Search

Nicolaides-Baraitser syndrome (NBS) is characterized by sparse hair, distinctive facial morphology, distal-limb anomalies and intellectual disability. We sequenced the exomes of ten individuals with NBS and identified heterozygous variants in SMARCA2 in eight of them. Extended molecular screening identified nonsynonymous SMARCA2 mutations in 36 of 44 individuals with NBS; these mutations were confirmed to be de novo when parental samples were available. SMARCA2 encodes the core catalytic unit of the SWI/SNF ATP-dependent chromatin remodeling complex that is involved in the regulation of gene transcription. The mutations cluster within sequences that encode ultra-conserved motifs in the catalytic ATPase region of the protein. These alterations likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity. The identification of SMARCA2 mutations in humans provides insight into the function of the Snf2 helicase family.

Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

Neurodevelopmental disorders that disturb speech and language are highly heritable. Isolation of the underlying genetic risk factors has been hampered by complexity of the phenotype and potentially large number of contributing genes. One exception is the identification of rare heterozygous mutations of the FOXP2 gene in a monogenic syndrome characterised by impaired sequencing of articulatory gestures, disrupting speech (developmental verbal dyspraxia, DVD), as well as multiple deficits in expressive and receptive language. The protein encoded by FOXP2 belongs to a divergent subgroup of forkhead-box transcription factors, with a distinctive DNA-binding domain and motifs that mediate hetero- and homodimerisation. FOXP1, the most closely related member of this subgroup, can directly interact with FOXP2 and is co-expressed in neural structures relevant to speech and language disorders. Moreover, investigations of songbird orthologues indicate that combinatorial actions of the two proteins may play important roles in vocal learning, leading to the suggestion that human FOXP1 should be considered a strong candidate for involvement in DVD. Thus, in this study, we screened the entire coding region of FOXP1 (exons and flanking intronic sequence) for nucleotide changes in a panel of probands used earlier to detect novel mutations in FOXP2. A non-synonymous coding change was identified in a single proband, yielding a proline-to-alanine change (P215A). However, this was also found in a random control sample. Analyses of non-coding SNP changes did not find any correlation with affection status. We conclude that FOXP1 mutations are unlikely to represent a major cause of DVD.

FOXP2, the first gene to have been implicated in a developmental communication disorder, offers a unique entry point into neuromolecular mechanisms influencing human speech and language acquisition. In multiple members of the well-studied KE family, a heterozygous missense mutation in FOXP2 causes problems in sequencing muscle movements required for articulating speech (developmental verbal dyspraxia), accompanied by wider deficits in linguistic and grammatical processing. Chromosomal rearrangements involving this locus have also been identified. Analyses of FOXP2 coding sequence in typical forms of specific language impairment (SLI), autism, and dyslexia have not uncovered any etiological variants. However, no previous study has performed mutation screening of children with a primary diagnosis of verbal dyspraxia, the most overt feature of the disorder in affected members of the KE family. Here, we report investigations of the entire coding region of FOXP2, including alternatively spliced exons, in 49 probands affected with verbal dyspraxia. We detected variants that alter FOXP2 protein sequence in three probands. One such variant is a heterozygous nonsense mutation that yields a dramatically truncated protein product and cosegregates with speech and language difficulties in the proband, his affected sibling, and their mother. Our discovery of the first nonsense mutation in FOXP2 now opens the door for detailed investigations of neurodevelopment in people carrying different etiological variants of the gene. This endeavor will be crucial for gaining insight into the role of FOXP2 in human cognition.

