Hugo Moser - US grants

health science research support; health /scientific organization;

We propose biochemical and clinical studies in three groups of genetically determined disorders which are associated with mental retardation: Adrenoleukodystrophy, the sialidoses and genetically determined disorders of the urea cycle. Adrenoleukodystrophy is an X-linked disorder associated with the accumulation of very long chain fatty acids in the white matter of the nervous system and the adrenal cortex. We will search for the cause of this accumulation by a variety of approaches including the study of beta oxidation, with emphasis on peroxisomal oxidation, and by studies in cultured skin fibroblasts. We will conduct a therapeutic trial of dietary restriction of very long chain fatty acids. The sialidoses represent a newly recognized group of disorders, which may include four distinct subtypes. We will identify the nature of the accumulated sialoproteins and gangliosides, and purify and study the sialidases with the aid of newly synthesized substrates. Studies of genetically determined disorders of the urea cycle will focus on correlative behavioral and biochemical studies of heterozygotes, in follow-up of an observation that heterozygotes for ornithine transcarbamylase deficiency show slight but significant intellectual defects.

No Abstract Provided

We propose the second International Conference on the Rett Syndrome. This syndrome, first described in 1966, has attracted a great deal of recent interest. This interest is based upon: (1) The recent concensus that it represents a distinct clinical entity. (2) It is more common than previously recognized, with incidence estimated at 1:15,000. (3) It presents a remarkably consistent behavioral phenotype with an undoubted predominantly biological basis. (4) There is indication of a disturbance in brain dopamine metabolism. (5) The syndrome occurs only in females, indicating an as yet undefined abnormality in the X-chromosome. Interest and knowledge about this disorder is advancing at a rapid pace, and an international conference about this topic promises to provide new information of both clinical and basic interest.

ultracentrifugation; biomedical equipment resource;

genetic markers; genetic disorder; syndrome; pathologic process;

The 8th World Congress of the International Association for the Scientific Study of Mental Deficiency IASSMD will be held in Dublin from 21-25 August 1988. This proposal is to support the presentation of the important American research in mental retardation to an international group of professionals concerned with the etiology, prevention, treatment, education, and care of the mentally retarded. This congress is planned with modern facilities in an ancient center of intellectual tradition that will be convenient to Eurpopean and American scientists. The meeting will summarize the enormous advances that have been gained in the past few years. More important, the meeting will provide a platform for young scientists with new ideas at a time when we are looking ahead to the next millenium and the dawn of understanding brain development and function. The proposal requests funds to bring distinguished scientists to lead discussions and provide panel leadership, and to provide travel and living expenses to scientists whose presentations will be chosen on a competitive basis. Letters of solicitation for papers will be sent to each laboratory that has received research support from the Mental Retardation section of NICHD to include Mental Retardation Centers, University Associated Facilities, Holders of Program Projects, all American Departments of Pediatrics, participants in the Research Accomplishments Symposium, participants in the NICHD Evaluation and Assessment Report, and Mental Retardation Training Programs. In addition, the Journal of Pediatrics and the Journal of Mental Retardation Research will have notices announcing the availability of awards. A committee of scientists versed in neurology, psychology, genetics, and biochemistry will judge the submissions. The proposal will make a major contribution to the success of the IASSMD at a time when it is critically important to join in an international effort to prevent mental retardation and adhere to a rational for treatment.

biomedical equipment resource; biomedical equipment purchase;

mental retardation;

genetic markers; genetic disorder; syndrome; pathologic process;

mental retardation;

The key biochemical abnormality in X-linked adrenoleukodystrophy (ALD) is the accumulation of saturated very long chain fatty acids (VLCFA) in tissues and body fluids, due to a genetic defect of a peroxisomal enzyme that normally degrades these substances. ALD affects mainly the adrenal cortex, nervous system white matter and testis. While the endocrine deficits can be helped by steroid replacement, the neurological disability cannot be treated and often leads to severe disability and premature death. Neurological involvement ranges from rapid cerebral demyelination with mean age of onset at age 7.2 + 1.7 (SD) years, to much more slowly progressive spinal cord and peripheral nerve involvement in adults (adrenomyeloneuropathy). Our laboratory conducts a national program for the diagnosis of X-linked ALD and peroxisomal disorders, and through this program has identified more than 700 males with X-linked ALD, by far the largest group of patients with this disorder anywhere. Recent studies have demonstrated that a new dietary approach can normalize the levels of saturated VLCFA in the plasma of patients with ALD within 2-4 weeks. The regimen involves the oral administration of a glycerol trierucate (GTE) oil together with certain other dietary modifications. Diagnosis ALD can be achieved in the early postnatal period (as well as prenatally), at least several years before the onset of neurological disability in untreated patients. The striking biochemical effect of the new regimen for the first time offers the opportunity to test whether early normalization of saturated VLCFA can prevent or ameliorate the neurological disability in ALD. The proposed study has three components: 1) a double- blinded trial involving adults with adrenomyeloneuropathy and neurologically involved ALD heterozygotes; 2) a prevention trial for neurologically asymptomatic boys with the biochemical defect of ALD; and 3) a study of neurologically symptomatic boys in whom the rate of neurological progression will be compared with that in more than 100 untreated childhood ALD patients who had previously been diagnosed in our laboratory.

