Peripheral Serotonin and Albinism

Study Overview
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Brief Summary
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Serotonin (5-HT or 5-hydroxytryptamine) is a monoamine primarily known for its role as a neurotransmitter in the central nervous system (CNS). However, the functions of serotonin go beyond its role in the central nervous system: different peripheral tissues have the capacity to produce and/or use serotonin locally, forming systems called micro-serotonergic systems. Among the peripheral roles of serotonin, previous work by the Iron and Immunity team, INSERM U1016, Institut Cochin (Paris), was able to show that serotonin has a positive role on erythropoiesis and the survival of red blood cells, and the team's ongoing work suggests that serotonin also impacts iron metabolism. In humans and in mouse models, several studies have suggested a role for serotonin in pigmentation. In certain syndromic forms of albinism such as Hermansky Pudlak syndrome, platelet serotonin levels are reduced in connection with a decrease in dense platelet granules (delta granules): this characteristic is even part of the diagnostic criteria. Preliminary data from the Iron and Immunity team found: Changes in serotonin levels in children with albinism compared to control patients, Changes in hemoglobin level and mean corpuscular volume (MCV) in children with albinism (towards anemia and microcytosis), Changes in the iron balance in children with albinism (towards iron deficiency). The hypothesis of this research is that peripheral serotonin plays a role in the clinical and biological manifestations of oculocutaneous albinism.

Detailed Description
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Serotonin (5-HT or 5-hydroxytryptamine) is a monoamine primarily known for its role as a neurotransmitter in the central nervous system (CNS). However, the functions of serotonin go beyond its role in the central nervous system: different peripheral tissues have the capacity to produce and/or use serotonin locally, forming systems called micro-serotonergic systems. Among the peripheral roles of serotonin, previous work by the Iron and Immunity team, INSERM U1016, Institut Cochin (Paris), was able to show that serotonin has a positive role on erythropoiesis and the survival of red blood cells, and the team's ongoing work suggests that serotonin also impacts iron metabolism. Albinism exhibits significant clinical and genetic heterogeneity with poor genotype-phenotype correlation, and nearly 15% of patients remain without a molecular diagnosis. There is no curative treatment for albinism. Patients with albinism suffer from physical disability throughout their lives, but can also suffer from psychological disability and discrimination. These patients are also more vulnerable to the effects of climate change. The unmet clinical needs are therefore enormous. In humans and in mouse models, several studies have suggested an unexpected role for serotonin in skin pigmentation at several levels. Transcriptomic studies revealed that the Tph1 gene, responsible for serotonin synthesis outside the CNS, as well as serotonin receptors, were expressed in melanocytic and keratinocytic cell lines. Other studies have indicated that serotonin enhances melanogenesis in three melanocyte cell lines (B16F10, SK-MEL-2, Melan-a). Finally, studies suggest that serotonin is involved in pathologies such as certain congenital dyschromias, Rett syndrome and vitiligo. In certain syndromic forms of albinism such as Hermansky Pudlak syndrome, platelet serotonin levels are reduced in connection with a decrease in dense platelet granules (delta granules): this characteristic is even part of the diagnostic criteria. Preliminary data from the Iron and Immunity team found: Changes in serotonin levels in children with albinism compared to control patients, Changes in hemoglobin level and mean corpuscular volume (MCV) in children with albinism (towards anemia and microcytosis), Changes in the iron balance in children with albinism (towards iron deficiency). The hypothesis of this research is that peripheral serotonin plays a role in the clinical and biological manifestations of oculocutaneous albinism. The study will assess serotonin and its metabolites in the serum of patients with albinism, and compare the results with controls patients. The level of serotonin and its metabolites will be correlated with the different genotypes, and with the severity of albinism within the same genotypes. This study also wish to explore the impact of serotonin levels in the development of anemia, microcytosis and/or iron deficiency in patients with albinism. Complete blood counts and iron studies in patients with albinism will be compare to those of control patients too.

Official Title
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Role of Peripheral Serotonin in Oculocutaneous Albinism

Conditions
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Oculocutaneous Albinism

Intervention / Treatment
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* Other: Dosage of serotonin and metabolites
* Other: Blood parameters


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients: Patients with albinism aged 2 to 17 years Followed in the MAGEC-Necker reference center (reference center for rare diseases of the skin and mucous membranes of genetic origin), during the inclusion period Information of parental authority holders of patients and patients of understanding age, and collection of consent from parental authority holders and patients. Controls: Patients aged 2 to 17 years old Having consulted in Necker hospital during the inclusion period in the emergency and surgical services and whose care required a blood test analyzed in the hematology laboratory of the Necker hospital. Normal complete blood count (CBC) Normal C-reactive protein test (CRP) Absence of opposition from parental authority holders within one month of after sending the study information note. Exclusion Criteria: Patients: - Inability to have a blood test Controls: Abnormal blood count Elevation of CRP above laboratory standard

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 17 Years

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Patients<br>Patients with albinism aged 2 to 17 years old and followed in the MAGEC-Necker reference center (reference center for rare diseases of the skin and mucous membranes of genetic origin), during the inclusion period. During an initial or a follow-up consultation for patients with albinism, an additional volume of blood will be drawn during a blood sample drawn as part of routine care. | Other: Dosage of serotonin and metabolites<br>* The dosages of serotonin and its metabolites will be performed by the INSERM U1016 unit at Cochin Institute.<br>Other: Blood parameters<br>* The characterization of blood parameters : complete blood count (CBC), reticulocytes, C-reactive protein (CRP), iron studies (ferritin, serum iron, transferrin and transferrin saturation), hemoglobin electrophoresis, erythropoietin, will be added using standard methods at the Necker hematology laboratory if not carried out as part of the routine care.<br>|
| Control patients<br>Control patients are patients who were seen at Necker-Enfants Malades Hospital during the inclusion period, in the emergency and surgical departments, and whose care required a blood test analyzed in the Necker-Enfants Malades Hospital hematology laboratory. These patients will be selected on their age (2 to 17 years old), and must have a normal complete blood count and CRP. Leftover blood not used by the hospital hematology laboratory will be used for study analyses. | Other: Dosage of serotonin and metabolites<br>* The dosages of serotonin and its metabolites will be performed by the INSERM U1016 unit at Cochin Institute.<br>Other: Blood parameters<br>* The characterization of blood parameters : complete blood count (CBC), reticulocytes, C-reactive protein (CRP), iron studies (ferritin, serum iron, transferrin and transferrin saturation), hemoglobin electrophoresis, erythropoietin, will be added using standard methods at the Necker hematology laboratory if not carried out as part of the routine care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of serotonin and its metabolites in serum | Levels of serotonin and its metabolites in serum in children with albinism, compared with control children. | Day 0 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation between serotonin levels and molecular subtype of albinism | Sequencing allowing molecular characterization of albinism is an integral part of diagnosis. | Day 0 | 
| Correlation between serotonin levels and severity of albinism | The severity of albinism : cutaneous severity is based on clinical estimation, and ophthalmological severity on visual acuity values and degree of foveal hypoplasia. | Day 0 | 
| Correlation between serotonin levels and iron studies | Determination of ferritin, serum iron, transferrin and transferrin saturation. | Day 0 | 
| Correlation between serotonin levels and hemoglobin | Results of complete blood count, reticulocytes, hemoglobin electrophoresis in case of microcytosis, and erythropoietin dosage. | Day 0 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Oculocutaneous albinism, Peripheral serotonin, Anemia, Microcytosis, Iron deficiency