Aim: To describe the nature and prevalence of hearing loss in Fabry disease, and its response to enzyme replacement therapy (ERT) with agalsidase alfa., Methods: Fifteen male patients with Fabry disease were enrolled in a randomized, double-blind study and received placebo (n = 8) or ERT (n = 7) with agalsidase alfa for 6 months. This was followed by an open-label extension of 36 months thus far. Alongside this trial, an additional eight men and two women have so far received open-label ERT for between 6 and 30 months. Pure-tone audiometry, impedance audiometry and otoacoustic emission testing were performed at 0 (baseline), 6, 18, 30 and 42 months., Results: Nine patients (36%) had bilateral and ten (40%) had unilateral high-frequency sensorineural hearing loss (SNHL). Three (12%) had unilateral middle ear effusions with conductive losses persisting beyond 6 months. Only five patients (20%) had normal hearing. The high-frequency SNHL deteriorated over the first 6 months in both placebo and active treatment groups by a median 6.3 dB (p < 0.0001, Wilcoxon matched-pairs). This hearing loss subsequently improved above baseline by 1.5 dB at 18 months (p = 0.07), by 5.0 dB at 30 months (p = 0.006) and by 4.0 dB at 42 months (p = 0.01)., Conclusion: Significant hearing loss, usually high-frequency SNHL, is a common manifestation of Fabry disease in adults. Alpha-galactosidase A replacement therapy with agalsidase alfa appears to reverse the hearing deterioration in these patients. This improvement, however, is gradual, suggesting the need for long-term ERT.

The objective of this document is to provide health care professionals with recommendations for genetic counseling and testing of individuals with a suspected or confirmed diagnosis of Fabry disease, with a family history of Fabry disease, and those identified as female carriers of Fabry disease. These recommendations are the opinions of a multicenter working group of genetic counselors, medical geneticists, and other health professionals with expertise in Fabry disease counseling, as well as an individual with Fabry disease who is a founder of a Fabry disease patient advocacy group in the United States. The recommendations are U.S. Preventive Task Force Class III, and they are based on clinical experience, a review of pertinent English-language articles, and reports of expert committees. This document reviews the genetics of Fabry disease, the indications for genetic testing and interpretation of results, psychosocial considerations, and references for professional and patient resources. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. The professional judgment of a healthcare provider, familiar with the facts and circumstances of a specific case, will always supersede these recommendations.

Anderson Fabry Disease (AFD) is an extremely painful and debilitating multi-system X-linked disorder due to alpha-galactosidase enzyme deficiency. To date, no baseline data on health-related quality-of-life (HR-QoL) have been reported in males affected with this condition. In this study, 38 males with AFD completed Medical Outcomes Study Short Form, EuroQoL questionnaires and an AFD-specific questionnaire prior to the start of a trial involving replacement therapy with alpha-galactosidase. Results from these questionnaires were compared to the results from a similar HR-QoL study in males with severe haemophilia (factor VIII/IX deficiency) that used the same questionnaires and to the results of two large normative studies. The results on both questionnaires showed that in most instances males with AFD recorded significantly lower HR-QoL compared with males in the general population and individuals with severe haemophilia after adjusting for differences in age. These findings suggest therefore, that the scope for improvement in HR-QoL as a result of treatment with an appropriate agent is extremely large.

Objectives: To determine the natural history of Anderson-Fabry disease (AFD) as a baseline for efficacy assessment of potentially therapeutic drugs., Design: The first large cross sectional study of a patient cohort from the AFD clinical and genetic register (UK), maintained for the last 15 years., Measures: Prevalence, mortality, frequency of AFD manifestations, and impact of disease on patient lives, assessed from the AFD register and the disease specific questionnaire., Results: The median cumulative survival was 50 years (n=51), which represents an approximately 20 year reduction of life span. Neuropathic pain was present in 77% (n=93) with mean pain score of 5 (scale 0-10) despite treatment with anticonvulsants and opiates. Pain stopped in only 11%. Cerebrovascular complications developed in 24.2% and renal failure in 30%. The onset and progression of serious AFD manifestations was highly variable. The relationship of gastrointestinal manifestations on weight, using body mass index (BMI), was significant (p=0.01). High frequency sensorineural deafness was confirmed in 78% of audiograms. Neuropathic pain and angiokeratoma were absent in five adult males (approximately 5%). Median age at diagnosis of AFD was 21.9 years (n=64)., Impact of Disease: Attendance at school, sports, and social activity were significantly affected by AFD. Only 56.6% (n=46) of patients were employed. Psychosexual effects of genital angiokeratoma, genital pain, and impotence were not previously recognised., Conclusion: The majority of males experience multiple disease manifestations and the duration of neuropathic pain was lifelong. The AFD register proved useful for the determination of baseline disease parameters in this cohort.

