Effect of NOTCH2NLC Gene Variations on NIID Clinical Features (NOTCH2NLC-NIID)

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 Overview

• Status: Recruiting
• Conditions: Neuronal Intranuclear Inclusion Disease (NIID)
• Intervention / Treatment: Other: No Intervention: Observational Cohort

• Study Type: Observational
• Enrollment (Estimated): 12

Contacts and Locations

• Study Contact: Name: Xian Wang, Principal Investigator; Phone Number: +86-13269087917; Email: wangxian_2022@uestc.edu.cn

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China, 610072
      • Recruiting
      • Qingyang District
      • Contact: Xian Wang, Principal Investigator; Phone Number: +86-13269087917; Email: wangxian_2022@uestc.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

This study will enroll approximately 12 participants from a single family (pedigree) with NOTCH2NLC-related neuronal intranuclear inclusion disease (NIID). The study population comprises three categories of family members: individuals with a clinical diagnosis of NIID, asymptomatic carriers of the NOTCH2NLC GGC repeat expansion, and healthy relatives who do not carry the expansion. All participants are adults aged 18 to 85 years recruited from the Health Management Center of Sichuan Provincial People's Hospital in China. Given the rarity and genetic nature of the disease, this single-family design is intended to control for shared genetic background and environmental factors while examining the effect of different GGC repeat characteristics on clinical phenotype.

Description

Inclusion Criteria:

• Member of a single family (pedigree) with known NOTCH2NLC-related neuronal intranuclear inclusion disease (NIID), including clinically diagnosed patients, asymptomatic GGC repeat expansion carriers, and healthy relatives without the expansion.
• Age 18 to 85 years at the time of enrollment.
• Able and willing to undergo genetic testing for NOTCH2NLC (including long-read sequencing) and a skin punch biopsy.
• Able to provide written informed consent.

Exclusion Criteria:

• Unstable vital signs or any acute medical condition that would interfere with study participation.
• Any condition that, in the opinion of the investigator, makes the participant unsuitable for the study.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

NIID Family Cohort; This is a single observational cohort consisting of approximately 12 members of the same family affected by neuronal intranuclear inclusion disease (NIID) caused by GGC repeat expansions in NOTCH2NLC. The cohort includes individuals with clinically diagnosed NIID, asymptomatic carriers of the repeat expansion, and healthy relatives without the expansion. After informed consent, all participants will undergo baseline assessments including clinical evaluation, peripheral blood collection for long-read and transcriptome sequencing, a skin punch biopsy for immunohistochemistry, and brain MRI/neurophysiological tests if clinically indicated. Participants will be followed prospectively every 6 months for 2 years (5 visits total). Follow-up visits include cognitive, motor, autonomic, and quality-of-life assessments, along with neurological examination and repeat imaging/electrophysiology as needed. A second blood sample for transcriptome sequencing will be collected at the 24-month visit. No

Other: No Intervention: Observational Cohort; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical 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.	Baseline and at Months 6, 12, 18, and 24

Collaborators and Investigators

• Sponsor: Sichuan Academy of Medical Sciences

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): February 1, 2029

Study Registration Dates

• First Submitted: June 1, 2026
• First Submitted That Met QC Criteria: June 24, 2026
• First Posted (Actual): June 26, 2026

Study Record Updates

• Last Update Posted (Actual): June 26, 2026
• Last Update Submitted That Met QC Criteria: June 24, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: NIID, NOTCH2NLC, GGC repeat expansion
• Additional Relevant MeSH Terms: Neuronal intranuclear inclusion disease
• Other Study ID Numbers: IRB No. 305 (2026)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO