Peripheral Serotonin and Albinism

Oculocutaneous Albinism Clinical Trial

— SEPIAs  

Official title:

Role of Peripheral Serotonin in Oculocutaneous Albinism

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06138509
• Other study ID #: APHP230808
• Secondary ID: 2023-A01431-44
• Status: Recruiting
• Start date: February 6, 2024
• Est. completion date: February 2026

Study information

• Verified date: February 2024
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Smail HADJ-RABIA, MD, PhD
• Phone: 1 44 49 46 62
• Email: smail.hadjrabia[@]aphp.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 160
• Est. completion date: February 2026
• Est. primary completion date: February 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 17 Years

Eligibility

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

Related Conditions & MeSH terms

• Albinism
• Albinism, Oculocutaneous
• Oculocutaneous Albinism

Intervention

Other:
• Dosage of serotonin and metabolites
The dosages of serotonin and its metabolites will be performed by the INSERM U1016 unit at Cochin Institute.
• Blood parameters
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.

Locations

Country	Name	City	State
France	Hôpital Necker-Enfants Malades	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

References & Publications (15)

Amireault P, Hatia S, Bayard E, Bernex F, Collet C, Callebert J, Launay JM, Hermine O, Schneider E, Mallet J, Dy M, Cote F. Ineffective erythropoiesis with reduced red blood cell survival in serotonin-deficient mice. Proc Natl Acad Sci U S A. 2011 Aug 9;108(32):13141-6. doi: 10.1073/pnas.1103964108. Epub 2011 Jul 25. — View Citation

Amireault P, Sibon D, Cote F. Life without peripheral serotonin: insights from tryptophan hydroxylase 1 knockout mice reveal the existence of paracrine/autocrine serotonergic networks. ACS Chem Neurosci. 2013 Jan 16;4(1):64-71. doi: 10.1021/cn300154j. Epub 2012 Nov 7. — View Citation

English KB, Wang ZZ, Stayner N, Stensaas LJ, Martin H, Tuckett RP. Serotonin-like immunoreactivity in Merkel cells and their afferent neurons in touch domes from the hairy skin of rats. Anat Rec. 1992 Jan;232(1):112-20. doi: 10.1002/ar.1092320112. — View Citation

Enkhtaivan E, Lee CH. Role of Amine Neurotransmitters and Their Receptors in Skin Pigmentation: Therapeutic Implication. Int J Mol Sci. 2021 Jul 28;22(15):8071. doi: 10.3390/ijms22158071. — View Citation

Fouquet G, Coman T, Hermine O, Cote F. Serotonin, hematopoiesis and stem cells. Pharmacol Res. 2019 Feb;140:67-74. doi: 10.1016/j.phrs.2018.08.005. Epub 2018 Aug 11. — View Citation

Johansson O, Liu PY, Bondesson L, Nordlind K, Olsson MJ, Lontz W, Verhofstad A, Liang Y, Gangi S. A serotonin-like immunoreactivity is present in human cutaneous melanocytes. J Invest Dermatol. 1998 Dec;111(6):1010-4. doi: 10.1046/j.1523-1747.1998.00460.x. — View Citation

Lee HJ, Park MK, Kim SY, Park Choo HY, Lee AY, Lee CH. Serotonin induces melanogenesis via serotonin receptor 2A. Br J Dermatol. 2011 Dec;165(6):1344-8. doi: 10.1111/j.1365-2133.2011.10490.x. Epub 2011 Oct 17. — View Citation

Liu L, Fu M, Pei S, Zhou L, Shang J. R-Fluoxetine Increases Melanin Synthesis Through a 5-HT1A/2A Receptor and p38 MAPK Signaling Pathways. Int J Mol Sci. 2018 Dec 25;20(1):80. doi: 10.3390/ijms20010080. — View Citation

Maurer-Spurej E, Dyker K, Gahl WA, Devine DV. A novel immunocytochemical assay for the detection of serotonin in platelets. Br J Haematol. 2002 Mar;116(3):604-11. doi: 10.1046/j.0007-1048.2001.03302.x. — View Citation

Schallreuter KU, Salem MA, Gibbons NC, Martinez A, Slominski R, Ludemann J, Rokos H. Blunted epidermal L-tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 1: Epidermal H2O2/ONOO(-)-mediated stress abrogates tryptophan hydroxylase and dopa decarboxylase activities, leading to low serotonin and melatonin levels. FASEB J. 2012 Jun;26(6):2457-70. doi: 10.1096/fj.11-197137. Epub 2012 Mar 13. — View Citation

Slominski A, Pisarchik A, Semak I, Sweatman T, Wortsman J, Szczesniewski A, Slugocki G, McNulty J, Kauser S, Tobin DJ, Jing C, Johansson O. Serotoninergic and melatoninergic systems are fully expressed in human skin. FASEB J. 2002 Jun;16(8):896-8. doi: 10.1096/fj.01-0952fje. Epub 2002 Apr 23. — View Citation

Slominski A, Pisarchik A, Zbytek B, Tobin DJ, Kauser S, Wortsman J. Functional activity of serotoninergic and melatoninergic systems expressed in the skin. J Cell Physiol. 2003 Jul;196(1):144-53. doi: 10.1002/jcp.10287. — View Citation

Thompson JH. Iron absorption and serotonin (5-hydroxytryptamine) antagonism. Arch Int Pharmacodyn Ther. 1965 Aug;156(2):249-54. No abstract available. — View Citation

Yabut JM, Crane JD, Green AE, Keating DJ, Khan WI, Steinberg GR. Emerging Roles for Serotonin in Regulating Metabolism: New Implications for an Ancient Molecule. Endocr Rev. 2019 Aug 1;40(4):1092-1107. doi: 10.1210/er.2018-00283. — View Citation

Zhou L, Cai M, Ren Y, Wu H, Liu M, Chen H, Shang J. The different roles of 5-HT1A/2A receptors in fluoxetine ameliorated pigmentation of C57BL/6 mouse skin in response to stress. J Dermatol Sci. 2018 Dec;92(3):222-229. doi: 10.1016/j.jdermsci.2018.10.002. Epub 2018 Oct 25. — View Citation

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Correlation between serotonin levels and molecular subtype of albinism	Sequencing allowing molecular characterization of albinism is an integral part of diagnosis.	Day 0
Secondary	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
Secondary	Correlation between serotonin levels and iron studies	Determination of ferritin, serum iron, transferrin and transferrin saturation.	Day 0
Secondary	Correlation between serotonin levels and hemoglobin	Results of complete blood count, reticulocytes, hemoglobin electrophoresis in case of microcytosis, and erythropoietin dosage.	Day 0