Prenatal death in Fraser syndrome

Cryptophthalmos may be partial or complete, unilateral or bilateral, apparently nonsyndromal or syndromal. A recent study of 2 stillborn infants at the University of Utah prompted an analysis of the developmental aspects of the syndromal form (Fraser syndrome). We conclude that, per se, cryptophthalmos is a developmental field defect on the basis of heterogeneity (autosomal dominant and recessive forms) and phylogeneity (occurrence also in the pheasant, rabbit, pigeon, dog, and mouse). In humans this autosomal recessive disorder maps to 4q21, is homologous to the bleb (bl/bl) mouse, and is due to mutations in the FRAS1 gene that codes for a 4007 amino acid protein 85% identical to the Fras1 gene of the bleb mouse. Commonest anomalies in humans are cryptophthalmos, cutaneous syndactyly of digits, abnormal ears and genitalia, renal agenesis, and congenital heart defects. Almost half of affected infants are stillborn or die in infancy, and mental retardation is common. The pathogenesis evidently involves abnormal epithelial integrity during prenatal life. Older (mostly German) publications, some dating to the 19th century, provide a fascinating historical insight into the process of syndrome delineation.     

Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2).

Mutations in the MECP2 (methyl-CpG-binding protein 2) gene are known to cause Rett syndrome, a well-known and clinically defined neurodevelopmental disorder. Rett syndrome occurs almost exclusively in females and for a long time was thought to be an X-linked dominant condition lethal in hemizygous males. Since the discovery of the MECP2 gene as the cause of Rett syndrome in 1999, MECP2 mutations have, however, also been reported in males. These males phenotypically have classical Rett syndrome when the mutation arises as somatic mosaicism or when they have an extra X chromosome. In all other cases, males with MECP2 mutations show diverse phenotypes different from classical Rett syndrome. The spectrum ranges from severe congenital encephalopathy, mental retardation with various neurological symptoms, occasionally in association with psychiatric illness, to mild mental retardation only. We present a 21-year-old male with severe mental retardation, spastic tetraplegia, dystonia, apraxia and neurogenic scoliosis. A history of early hypotonia evolving into severe spasticity, slowing of head growth, breathing irregularities and good visual interactive behaviour were highly suggestive of Rett syndrome. He has a de novo missense mutation in exon 3 of the MECP2 gene (P225L). The clinical spectrum and molecular findings in males with MECP2 mutations are reviewed.     

The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes

PURPOSE OF REVIEW: Infantile spasms, mental retardation, autism, and dystonia represent disabling diseases for which little etiologic information is available. Mutations in the Aristaless related homeobox gene (ARX) have been found in patients with these conditions. This discovery provides important genetic information and may ultimately offer treatment options for these patients. RECENT FINDINGS: Recent work has demonstrated that mutations in ARX cause X-linked West syndrome, X-linked myoclonic epilepsy with spasticity and intellectual disability, Partington syndrome (mental retardation, ataxia, and dystonia), as well as nonsyndromic forms of mental retardation. Patients with these aforementioned diseases and ARX mutations were not reported to have brain imaging abnormalities. In contrast, mutations in ARX mutations have also been found in X-linked lissencephaly with abnormal genitalia, which typically includes severe brain malformations (lissencephaly, agenesis of the corpus callosum, and midbrain malformations), intractable seizures, and a severely shortened lifespan. ARX knockout mice manifest defects in overall neuroblast proliferation as well as selective abnormalities in gamma-aminobutyric acid-ergic interneuron migration. Consistent with these findings in mice, phenotype/genotype studies in humans suggest that truncating mutations cause X-linked lissencephaly with abnormal genitalia, and insertion/missense mutations result in epilepsy and mental retardation without cortical dysplasia. SUMMARY: Mutations in the homeobox gene, ARX, cause a diverse spectrum of disease that includes cognitive impairment, epilepsy, and in another group of patients severe cortical malformations. Although the precise prevalence of ARX mutations is unclear, ARX may rival Fragile X as a cause of mental retardation and epilepsy in males.     

