Altered neurochemical markers in Rett's syndrome.

Rett's syndrome (RS) is a neurologic disorder associated with severe mental deficiency and neurologic manifestations of cortical and extrapyramidal origin. The present report is a preliminary postmortem brain study that compares the levels of endogenous biogenic amines and selected neurotransmitter receptors in five cases with RS and six normal controls of similar age. The level of choline acetyltransferase activity was reduced in several cortical and subcortical regions.

Association between haplotypes and specific mutations in Swiss cystic fibrosis families.

Cystic fibrosis (CF) is the most common severe autosomal recessive genetic disorder in Caucasian populations, with an incidence of about 1 in 2000 live births, implying a carrier frequency of about 1 in 22. In 1989, the CF gene was isolated and characterized and the major mutation (delta F508), a 3-bp deletion that results in the loss of a phenylalanine residue at position 508, was detected. To determine the frequency of the delta F508 mutation and the predicted number of additional mutations in our population, we have undertaken a collaborative study of 215 CF patients and 175 CF parents in Switzerland.

Peroxisomal disorders.

Peroxisomal disorders occur more frequently and have a wider range of clinical manifestations than has been realized in the past. Precise diagnosis can be achieved with non-invasive biochemical assays and all can be diagnosed prenatally, thus providing the option of genetic counseling. Specific therapy is being evaluated for one of these disorders (adrenoleukodystrophy).

Behavioral treatment of sleep dysfunction in patients with the Rett syndrome.

Aberrant sleep patterns are commonly experienced by girls with the Rett syndrome. In this investigation, the problematic sleep of three girls with the Rett syndrome was regulated using a bedtime fading procedure with response cost. The treatment involved systematically delaying the bedtime and utilized a response cost component, removing the child from bed for one hour, when the child did not experience short latency to sleep onset.

Peroxisomal disorders.

The concept that there are human disease states that are associated with abnormal peroxisomal function is of recent origin. This is due in part to the relatively recent discovery of the organelle itself by de Duve in 1983, and to the earlier belief that it was a vestigial structure in mammals. The recognition that the organelle is significant in mammals was ushered in by Paul Lazarow's observation that rat peroxisomes catalyze the beta-oxidation of fatty acids.

Adrenoleukodystrophy.

X-linked adrenoleukodystrophy (ALD) is a disorder of very long chain fatty acid (VLCFA) metabolism that can be diagnosed by demonstrating increased levels of VLCFA in plasma and, prenatally, by similar assays in cultured amniocytes or chorionic vilus samples. ALD causes Addison disease frequently in men and occasionally in women. Prompt diagnosis is important for genetic counseling and for the institution of therapies aimed to prevent or ameliorate the progressive neurologic disability that often is associated with this illness.

The 22-kD peroxisomal integral membrane protein in Zellweger syndrome--presence, abundance, and association with a peroxisomal thiolase precursor protein.

The primary genetic defect of Zellweger syndrome may be related to defective synthesis or impaired import of peroxisomal proteins. We analyzed the presence and measured the abundance of the 22-kD peroxisomal integral membrane protein (PMP) in patients with Zellweger syndrome. We determined the intracellular localization of the 22-kD PMP and compared it with the localization of a peroxisomal 44-kD thiolase precursor protein.

Quantitative magnetic resonance imaging in Rett syndrome.

Rett syndrome (RS) is a progressive neurological disorder of females, characterized by the early onset of autistic behavior, ataxia, and "handwringing" movements. The present magnetic resonance imaging study was undertaken with the purpose of investigating whether structural brain abnormalities of RS patients are similar to those recently reported in autism. The subject population consisted of eight patients and an equal number of age- and sex-matched controls.

X-linked centronuclear myopathy: mapping the gene to Xq28.

The X-linked recessive centronuclear/myotubular myopathy (XLR-CNM/MTM1), a severe neonatal disorder characterized by generalized hypotonia, muscle weakness and primary asphyxia, has recently been mapped to Xq28. This report presents linkage analysis data of eight families with X-linked centronuclear myopathy. Four probes from the region Xq26-27 and five Xq28 probes were used to get more precise gene localization and marker order.

Clinical aspects of adrenoleukodystrophy and adrenomyeloneuropathy.

Adrenoleukodystrophy (ALD) is an X-linked recessive disorder that affects mainly the nervous system white matter and the adrenal cortex. It is associated with an abnormal accumulation of saturated very long chain fatty acids and can be diagnosed by demonstrating an excess of these substances in plasma or red cells. Our laboratory has identified more than 900 hemizygotes and 1,000 heterozygotes.

Severe neonatal asphyxia due to X-linked centronuclear myopathy.

Severe neonatal centronuclear myopathy is inherited as an X-linked condition characterized by primary asphyxia, extreme muscular hypotonia and absent spontaneous movements. We report seven cases from three families to point out the importance of diagnosis with regard to prognosis, outcome and genetic counselling. In hypotonic diseases, analysis of cerebrospinal fluid, electromyography, nerve conduction velocity creatine kinase and a skin biopsy for fibroblast cultures for metabolic investigations are usually carried out.

Arachidonic acid metabolism in fibroblasts from patients with peroxisomal diseases: response to interleukin 1.

Prostaglandin E2 synthesis and eicosanoid biosynthetic enzyme activities (arachidonyl CoA synthetase, cyclooxygenase and phospholipase A2) were measured in dermal fibroblasts from patients with metabolic disorders of peroxisomal origin and compared to those from normal subjects and patients with other metabolic disorders of lipid metabolism. Basal- as well as interleukin 1-stimulated prostaglandin E2 syntheses were higher in fibroblasts from patients with X-linked adrenoleukodystrophy, the Zellweger cerebrohepatorenal syndrome and rhizomelic chondrodysplasia punctata than in normals. Basal cyclooxygenase and phospholipase A2 activities were elevated in most of the peroxisomal disease cells.

Peroxisomal disorders: complementation analysis using beta-oxidation of very long chain fatty acids.

Complementation studies, using fused cell lines from patients with peroxisomal disorders, have shown correction of defective plasmalogen synthesis and phytanic acid oxidation as well as an increase in the number of peroxisomes. At least six complementation groups have been reported. We demonstrate here that complementing cell lines also acquire the ability to oxidize very long chain fatty acids (VLCFA), and that complementation groups defined with this technique are identical to those reported previously when plasmalogen synthesis was used as the criterion for complementation.

Peroxisomal disorders.

Although peroxisomes were once considered a vestige, their importance in cellular metabolism is clearly established by the many inherited diseases that have been described in the past two decades. Unfortunately there is no definitive treatment for the various disorders, but based on the recognition of the biochemical abnormalities, prenatal testing and appropriate genetic counseling can be provided. It is essential for clinicians to be aware of this group of diseases, as diagnosis and further study of these patients are essential in understanding the basic etiologic mechanisms underlying these complex groups of disorders.

Cognitive impairment in adult-onset adrenoleukodystrophy.

Adrenoleukodystrophy (ALD) is a progressive X-linked disorder that produces pathological changes, mainly in the adrenal cortex and the white matter of the central nervous system. The main biochemical abnormality is the accumulation of saturated unbranched fatty acids with a chain length of 24 or more, referred to as very-long-chain fatty acids (VLCFA). Affected children develop large zones of demyelination associated with perivascular lymphoctyic infiltrations resembling those seen in multiple sclerosis.

Haplotype analysis for CF-linked DNA polymorphisms in Switzerland.

A total of 295 patients, parents and unaffected sibs from 106 CF-families in central and northeastern Switzerland were investigated with probes 7C22(D7S16), metH, metD, pKM19, pXV-2c and pJ3.11(D7S8) for eight DNA polymorphisms (RFLP's). Linkage disequilibrium to the CF locus and haplotype frequencies were compared to those in other populations.

RFLPs for Duchenne muscular dystrophy cDNA clones 9 and 10.

The complete 14-kb cDNA for the gene causing the X-linked recessive muscular dystrophy (MD) type Duchenne (DMD) and Becker (BMD) has recently been cloned and made available for deletion/duplication screening in patients. It detects 65 exon-containing nonpolymorphic HindIII fragments spread over a gene locus of about 2,000 kb. When the entire DMD cDNA is used, deletions/duplications can be found in about 65%-70% of affected patients, permitting direct carrier detection by densitometric scanning.

[Principles of DNA diagnosis].

In an ever-increasing number of the more than 4000 known genetic diseases with Mendelian inheritance, the geneloci have been mapped. In such cases it is possible to predict by DNA techniques whether or not family members are carriers of the mutation and risk having affected children. Using the same methods, disease can also be predicted prenatally from chorionic villi biopsies (CVS) as early as the ninth week of pregnancy.

X linked neonatal centronuclear/myotubular myopathy: evidence for linkage to Xq28 DNA marker loci.

We have studied the inheritance of several polymorphic Xq27/28 DNA marker loci in two three generation families with the X linked neonatal lethal form of centronuclear/myotubular myopathy (XL MTM). We found complete linkage of XLMTM to all four informative Xq28 markers analysed, with GCP/RCP (Z = 3.876, theta = 0.

The red-green visual pigment gene region in adrenoleukodystrophy.

Although recent data established that a specific very-long-chain fatty acyl-CoA synthetase is defective in X-linked adrenoleukodystrophy (ALD), the ALD gene is still unidentified. The ALD locus has been mapped to Xq28, like the red and green color pigment genes. Abnormal color vision has been observed in 12 of 27 patients with adrenomyeloneuropathy (AMN), a milder form of ALD.