Costeff syndrome: clinical features and natural history

Abstract

Costeff syndrome (CS) is a rare autosomal-recessive neurological disorder, which is known almost exclusively in patients of Iraqi Jewish descent, manifesting in childhood with optic atrophy, ataxia, chorea and spastic paraparesis. Our aim was to study the clinical spectrum of CS and natural history using a cross-sectional study design. Consecutive patients with CS were recruited to the study. Patients were diagnosed based on clinical features, along with elevated urinary levels of methylglutaconic and methylglutaric acid, and by identification of the disease-causing mutation in the OPA3 gene in most. All patients were examined by a neurologist and signs and symptoms were rated. 28 patients with CS (16 males, 21 families, age at last observation 28.6 ± 16.1 years, range 0.5-68 years) were included. First signs of neurological deficit appeared in infancy or early childhood, with delayed motor milestones, choreiform movements, ataxia and visual disturbances. Ataxia and chorea were the dominant motor features in childhood, but varied in severity among patients and did not seem to worsen with age. Pyramidal dysfunction appeared later and progressed with age (r = 0.71, p < 0.001) leading to spastic paraparesis and marked gait impairment. The course of neurological deterioration was slow and the majority of patients could still walk beyond the fifth decade. While visual acuity seemed to deteriorate, it did not correlate with age. CS is a rare neurogenetic disorder that causes serious disability and worsens with age. Spasticity significantly increases over the years and is the most crucial determinant of neurological dysfunction.

Optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy caused by a de novo OPA3 mutation

“…Costeff syndrome, also known as type III 3-methylglutaconic aciduria, is caused by autosomal recessive OPA3 mutations and, to date, has been reported almost exclusively among patients of Iraqi-Jewish descent (Yahalom et al 2014). Patients with Costeff syndrome usually present with early-onset bilateral optic atrophy, later-onset spasticity, extrapyramidal dysfunction, cerebellar ataxia, and mild cognitive defect (Anikster et al 2001; Sofer et al 2015).…”

Multiple Causes of Pediatric Early Onset Chorea—Clinical and Genetic Approach

“…37 Recently, we described the clinical features and natural history of 28 patients with CS. 36 Chorea and ataxia did not seem to worsen significantly with age. Pyramidal signs and spastic paraparesis developed later, progressed continuously, and significantly contributed to ambulation difficulties.…”

“…30,[33][34][35] The disease usually presents with hypotonia, developmental delay, chorea, and mild ataxia in the first year. 29,31,36 The extrapyramidal movements can be very severe and thus prevent motor skill achievements. 37 Recently, we described the clinical features and natural history of 28 patients with CS.…”

Disrupted mitochondrial function in the Opa3L122Pmouse model for Costeff Syndrome impairs skeletal integrity

“…Given that the processes of longitudinal bone growth and skeletal remodelling are remarkably similar in rodents and humans (50), our data have significant implications for individuals with Costeff syndrome. Although evidence has recently emerged of limb dystonia (51,52) and ataxia (52,53), there do not appear to be any extant studies of skeletal development, bone microarchitecture or fracture risk in the identified Costeff syndrome kindreds. Although it is possible that the skeletal impairment in the Opa3 L122P mice relates to the specific mutation in this model, Costeff syndrome has been reported in humans with mutations in exon2 of Opa3 (19,23).…”