NIH GUIDE, Volume 23, Number 7, February 18, 1994

PA NUMBER:  PA-94-037



National Institute of Child Health and Human Development


The purpose of this Program Announcement (PA) is to encourage grant

applications on genetic disorders that cause mental retardation.

This includes research on molecular genetic mechanisms, biochemical

and neuropathological processes in the brain, behavioral genetics,

and other developmental processes that result in abnormal cognitive

function.  Research should be directed towards the screening,

diagnosis, treatment, prevention, and/or amelioration of mental

retardation and related developmental disabilities.


The Public Health Service (PHS) is committed to achieving the health

promotion and disease prevention objectives of "Healthy People 2000,"

a PHS-led national activity for setting priority areas.  This PA,

Genetic Disorders Causing Mental Retardation, is related to the

priority area of chronic disabling conditions and maternal and infant

health.  Potential applicants may obtain a copy of "Healthy People

2000" (Full Report:  Stock No. 017-001-00474-0) or "Healthy People

2000" (Summary Report:  Stock No. 017-001-00473-1) through the

Superintendent of Documents, Government Printing Office, Washington,

DC 20402-9325 (telephone 202-783-3238).


Applications may be submitted by foreign and domestic, for-profit and

non-profit organizations, public and private, such as universities,

colleges, hospitals, laboratories, units of State and local

governments, and eligible agencies of the Federal government.

Foreign institutions are not eligible for First Independent Research

Support and Transition (FIRST) (R29) awards.  Applications from

minority individuals and women are encouraged.


Support of this program will be through the NIH research project

grant (R01), FIRST (R29) award, and program project (P01) mechanisms.

Investigators interested in submitting a program project are strongly

encouraged to consult with NICHD program staff in the preparation of

their applications.  Applications of a multi-disciplinary nature may

also be considered through the Interactive Research Project Grants

(IRPG) program.



About one-third of all genetic disorders show some neurological

involvement, and many of these represent neurodegenerative diseases

of infancy.  Genetic or genetically-influenced conditions rank among

the leading causes of organically-based mental retardation.  These

problems can be addressed through studies of the location,

organization, and regulation of genetic material.  This may include

research on molecular genetic mechanisms (genomic imprinting, triplet

repeats, mitochondrial inheritance), gene mapping, enzymatic

function, behavioral genetics, prenatal diagnosis, genetic

counseling, epidemiologic studies, animal models, and gene therapy.

Major areas of interest include:

o  Inborn errors of metabolism that specifically impact on brain

function.  This research focuses brain pathophysiology due to

imbalances in amino acids, mucopolysaccharides, purines, lipids, and

carbohydrates, or the dysfunction of cellular organelles (e.g.,

mitochondria, peroxisomes, lysosomes, or Golgi) that contributes to

mental retardation and developmental disabilities.  We are especially

interested in the development of therapeutic strategies (genetic or

pharmacological) that aid in the diagnosis and clinical management of

these disorders.  Specific examples of metabolic disorders with

prominent MRDD include phenylketonuria, maternal phenylketonuria,

Lesch-Nyhan, galactosemia, and adrenoleukodystrophy.

o  Down Syndrome is the leading genetic cause of mental retardation,

occurring in about 1/800-1000 births.  Research on Down Syndrome may

focus on the behavioral heterogeneity, critical genes on chromosome

21, Alzheimer-like pathology, gene dosage compensation, chromosomal

nondisjunction, cellular mosaicism, animal models, epidemiology, and

prenatal screening issues.

o  Chromosomal abnormalities occur in three to four percent of live

births.  This may include aberrations associated with chromosome

number, morphology, or structure.  Partial deletions or duplications

of chromosomal material are associated with contiguous gene syndromes

(e.g., Charcot-Marie-Tooth, Smith-Magenis, Prader-Willi, Angelman, or

WAGR), which often involve mental retardation.  Chromosomal

abnormalities may also affect placental development (confined

placental mosaicism).  Within the context of mental retardation, we

are interested in molecular mechanisms that give rise to specific

chromosomal abnormalities, genetic regulatory mechanisms (eg. genomic

imprinting, uniparental disomy), epigenetic phenomena, and the

identification of specific genes that affect brain function.

