MEHMO Natural History and Biomarkers

Study Overview
=================
Brief Summary
-----------------
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.

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: Identify disease-reflective fluid biomarkers Develop a disease severity rating scale or classification algorithm Assess tolerability and feasibility of study evaluations 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: Mean difference of candidate fluid biomarkers level in affected versus carrier versus unaffected individuals Correlation of rating scale or classification algorithm to age, genotype, or other variables Frequency of completed evaluations and reasons for Noncompletion Study Population: 25 affected individuals 1-week of age or older 25 EIF2S3-variant carrier individuals 1-month of age or older 50 unaffected individuals 1 month of age or older of any sex, race, ethnicity, geographic location who can participate without increased risk to personal health.

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

Conditions
-----------------
Microcephaly, Intellectual Disability, Epilepsy, Hypogonadisms, Nervous System Malformations, Obesity

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria To be eligible to participate in this study, an individual must meet the following criteria: Be greater than or equal to 1-week of age if affected, or greater than or equal to 1-month of age if unaffected. 19 For Screening: Have a combination of signs/symptoms suggestive of MEHMO syndrome, AND no or inconclusive molecular testing. For Main Study 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 Be a first-degree relative of an individual with EIF2S3-related MEHMO syndrome, AND a carrier of the pathogenic or likely pathogenic variant. OR 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.

Ages Eligible for Study
-----------------
Minimum Age: 1 Week
Maximum Age: 100 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Affected<br>Individuals who have MEHMO syndrome or eIF2-pathway related conditions 1-week of age or older. | |
| Carrier<br>EIF2S3-variant carrier individuals 1-month of age or older. | |
| Unaffected Non-carrier<br>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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
MEHMO, X-linked MEHMO Syndrome, eIF2-Pathway Related Conditions, EIF2S3