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

PA NUMBER:  PA-94-035

P.T. 34




National Institute of Neurological Disorders and Stroke


The National Institute of Neurological Disorders and Stroke (NINDS)

announces the reissuance of a program announcement (originally

published July 18, 1985) to notify the scientific community of

continuing NINDS interest in the submission of research grant

applications concerning neurogenetic disorders.


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

promotion and disease prevention goals of "Healthy People 2000," a

PHS-led national activity for setting priorities.  This program

announcement, Neurogenetic Disorders of Infancy and Childhood, is

related to the priority areas of chronic disabling conditions and

maternal and infant health.  Potential applicants may obtain a copy

of "Healthy People 2000" (Full Report:  No. 017-001-474-0, or 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

organizations, public and private, such as universities, colleges,

hospitals, laboratories, units of State or local governments, and

eligible agencies of the Federal government.  Foreign institutions

are not eligible for First Independent Research Support and

Transition (FIRST) (R29) awards, program projects (P01), and center

grants (P50).  Applications from minority individuals and women are



Applicants may use the research project grant (R01), program project

(P01), center grants (P50), and FIRST (R29) award.  Prospective

applicants are encouraged to communicate with the NINDS program

contact listed under INQUIRIES regarding the appropriate funding




It is estimated that of the 3,000 known genetic disorders, as many as

one-third are primarily neurologic or have important neurologic

involvement.  Most of them have a low incidence, but collectively

they represent an enormous burden on affected individuals, their

families, and society.  Many of these neurogenetic disorders manifest

themselves early in life leading to either a premature death or to a

lifelong disability with significant attendant psychological and

economic hardships.

Any attempt to group all the neurogenetic diseases of early life is

somewhat arbitrary given that for many the underlying pathological

mechanisms are incompletely understood.  Examples of disorders of

interest to the NINDS include:

1.  Hereditary ataxias and related disorders such as Friedreich

ataxia, ataxia telangiectasia, olivopontine cerebellar degeneration,

Ramsay Hunt syndrome, abetalipoproteinemia, Machado-Joseph disease,

and familial spastic paraparesis.

2.  Movement disorders such as Juvenile Huntington disease, the

dystonias including blepharospasm and spasmodic torticolis, tremor,

myoclonus, and Hallervorden-Spatz disease.

3.  Phakomatoses, or neurocutaneous syndromes such as

neurofibromatosis, tuberous sclerosis, Sturge-Weber, and Von

Hippel-Landau disease.

4.  Mitochondrial encephalomyopathies such as the MELAS syndrome,

Kearns-Sayre, and Leigh disease.

5.  Hereditary disorders of  nerve and muscle such as infantile

spinal muscular atrophy, Charcot-Marie-Tooth disease, hereditary

sensory and autonomic neuropathies, genetic myasthenic syndromes,

metabolic myopathies, muscular dystrophies, and myotonias.

In addition to diseases that have their major effects on the nervous

system, many inborn errors of metabolism affect several systems,

including the nervous system.  The NINDS is interested in supporting

research in the metabolic diseases where the research proposed is

directed at the nervous system manifestations of the disorder.

Examples of these metabolic diseases include, but are not limited to:

1.  Disorders of lipid metabolism such as Gaucher disease,

Niemann-Pick disease, the neuronal ceroid lipofuscinoses including

Batten disease, the leukodystrophies, and the gangliosidoses

including Tay-Sachs disease.

2.  Disorders of carbohydrate metabolism such as galactosemia and

hereditary fructose intolerance.

3.  Glycogen storage diseases such as Von Gierke, Lafora disease, and

Pompe disease.

4.  Organic acidurias such as proprionic acidemia and methylmalonic


5.  Disorders of purine metabolism such as Lesch-Nyhan syndrome, and


6.  Disorders of amino acid metabolism and transport such as

phenylketonuria, homocystinuria, maple syrup urine disease, urea

cycle defects, Hartnup disease, and Lowe syndrome.

7.  Disorders of mucopolysaccharide metabolism such as Hunter,

Hurler, and Sanfilippo syndromes.

8.  Disorders of metal metabolism such as Wilson disease and Menkes


There are numerous other neurological disorders that also result from

genetic abnormalities such as the Laurence-Moon-Bardet-Biedl,

Aicardi, Sjogren-Larsson, Prader-Willi and Angelman syndromes.  In

addition to those diseases that have a recognizable pattern of

inheritance, there are many other neurological disorders that seem to

have, in some cases, a familial basis.  These may well represent

neurogenetic disorders with multifactorial etiology.  Such diseases

can be as diverse as disorders of defective cellular migration (such

as lissencephaly, heterotopias), neural tube defects, congenital

hydrocephalus, myoclonic epilepsy, and narcolepsy.

Research Goals and Scope

Grant applications to study human neurogenetic disorders involving

affected individuals and their family members are encouraged.

Because the phenotypes of many neurogenetic disorders do not appear

until childhood or early adolescence, the development of animal

models is also important.  Such models could make possible the

detection of early biochemical changes, allow characterizations of

the chemical pathology, and facilitate study of how genetic mutation

disrupts the normal pathways of nervous system function.