Fragile X syndrome

Fragile X syndrome is the most common familial form of mental retardation. This X-linked disorder affects one in every 1000 males and one in every 2000 females. The female carrier rate in the general population is estimated to be 1/600. A fragile site at the distal long arm of the X chromosome (Xq 27.3) is the hallmark cytogenetic feature of the syndrome. Clinical features include physical as well as cognitive and neuropsychological deficits. Although fragile X syndrome follows an X-linked pattern of inherltance (which explains the predominance of affected males), females can also beaffected,Many inconsistencies exist between the genetic inheritance pattern of fragile X and traditional Mendelian inheritance tenets of most X-linked diseases. Due to recent molecular advances, our understanding of the perplexing genetic issues surrounding fragile X syndrome has grown and diagnostic techniques have become both reliable and readily available.     

转录辅助调节因子HCFC1突变致罕见X连锁甲基丙二酸尿症CblX型一家系报告

目的探讨X连锁甲基丙二酸尿症CblX家系的临床及基因特点。方法回顾性分析1例经血液及尿液分析发现甲基丙二酸尿症,并采用靶向捕获二代测序进行HCFC1基因分析诊断的X连锁甲基丙二酸尿症患儿的临床资料。结果患儿,男,于2月龄时出现抽搐,智力运动障碍,5月龄时表现癫痫、重度发育落后,尿甲基丙二酸、血液丙酰肉碱增高,血浆总同型半胱氨酸增高,符合甲基丙二酸尿症合并同型半胱氨酸血症。甲基丙二酸尿症相关常染色体基因分析未见突变,X染色体转录辅助调节因子HCFC1第3外显子存在c.344C??T(p.Ala115Val)半合子突变,证实为CblX型甲基丙二酸尿症。患儿父母健康,曾有一子生后重度智力、运动障碍,合并难治性癫痫,于6月龄夭折。患儿母亲携带相同的突变,尿液可检出少量甲基丙二酸,血浆同型半胱氨酸轻度增高。患儿父亲未携带突变。结论以新一代测序技术首次确诊我国1例X连锁CblX型甲基丙二酸尿症家系。     

Monogenic causes of nonspecific X-linked mental retardation molecular aspects

Mental retardation (MR) is a symptom in a large group of clinical conditions and affects around 3% of the population. MR is divided into syndromic, if it is characterized by distinctive clinical features and nonspecific when mental retardation is the only defining manifestation. Although genetic causes of X-linked mental retardation (XLMR) are heterogenous and complex, recent findings have led to the identification of an increasing number of genes involved in these conditions. Eight genes involved in nonspecific X-linked mental retardation have been identified so far, including FMR2, GDI1, OPHN1, PAK3, ARHGEF6, IL1RAPL, TM4SF2, and FACL4. Four other MECP2, RSK2, ARX, ATR-X are involved in syndromic and nonspecific forms of MR. Recent research has shown that these genes encode for proteins involved in signaling pathways which regulate cytoskeleton organization, synaptic vesicle transport and establishment of connections between neuronal cells. These findings provide insight into the molecular mechanisms of crucial processes for the development of intellectual and cognitive functions.     

Clinical genetic evaluation of the child with mental retardation or developmental delays

This clinical report describes the clinical genetic evaluation of the child with developmental delays or mental retardation. The purpose of this report is to describe the optimal clinical genetics diagnostic evaluation to assist pediatricians in providing a medical home for children with developmental delays or mental retardation and their families. The literature supports the benefit of expert clinical judgment by a consulting clinical geneticist in the diagnostic evaluation. However, it is recognized that local factors may preclude this particular option. No single approach to the diagnostic process is supported by the literature. This report addresses the diagnostic importance of clinical history, 3-generation family history, dysmorphologic examination, neurologic examination, chromosome analysis (> or =650 bands), fragile X molecular genetic testing, fluorescence in situ hybridization studies for subtelomere chromosome rearrangements, molecular genetic testing for typical and atypical presentations of known syndromes, computed tomography and/or magnetic resonance brain imaging, and targeted studies for metabolic disorders.     