An inherited deficiency of the enzyme alpha-galactosidase A is manifest clinically as Anderson-Fabry disease. Most affected patients present with severe peripheral pain in childhood or early adult life, and frequently progress to multi-organ failure by the 4th or 5th decades. The present review examines the probable mechanisms that contribute to pain in these patients, and outlines some of the treatment options that are currently used. The successful outcome of the first two trials of enzyme replacement therapy suggest that this disease might be amenable in the future to gene therapy.

We present a family with adult onset autosomal dominant polycystic kidney disease (ADPKD) in two generations, linked to the PKD1 locus and with paternal transmission to the fetus. The fetus carried the PKD1 haplotype and was, therefore a gene carrier. Progressive hyperechogenic renal enlargement, but no cysts, was documented by serial fetal ultrasounds at 21, 23 and 34 weeks of gestation. Surprisingly, the newborn renal scan showed normal sized kidneys with apparently normal corticomedullary differentiation. However, at 11 months of age, the evolution of cysts in one kidney, and then in the other kidney at 20 months, was documented by ultrasound in the absence of clinical symptoms or signs. The observed normalisation of fetal renal ultrasound appearances at birth has not previously been described in fetuses presenting with PKD1.

We describe four prenatal diagnoses in a family with autosomal dominant polycystic kidney disease. Two pregnancies were terminated following the detection of enlarged echogenic fetal kidneys with cysts. Histopathological examination confirmed the diagnosis of polycystic kidney disease. Linkage to PKD1 was obtained by the analysis of DNA from relatives in three generations and from paraffin blocks and formalin fixed fetal tissues. Prenatal DNA analysis in subsequent pregnancies identified one unaffected fetus and one fetus carrying the high risk PKD1 allelle. Information on survival and subsequent outcome of PKD cases presenting in utero was requested by this family before prenatal testing was performed. Of 83 reported cases of ADPKD presenting in utero (excluding termination of pregnancy) or in the first few months of life, 43% died before 1 year. Longitudinal follow up of 24 children in two studies showed that 67% of survivors developed hypertension, of whom three had end stage renal failure at a mean age of 3 years.

A novel mutation, C118T, in exon 2 of the acid alpha-glucosidase gene has been found in an infant with glycogen storage disease type II. This mutation is predicted to result in protein truncation. The phenotype was that of the severe infantile form of the disorder with lack of motor development, but with eye regard, social smile and vocalization. The parents were heterozygous for C118T and belong to an Islamic community opposed to termination of pregnancy. As the C118T mutation results in the loss of one of two AvaI sites present in an informative PCR product, reliable premarriage carrier detection became possible and was acceptable to the members of this extended family.

Progress in genetics and molecular medicine has led to characterization of many disorders at the level of specific genes. Techniques for reliable diagnosis of these disorders have been developed in parallel. Attempts are currently being made to develop DNA-based therapeutic procedures to correct genetic diseases. These procedures are known under a common name of gene therapy. The initial step in gene therapy is the delivery of the gene of interest into target cells. There are several conceptually different approaches to achieve this, e.g. targeting can be accomplished by using viral vectors (transduction) or DNA-mediated routes (transformation) either ex vivo or in vivo. The selection of vector systems and the choice of delivering genes either into isolated cells or directly in the organism depend on factors like: the nature of target cell or organ, the levels of expression required, stability and/or regulation of expression, safety, etc. Many viruses have been adapted for use as vectors for gene therapy, according to their specific properties. Viral genomes have been modified to remove their ability to replicate and to increase the cloning capacity. Non-viral gene delivery systems rely on cellular mechanisms to import DNA into the cell nucleus and different methods to enhance DNA uptake have been attempted. Despire many significant achievements there are still obstacles to the development of effective clinical products. Most significant are the low levels and stability of expression of introduced genes and immune responses to vectors and/or gene products.

For most disorders the ideal goal of gene therapy is the repair of the mutated gene in the target tissue. However, the techniques required for such an approach are still at an early stage of development. Most current research is directed towards delivery of normal gene sequences in order to generate active protein and compensate for the lack of endogenous production. This approach may be suitable for the treatment of recessive monogenic disorders, but is inappropriate for dominantly inherited disorders. Therefore, gene therapy was originally intended as a most promising approach for the treatment of inborn errors of metabolism. However, apart from the correction of heritable genetic disorders, gene delivery has many potential applications including treatment of malignancies, atherosclerosis and vascular proliferative disorders, rheumatoid arthritis and viral infections. The authors discuss significant examples marking progress in the development of gene therapy for specific diseases, present some hopes and hurdles that have arisen from some recent preclinical and early clinical trials.

