Diagnosis and Treatment of Patients With Inborn Errors of Metabolism

We propose to characterize the etiology and natural history of rare inborn errors of
metabolism and other genetic disorders, both known and yet-to-be discovered. In so doing, we
will expand our knowledge about these disorders and provide access to patients of interest
for research, teaching, and clinical experience. Individual patients seen under this protocol
have prompted the establishment of specific disease-related protocols involving intensive
natural history studies and innovative therapies. In addition to its longstanding role in
investigating individuals who are of interest to the Section on Human Biochemical Genetics,
this protocol provides one possible avenue (in addition to other NIH protocols) for admitting
patients who are part of the NIH Undiagnosed Diseases Program.

- Inclusion/Exclusion criteria

Patients enrolled in this protocol will have been referred with a known or suspected inborn
error of metabolism, heritable disorder, or genetic predisposition. Examples include
inherited developmental defects or diatheses toward infections, cancer, or an
environmentally induced disease. The principal investigator, along with consulting
specialists, will review the medical records of prospective subjects and offer admission
based upon the potential to help the individual, to learn from the patient, or to initiate
clinical or basic research suggested by the patient s workup. Prior to late 2008, patients
enrolled in this protocol had disorders of current or potential future research interest to
the Principal Investigator or an Associate Investigator. Approximately 400 such patients
were enrolled over the course of 32 years.

Beginning in 2008, the protocol became one of the vehicles for admitting patients with a
broader range of inborn errors of metabolism (e.g., those with immune defects,
developmental disorders, cancer diatheses, etc.) through the NIH UDP. There are several
aspects of this process:

1. Screening and triaging. Records are reviewed by the UDP Director for completeness
and missing articles (e.g., images, biopsy slides) are requested. The UDP Director
assigns records for review to consultants based upon the specialty involved, and
copies of the records are distributed to 1-5 experts.

2. Criteria for eligibility. Eligibility criteria include novelty of clinical
findings, multiple family members affected, or an objective laboratory or imaging clue
to pursue. Of course, patients have to be able to travel, as well.

3. Roles of the UDP personnel. The UDP Director performs the triage, makes the final
decision, and signs the decision letters. The consultants are NIH clinical specialists
from the Clinical Center departments and the ICs. A group of nurse practitioners and
one physician s assistant communicate about medical issues with patients and referring
physicians. Support personnel obtain missing articles, copy records, file them, send
out letters of receipt, enter information in the Lab Matrix database, and answer phone
calls.

4. Consent timing and process. In general, consent is obtained by the care team upon
admission. Occasionally, a patient or family member gives consent for a blood draw
locally; this is obtained by an Associate Investigator over the phone and in writing.

Patients apply with a summary letter from their referring physician and with their medical
records; the cases are then reviewed by members of a large group of NIH consultants. If any
of those consultants finds that an applicant qualifies for her/his protocol (in any
institute), the patient is invited to enroll in that protocol. The UDP connects the patient
with the principal investigator; there is no involvement of protocol 76-HG-0238.

For patients not selected by other services, the UDP Director, based largely on specialists
recommendations, makes the final decision regarding acceptance or rejection with respect to
protocol 76-HG-0238. The UDP has evolved such that the majority of its patients are now
being enrolled in 76-HG-0238.

Once a patient is enrolled in 76-HG-0238, her/his management is the same regardless of
whether or not entry was through the UDP. Specifically, in each case, all testing except
the skin biopsy, DNA analysis, and research bloods is medically indicated and directed
toward diagnosis.

Some subjects will be relatives of patients with known diagnoses, and their specimens will
be obtained for the purpose of heterozygote testing or to serve as controls to help
diagnose the proband. All subjects shall be admitted as inpatients or outpatients at the
discretion of the principal investigator, based upon particular research interests and
expertise.

Individuals will be excluded from this protocol if they already have a diagnosis, if their
previous evaluations leave no clue to pursue, if they appear to have a known diagnosis that
has not been made, or if their subjective complaints far exceed any objective findings. We
will not admit patients under one month of age to this protocol. This exclusion occurs
because there is no urgency for a very early diagnosis and care is more readily proffered
to older individuals at the Clinical Center. Patients under one year of age will be
admitted only if they are medically stable and require admission to the Clinical Center for
diagnosis.

Normal adult volunteers will be enrolled to provide control blood and urine specimens. NIH
employees and members of their immediate families may participate in this protocol as
normal volunteers. We will follow the Guidelines for the Inclusion of Employees in NIH
Research Studies and will give each employee a copy of the NIH information sheet on
Employee Research Participation.

For NIH employees:

1. Neither participation nor refusal to participate will have an effect, either
beneficial or adverse, on the participant s employment or work situation.

2. The NIH information sheet regarding NIH employee research participation will be
distributed to all potential subjects who are NIH employees.

3. The employee subject s privacy and confidentiality will be preserved in accordance
with NIH Clinical Center policies, which define the scope and limitations of the
protections.

4. For NIH employee subjects, consent will be obtained by an individual independent of
the employee s team. Those in a supervisory position to any -12- employee and
co-workers of the employee will not obtain consent.

5. The importance of maintaining confidentiality when obtaining potentially sensitive and
private information from co-workers or subordinates will bereviewed with the study
staff at least annually and more often if warranted.