New X linked mental retardation syndrome

IntroductionResearching inherited mental retardation, from a diagnostic and aetiological point of view, is a great challenge. A particular type of mental retardation is the one linked to the X chromosome which is classified under syndromic and non-syndromic types, according to the presence or absence of a specific physical, neurological or metabolic pattern associated with mental retardation.Patients and methodFive generations of a family have been studied with eight males suffering from mental retardation. Six of these males were clinically tested using anthropometric indicators and genetic tests: high resolution karyotypes, fragile X research, linkage and MID1 and PQBP1 gene studies.ResultsAlong with mental retardation, the clinical study showed a pattern of microcephaly, micrognathia, osteoarticular and genital anomalies, short stature and other less frequent malformations. The linkage study mapped the possible causal gene of this mental retardation syndrome and multiple congenital abnormalities in the Xp11.23-q21.32 segment, with a LOD score of 2. As far as we know, a medical profile, similar to the one these patients have, linked to this X segment has not been described.ConclusionsWe suspect that this family has a “new syndrome” of mental retardation and multiple congenital anomalies linked to the X chromosome.     

Is it possible to make a clinical diagnosis of the fragile X syndrome in a boy?

Clinical observations were made on a series of 156 boys with severe mental retardation, before cytogenetic results were known. The clinical features that helped to distinguish the 14 boys with the fragile X chromosome from those without were: head circumference over the 50th centile, postpubertal testicular volume over the 50th centile, and an IQ between 35 and 70. If the above clinical features were all present, then the chance of finding the fragile X chromosome was 1 in 3.6, whereas the chance of finding this abnormality in any boy with severe idiopathic mental retardation, regardless of his clinical features, was 1 in 9. Two boys with fragile X syndrome did not, however, possess any of the above clinical features. Moreover, some of the other retarded boys had clinical features of the syndrome, or an X linked pedigree, but lacked the chromosome abnormality.     

Skewed X inactivation in healthy individuals and in different diseases

In female mammalian cells, one of the two X chromosomes is inactivated in early embryonic life. Females are mosaics for two cell populations, one with the maternal and one with the paternal X as the active chromosome. Skewed X inactivation is arbitrarily defined, often as a pattern where 80% or more of the cells show a preferential inactivation of one X chromosome. Inactivation is presumed to be permanent for all descendants of a cell; however, after about 55 years of age, the frequency of skewed X inactivation in peripheral blood cells increases, probably through selection. Unfavourable skewing of X inactivation, where the X chromosome carrying a mutant allele is the predominantly active X, has been found in affected female carriers of several X-linked disorders; however, for many X-linked disorders, a consistent relationship between the pattern of X inactivation and clinical phenotype has been difficult to demonstrate. One reason for this may be that peripheral blood cells are not a representative or relevant tissue in many disorders. In some severe X-linked disorders, post-inactivation selection takes place against the X chromosome carrying the mutant allele, leading to a completely skewed X-inactivation pattern. Skewed X inactivation has also been reported in young females with breast cancer, and may indicate an effect of X-linked genes on the development of this condition.Conclusion: The process of X inactivation and the resultant degree of skewing is clearly important for the expression of genetic diseases. It is also important to consider, however, that under normal conditions the frequency of skewed X inactivation increases with age in peripheral blood cells. Analysis of the expression of a large proportion of the genes on the X chromosome has revealed that X-chromosome inactivation is more heterogeneous than previously thought.     

The fragile X syndrome: history, diagnosis, and treatment

The fragile X (marker X) syndrome is a relatively common form of X-linked mental retardation. The karyotypic hallmark of the syndrome consists of a pronounced constriction near the terminus of the long arm of the X chromosome (fragile site), expressed in vitro only under conditions where thymidylate production is blocked (reduced folate levels and/or addition of methotrexate or 5-fluorodeoxyuridine). Clinical features associated with the syndrome include macroorchidism, large or prominent ears, and significant emotional dysfunction. In the present review, historical, diagnostic, biochemical, and clinical aspects of this syndrome are presented. Recent anecdotal reports of clinical improvement following high dose folic acid treatment will be discussed.     

ATR-X syndrome: a new mutation in the XNP/ATRX gene near the helicase domain]

The alpha-thalassemia/mental retardation syndrome, X linked, also named ATR-X syndrome is a X-linked mental retardation syndrome. Mutations have been found in the ATRX gene in about one half of the patients. We report a typical clinical case. The clinical evidence leads us to continue the analysis of the gene despite a negative first screening. Indeed a new mutation was found, just behind the helicase domain, bringing up the interest of an effective collaboration between physicians and biologists.     