We report a large kindred in which a punctate palmoplantar keratoderma (PPK) is associated with malignancy, including Hodgkin's disease, renal, breast, pancreatic and colonic adenocarcinomas. The family was traced through four generations, and over 320 individuals were identified, of whom 49 had punctate PPK. The punctate PPK appeared to be inherited as an autosomal dominant trait with variable penetrance. Ten of the 43 adults (23%) with punctate PPK developed malignancies, and five of these developed before the age of 50. Of the 271 unaffected individuals, six (2%) have developed malignancies, one prior to the age of 50. The association of keratoderma and malignancy is discussed.

We describe a single male infant who developed severe hydrops fetalis between 19 and 28 weeks of gestation. After delivery at 32 weeks he was treated by hemofiltration, prolonged ventilation and intravenous feeding. He had hypertelorism, orbital hypoplasia without proptosis, brachydactyly, frontal and temporal bossing of the skull, central hypotonia, communicating hydrocephalus, and severe delay in psychomotor development. Signs of connective tissue disorder included: osteopenia, pathological fracture, yellow/grey discolored teeth, blue sclerae and easy bruising. Laboratory investigations failed to reveal the cause of fetal hydrops or collagen abnormality. His mother and one sib had learning difficulties. Although some of these findings may be due to perinatal factors, the connective tissue abnormalities suggest a genetic syndrome in the heterogeneous group of osteogenesis imperfecta. This case either represents the more severe end of the spectrum of Type IV osteogenesis imperfecta or the mild end of the spectrum of Cole-Carpenter syndrome.

During a study of the gene coding for alpha-galactosidase (EC 3.2.1.22), the lysosomal enzyme deficient in Fabry's disease, RT-PCR amplification of alpha-galactosidase mRNAs obtained from three different tissues isolated from males revealed a substantial number of clones with a U to A conversion at the nucleotide position 1187. Such a modification of the coding sequence would result in an amino acid substitution in the C-terminal region (Phe396Tyr) of the enzyme. Neither PCR analysis of the genomic sequence nor the RT-PCR amplification of RNA obtained by in vitro transcription of the wild-type cDNA showed this change in the sequence. Multiple genes, pseudogenes are allelic variants were excluded. Hence, we propose RNA editing as a mechanism responsible for this base change in the alpha-galactosidase RNA.

We report two patients with severe combined immunodeficiency and short stature/short limb skeletal dysplasia. Case 1 presented at birth with rhizomelic shortening of the extremities and bowing of the femora. She developed clinical signs of severe combined immunodeficiency at 13 months and died at 21 months. Case 2 had severe prenatal shortening and bowing of the extremities and a small, malformed chest. Symptoms of severe combined immunodeficiency and severe failure to thrive developed soon after birth and she died at 5 months. The diagnosis of severe combined immunodeficiency in our patients was based on their clinical course and necropsy findings, supported in case 1 by the results of immune function tests. The results of investigation of immune function (immunoglobulins, lymphocyte subpopulations, lymphocyte function) are very variable in this syndrome as in other variants of severe combined immunodeficiency. Bone histopathology in both patients showed grossly irregular costochondral junctions, but normal transition of proliferating to hypertrophic chondrocytes. These cases belong to early lethal type 1 short limb skeletal dysplasia with severe combined immunodeficiency. Review of previously published cases with severe combined immunodeficiency and well documented skeletal findings show eight patients with prenatal onset of bowing and shortening of the extremities and metaphyseal abnormalities. These include two sib pairs concordant for the skeletal changes. In these cases, adenosine deaminase levels were not reported. An additional four published cases with associated adenosine deaminase deficiency had only mild metaphyseal abnormalities, but subsequently showed no linear growth.(ABSTRACT TRUNCATED AT 250 WORDS)

We report a mother and son with 5th, 6th, 7th, and bulbar cranial nerve paralysis, who had two similarly affected relatives. None of them had primary skeletal defects. Twenty-six previous reports of familial cases within the heterogeneous 'Möbius spectrum of defects' were reviewed. When cranial nerve palsies were associated with a primary skeletal defect, familial transmission was not found. No recurrence was noted in 31 cases with cranial nerve palsies associated with oral abnormalities and limb defects. The term Möbius syndrome should be restricted to cases with congenital 6th and 7th nerve paralysis with skeletal defects, who have a low recurrence risk (2%). The features in an index case which may indicate a higher risk of recurrence are the absence of skeletal defects, isolated facial palsy, deafness, ophthalmoplegia, and digital contractures. A recurrence risk of 25 to 30% in these cases appears reasonable.

In this preliminary study, non-invasive infrared thermography has been used to visualize individual sweat pores and whole body skin temperature patterns in subjects with X-linked hypohidrotic ectodermal dysplasia (XHED) and normal controls. The findings in eight obligate heterozygotes and four affected males were compared to six normal female controls and to six non-manifesting females at risk for carrier status. Sweat secretion from individual pores in circumscribed areas was imaged using a high spatial resolution SPRITE infrared detector system working in the 8-14 microns band. In seven out of eight obligate heterozygotes, skin areas devoid of active sweat glands were found on the face, the hands or the trunk. Tear front movement over the cornea was also visualized and abnormal patterns were identified in obligate heterozygotes. Whole body skin temperature patterns, obtained with an Agema 780 Medical Thermovision system, identified abnormal skin temperature distributions, including characteristic aberrant "cascade" back patterns, in obligate carriers. Two out of six "at risk" females had skin temperature patterns comparable with obligate heterozygotes and we have tentatively concluded that they are carriers. Thermal imaging may be used for the examination of "at risk" non-manifesting females in families with a single affected male. The results of this study suggest that the random X-inactivation in females with XHED, as well as producing relatively large skin areas with sweat pore aplasia, is also associated with abnormal temperature patterns that are consistent with altered peripheral vascular perfusion.

We report three cases of ring chromosome 5 [r(5)], two familial (mother and daughter) and one sporadic. The phenotype resembled that of the "ring syndrome" with prenatal onset of short stature, growth retardation, mild facial dysmorphism and normal psychomotor development. Extended metaphase and prometaphase chromosome preparations using G-, R- and Q-banding and scanning electron microscopy (SEM) failed to demonstrate deletion in the ring 5. Flow karyotype using the FACS cell sorter and peak area analysis showed the r(5) to be in the same position as the normal chromosome 5. The deletion that is presumably associated with ring formation appears to involve less that one megabase of DNA. In the "complex" rings, high resolution SEM showed fragile sites at the 5q34 and 5q35 region with frequent deletions at that site. A literature survey suggests that when a parent carries a ring chromosome about 80% of recognised pregnancies result in live birth. Of these, about half have a normal phenotype and karyotype, and half inherit the parental ring; about half of those acquiring the ring (20%) show significant mental retardation.

We present here a historical documentation of a female with X-linked hypohidrotic ectodermal dysplasia (XHED) and a de novo X/9 chromosome translocation. The patient was verbally reported by Dr. P.L. J. Cook to the HGM conference in 1973, but was subsequently lost to follow up. We have since traced her and confirmed the diagnosis of XHED with moderately severe mental retardation. According to Dr. P. L. J. Cook's records, fibroblast cell line AnLy GMO 705, was derived from this patient. Another female with a de novo X/12 chromosome translocation and hypohidrotic ectodermal dysplasia was recently reported. In both cases, the X chromosome breakpoint appears to be at Xq13.1.

We report on 2 brothers from a consanguineous Moslem family with prenatal onset of growth deficiency, microcephaly, hypoplastic genitalia, and convulsions from birth. Phenotypic anomalies consisted of a prominent glabella, arched eyebrows, a low upswept frontal hairline, a small pinched nose, large posteriorly rotated ears with overfolded upper helices, partial camptodactyly, and widespaced nipples. Psychomotor development was absent, and there was marked failure to thrive. Death occurred at ages 21 days and 7 months, respectively. Postmortem examination on one child showed dilated cerebral ventricles and hydronephrosis. Microcephaly was detectable by fetal ultrasound in one brother at 17 weeks of gestation.

