Ocular manifestations of microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) syndrome associated with mutations in KIF11

Purpose Microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (MCLID) is an autosomal dominant condition. Mutations in KIF11 have been found to be causative in approximately 75% of cases. This study describes the ocular phenotype in patients with confirmed KIF11 mutations. Methods Standard ophthalmic examination and investigation including visual acuity, refraction and fundus examination was carried out in all patients. Fundus autofluorescence imaging (FAF) was performed in three patients, and four patients underwent spectral domain optical coherence tomography (OCT). Flash electroretinography (ERG) was performed in seven patients, and five underwent additional pattern electroretinography (PERG). Results The patients ranged in age from 2 to 10 years. Most presented with visual acuity loss. Fundus examination revealed lacunae of chorioretinal atrophy. Pigmentary macular changes and optic disc pallor were present in three of seven patients. Fundus autofluorescence demonstrated hypoautofluorescence at the macula in two of three patients. The lacunae of chorioretinal atrophy were hypoautofluorescent. The OCT showed atrophic maculae in three of four patients. Follow-up in one patient showed no deterioration of the vision over a 9-year period. The lesions appear not to be progressive on the follow-up imaging. Electrophysiology showed generalized rod and cone dysfunction and severe macular dysfunction. Inner retinal dysfunction was evident in three of seven patients. Conclusions Patients with KIF11 mutations show a specific ocular phenotype with variable expressivity and intrafamilial variability. Macular atrophy and dysfunction have not been consistently documented before. The fundus lesions appear non-progressive. The findings assist in providing an accurate diagnosis and thus improving the management and follow-up of patients with this syndrome.

Friedreich Ataxia

Friedreich ataxia (FRDA) is an autosomal recessive disease characterized by progressive neurological and cardiac abnormalities. It has a prevalence of around 2×10⁵ in whites, accounting for more than one-third of the cases of recessively inherited ataxia in this ethnic group. FRDA may not exist in nonwhite populations.The first symptoms usually appear in childhood, but age of onset may vary from infancy to adulthood. Atrophy of sensory and cerebellar pathways causes ataxia, dysarthria, fixation instability, deep sensory loss, and loss of tendon reflexes. Corticospinal degeneration leads to muscular weakness and extensor plantar responses. A hypertrophic cardiomyopathy may contribute to disability and cause premature death. Other common problems include kyphoscoliosis, pes cavus, and, in 10% of patients, diabetes mellitus.The FRDA gene (FXN) encodes a small mitochondrial protein, frataxin, which is produced in insufficient amounts in the disease, as a consequence of the epigenetic silencing of the gene triggered by a GAA triplet repeat expansion in the first intron of the gene. Frataxin deficiency results in impaired iron-sulfur cluster biogenesis in mitochondria, in turn leading to widespread dysfunction of iron-sulfur center containing enzymes (in particular respiratory complexes I, II and III, and aconitase), impaired iron metabolism, oxidative stress, and mitochondrial dysfunction. Therapy aims to restore frataxin levels or to correct the consequences of its deficiency.