Skewed X inactivation in healthy individuals and in different diseases

In female mammalian cells, one of the two X chromosomes is inactivated in early embryonic life. Females are mosaics for two cell populations, one with the maternal and one with the paternal X as the active chromosome. Skewed X inactivation is arbitrarily defined, often as a pattern where 80% or more of the cells show a preferential inactivation of one X chromosome. Inactivation is presumed to be permanent for all descendants of a cell; however, after about 55 years of age, the frequency of skewed X inactivation in peripheral blood cells increases, probably through selection. Unfavourable skewing of X inactivation, where the X chromosome carrying a mutant allele is the predominantly active X, has been found in affected female carriers of several X-linked disorders; however, for many X-linked disorders, a consistent relationship between the pattern of X inactivation and clinical phenotype has been difficult to demonstrate. One reason for this may be that peripheral blood cells are not a representative or relevant tissue in many disorders. In some severe X-linked disorders, post-inactivation selection takes place against the X chromosome carrying the mutant allele, leading to a completely skewed X-inactivation pattern. Skewed X inactivation has also been reported in young females with breast cancer, and may indicate an effect of X-linked genes on the development of this condition.
Conclusion: The process of X inactivation and the resultant degree of skewing is clearly important for the expression of genetic diseases. It is also important to consider, however, that under normal conditions the frequency of skewed X inactivation increases with age in peripheral blood cells. Analysis of the expression of a large proportion of the genes on the X chromosome has revealed that X-chromosome inactivation is more heterogeneous than previously thought.     

Mosaic Turner syndrome and hyperinsulinaemic hypoglycaemia

BACKGROUND: A common and well recognised feature of Turner's syndrome (partial or total monosomy X) is impaired glucose tolerance or type 2 diabetes mellitus. A small percentage of patients with Turner's syndrome have a complex mosaic karyotype with atypical clinical features and mental retardation. METHODS/PATIENT: We report the first case of a child with a complex mosaic Turner genotype and hyperinsulinaemic hypoglycaemia responsive to diazoxide therapy. RESULTS: Cytogenetic analysis showed four cell lines: one with 45,X; the others with an additional small ring chromosome, a small marker chromosome, and both the ring and marker chromosomes, respectively. FISH studies showed the abnormal chromosomes to originate from an X. The X inactivation locus (XIST) was present in the ring, but not in the marker chromosome. CONCLUSIONS: The recognition of hypoglycaemia in children with atypical Turner's syndrome is important as persistent hypoglycaemia may lead to brain damage in addition to the risk of mental retardation. Further studies are required to understand whether the mosaic over--or underexpression of unidentified X chromosome gene(s) in the pancreatic beta-cells leads to hyperinsulinaemic hypoglycaemia.     

The fragile X syndrome (Martin-Bell syndrome). Clinical and cytogenetic findings in 16 prepubertal boys and in 4 of their 5 families

Clinical and cytogenetic findings from 16 prepubertal males with the fragile X syndrome (X-linked mental retardation with postpubertal macro-orchidism and fragile site at Xq27/8, or Martin-Bell syndrome) and from their families are reported. During the first postnatal years, protruding, large ears, full periorbital tissue, and thick septum and alae nasi were the most characteristic phenotypic findings, while after approximately 6 years of age a longish face with full lips and prominent maxilla and mandible became more distinct. It was estimated that a clinical suspicion of the fragile X syndrome could be made in most of the 16 boys from phenotypic findings in combination with the characteristic developmental profile described in our previous paper. The marker X chromosome was demonstrated in each of the 16 patients; the incidence of fra(X)-positive cells did not correlate with either age or the degree of mental retardation. 13 boys stemmed from 2 families, the other 3 were sporadic cases. In one family with 11 affected boys, the gene was transmitted by 4 brothers, grandfathers to the probands, who were intellectually normal; three of them did not show the clinical picture of the fragile X syndrome and did not express the marker. All mentally subnormal heterozygote females and one half of daughters of heterozygotes revealed the marker, but this was present only in a minority of non-retarded adult heterozygotes. In contrast to the overall incidence of about 1/4 to 1/3 mentally retarded heterozygotes, all 15 daughters of the four normal obligatory hemizygous brothers were of normal intelligence.     