Rett syndrome (RS) is a disorder that affects young girls and is characterized by progressive loss of cognitive function and ability to communicate, apraxia of hand movements, seizures, respiratory disturbances, ataxia, corticospinal tract involvement, and characteristic hand-wringing movements. It affects only females with an incidence of 1:10,000-1:15,000. Diagnosis depends upon the presence of a characteristic and remarkably consistent constellation of symptoms and signs. There is no diagnostic marker. It is proposed, but not proven, that RS is an X-linked dominant, lethal in males and reproductively lethal in females, with most cases representing new mutations. The present application is submitted 25 months after the initiation of P01 HD 23540, and requests support for an additional 3 years of multidisciplinary clinical and basic research studies designed to elucidate the pathogenesis of RS and to initiate therapy. It includes four highly interrelated components. Project 1 will conduct multidisciplinary evaluations of clinical features and therapeutic interventions in 100 patients with documented "classical" RS, and will carry out investigations to help clarify the genetic basis of RS. The other three projects are designed to test and extend a pathogenetic hypothesis developed during the 25 months of the current grant period; namely, that RS is a neurodegenerative disorder that affects most severely dopaminergic neurons in the substantia nigra and basal ganglia and cholinergic neurons in the basal forebrain. This hypothesis will be evaluated by the techniques of neuropathology (Projects 2a and 2b), neurochemistry (Project 3), Positron Emission Tomography (Project 4a) and Magnetic Resonance Imaging (Project 4b). This approach may clarify the pathogenesis of RS, but also will serve as a model of how a neonatal neurodegenerative process differs from disorders such as Alzheimer and Parkinson disease that affect at least in part the same neurons later in life. During this grant period, a series of therapeutic interventions will be sought and implemented.

This application for support of years 5 to 10 of the Mental Retardation Research Center (MRRC) at the Kennedy Krieger Institute and Johns Hopkins University is submitted in response to RFA HD-93-1. The MRRC includes an Administrative Core that provides general management and biostatistical services, and five research cores. The Genetics Core provides a centralized tissue culture and DNA facility, including an archive of transformed cell lines, specialized cytogenetic analyses, and a genetic data and processing resource. The Neuroscience Core provides quantitative measurements of neurotransmitters and receptors and, when available, their RNA and DNA progenitors, in body fluids and tissue sections, as well as specialized analytical and enzymatic studies of key metabolic intermediates. The Animal Facility Core provides and maintains stocks of genetically unique animals that serve as models for the understanding and therapy of human disease states, and also relates to a transgenic mouse and embryonal stem cell resource. The Neuroimaging Core provides specialized resources for the collection and quantitative analysis of data obtained by positron emission tomography, magnetic resonance imaging and spectroscopy. The Behavior Science Core aids in the design and collection of behavioral data, correlates behavioral and learning deficits with alterations in brain structure and function, and engages in compliance training that includes the preparation of research participants to cooperate with experimental protocols. The core units provide service to 90 investigators in 18 departments who have assembled 52 projects supported by NIH at a total annual direct fundings level of $14,716,280. The program addresses 19 of the 20 priority areas specified in RFA HD-93-1. There is a strong focus on interdisciplinary cooperation, including that between the behavioral and biomedical sciences, and on the prompt testing and utilization of research findings for the benefit of persons who are mentally retarded.

family genetics; adrenoleukodystrophy; phenotype; mental retardation; linkage mapping; diagnosis design /evaluation; genetic disorder; genotype; epidemiology; long chain fatty acid; sex linked trait; T lymphocyte; peroxisome; diagnostic tests; molecular pathology; endocrine disorder diagnosis; fatty acid metabolism; genetic disorder diagnosis; human therapy evaluation; clinical research; neuropsychological tests; human subject; laboratory mouse; polymerase chain reaction; magnetic resonance imaging; cell line;

