DeCure for Infantile cerebellar-retinal degeneration

In the Purkinje cell degeneration (pcd) mutant mouse, photoreceptor loss begins around the same time as Purkinje cell loss (between 3 and 5 weeks after birth) but proceeds slowly, with most photoreceptors gone by one year. An electron microscopy study of pcd/pcd mice from postnatal day 10 to 15 months found the first signs of photoreceptor degeneration as early as postnatal day 13, visible as vesicles 150–350 nm in diameter in the extracellular space next to the inner segments. These vesicles were tubular, some continuous with the inner segment membrane, and appeared to arise from tubular outpocketings that pinch off. Müller cells also showed swollen apical processes. This is described as an unusual form of photoreceptor degeneration.

In human congenital retinal dystrophies, the reported incidence of mental retardation in Leber’s congenital amaurosis has ranged from 10% to 87%. A prospective study of 38 children with congenital retinal dystrophies found that children with additional disorders in other systems or with central nervous system malformations or degenerations were significantly more likely to have learning disability than those without such problems. Most subgroups made little or no visual progress, except the group with associated hypoplasia of the cerebellar vermis. The study stresses the need for specialised techniques to delineate the visual diagnosis and paediatric perspective because of their relevance to cognitive and visual prognosis.

Three children presenting in infancy with severe visual defect, absent or barely recordable electroretinograms, and relatively well preserved visually evoked cortical potentials were later found to have vertical and horizontal saccade palsies with head thrusts but relatively good visual acuity. They were developmentally delayed and had systemic motor and speech defects, but their visual prognosis was relatively good. The authors consider these patients a clear subset of those diagnosed with congenital retinal dystrophy or Leber’s amaurosis. A separate case report describes a girl with CEP290 mutations who from early infancy had a retinitis pigmentosa–like retinal degeneration with visual adaptation problems in cone cell functioning; symptoms initially mimicked cerebral visual impairment. Repeated assessments from age 3 to 9 years confirmed stable retinal functions.

What is still missing is a unified molecular explanation linking the cerebellar and retinal degeneration in these syndromes, and any clinical trial of a drug or intervention. No therapy is tested or proposed in these abstracts. The human studies are small case series or single reports, and the mouse work is purely descriptive. Stratification by genotype (e.g., CEP290) and by presence of cerebellar or systemic involvement is needed before any treatment pathway can be designed. Funding for natural history studies and for developing animal models that recapitulate the human condition remains absent.