Fragile X syndrome: current knowledge]

Fragile X syndromes is a disease characterized by the association of mental retardation and dysmorphic features to a fragile site on Xq27-3. It is a frequent genetic disorder (1 in 1,500 males) recognized only 20 years ago but remaining difficult to understand, because its transmission among generations does not correspond to the classical model of recessivity linked to chromosome X. In fact, carrier females can express the disease and transmitting males can be normal. With DNA probes, molecular biology has contributed to genetic counselling and prenatal diagnosis. Restriction polymorphisms have long been used to study the inheritance of fragile X syndrome and DNA markers' analysis improved risk estimates for carriers. From a clinical viewpoint, there was a need for more closely linked probes to help in prenatal diagnosis and to assess carrier status and hence reduce risk of recombination. In 1991, new probes allowed direct diagnosis of the Fra (X) mutation and a gene was sequenced. Nevertheless the understanding of the mechanism involved in the underlying mutation is still unknown. Geneticists, cytogeneticists and biologists must collaborate further to elucidate the fragile site mystery.     

The molecular basis of ornithine transcarbamylase deficiency

The ornithine transcarbamylase (OTC) gene is located on the short arm of the X-chromosome and encodes the second enzyme of the urea cycle. OTC deficiency is an X-linked disorder that causes hyperammonemia leading to brain damage, mental retardation and death. The clinical and biochemical phenotype is extremely variable and can only partially be explained by the genotype. We identified mutations in the OTC gene of more than 150 patients with OTC deficiency. The "neonatal onset" group of patients has mutations that abolish enzyme activity, whereas the "late onset group" shows partial enzyme deficiency to variable degree. Of the mutations, 60% are associated exclusively with acute neonatal hyperammonemic coma while the remaining cause "late onset" disease. Several symptomatic and asymptomatic adults have now been identified to have deleterious mutations in the OTC gene leading to predisposition to hyperammonemia. Conclusion The enlarging clinical, biochemical and molecular spectrum observed in patients with ornithine transcarbamylase deficiency suggests that this disorder behaves like a single gene disorder at one end of the spectrum and as a multi-factorial disease at the other.     

Biology of the X chromosome.

The biology of the X chromosome is unique, as there are two Xs in females and only a single X in males, whereas the autosomes are present in duplicate in both sexes. The presence of only a single autosome, which can occur as a result of an error in meiotic segregation, is invariably an embryonic lethal event. Monosomy for the X chromosome is viable because of dosage compensation, a system found in all organisms with an X:Y form of sex determination, which brings about equality of expression of most X-linked genes in females and males. In mammals, the dosage compensation system involves silencing of most of the genes on one X chromosome; it is called X chromosome inactivation. In this review, we focus first on recent advances in our understanding of the molecular basis of the X inactivation mechanism. Then we consider an unusual feature of X inactivation, the mosaic nature of the female and subsequent exposure to somatic cell selection.     

Health supervision for children with fragile X syndrome

Fragile X syndrome (an FMR1-related disorder) is the most commonly inherited form of mental retardation. Early physical recognition is difficult, so boys with developmental delay should be strongly considered for molecular testing. The characteristic adult phenotype usually does not develop until the second decade of life. Girls can also be affected with developmental delay. Because multiple family members can be affected with mental retardation and other conditions (premature ovarian failure and tremor/ataxia), family history information is of critical importance for the diagnosis and management of affected patients and their families. This report summarizes issues for fragile X syndrome regarding clinical diagnosis, laboratory diagnosis, genetic counseling, related health problems, behavior management, and age-related health supervision guidelines. The diagnosis of fragile X syndrome not only involves the affected children but also potentially has significant health consequences for multiple generations in each family.     

Fragile X syndrome

The fragile X syndrome is the most common inherited form of mental retardation known. Its phenotype includes large or prominent ears, macroorchidism, and characteristic behavioral problems. It has attracted the interest of cytogeneticists and molecular biologists because of its characteristic fragile site on the X chromosome. It has puzzled geneticists because of its unusual inheritance pattern involving nonpenetrant males. This syndrome has also spearheaded an appreciation of cytogenetic abnormalities in the etiology of all degrees of developmental delay.