Histidine Therapy: A Project to Treat HARS Deficiency

Study Overview
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Brief Summary
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This study evaluates the role of histidine in patients with HARS Syndrome. Children with HARS Syndrome will receive oral nutritional supplementation with histidine at a dose which will be increased in the event of acute febrile illness. Vision, hearing and plasma biomarkers will be monitored throughout the study period.

Detailed Description
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HARS syndrome is a progressive degenerative disease affecting eyesight and hearing caused by a mutation in the HARS gene which codes for an enzyme involved in protein synthesis. HARS syndrome has been exclusively found in the Old Order Amish communities in Southwestern Ontario and in Pennsylvania. Children with this disorder initially have normal vision and hearing, but with a febrile illness, can have a sudden loss of vision and hearing, as well as visual hallucinations. There is some evidence that vision loss progresses, albeit at a slower rate, even without a febrile incident. In more severe cases, fluid accumulates in the lungs (acute respiratory distress syndrome or ARDS) which can cause a drop in oxygen levels and sometimes death. There is currently no specific treatment for HARS syndrome, apart from supportive care. Anecdotal evidence of an adult with HARS syndrome who was treated with the amino acid L-histidine suggests that there was an improvement in vision, however there were no baseline objective measurements of vision prior to the use of histidine. We have designed a pilot project in which histidine will be given to children with HARS for 6 months. Investigators hypothesize that the histidine will be well tolerated and easily administered, without side effects. Investigators will monitor vision, hearing and bloodwork to determine if there is any change during the course of treatment. As well, investigators plan to administer increased doses of histidine during acute illnesses, hoping to prevent deterioration in breathing due to ARDS. The results of this initial pilot project may pave the way for a longer term study of the use of histidine.

Official Title
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Histidine Therapy: A Project to Treat HARS Deficiency

Conditions
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HARS Syndrome

Intervention / Treatment
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* Dietary Supplement: L-Histidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have molecularly confirmed HARS syndrome (Y454S homozygous). Capable of giving informed consent or assent, or have an acceptable surrogate capable of giving consent on the participant's behalf. Participant or surrogate decision maker is able to understand the study procedures and comply with them throughout the course of the study. Able to take solid foods (ie applesauce) or swallow capsules (in younger children, capsule may be broken and contents mixed with applesauce). At least 1 year of age or greater than 8 kg in weight (since histidine is supplied as a minimal dose of 500 mg/capsule. Exclusion Criteria: Unable or unwilling to give informed consent. Unable to understand instructions or unable to attend clinic visits. Children less than 1 year of age or less than  8kg in weight (since histidine is supplied as 500 mg capsules).
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Participants are given L-Histidine supplements and were prescribed to take 50mg/kg twice daily.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>L-Histidine in 500mg capsules taken at a dose of 50mg/kg to maintain high-normal serum histidine levels | Dietary Supplement: L-Histidine<br>* L-Histidine in 500mg capsules taken at a dose of 50mg/kg to maintain high-normal serum histidine levels<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual acuity maintenance or improvement | Changes from baseline eye exam | 2 years | 
| Visual acuity maintenance or improvement | Changes from baseline electroretinography | 2 years | 
| Visual acuity maintenance or improvement | Changes from baseline ocular coherence tomography | 2 years | 
| Auditory ability maintenance or improvement | Changes from baseline auditory brainstem response | 2 years | 
| Auditory ability maintenance or improvement | Changes from baseline autoacoustic emissions | 2 years | 
| Auditory ability maintenance or improvement | Changes from baseline routine ear exam | 2 years | 
| Auditory ability maintenance or improvement | Changes from baseline audiometry | 2 years | 
| Changes in severity of acute febrile illness | Measured by length of hospital stay | 2 years | 
| Changes in severity of acute febrile illness | Measured by requirement for intensive care unit transfer | 2 years | 
| Changes in severity of acute febrile illness | Measured by number of hospitalizations | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarker Changes | Changes to inflammatory markers, HARS protein, HARS antibodies, Amino acid levels and biochemical markers as a result of histidine therapy | 2 years | 
| Plasma level maintenance | Does histidine supplementation result in increased plasma histidine levels | 1 month |