o  X-linked disorders may explain why males show a 25 to 35 percent

higher incidence of mental retardation than females.  We welcome

research on genetic mechanisms specific to the X-chromosome (e.g.,

X-inactivation, gene regulation) that may be relevant to

understanding some forms of X-linked mental retardation.

o  Fragile X syndrome is the leading cause of heritable mental

retardation, affecting about 1/1400 males and 1/2500 females.  The

genetic defect is an unstable region of DNA on the X chromosome which

becomes highly expanded when transmitted through the maternal

lineage.  Research on the expansion and transmission of triplet

repeats, how they affect gene function, and the role of the FMR gene

in brain function is encouraged.  Support studies on the detection,

behavioral assessment, and epidemiology of Fragile X syndrome in

normal populations and in children with learning disabilities is also


o  Rett syndrome is a neurological disorder that results in arrested

development of motor and social skills at an early age, but it only

appears in young girls (1/15,000 female births).  The occurrence of

this disorder suggests that it may involve spontaneous dominant

mutations on the X chromosome, but more complex genetic models need

to be considered.  Research into the underlying defect in Rett

Syndrome and how it affects brain development and behavior is

especially encouraged.

o  Neural tube defects are among the most frequent and severe

anomalies of central nervous system development, occurring in about

1/1000 live births.  Although it appears that environmental as well

as genetic factors play a role, the etiology and pathogenesis of

these malformations are poorly understood.  We support investigations

in the genetic basis of neural tube defects, including the role of

modifier genes that influence expression and penetrance, genetic

networks (temporal and spatial) important for pattern formation in

the developing brain and spinal cord, and animal models to elucidate

mechanisms of normal neural tube development and to define the early

developmental miscues that result in abnormal neural function.

o  Mitochondrial inheritance may explain some forms of mental

retardation that cluster within families.  Defects in oxidative

phosphorylation and its by-products would be expected to impact most

heavily on tissues like brain that have high energy demands and are

sensitive to their metabolic environment.  In order to understand the

role of mitochondrial defects in mental retardation, we support

research on mitochondrial genetics, regulation of mitochondrial

function, replication, interaction of nuclear-encoded genes, and the

development of model systems.

o  Development of animal models for specific brain disorders is

rapidly advancing, thanks to advances in transgenic manipulation,

stem cell culture, and embryology. We support the use of animal

models for the study of pathophysiological mechanisms associated with

brain dysfunction and the development of clinical strategies for the

management of these disorders.  We encourage research in behavioral

genetics and comparative physiology in order to develop appropriate

physiological and behavioral assessments.

o  Heterozygotes (carriers) often present phenotypic heterogeneity,

which can complicate clinical management and counseling.  In order to

improve the assessment and treatment of mental retardation, we

support research into the mechanisms of variable penetrance, allelic

differences, genetic background, germ line mosaicism, X-inactivation,

and/or environmental differences in the expression of genetic


o  Prenatal screening is central to the diagnosis and management of

mental retardation and developmental disabilities.  We support

research in the development of safe and accurate methods for

assessing the genetic status of the fetus, including amniocentesis,

chorionic villus sampling, and analysis of fetal cells in the

maternal circulation.  We also support research in population

genetics and the ethical, social, and legal consequences of these


o  Gene therapy is being developed for the treatment of specific

genetic disorders that affect brain function.  We encourage research

in those disorders in which mental retardation is the primary

clinical manifestation.  This may include development of improved

vectors for brain tissue, transcriptional and translational control

of inserted genes, physiological studies on the expression and

function of gene products within the brain, transplantation of

genetically- modified cells or tissues, and relevant animal models.





NIH policy is that applicants for NIH clinical research grants and

cooperative agreements are required to include minorities and women

in study populations so that research findings can be of benefit to

all persons at risk of the disease, disorder or condition under

study; special emphasis must be placed on the need for inclusion of

minorities and women in studies of diseases, disorders and conditions

which disproportionately affect them.  This policy is intended to

apply to males and females of all ages.  If women or minorities are

excluded or inadequately represented in clinical research,

particularly in proposed population-based studies, a clear and

compelling rationale must be provided.

The composition of the proposed study population must be described in

terms of gender and racial/ethnic group.  In addition, gender and

racial/ethnic issues should be addressed in developing a research

design and sample size appropriate for the scientific objectives of

the study.  This information must be included in the form PHS 398

(rev. 9/91) in Sections 1-4 of the Research Plan AND summarized in

Section 5, Human Subjects.  Applicants are urged to assess carefully

the feasibility of including the broadest possible representation of

minority groups. However, NIH recognizes that it may not be feasible

or appropriate in all research projects to include representation of

the full array of United States racial/ethnic minority populations

(i.e., Native Americans (including American Indians or Alaskan

Natives), Asian/Pacific Islanders, Blacks, Hispanics).  The rationale

for studies on single minority population groups must be provided.

For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology,

prevention (and preventive strategies), diagnosis, or treatment of

diseases, disorders or conditions, including but not limited to

clinical trials.

The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded.  However,

every effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including


If the required information is not contained within the application,

the review will be deferred until the information is provided.

Peer reviewers will address specifically whether the research plan in

the application conforms to these policies.  If the representation of

women or minorities in a study design is inadequate to answer the

scientific question(s) addressed AND the justification for the

selected study population is inadequate, it will be considered a

scientific weakness or deficiency in the study design and will be

reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required

to address these policies.  NIH funding components will not award

grants or cooperative agreements that do not comply with these



Applications are to be submitted on the grant application form PHS

398 (rev. 9/91) and will be accepted at the standard application

deadlines as indicated in the application kit.  The receipt dates for

applications for AIDS-related research are found in the PHS 398 (rev.

9/91) instructions.

Application kits are available at most institutional offices of

sponsored research and may be obtained from the Office of Grants

Information, Division of Research Grants, National Institutes of

Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone

301/594-7249.  The title and number of the announcement must be typed

in Section 2a on the face page of the application.

Applications for the FIRST Award (R29) must include at least three

sealed letters of reference attached to the face page of the original

application.  FIRST Award (R29) applications submitted without the

required number of reference letters will be considered incomplete

and will be returned without review.

The completed original application and five legible copies must be

sent or delivered to:

Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**


Several other Institutes at the National Institutes of Health also

have an interest in supporting areas of research covered by this PA.

Applications will be assigned on the basis of established Public

Health Service referral guidelines and some applications may receive

dual assignments.  In the case of R01 and R29 applications, they will

be reviewed for scientific and technical merit by study sections of

the Division of Research Grants, NIH, in accordance with the standard

NIH peer review procedures and criteria.  Program project

applications will be reviewed by initial review groups organized by

the Institute to which the application is assigned.  Following

scientific-technical review, the applications will receive a

second-level review by the Institute's national advisory council.


Applications will compete for available funds with all other approved

applications.  The following will be considered in making funding


o  Quality of the proposed project as determined by peer review

o  Availability of funds

o  Program balance among research areas of the announcement


Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Ralph Nitkin

Mental Retardation and Developmental Disabilities Branch

National Institute of Child Health and Human Development

6100 Executive Boulevard, Room 4B09

Bethesda, MD  20892

Telephone:  (301) 496-1383

FAX:  (301) 402-2085

Direct inquiries regarding fiscal matters to:

Mr. E. Douglas Shawver

Office of Grants and Contracts

National Institute of Child Health and Human Development

6100 Executive Boulevard, Room 8A-17

Bethesda, MD  20892

Telephone:  (301) 496-1303


This program is described in the Catalog of Federal Domestic

Assistance No. 93.865, Research for Mothers and Children.  Awards are

made under authorization of the Public Health Service Act, Title IV,

Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC

241 and 285) and administered under PHS grants policies and Federal

Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not

subject to the intergovernmental review requirements of Executive

Order 12372 or Health Systems Agency review.


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