Areas of research interest include, but are not limited to, the


A.  Clinical Pathologic Correlations.  Studies are needed to

delineate the relationship of the clinical picture to pathological

findings.  Histopathological studies, including neurochemical studies

of fresh tissue, which provide data for basic understanding of the

relationship between pathophysiology and the evolution of clinical

signs and symptoms, as well as the course of the disorder are


B.  Genetics.  Classical genetic studies have been used to establish

the mode of inheritance for many of these disorders.  This

information will provide insight as to whether etiologic

heterogeneity exists, and if sporadic cases are due to reduced

penetrance or represent phenocopies.  The most important

contributions of genetic studies would be to establish the linkage

relationships of the genes responsible for these disorders, and the

identification of the defective gene and its normal biological role.

State of the art methodologies for such studies should be used.

C.  Biochemistry.  Studies should be directed at discovering the

metabolic defect in each of these disorders and identifying its

molecular basis.  Successful biochemical studies will lead to an

understanding of the pathogenic mechanisms and make possible the

recognition of the heterozygote.  Currently available advanced and

sophisticated methodologies should be brought to bear on this

important research.

D.  Neuroimaging.  New neuroimaging technologies (PET, SPECT, MRI)

can be applied to neurogenetic research problems and provide

important clues about brain function under pathophysiological

conditions and allow for correlation with the clinical disease state.

E.  Neuroepidemiology.  There are some neurological diseases in which

the genetic abnormality may not be the primary reason for the

expression of the disorder.  Epidemiological study of at risk

families or clusters of cases might provide important clues of the

interaction between genetic and non-genetic factors in producing the

clinical symptomatology.





NIH policy is that applicants for NIH clinical research grants and

cooperative agreements will be 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 should be placed on the need for

inclusion of minorities and women in studies of diseases, disorders,

and conditions that 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

compelling rationale should be provided.

The composition of the proposed study population must be described in

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

racial or ethnic issues should be addressed in developing a research

design and sample size appropriate for the scientific objectives of

the study. This information should be included in the form PHS 398 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, the NIH recognizes that it may not be feasible or

appropriate in all research projects to include representation of the

full array of Unites States racial or ethnic minority populations:

Native Americans (including American Indians or Alaska Natives),

Asian or Pacific Islanders, Blacks, and Hispanics).  The rationale

for studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human

biomedical and behavioral studies of etiology, epidemiology,

prevention (and prevention 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 or ethnic minorities when it is important to apply the results

of the study broadly.  This directive should be addressed by


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' population, including


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 the NIH are

required to address these policies.  If the required information is

not contained within the application, the review will be deferred

until the information is provided. 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) according to the instructions included in the

application package.  These application packages are available at the

offices of sponsored research of most institutions eligible to

receive Federal grants and 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.

Applicants for program project grants should request a copy of the

NINDS Guidelines:  Program Project and Research Center Grants from

the program staff listed under INQUIRIES.  Receipt dates for new

research project grant (R01) applications and FIRST (R29) awards and

for program project (P01) and center grant (P50) applications are

February 1, June 1, and October 1.

FIRST applications must include at least three sealed letters of

reference attached to the face page of the original application.

FIRST applications submitted without the required number of reference

letters will be considered incomplete and will be returned without


On page 1 of form PHS 398, check "YES" in Item 2a, enter the number

of this Program Announcement in the space provided, and provide the

name of this Program Announcement (Neurogenetic Disorders of Infancy

and Childhood) in the blank space labeled "Title."

Use the mailing label provided in the application package to mail the

signed original and five exact copies of it to:

Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**

For program projects or center grants, submit the original and three

copies to the Division of Research Grants.  An additional two copies

of the program project or center grant application must be sent to

Dr. Judy Small at the address listed under INQUIRIES to expedite the

processing of these applications for multidisciplinary efforts.


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.


The standard review criteria will be used to assess the scientific

merit of applications.  Applications will compete for available funds

with all other applications.  The following will be considered when

making funding decisions:

o  quality of the proposed projects as determined by peer review,

o  availability of funds, and

o  program balance among research areas.


Written and telephone inquiries are encouraged.  The opportunity to

clarify any issues or questions from potential applicants is welcome.

Questions concerning scientific aspects of this Program Announcement

and application procedures may be addressed to:

Dr. Judy A. Small

Division of Convulsive, Developmental, and Neuromuscular Disorders

National Institute of Neurological Disorders and Stroke

Federal Building, Room 8C04

Bethesda, MD  20892

Telephone:  (301) 496-5821

FAX:  (301) 402-0887

Questions concerning fiscal aspects of this Program Announcement may

be addressed to:

Mr. King P. Bond, Jr.

Grants Management Branch

National Institute of Neurological Disorders and Stroke

Federal Building, Room 1004

Bethesda, MD  20892

Telephone:  (301) 496-9231


This program is described in the Catalogue of Federal Domestic

Assistance, Number 93.853, Clinical Research Related to Neurological

Disorders, and 93.854, Biological Basis Research in the

Neurosciences.  Grants will be awarded under the authority of the

Public Health Service Act, Title IV, Section 301 (Public Law 78-410,

as amended:  42 USC 241) and administered under PHS grants policies

and Federal Regulations 42 CFR Part 52 and 45 CFR 74.  This program

is not subject to Health Services Agency review of the

intergovernmental review requirements of Executive Order 12372.


Return to 1994 Index

Return to NIH Guide Main Index

Office of Extramural Research (OER) - Home Page Office of Extramural
Research (OER)
  National Institutes of Health (NIH) - Home Page National Institutes of Health (NIH)
9000 Rockville Pike
Bethesda, Maryland 20892
  Department of Health and Human Services (HHS) - Home Page Department of Health
and Human Services (HHS) - Government Made Easy

Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, Audio or Video files, see Help Downloading Files.