Natural History Study for DNA Repair Disorders

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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Natural History Study for DNA Repair Disorders

Conditions
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DNA Repair Disorder, Cockayne Syndrome, Xeroderma Pigmentosum, Trichothiodystrophy

Intervention / Treatment
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* Other: Interval History
* Other: Physical Examination
* Other: ECAB Assessment
* Other: Gait Assessment
* Other: Specimen Sample Collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Cockayne syndrome (CS), xeroderma pigmentosum (XP), or trichothiodystrophy (TTD), based on genetic testing and/or key clinical characteristics l characteristics Has one or more of the following neurodevelopmental or neurological complications Gross motor delay (non-ambulatory or started walking after age 18 months) Language delay (non-verbal or started talking after 18 months) Altered muscle tone (hypertonia, dystonia, hypotonia) Gait difficulties, including stiff gait, short stride, frequent falls, use of orthotics, use of walker Tremors Microcephaly Is a family member of an individual with the above condition No restrictions regarding current ambulatory status Minimum age for enrollment eligibility will be 6 months due to fragility of neonates with severe forms of DNA repair disorders and limitations of motor assessment scales in infants younger than 6 months. There will be no maximum age for enrollment eligibility. No restrictions regarding gender, race, or ethnicity. Voluntary written consent from the participant if adult capable of consenting or parent/guardian if minor or not capable of consenting Written consent of Legally Authorized Representative if enrolling adult lacks capacity to consent Exclusion Criteria: Any prior history of systemic gene or cell-based therapy Current participation in an interventional clinical trial

Ages Eligible for Study
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Minimum Age: 6 Months

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Diagnosed<br>Patients who are diagnosed with a DNA Repair Disorder | Other: Interval History<br>* 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: How the participant's appetite and general weight trajectory has been since the last assessment Any episodes of unexplained bleeding or bruising Any jaundice General level of alertness and interaction with family and others Any changes in cognitive function such as speech, following commands, comprehension Any changes in motor function, including the development of tremors and stiffness in movements<br>Other: Physical Examination<br>* 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.<br>Other: ECAB Assessment<br>* 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<br>Other: Gait Assessment<br>* For ambulatory participants, the physical therapist will also assess standardized gait outcome measures, including: Gait Speed: may be measured over a 10 meter distance, assessing both comfortable walking speed and fast walking speed 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. 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) Dynamic Gait Index (DGI): assesses 8 balance challenges while walking<br>Other: Specimen Sample Collection<br>* 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.<br>|
| Control<br>Healthy family members of enrolled diagnosed participants. | Other: ECAB Assessment<br>* 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<br>Other: Gait Assessment<br>* For ambulatory participants, the physical therapist will also assess standardized gait outcome measures, including: Gait Speed: may be measured over a 10 meter distance, assessing both comfortable walking speed and fast walking speed 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. 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) Dynamic Gait Index (DGI): assesses 8 balance challenges while walking<br>Other: Specimen Sample Collection<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Longitudinal stability of cerebellar and gait function on neurological examination | 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. | 3 years | 
| Longitudinal stability of motor function using gait speed measurement | Longitudinal stability of motor function in study participants as assessed by gait speed measured over a 10 meter distance | 3 years | 
| Longitudinal stability of motor function using 10 meter walk/run test |  | 3 years | 
| Longitudinal stability of motor function using Timed Up and Go (TUG) test |  | 3 years | 
| Longitudinal stability of motor function using the Dynamic Gait Index (DGI) |  | 3 years |