In two cases of nonketotic hyperglycinemia treated from early ages with strychnine sulphate, the patients demonstrated persistent severe psychomotor retardation and seizures. Strychnine therapy improved tone and feeding, but did not seem to alter fundamentally the course of the disease in either patient.

A syndrome is described, consisting of severe neurogenic distal wasting, generalised muscle weakness, absent ankle reflexes, pyramidal signs, mental retardation, optic atrophy and retinal colloid bodies. A sural nerve biopsy from one case showed loss of nerve fibres suggesting the diagnosis of hereditary motor and sensory neuropathy. Progression of the disorder was very slow, all patients still being able to walk more than 20 years after the onset. The persons affected with this syndrome were two brothers and their female cousin from a large Gujerati pedigree where consanguinity was high. Autosomal recessive inheritance is therefore suggested.

We have measured the rate of purine synthesis de novo in blood mononuclear cells in vitro and the activities of the purine salvage enzymes [hypoxanthine phosphoribosyltransferase (HPRT; EC 2.4.2.8), adenine phosphoribosyltransferase (APRT; EC 2.4.2.7)] and ribosephosphate pyrophosphokinase (PP-ribose-P synthetase; EC 2.7.6.1)] and the concentration of phosphoribosylpyrophosphate (PP-ribose-P) in the erythrocytes of affected family members. These subjects belong to families where hyperuricaemia and renal failure occur together early in life, and the genetic transmission follows an autosomal dominant mode of inheritance. We term this syndrome, familial hyperuricaemic nephropathy. No significant differences were detected in either the rates of purine synthesis de novo in vitro between the index patients and the control subjects with respect to the enzyme activities or the PP-ribose-P concentrations. Two groups of controls were used, healthy individuals and patients with a comparable degree of renal failure due to non-immune complex renal disease. Mononuclear cells from patients with Lesch-Nyhan syndrome (congenital HPRT deficiency) showed the expected acceleration of purine synthesis de novo in vitro. The accelerated purine synthesis de novo in vitro associated with phytohaemagglutinin-induced lymphocyte transformation was detectable by the method used. We conclude that familial hyperuricaemic nephropathy is not due to a metabolic lesion which causes accelerated purine synthesis de novo. This suggests that the primary abnormality may be a failure of the renal tubular net excretion of urate.

The blood-brain barrier of rats was opened reversibly by infusing a hyperosmotic solution of arabinose into the external carotid artery. Permeability was increased maximally in the first 15 min and remained slightly elevated at 1 hr. Osmotic barrier opening significantly increased brain uptake of intravenously injected alpha-mannosidase (alpha-D-mannoside mannohydrolase, EC 3.2.1.2.4) (derived from human placenta) and horseradish peroxidase (donor:hydrogen-peroxide oxidoreductase, EC 1.11.1.7). By injection of 4 X 10(5) units of alpha-mannosidase into an animal, brain activity rose to about twice the normal control activity of the enzyme. After 30 min, activity of administered enzyme in the extracellular space of the brain was calculated to be 30% of the serum concentration. Biochemical and histological studies with horseradish peroxidase showed that exogenously administered enzyme entered the brain extracellular space immediately after barrier opening and was incorporated within neuronal lysosomal packets during the next 24 hr. Measurable peroxidase activity was found in brain as much as 72 hr after osmotic treatment. The results demonstrate that the blood-brain barrier can be reversibly opened to enzymes, that a glycoprotein enzyme is incorporated into neuronal lysosomes, and that the brain may now be considered a potential target for enzyme replacement therapy in heritable metabolic disorders.

We report investigations of benzoate and glycine metabolism and glycine acyltransferase activity in rats. These studies provide insights related to the therapy and pathophysiology of human nonketotic hyperglycinemia. Liver acyltransferase activity increased sharply postnatally from low levels at birth, but transferase activity was absent in the brain. The enzyme level was unchanged in either organ after administration of 2,3,7,8-tetrachlordibenzodioxin, phenobarbital, benzoate or a high glycine diet. Brain and liver glycine levels remained unaltered during acute or chronic benzoate-induced reductions in plasma glycine levels. Plasma and brain glycine contents were measured in rats at different ages following a single injection of 3 mg glycine/g body weight; after injection, glycine levels in the brain were comparable in severely symptomatic neonatal rats and older asymptomatic rats, suggesting a similar glycine influx but a selective susceptibility of the newborn brain to toxicity from acute hyperglycinemia. When a 3.4% glycine diet was ingested for up to 30 days ad libitum, levels of plasma glycine rose about 4- to 5-fold from those achieved on a diet containing one tenth as much glycine, but brain and liver glycine concentrations increased only 2-fold or less in the chronically hyperglycinemic animals.

