Symptoms and General Pathology

All Conditions

Neoplasms

Skin and Connective Tissue Diseases

Diseases and Abnormalities at or Before Birth

Nutritional and Metabolic Diseases

Musculoskeletal Diseases

Nervous System Diseases

Gland and Hormone Related Diseases

Rare Diseases

Syndrome

Skin Neoplasms

Congenital Abnormalities

Xeroderma Pigmentosum

Skin Diseases, Genetic

Cockayne Syndrome

Trichothiodystrophy Syndromes

Ichthyosis

Skin Diseases

Skin Abnormalities

Infant, Newborn, Diseases

Keratosis, Actinic

Keratosis

Precancerous Conditions

Genetic Diseases, Inborn

Photosensitivity Disorders

Pigmentation Disorders

DNA Repair-Deficiency Disorders

Metabolic Diseases

Dwarfism

Bone Diseases

Bone Diseases, Developmental

Heredodegenerative Disorders, Nervous System

Neurodegenerative Diseases

Abnormalities, Multiple

Trichothiodystrophy

Subjects with clinical and/or laboratory documentation of typical features or suggestiveclinical features of XP, CS, TTD, or overlap syndromes

Family members of patients with XP, CS, TTD, or overlap syndromes

Michael R Sargen, M.D.

Four rare genetic diseases, xeroderma pigmentosum (XP), Cockayne syndrome (CS), the XP/CS complex and trichothiodystrophy (TTD) have defective DNA excision repair although only XP has increased cancer susceptibility. We plan to perform careful clinical examination of selected patients with XP, XP/CS, CS, or TTD and follow their clinical course. We will obtain tissue (skin, blood, hair, buccal swabs) for laboratory examination of DNA repair and for genetic analysis. We hope to be able to correlate these laboratory abnormalities with the clinical features to better understand the mechanism of cancer prevention by DNA repair. Patients will be offered counseling and education for cancer control.

Three rare genetic diseases, xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD) have defective DNA excision repair although only XP has increased cancer susceptibility. We plan to perform careful clinical examination of selected patients with XP, CS, TTD, or overlap syndromes to follow their clinical course. We will obtain tissue (skin, blood, hair, or buccal cells) for laboratory examination of DNA repair and for histologic, protein, biochemical, and genetic analysis. We hope to be able to correlate these laboratory abnormalities with the clinical features to better understand the mechanism of cancer prevention by DNA repair. Patients will be offered counseling and education for cancer control.

Examination of Clinical and Laboratory Abnormalities in Patients With Defective DNA Repair: Xeroderma Pigmentosum, Cockayne Syndrome, or Trichothiodystrophy

.All IPD recorded in the medical record will be shared with intramural investigators upon request. @@@@@@In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

Proportion of patients with three rare genetic diseases; xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD)and overlap syndromes

-To confirm suspected cases of XP, CS, TTD, XP/TTD or overlap syndrome patients by review of clinical records, by clinical examination and by laboratory testing -To document presence (or absence) of cancers (skin, eye, tongue, or internal) in XP, XP/CS, CS, TTD, XP/TTD and other overlap syndrome patients-To document atypical clinical features or unusual environmental exposures of patients with XP, XP/CS, CS, TTD, XP/TTD and otheroverlap syndromes

obtain tissue (skin, blood, hair or buccal cells) from XP, CS, TTD, XP/TTD or overlap syndrome patients, their first-degree relatives and healthy volunteers for establishment of cell cultures and for examination of DNA repair and genetic analysis

identify molecular defects in the DNA repair or other genes in cells from patients with XP, CS, TTD, XP/TTD or overlap syndromes and toattempt to correlate the defects with the clinical features

follow the clinical course of selected patients with XP, CS, TTD, XP/TTD or overlap syndromes

National Cancer Institute (NCI)

Patients who are diagnosed with a DNA Repair Disorder

Healthy family members of enrolled diagnosed participants.

The study coordinator or another team member will review standard health questions relevant to DNA repair disorders. The control group will not undergo an interval history. These questions will include:

1. How the participant's appetite and general weight trajectory has been since the last assessment
2. Any episodes of unexplained bleeding or bruising
3. Any jaundice
4. General level of alertness and interaction with family and others
5. Any changes in cognitive function such as speech, following commands, comprehension
6. Any changes in motor function, including the development of tremors and stiffness in movements

Interval History

A board-certified neurologist (the principal investigator) will perform a general physical examination and a neurological examination and complete a standard CRF to document relevant findings. The control group will not undergo a physical examination.

