Published on
Faced with a rare disease, it is sometimes difficult to make a precise diagnosis, especially in very young patients, even infants.
The importance of making the right diagnosis...
Diseases of the transmission of visual information from the photoreceptors of the retina to the neurons of the optic nerve are known as congenital stationary night blindness. This name refers to the typical form of the disease which manifests itself from birth by poor vision or even total blindness in the dark which does not evolve over time.
There are atypical forms grouped under the name of incomplete congenital stationary night blindness, in which the visual transmission defect results in daytime vision disorders, with or without disturbance of night vision. These latter forms are characterized at birth by a phobia of light (photophobia) and a nystagmus (involuntary and jerky oscillation of the eyeball) testifying to a defect of the central retina. They are extremely rare and often confused with another retinal disease, more frequent and better known to ophthalmologists, Leber's congenital amaurosis, whose visual manifestations are identical at birth.
The same initial presentation but a very different evolution, since Leber's congenital amaurosis, as well as the other severe and early malvoyances which are related to it, are progressive affections with progressive death of the photosensitive cells of the retina. Moreover, it is not uncommon for neurological, renal, bone, liver, etc. disorders to be added.
The electroretinogram is a key examination in the differential diagnosis. However, it is difficult to perform in very young children, who must be under general anesthesia beforehand. It is not uncommon that without this examination, or in the face of uncertain tracings, the diagnosis of Leber congenital amaurosis is given by default, leaving the spectre of worsening of the malvoyance and extraocular damage that may eventually engage the patient's vital prognosis. The identification of the genetic origin of the malvoyance in an infant is today one of the surest means to distinguish these two pathologies and to reassure the parents on the evolution of their child's disease for those who will be affected by an incomplete stationary night blindness, or to set up a follow-up of the ocular functions, even extraocular, for the others.
Thanks to a genomic analysis and with the collaboration of Elfride De Baere's team from the Centre for Medical Genetics and the Department of Molecular Medicine at Ghent University in Belgium, Isabelle Perrault, researcher in charge of the genetic decoding of these disorders in Jean-Michel Rozet's team, was able to identify a loss of function of the RIMS2 gene in four unrelated families of Senegalese, French and Saudi origin, referred to a genetics consultation for Leber congenital amaurosis.
...to better understand the evolution of the disease
"Although no mutation of this gene had been reported before, we knew that RIMS2 encodes a protein important for the synaptic transmission of the visual signal by the photoreceptors, suggesting a diagnosis of incomplete congenital night blindness instead of the initial diagnosis of Leber's congenital amaurosis in these families," Isabelle Perrault explains. This hypothesis was confirmed in all the patients reexamined, with the demonstration of evocative electroretinographic tracings and an absence of photoreceptor cell loss, even in adulthood.
In collaboration with Isabelle Audo and Christina Zeitz at the Institut de la Vision in Paris, other mutations in the RIMS2 gene have been identified in proven cases of congenital night blindness, confirming the involvement of this gene in this disease.
Thus, the fact that for patients, the diagnosis of Leber's amaurosis is corrected to congenital night blindness is good news. However, if it is true that such a diagnostic correction allowed until now to reassure the parents of young children about the absence of extra-ocular damage, the RIMS2 case has called into question this certainty.
Indeed, in addition to being important for photoreceptors, Isabelle Perrault and Elfride de Baere have shown that in humans, RIMS2 is expressed in Purkinje cells (brain) and pancreatic cells involved in insulin secretion. Therefore, a neurological examination and a metabolic workup were requested and revealed autistic disorders in all patients examined, and an abnormality of glucose homeostasis, indicating an involvement of the pancreas, in the oldest patient.
The description of this new disease and the identification of the gene involved have permanently modified the management of the earliest cases of incomplete congenital night blindness, which should no longer be considered as purely retinal diseases. The discovery of neurological and pancreatic involvement in certain forms, even very rare ones, must invite the greatest caution when it comes to evoking the extra-ocular prognosis in a child for whom the diagnosis of incomplete congenital night blindness is evoked.
It should be noted that Sabrina Méchaussier, a third-year thesis student in Jean-Michel Rozet's laboratory, and first author of this publication, was awarded the prize for best poster by the European Society of Human Genetics 2020, in the clinical research category.