A family is described where a mother and three sons have an unusual form of ectodermal dysplasia that may have been described in the medical literature only once before. The unusual manifestations in this family are mild short stature, sparse scalp hair, skin pigmentation and a transient urticarial-like reaction on the hands and arms. The mother and one son demonstrated a single, upper central incisor and the mother and another son had hypoplastic thumbs. The mother alone had hyperkeratosis of the palms and soles. The inheritance pattern is most likely autosomal dominant, although X-linked dominant inheritance cannot be excluded.

Genetic linkage studies were carried out in families with X-linked hypohidrotic ectodermal dysplasia (C-S-T syndrome). A DNA probe DXYS1 (pDP34), which maps both to the proximal part of the long arm of the X chromosome, Xq13-Xq21, and proximally on Yp, was used to detect a TaqI restriction fragment length polymorphism of the X-chromosomal locus in the DNA samples from 11 families. This locus was found to be closely linked to the X-linked hypohidrotic ectodermal dysplasia locus, with a lod score of 2.66 at recombination fraction (theta) of 0.06 (90% confidence limits 0.01-0.26). Only one crossover was observed in nineteen meioses. This indicates that the probe DXYS1 is closely linked to the X-linked hypohidrotic ectodermal dysplasia locus and is likely to facilitate carrier detection and prenatal diagnosis tests.

We report on a family in which a mother and her 2 offspring presented with bilateral radial defects and absent thumbs. In addition, Duane anomaly was present in both offspring, one of whom also had anal stenosis. Clinical investigation showed no skeletal, cardiac, or urogenital abnormalities. Autosomal dominant transmission of radial defects is suggested, with Duane anomaly and anal stenosis representing manifestations of the same gene.

A family is presented with short stature, femoral epiphyseal dysplasia, mild vertebral changes, and sensorineural deafness inherited as an autosomal dominant trait. Myopia and retinal detachment presenting in adult life were also present in some affected members. We suggest that this disorder may be a distinct entity within the spondyloepiphyseal dysplasia group of disorders.

We report four patients with hypertrichosis cubiti who were referred for investigation of short stature. Two males, whose height was on and just below the 3rd centile respectively, were sporadic cases and two females with disproportionate short stature were mother and daughter. Radiological changes present in the familial cases were non-specific and biochemical investigations were normal. Of the four other published cases, two were sporadic and of normal height. The other two were sibs with short stature and their parents were heterozygous for the Weill-Marchesani syndrome. We were unable to ascertain whether hypertrichosis cubiti cosegregates with the same type of skeletal dysplasia or elucidate the type of genetic transmission of hypertrichosis cubiti alone.

Anderson Fabry disease is an X-linked lysosomal storage disorder caused by alpha-galactosidase A deficiency. Hemizygous males and some heterozygous females develop renal failure and cardiovascular complications in early adult life. We have investigated six large UK families to assess the possible linkage of five polymorphic DNA probes to the Anderson Fabry locus, previously localised to Xq21-24. No recombination was found between Anderson Fabry disease and DXS87, DXS88 and DXS17, which gave lodmax = 6.4, 6.4 and 5.8 respectively at theta = 0.10, (upper confidence limit 0.10). DXS3 gave lodmax 2.9 at theta = 0.10 (upper confidence limit 0.25). DXYS1 was excluded from linkage. The best fit map (DXYS1/DXS3) theta = 0.192 (DXS17/DXS87/DXS88/Anderson Fabry locus) provided no information about the order of loci in parentheses due to the absence of recombinants. The close linkage of DXS17, DXS87 and DXS88, together with alpha-galactosidase A estimation, can be used for antenatal diagnosis and carrier detection until the application of a gene specific probe has been evaluated.