DESCRIPTION (provided by applicant): X-linked adrenoleukodystrophy (X-ALD) affects mainly the nervous system white matter and axons and the adrenal cortex. Its incidence is approximately 1:17,000. Phenotypic expression varies often within the same family and in males ranges from the childhood cerebral form, which may lead to total disability and death by 10 years of age, to adrenomyeloneuropathy (AMN), which presents in the middle or late twenties as a paraparesis that is slowly progressive over decades. Women heterozygous for X-ALD may develop an AMN-like syndrome in middle age or later. Most males have primary adrenocortical insufficiency which responds to steroid replacement therapy. Accumulation of very long chain fatty acids (VLCFA) is the principal biochemical abnormality. The defective gene codes for a peroxisomal membrane protein (ALDP). There is no consistently effective therapy for the neurologic manifestations. Bone marrow transplantation benefits patients with early cerebral involvement but carries a high risk. The investigators propose a longitudinal cohort study and two Phase II therapeutic trials. Specific Aim 1 will establish a network of five clinical centers: The Kennedy Krieger Institute in Baltimore, the Texas Children's Hospital in Houston, the Massachusetts General Hospital in Boston, the University of Minnesota in Minneapolis, and the University of California at San Francisco. The Program will be coordinated by the Center for Clinical Trials at the Johns Hopkins Bloomberg School of Public Health. Specific Aim 2 will establish a cohort of 300 male X-ALD patients and 100 women heterozygous for X-ALD to permit a longitudinal study of natural history. Follow-up will utilize objective and validated measures of neurologic and neuropsychologic function, and quality of life. Neuroimaging studies have been shown to be valuable surrogate markers of the cerebral disease and will be scored independently by two neuroradiologists using an electronic transmission system developed for this purpose with the support from the National Library of Medicine. Newly developed quantitative tests will be used to aid assessment progression of AMN. Specific Aim 3 will conduct safety-efficacy studies of 4-phenylbutyrate therapy in patients with the cerebral forms of X-ALD, and a placebo controlled trial of insulin-like growth factor-1 in male patients with AMN and heterozygous women with an AMN like syndrome.

disease /disorder model; library; model; person with disability

[unreadable] DESCRIPTION (provided by applicant): We propose to conduct a double-masked placebo controlled study of Glyceryl Trioleate-Glyceryl Trierucate (Lorenzo's Oil (LO) therapy in Adrenomyeloneupathy (AMN), the adult form of X-linked adrenoleukodystrophy (X-ALD). AMN is slowly progressive. It is a distal axonopathy that involves the long tracts of the spinal cord and differs from the rapidly progressive inflammatory cerebral forms that most commonly affect boys and adolescents. All forms of X- ALD are associated with the abnormal accumulation of very long chain fatty acids (VLCFA) in plasma and tissues The oral administration of LO normalizes plasma VLGFA levels in X-ALD patients within four weeks, and various therapeutic trials have been conducted during the last 14 years. While previous therapeutic trials of LO in patients with the cerebral forms of X-ALD were disappointing, recent studies suggest that it is beneficial in two types of X-ALD 1) as a preventive of neurological involvement in asymptomatic boys, and 2) in AMN where it appears to slow the rate of progression. None of the previous studies have been controlled and we now propose the first placebo-controlled trial. It will be a three-year study that will involve 120 men with AMN who do not have evidence of cerebral involvement and 120 women who are heterozygous for X-ALD and have an AMN-like syndrome. The study will be conducted at the Kennedy Krieger Institute and the General Clinical Research Center at the Johns Hopkins Medical Institutions. The study will be coordinated by Westat. The rate of progression will be compared in the LO and placebo groups. The Kurtzke EDDS score will be the primary outcome measure. A variety of secondary outcome measures will also be used. A novel part of the study is the utilization and validation of newly developed markers, namely quantitative tests of sensation, strength and balance in the motion analysis laboratory, and magnetic transfer imaging studies of the dorsal columns in the cervical cord. These markers test the function and structure of the parts of the nervous system that are most severely involved in AMN. Our preliminary studies suggest that they may permit more sensitive and rapid assessment of the rate of progression than can be achieved with current techniques. This would facilitate and speed the evaluation of all therapeutic interventions in AMN. These techniques may also be applicable to the study of other spinal cord disorders. [unreadable] [unreadable] [unreadable]