Hereditary human retinal degenerative diseases usually affect the mature photoreceptor topography by reducing the number of cells through apoptosis, resulting in loss of visual function. Only one inherited retinal disease, the enhanced S-cone syndrome (ESCS), manifests a gain in function of photoreceptors. ESCS is an autosomal recessive retinopathy in which patients have increased sensitivity to blue light; perception of blue light is mediated by what is normally the least populous cone photoreceptor subtype, the S (short wavelength, blue) cones. People with ESCS also suffer visual loss, with night blindness occurring from early in life, varying degrees of L (long, red)- and M (middle, green)-cone vision, and retinal degeneration. The pattern of retinal dysfunction is a constant among ESCS patients, but the degree of clinically evident retinal degeneration can vary from minimal to severe. The latter condition is known as Goldmann-Favre syndrome. The altered ratio of S- to L/M-cone photoreceptor sensitivity in ESCS may be due to abnormal cone cell fate determination during retinal development (summary by Haider et al., 2000). Goldmann-Favre syndrome is characterized by a liquefied vitreous body with preretinal band-shaped structures (veil), macular changes in the form of retinoschisis or edema and pigmentary degeneration of the retina with hemeralopia and extinguished electroretinogram. Cataract is a complication. The disorder is to be distinguished from X-linked retinoschisis (312700) and from autosomal dominant hyaloideoretinal degeneration (143200).

Congenital myasthenic syndrome-12 is an autosomal recessive neuromuscular disorder characterized by onset of proximal muscle weakness in the first decade. EMG classically shows a decremental response to repeated nerve stimulation. Affected individuals show a favorable response to acetylcholinesterase (AChE) inhibitors (summary by Senderek et al., 2011). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).

X-linked congenital retinoschisis (XLRS) is characterized by symmetric bilateral macular involvement with onset in the first decade of life, in some cases as early as age three months. Fundus examination shows areas of schisis (splitting of the nerve fiber layer of the retina) in the macula, sometimes giving the impression of a spoke wheel pattern. Schisis of the peripheral retina, predominantly inferotemporally, occurs in approximately 50% of individuals. Affected males typically have 20/60 to 20/120 vision. Visual acuity often deteriorates during the first and second decades of life but then remains relatively stable until the fifth or sixth decade.

CLCN2-related leukoencephalopathy is characterized by nonspecific neurologic findings, mild visual impairment from chorioretinopathy or optic atrophy, male infertility, and characteristic findings on brain MRI. Neurologic findings include mild ataxia (action tremor and gait instability following initially normal motor development; occasionally, mild spasticity), cognitive impairment in some (typically mild, rarely severe), psychiatric symptoms in some (depression and schizophrenia-like symptoms), headaches in some (usually intermittent, severe, and diffuse) and auditory symptoms in some (hearing loss, tinnitus, vertigo). Affected individuals remain ambulatory, do not require support for walking, and rarely become blind. To date CLCN2-related leukoencephalopathy has been reported or identified in 31 individuals from 30 families. It is not yet known if the findings occurring in a few individuals (i.e., epilepsy and paroxysmal kinesigenic dyskinesia) are part of the phenotypic spectrum or unrelated findings.