This study aims to understand how differences in the NOTCH2NLC gene affect the symptoms and course of neuronal intranuclear inclusion disease (NIID), a rare inherited neurological disorder. NIID is caused by an abnormal expansion of a GGC DNA repeat in the NOTCH2NLC gene, but members of the same family can have very different repeat sizes and patterns, leading to a wide variety of problems-such as difficulties with memory, movement, sensation, or involuntary body functions. The main goal is to uncover how these genetic differences (repeat length and interruption pattern) contribute to the severity and type of symptoms. The study is being conducted at Sichuan Provincial People's Hospital and will enroll approximately 12 individuals from a single family, including those diagnosed with NIID, family members who carry the genetic change but are not yet sick, and healthy relatives. Participants must be 18-85 years old, able to complete genetic testing and a small skin biopsy, and willing to provide informed consent. Those who are medically unstable or otherwise unable to participate will not be enrolled. The study has both a retrospective part (collecting past medical records) and a prospective follow-up. At the beginning, all participants will have a physical exam, provide a blood sample (for long-read DNA sequencing and RNA sequencing), and undergo a 3-mm skin biopsy to look for disease-related protein deposits. Brain MRI and nerve/muscle electrical tests will also be performed if not done recently. After this baseline visit, everyone will be followed every 6 months for a total of 2 years (5 visits total). Each follow-up visit includes assessments of thinking, memory, movement, autonomic function, pain, and quality of life, along with a neurological exam and repeat imaging/electrical tests as needed. At the final 24-month visit, another blood sample will be taken for RNA sequencing to see how gene activity changes over time. This is an observational study; there is no experimental treatment. Participants will be compensated a total of ¥3,000 across all visits for their time and travel. All data and samples will stay in China and will not be shared internationally.
Study Type
OBSERVATIONAL
Enrollment
12
This is an observational study. No investigational drug, device, biologic, or procedure is administered. Participants receive only standard clinical assessments, genetic testing, skin biopsy, and regular follow-up evaluations as described in the protocol.
Qingyang District
Chengdu, Sichuan, China
RECRUITINGClinical Severity Score and Its Correlation with NOTCH2NLC GGC Repeat Characteristics
The primary outcome is a composite clinical severity score that integrates cognitive function (assessed by Mini-Mental State Examination \[MMSE\] and Montreal Cognitive Assessment \[MoCA\]), motor function (including extrapyramidal and pyramidal signs), autonomic function (e.g., orthostatic blood pressure changes, heart rate variability), and peripheral nerve function (based on nerve conduction studies and clinical examination). Each domain is rated on a standardized scale, and the total score reflects overall neurological impairment, with higher scores indicating greater severity. The relationship (correlation coefficient) between this score and the NOTCH2NLC GGC repeat number and interruption pattern (defined by long-read sequencing) will be evaluated at baseline and over time.
Time frame: Baseline and at Months 6, 12, 18, and 24
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