MEHMO Natural History and Biomarkers

Investigations of Individuals With MEHMO Syndrome or eIF2-Pathway Related Conditions

This observational natural history study will follow individuals with MEHMO (Mental disability, Epileptic seizure, Hypopituitarism/Hypogenitalism, Microcephaly, Obesity) syndrome or an eIF2-pathway related disorder, who have symptoms such as intellectual delay, seizures, abnormal hormone and blood sugar levels, and decreased motor skills.

No current treatment for these conditions is available. A major impediment to the testing of potential therapeutic interventions is the lack of well-defined outcome measures. This protocol seeks to identify biochemical and clinical markers to monitor disease progression, and better understand the natural history of these conditions.

Any person diagnosed with MEHMO syndrome or related conditions, who can travel to the NIH Clinical Center can participate in this study.

The study involves:

• General health assessment and evaluation
• Imaging studies
• Laboratory tests
• Collection of blood, urine, spinal fluid, skin biopsy.

Study Overview

• Status: Recruiting
• Conditions: Epilepsy; Obesity; Intellectual Disability; Microcephaly; Nervous System Malformations; Hypogonadisms

Detailed Description

Study Description: This is a prospective natural history study of individuals who have MEHMO syndrome or eIF2-pathway related conditions, or who are carriers of EIF2S3-related conditions to generate hypotheses for further understanding of disease pathophysiology, diagnosis, prognosis, management, and treatment. The protocol aims to enroll and follow affected or carrier individuals longitudinally to establish a repository of concurrent evaluations and biomaterials, as well as to enroll unaffected individuals for collection of informative comparable data and samples.

Objectives:

Primary Objective:

Characterize the presentation of MEHMO syndrome and eIF2 pathway related conditions.

Secondary Objectives:

1. Identify disease-reflective fluid biomarkers
2. Develop a disease severity rating scale or classification algorithm
3. Assess tolerability and feasibility of study evaluations
4. Establish a repository of participant data and samples for future research

Endpoints:

Primary Endpoint:

Frequency and time-to-event of signs and symptoms.

Secondary Endpoints:

1. Mean difference of candidate fluid biomarkers level in affected versus carrier versus unaffected individuals
2. Correlation of rating scale or classification algorithm to age, genotype, or other variables
3. Frequency of completed evaluations and reasons for noncompletion

• Study Type: Observational
• Enrollment (Estimated): 150

Contacts and Locations

• Study Contact: Name: An N Dang Do, M.D.; Phone Number: (301) 496-8849; Email: an.dangdo@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: An Dang Do, M.D.; Phone Number: 301-496-8849; Email: an.dangdo@nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Inclusion Criteria: An individual must be > 1-week of age if affected, or > 1-month of age if unaffected. For Screening: Have a combination of signs/symptoms suggestive of MEHMO syndrome, AND no or inconclusive molecular testing. For Main Study: 1. Have a combination of signs/symptoms suggestive of MEHMO syndrome, AND disease-associated variant(s) or variant(s) of uncertain significance in one of the eIF2-pathway related genes OR 2. Be a first-degree relative of an individual with EIF2S3-related MEHMO syndrome, AND a carrier of the pathogenic or likely pathogenic variant. OR 3. Be a non-affected, non-carrier family member of an individual with MEHMO syndrome or an eIF2-pathway related condition. Exclusion Criteria: Any individual who, in the opinion of the Investigators, is unable to comply with the protocol or have medical conditions that would potentially increase the risk of participation.

Description

• INCLUSION CRITERIA:

To be eligible to participate in this study, an individual must meet the following criteria:

Be >= 1-week of age if affected, or >=1-month of age if unaffected.

For Screening:

1. Have a combination of signs/symptoms suggestive of MEHMO syndrome,

   AND

   no or inconclusive molecular testing.

   OR

2. Be a relative of an individual with MEHMO syndrome/eIF2-related condition and whose genetic may be informative for research.

For Main Study:

1. Have a combination of signs/symptoms suggestive of MEHMO syndrome,

   AND

   disease-associated variant(s) or variant(s) of uncertain significance in one of the eIF2-pathway related genes

   OR

2. Be a relative of an individual with MEHMO syndrome/eIF2-related condition, AND a carrier of the pathogenic or likely pathogenic variant.

   OR

3. Be a non-affected, non-carrier family member of an individual with MEHMO syndrome or an eIF2-pathway related condition.

EXCLUSION CRITERIA:

Any individual who, in the opinion of the Investigators, is unable to comply with the protocol or have medical conditions that would potentially increase the risk of participation will be excluded from participation in this study.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Affected; Individuals who have MEHMO syndrome or eIF2-pathway related conditions 1-week of age or older.
Carrier; EIF2S3-variant carrier individuals 1-month of age or older.
Unaffected Non-carrier; Unaffected individuals 1 month of age or older who are 1st degree relative of an affected individual

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Characterize the presentation of MEHMO syndrome and eIF2-pathway related conditions.	Frequency and time-to-event of signs and symptoms. These will allow systematic and potentially quantitative measures of disease presentation that can then be operationalized to develop disease rating scale(s) and correlative measures for candidate biomarkers.	Ongoing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identify disease-reflective fluid biomarkers	Difference and range of candidate fluid biomarkers level in affected vs. carrier vs. unaffected individuals. Sensitive or specific quantitative markers will allow for improved diagnosis, management, and treatment of MEHMO syndrome or eIF2-pathway related disorders.	Ongoing
Develop a disease severity rating scale or classification algorithm.	A quantitative rating scale or classification algorithm that reflects other disease aspects will provide a standardized tool for communication amongst all involved in the clinical care and research of MEHMO syndrome or eIF2-pathway related disorders.	Ongoing
Assess tolerability and feasibility of study evaluations.	Frequency of completed evaluations and reasons for non-completion will inform design of future trials for MEHMO syndrome or eIF2-pathway related disorders.	Ongoing
Characterize EIF2S3-carrier phenotype.	Frequency and time-to-event of signs and symptoms at disease-relevant intervals will provide a systematic evaluation of EIF2S3- carrier phenotype.	Ongoing
Establish a repository of participant data and samples for future research.	A repository of concurrently collected participant data and samples for future research will provide resources for future research towards understanding the disease and developing interventions.	Ongoing

Collaborators and Investigators

• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: An N Dang Do, M.D., Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2023
• Primary Completion (Estimated): September 1, 2053
• Study Completion (Estimated): September 1, 2053

Study Registration Dates

• First Submitted: August 30, 2023
• First Submitted That Met QC Criteria: August 30, 2023
• First Posted (Actual): August 31, 2023

Study Record Updates

• Last Update Posted (Actual): April 27, 2026
• Last Update Submitted That Met QC Criteria: April 24, 2026
• Last Verified: April 23, 2026

More Information

Terms related to this study

• Keywords: MEHMO; X-linked MEHMO Syndrome; eIF2-Pathway Related Conditions; EIF2S3
• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Nutrition Disorders; Overnutrition; Body Weight; Neurobehavioral Manifestations; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Congenital Abnormalities; Neurodevelopmental Disorders; Overweight; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Intellectual Disability; Epilepsy; Microcephaly; Nervous System Malformations; MEHMO syndrome
• Other Study ID Numbers: 10001681; 001681-CH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Requests for sharing of relevant IPD for clinical management purpose or directly from the individual participant will be considered on case basis and are not guaranteed to result in sharing of IPD.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No