytochromes P450 that participate in xenobiotic metabolism and steroidogenesis. Mutations in the POR gene lead to apparent diminished activity of some P450 enzymes. Association of CYPOR with ABS discloses new facts about this disease and recent research shows that patients with ABS-like skeletal anomalies, but with mutations in the POR gene and disordered steroidogenesis, represent a new disorder called POR deficiency.

X-linked dominant chondrodysplasia punctata (CDPX2): multisystemic impact of the defect in cholesterol biosynthesis.

Chondrodysplasia punctata represents clinically and genetically a heterogeneous group of disorders characterized by the presence of multiple congenital anomalies and stippled epiphyses. We present clinical course of the disease and the results of metabolic, X-ray and molecular analyses in 19-months old girl with X-linked dominant chondrodysplasia punctata with intrauterine growth retardation, craniofacial dysmorphy, cataracts, cutaneous anomalies including ichthyosis, asymmetric rhizomesomelic shortness of the limbs, deformity of the spine, club foot, polydactyly, syndactyly, epiphyseal stippling and low cholesterol (2.29 mmol/l). Spectrophotometric analysis revealed the presence of abnormal pattern of cholesterol precursors in blood. The increased level of 8-dehydrocholesterol (42.2 micromol/l, controls < 1) and 7-dehydrocholesterol (25.5 micromol/l, controls < 1) recognised with GC/MS suggested an endogenous defect of cholesterol biosynthesis. The diagnosis of X-linked dominant chondrodysplasia punctata (CDPX2) was confirmed by the molecular analysis. Sequencing of the EBP gene encoding for 3beta-hydroxysteroid-delta8,delta7-isomerase revealed the presence of "de novo" heterozygous mutation c.327C>T (p.Arg110Stop). High cholesterol diet normalized cholesterol level (3.28 mmol/l) but it had no influence on the unfavourable prognosis of the disease. Low level of cholesterol with abnormal sterol profile in a child with congenital development anomalies represent an important laboratory marker suggesting an inherited defect of cholesterol biosynthesis.

[Case reports of patients with a marker chromosome]. / Kazuistiky pacientu s marker chromozómy.

Small, usually supernumerary chromosomes, denoted as marker chromosomes or markers, can be represented by various phenotypic expression, that depends on their origin and extent. Our article presents results of molecular cytogenetic analysis (FISH) of 34 patients with identified marker chromosome. In 21 cases a marker derived from acrocentric chromosome was identified, in 9 cases markers of gonosomal origin [der(X), der(Y)], and in 4 patients markers of some other chromosomes (5, 17, 18) were proved. The most frequent marker was that originating from chromosome 15 (8 cases). Two patients with different phenotype, markedly influenced by the extent of pseudoizodicentric chromosome 15 are described. In accordance with hitherto presented data, presence of supernumerary copies of the critical region PWACR (it is the partial trisomy, resp. tetrasomy 15q11-q13) in majority of cases brings about serious affection described as syndrome of the inverted duplication of chromosome 15. The most typical symptoms are psychomotoric retardation, hypotony, neurological symptoms and autistic features. The article stresses the importance of FISH method in the prenatal examination of marker chromosomes.

Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects.

Inherited defects of skull ossification often manifest as symmetric parietal foramina (PFM; MIM 168500). We previously identified mutations of MSX2 in non-syndromic PFM and demonstrated genetic heterogeneity. Deletions of 11p11-p12 (proximal 11p deletion syndrome, P11pDS; MIM 601224) are characterized by multiple exostoses, attributable to haploinsufficiency of EXT2 and PFM. Here we identify ALX4, which encodes a paired-related homeodomain transcription factor, as the PFM disease gene in P11pDS.

[Cooperation between genetic counseling centers, cytogenetic laboratories and in vitro fertilization centers in the treatment of reproductive disorders]. / Soucinnost genetické poradny, cytogenetické laboratore a centra IVF pri lécbe poruch plodnosti.

The techniques of assisted reproduction have recently become the most effective methods of treatment of infertility; namely ICSI (intra-cytoplasmic sperm injection), MESA (microepididymal sperm aspiration), TESA (testicular sperm aspiration) and TESE (testicular sperm extraction). The techniques have been increasingly successful, even above the average efficiency of classical IVF (in vitro fertilization). It can be demonstrated by the percentage of ICSI-aided births percentage per 100% of embryotransfers in ISCARE; 1996 = 21.3%, 1997 = 26.15%, 1998 = 29.7%. The successful use of these techniques is associated with the rise of risks which result from the selection of couples for assisted reproduction with genetic-based infertility and with the rise of risks involving the introduction of genetic-based defects in to the next generation. Presently, a list of indications is being developed, which, while still not accepted officially, identifies patients for genetic counselling. Only the counselling center has the competence to estimate genetic risks over generations. Subsequently, after selection by the center, during 1997 and 1998 the chromosomes of 731 patients were cytogenetically examined, representing 429 infertile couples from the centres ISCARE, PRONATAL, FERTIMED, and CAR 1. LF UK. Within these 429 couples, belonging to four groups of indications, the cytogenetic examination was informative in 8.15%. This finding of a relatively high percentage (10 times more than in the general population) confirms the validity of the list of indications and the necessity of cooperation among the genetic counselling center, cytogenetic laboratory and the IVF centre.

[Cleft lip and palate--prenatal diagnosis and counseling]. / Rozstep rtu a patra--prenatální diagnostika a poradenství.

The most frequent congenital developmental defect in the orofacial region are, no doubt, facial clefts which are a serious stress for health professionals and the population. Depending on the type of cleft, the prevalence is between 1 : 1000-2800 births. According to contemporary views in the etiology of orofacial clefts participate genetic as well as environmental factors. That means that specific genetic factors create a certain "sensitivity" for specific factors of the external environment which act as a trigger mechanism and combined they produce the cleft. Cleft lip can be diagnosed already during the 13th week of gestation, while a cleft palate is not necessarily apparent till after the 18th week of gestation as the maxilla is in the process of joining. Presentation of the foetal face and its profile is thus important in particular during the second trimester of gestation and should be part of ultrasonographic screening between the 18th and 20th week of gestation. As more than 8% of facial clefts are associated with chromosomal abnormalities, in all affected foetuses karyotyping is done. The prognosis of satisfactory cosmetic and functional repair in cleft lip and in cleft lip and palate is favourable. In case of associated malformations all depends on the type and severity of these associated defects or on the diagnosis of the syndrome. If median clefts are extensive or associated with cerebral anomalies, the prognosis is as a rule poor. Prenatal diagnosis and management of defects of the orofacial area calls for collaboration of the obstetrician, neonatologist and plastic surgeon already in the stage when the defect is detected to give the expectant mother an opportunity to obtain accurate and unbiased information on possible treatment and prognosis for the foetus.

Brachytelephalangic chondrodysplasia punctata with distinctive phenotype and normal karyotype.

We present two sibs with a distinctive phenotype and with stippled calcifications of the tarsal bones and sacro-coccygeal spine. They represent an apparently "new" form of chondrodysplasia punctata.

Severe limb abnormalities: Nievergelt or new syndrome?

Since the characteristic mesomelic limb abnormalities of the autosomal-dominant Nievergelt syndrome (NS) may be casually nonspecific, we are unsure whether our patient with these abnormalities but also with severe, symmetrical hand and foot anomalies has an unusual form of Nievergelt syndrome or a previously apparently undescribed syndrome. This infant's condition could represent an autosomal-dominant new mutation, or an autosomal or X-linked recessive disorder.

Foramina parietalia permagna: report of nine cases in one family.

Nine members of a family with foramina parietalia permagna (FPP), inherited as an autosomal dominant trait are reported. Although usually benign, FPP may be associated with other malformations.

Opsismodysplasia: a case report.

A 6-month-old boy with opsismodysplasia is reported. The purpose of this paper is to draw attention to severe ureteric reflux and incidence of pseudo-obstruction, findings not previously reported in opsismodysplasia. They are most likely the result of an intrinsic neuromuscular defect which also affects the skeletal muscles. Another new feature, not reported in opsismodysplasia, was dilatation of ventricles probably secondary to brain atrophy.

[Mucolipidosis II (I cell disease). First case report in the Czech Republic and prenatal diagnosis in a family]. / Mukolipidóza II (I cell disease). Popis prvého prípadu v Ceské republice a prenatální diagnóza v rodine.

The authors describe the first case of mucolipidosis II in the Czech Republic. The cause of this autosomal recessive hereditary disease is deficient synthesis of mannoso-6-phosphate ligand on precursors of lysosomal enzymes which normally make their transport into the lysosomal system possible. The diagnosis was proved by the presence of typical lysosomal cumulation in bioptic specimens and extremely elevated activity of lysosomal enzymes in the patient's serum caused by their non-regulated secretion and subsequent intracellular depletion. During the second pregnancy in the family prenatal diagnosis was made. A normal range of lysosomal enzyme activities in the supernatant of the amniotic fluid and in cultivated chorionic villi along with normal results of ultrastructural examination of the chorionic villus indicated the development of an intact foetus.

Lethal kyphomelic dysplasia.

A lethal form of kyphomelic dysplasia with severe bowing of the long bones of the lower extremities is reported.