Physical Examination

An Early Clinical Assessment of Balance (ECAB) will be performed by the physical therapist. Part I can be assessed in all affected individuals, and Part II requires ambulation. For non-ambulatory individuals, only Part I will be applied. The items in the ECAB are summarized as follows:

Part I. Head and trunk postural control (maximum 36 points) Head righting - lateral (right and left) Head righting - extension Head righting - flexion Rotation in trunk (right and left) Equilibrium reactions in sitting (right and left) Protective extension - side Protection extension - backward Part II. Sitting and standing postural control (maximum 64 points) Sitting with back unsupported but feet supported on floor or on a stool Sitting to standing Standing unsupported with eyes closed Standing unsupported with feet together Turns 360 degrees Placing alternate foot on the step while standing unsupported

ECAB Assessment

For ambulatory participants, the physical therapist will also assess standardized gait outcome measures, including:

1. Gait Speed: may be measured over a 10 meter distance, assessing both "comfortable" walking speed and "fast" walking speed
2. 10-meter walk/run: timed assessment at fastest gait attainable. This assessment would be omitted for those participants who are determined to have a high fall risk.
3. Timed Up and Go (TUG): time to stand from a chair, walk 3 meters, go around a cone, and return to the chair (with or without an assistive device)
4. Dynamic Gait Index (DGI): assesses 8 balance challenges while walking

Gait Assessment

Total blood volumes collected at each visit will be limited to 5mL/kg body weight, with a maximum of 18mL.

Saliva samples may be obtained if research is taking place where blood samples cannot be drawn or transferred.

Specimen Sample Collection

Erin Aguero

Peter Kang, MD

Natalya Alassy, MBS

This will be a single-center, single-arm, non-interventional natural history study to evaluate the longitudinal clinical course, functional outcome measures, and candidate biomarkers for individuals with DNA repair disorders, including Cockayne syndrome (CS), xeroderma pigmentosum (XP), and trichothiodystrophy (TTD).

This will be a single-center, single-arm, non-interventional natural history study to evaluate the longitudinal clinical course, functional outcome measures, and candidate biomarkers for individuals with DNA repair disorders, including Cockayne syndrome (CS), xeroderma pigmentosum (XP), and trichothiodystrophy (TTD). Our hypothesis is that a reliable and reproducible baseline natural history course can be established for DNA repair disorders using the Early Childhood Assessment of Balance (ECAB) as a primary endpoint and other measures as secondary and exploratory endpoints that may be used in future therapeutic clinical trials.

1. Comprehensive metabolic panel (CMP) that includes electrolytes, ALT, AST, and LDH.
2. GGT
3. Bilirubin
4. Complete blood count (CBC)
5. Neurofilament light (NfL)40-42
6. Glial fibrillary acidic protein (GFAP)43
7. Total tau (t-tau)44
8. Ubiquitin C-terminal hydrolase (UCHL1)45

Natural History Study for DNA Repair Disorders

This study will be conducted in accordance with the following publication and data sharing policies and regulations: National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the published results of NIH funded research. It requires scientists to submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for publication.

This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals.

We have selected the following 4 biomarkers to be measured in serum samples at each study visit:

1. Neurofilament light (NfL)
2. Glial fibrillary acidic protein (GFAP)
3. Total tau (t-tau)
4. Ubiquitin C-terminal hydrolase (UCHL1)

We have selected the following 4 biomarkers to be measured in serum samples at each study visit:

1. Neurofilament light (NfL)40-42
2. Glial fibrillary acidic protein (GFAP)43
3. Total tau (t-tau)44
4. Ubiquitin C-terminal hydrolase (UCHL1)45 To determine whether a serum biomarker can track disease status and progression and serve as a secondary outcome measure. To determine genetic diagnoses for those who are genetically undiagnosed, and to use transcriptomic analyses to seek additional biomarker candidates.

The longitudinal stability of cerebellar and gait function will be assessed by the presence or absence of tremors (absence = 1, presence = 0), dysmetria (absence = 1, presence = 0), dysdiadochokinesia (absence = 1, presence = 0) and Gowers sign (absence = 1, presence = 0). The scores will be added to yield a total score ranging from 0 to 4, with 4 representing the best performance.

Longitudinal stability of motor function in study participants as assessed by gait speed measured over a 10 meter distance

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Examination of Clinical and Laboratory Abnormalities in Patients With Defective DNA Repair: Xeroderma Pigmentosum, Cockayne Syndrome, or Trichothiodystrophy	NCT00001813	Cockayne Syndro... Skin Neoplasms Xeroderma Pigme... Trichothiodystr... Genodermatosis		6 Weeks -	National Institutes of Health Clinical Center (CC)
Natural History Study for DNA Repair Disorders	NCT05484570	DNA Repair Diso... Cockayne Syndro... Xeroderma Pigme... Trichothiodystr...	Interval Histor... Physical Examin... ECAB Assessment Gait Assessment Specimen Sample...	6 Months -	University of Minnesota

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