Better understanding hereditary eye diseases

During the last thirty years, discoveries of hereditary eye diseases have multiplied thanks to the work of Jean-Michel Rozet at Imagine. They highlight the extraordinary genetic heterogeneity of the great majority of these diseases.

Research Acceleration

According to the latest figures from the World Health Organization (WHO), worldwide, 1.3 billion people live with a visual impairment and 80% of cases could be avoided through a medical intervention.

Jean-Michel Rozet is a Doctor in genetic science at Paris Descartes University and an INSERM Research Director. He trained in genetics with Prof. Arnold Munnich becoming a student of Dr Josseline Kaplan, who he succeeded in 2009 as head of the laboratory of genetics in ophthalmology at Imagine Institute of genetic diseases. Continuing the pioneer work initiated at the end of the 1980s, his research relates to congenital eye malformations, and degenerative disorders of the optic nerve and the photosensitive retina, for which treatment is in the very early stages at best, most often nonexistent.

Jean-Michel Rozet
Jean-Michel Rozet © Laurent Attias

Diseases of genetic origin

At the start of the 1980s, we knew nothing about the genes, mutations and biological mechanisms at the origin of these diseases that inevitably evolve to blindness when they are not congenital. Treating patients and people at risk of passing on the disease in families was extremely limited, even nonexistent. Under the leadership of Dr Josseline Kaplan, a research team established in France, at Necker-Enfants malades hospital AP-HP, to be at the service of the earliest and most severe hereditary vision diseases, genome exploration tools emerged and brought spectacular developments in the early 2000s, leading to genome sequencing within a few days and for just a few hundred Euros.

In total, today the laboratory of genetics in ophthalmology has successfully identified many genes for emblematic diseases such as:

  • Leber congenital amaurosis, the earliest and most severe of all degenerative retinal diseases, causing blindness from birth or in the first few months of life,
  • Stargardt disease, a disease in children and young adults that affects the central area of the retina leading to a progressive loss of visual acuity and is similar to the very common age-related macular degeneration (AMD),
  • Kjer’s disease and other optic neuropathies that progressively destroy the optic nerve fibers, the integrity of which is essential in transferring visual information to the brain,
  • congenital microcoria, an extremely rare disease in the development of the iris and a study model for common glaucoma, which affects 4% of the general population,


  • Gillespie syndrome, a rare disease in the development of the iris and brain, with a mode of transmission unknown for a long time, adding risk to genetic counseling for families.


More and more adapted treatments

Discoveries made over the last thirty years have highlighted the extraordinary genetic heterogeneity (the disease can be due to mutations in several genes, but just one of them is altered in a particular family) of the great majority of hereditary eyesight diseases. These studies by Josseline Kaplan and Jean-Michel Rozet are no exception to this rule. Knowledge of genes and mutations responsible for these diseases has transformed genetic advice, for example by helping determine with certainty the risk of recurrence of the disease in families. Beyond this, the work carried out by Josseline Kaplan and Jean-Michel Rozet has completely changed the treatment for several of these diseases. This is particularly the case for Leber congenital amaurosis for which they have modified the definition with the discovery of a transient improvement of visual performance in some children who can then attend school with sighted children, when others have to enroll in a school for the partially sighted. They have also contributed to the research that establishes a link between some forms of Leber congenital amaurosis and ciliopathies, a disease family variably affecting the retina, kidney, brain and bone development. However, most importantly, they have demonstrated that a very strong connection exists between the gene in question and the evolution of the disease, not only in the eye but also outside of the eye. In other words, knowing the gene for the disease in all young children will help, in many cases, to reassure parents with a reassuring visual prognosis and confidence in the absence of renal, neurological or bone damage.

Improving the treatment for optic nerve hereditary diseases (optic neuropathies) is also true. Josseline Kaplan and Jean-Michel Rozet have brought forms of the disease out of the shadows that have been ignored for a long time but prove to be relatively common today and readily affect all young children. They have identified several of the genes in question, knowledge of which helps to put mitochondria at the center of these optic nerve diseases.


Hereditary optic neuropathies

Hereditary optic neuropathies are neurodegenerative diseases of retinal ganglion cells responsible for receiving visual information from photosensitive cells and transmitting it to the cortex. Progressive loss of these cells and their axons, which form the optic nerve, is responsible for severe visual impairment, even blindness. These disorders can occur at various ages from the first months of life to the 4th and 5th decades. At the end of the 1980s, the first responsible mutations were identified in the mitochondrial DNA, transmitted strictly from the maternal side. The major gene for non-maternal forms, OPA1, was identified in the year 2000 by Prof. Christian Hamel in collaboration with Guy Lenaers, now the director of the center for research and education in mitochondrial medicine (PREMMi) in Angers, Josseline Kaplan, Jean-Michel Rozet and Prof. Dominique Bonneau, head of the Biochemistry and Genetics Department of CHU Angers.

These discoveries have given a different view of optic neuropathies. Although disabling, these eye diseases undoubtedly have to be considered as a manifestation of mitochondrial diseases at minimum. The latest results of the collaborative work initiated by Prof. Christian Hamel nearly 20 years ago, have only supported this new idea with the identification of fatal neonatal encephalopathy gene mutations DNM1L, in three multigenerational families with strictly isolated optic neuropathy. Beyond this, this discovery sheds a new light on the complexity of the mechanisms responsible for cell death in the optic nerve. Surprisingly, DNM1L and OPA1 have diametrically opposed functions. The first is involved in mitochondrial fission, when the second intervenes in their fusion. The subtle balance between these two forces, fusion and fission, is therefore a key element in the physiology of the optic nerve, probably to ensure energy efficient distribution throughout the optic nerve.

The work of Josseline Kaplan and Jean-Michel Rozet also reveals that almost all the genes that they have discovered are also involved in mitochondrial diseases combining neurological and muscular disorders, sometimes extremely severe, that can lead to early death “The genes involved are identical, but the mutations are less severe in hereditary nonsyndromic optic neuropathies, notes Jean-Michel Rozet. This discovery has completely changed the treatment of optic neuropathies, which we can now put to one end of the severity spectrum for mitochondrial diseases.”

This biological description for eye diseases paves the way for treatment that is better adapted to the risks and the evolution of symptoms, even their anticipation. It is also the indispensable condition in the search for treatment that can restore the altered mechanisms.


Time for treatments

Today, it is time to develop new therapeutic strategies. These many developments are made difficult by the extreme genetic heterogeneity, which is often accompanied by a variability of biological mechanisms leading to the disease; this is particularly the case for Leber congenital amaurosis where many retinal functions can be involved, such as the visual transduction cascade, vitamin A metabolism, protection against light-induced damage, ciliary intracellular transport, etc. Concerning this disease, treatment with gene therapy is awaiting approval: it consists of transporting a normal version of the gene to the retina, called RPE65, which is responsible for 6 to 16% of all cases of Leber congenital amaurosis.

At the same time, Jean-Michel Rozet’s team are developing another approach to repair genes through an intravitreal injection (a widely used method of administration in ophthalmology, particularly to treat age-related macular degeneration) of small oligonucleotides. Today, phase 2 and 3 trials are ongoing to evaluate this therapeutic strategy.

From diagnosis to therapeutic development, the patient has always been the driver of research for Jean-Michel Rozet and his team: The 1st impact is for them, explains the researcher, who participates in many care networks, is involved with patient associations, takes part in meetings for multidisciplinary discussions and clinical data presented by doctors is compared to molecular data generated in the laboratory. This approach from patient to patient is a real accelerator in progress.

Without a doubt, new discoveries will soon emerge, always keeping in mind their specific applications for young children affected by eye diseases.