Peripheral blood epi-signature of Claes-Jensen syndrome enables sensitive and specific identification of patients and healthy carriers with pathogenic mutations in KDM5C.

Background: Claes-Jensen syndrome is an X-linked inherited intellectual disability caused by mutations in the KDM5C gene. Kdm5c is a histone lysine demethylase involved in histone modifications and chromatin remodeling. Males with hemizygous mutations in KDM5C present with intellectual disability and facial dysmorphism, while most heterozygous female carriers are asymptomatic. We hypothesized that loss of Kdm5c function may influence other components of the epigenomic machinery including DNA methylation in affected patients. Results: Genome-wide DNA methylation analysis of 7 male patients affected with Claes-Jensen syndrome and 56 age- and sex-matched controls identified a specific DNA methylation defect (epi-signature) in the peripheral blood of these patients, including 1769 individual CpGs and 9 genomic regions. Six healthy female carriers showed less pronounced but distinctive changes in the same regions enabling their differentiation from both patients and controls. Highly specific computational model using the most significant methylation changes demonstrated 100% accuracy in differentiating patients, carriers, and controls in the training cohort, which was confirmed on a separate cohort of patients and carriers. The 100% specificity of this unique epi-signature was further confirmed on additional 500 unaffected controls and 600 patients with intellectual disability and developmental delay, including other patient cohorts with previously described epi-signatures. Conclusion: Peripheral blood epi-signature in Claes-Jensen syndrome can be used for molecular diagnosis and carrier identification and assist with interpretation of genetic variants of unknown clinical significance in the KDM5C gene.

A homozygous FITM2 mutation causes a deafness-dystonia syndrome with motor regression and signs of ichthyosis and sensory neuropathy.

A consanguineous family from Pakistan was ascertained to have a novel deafness-dystonia syndrome with motor regression, ichthyosis-like features and signs of sensory neuropathy. By applying a combined strategy of linkage analysis and whole-exome sequencing in the presented family, a homozygous nonsense mutation, c.4G>T (p.Glu2*), in FITM2 was identified. FITM2 and its paralog FITM1 constitute an evolutionary conserved protein family involved in partitioning of triglycerides into cellular lipid droplets. Despite the role of FITM2 in neutral lipid storage and metabolism, no indications for lipodystrophy were observed in the affected individuals. In order to obtain independent evidence for the involvement of FITM2 in the human pathology, downregulation of the single Fitm ortholog, CG10671, in Drosophila melanogaster was pursued using RNA interference. Characteristics of the syndrome, including progressive locomotor impairment, hearing loss and disturbed sensory functions, were recapitulated in Drosophila, which supports the causative nature of the FITM2 mutation. Mutation-based genetic counseling can now be provided to the family and insight is obtained into the potential impact of genetic variation in FITM2.

Optic nerve atrophy in propionic acidemia.

OBJECTIVE: Propionic acidemia is a rare metabolic disorder that is diagnosed in the early neonatal period. The disorder is characterized by life-threatening ketoacidosis, lethargy, failure to thrive, and developmental delay. Herein we report the ocular findings in a prospective series of six patients with propionic acidemia. DESIGN: Prospective case series. PARTICIPANTS: Six children (three male and three female) between the ages of 2 and 10 years with propionic acidemia who were examined at Children's Hospital Los Angeles. METHODS: A complete ophthalmic examination was performed on each of the six children. The examination included visual acuity testing, ocular motility, anterior segment examination, and funduscopic evaluation. Emphasis was placed on the function of the optic nerve and on the appearance of the optic disc, looking for possible atrophic changes. MAIN OUTCOME MEASURES: The clinical appearance of the optic disc and evidence of optic neuropathy. RESULTS: Optic nerve atrophy was present exclusively in all of the male patients in the series; none of the female patients demonstrated any detectable impairment of optic nerve function. The optic nerve atrophy was symmetric and age dependent and varied from moderate to severe. There were no other anterior or posterior segment abnormalities, other than one case of unilateral morning glory syndrome, diagnosed at birth. There was no correlation between metabolic control and the development and progression of optic nerve atrophy. CONCLUSIONS: Males with propionic acidemia have moderate to severe bilateral optic atrophy.

Optic atrophy in association with cobalamin C (cblC) disease.

PURPOSE: To report the association of optic atrophy with cobalamin C (cblC) disease. METHODS: Descriptive case reports on three patients, two of whom were siblings. RESULTS: All three patients with cblC disease exhibited bilateral optic atrophy with decreased visual acuity. Of the two siblings, the younger sister had received cobalamin supplements from birth and the mother had been given cobalamin supplements prenatally. CONCLUSION: These three cases confirm the association of optic atrophy with cblC disease. Early treatment with cobalamin supplements does not appear to prevent the development of optic atrophy.

[Optic neuropathy in type-1 diabetes and acetylsalicylic acid-refractory thrombocyte activation]. / Opticusneuropathie bei Typ-I-Diabetes und Acetylsalicylsäure-refraktärer Thrombozytenaktivierung.

A 26-year-old female with severe complications from type I diabetes mellitus of 17 years' duration (proliferative retinopathy, nephropathy with renal failure and nephrotic syndrome) developed rapid deterioration of vision in the right eye to 6/60 over a period of several weeks. There were no other neurological signs. Ophthalmological examination showed no worsening of the diabetic retinopathy, but the presence of bilateral optic atrophy, confirmed by visual evoked potentials. CT scan did not reveal any retrobulbar process, and MR scans of both the optic nerves and the visual pathways were unremarkable. The clinical features and the investigations pointed towards ischaemic optic atrophy. Detailed platelet studies showed intravascular platelet activation and an ADP-inducible increase in aggregation, although thromboxane formation was almost absent because of cyclooxygenase inhibition by acetylsalicylic acid. These findings suggest that the ischaemia was due to microcirculatory disturbances secondary to diabetic microangiopathy and platelet hyperreactivity.

[Changes in hemorheology of traumatic optic nerve atrophy].

Whole blood viscosity (WBV), plasma viscosity (PV), hematocrit, erythrocyte sedimentation rate (ESR) and fibrinogen were assayed in 20 patients with traumatic optic nerve atrophy. The results of each item in the above examinations has been compared with that of the control group. It has been demonstrated that WBV, PV, ESR and fibrinogen in the patient group were significantly higher than that in the control group (P less than 0.01). But the ESR and fibrinogen of the treatment group were significantly lower than that in the pretreatment group (P less than 0.01). The authors suggest that the result of changes in hemorheology of traumatic optic nerve atrophy is a kind of reverse phenomenon.

Effects of optic atrophy on retinal blood flow and oxygen saturation in humans.

Retinal blood flow and oxygen saturation were evaluated in patients with unilateral inner retinal degeneration secondary to neurogenic optic atrophy. Arteriovenous O2 saturation for temporal and nasal vascular segments of the affected eyes, evaluated by retinal vessel oximetry, was 12% +/- 9% higher than in the fellow eyes (seven patients). Blood flow in the temporal retinal arteries of the affected eyes, measured by the laser Doppler technique, was 48% +/- 20% lower than in the fellow eyes (four patients). The combination of these results indicated a 40% +/- 29% reduction in O2 delivery in the affected eyes (four patients), thereby quantifying the decrease in retinal metabolism that resulted from inner retinal degeneration.

Red cell glutathione in Leber's optic atrophy.

Red cell glutathione has been assayed in a family affected by Leber's optic atrophy. The results are in agreement with a defective cyanide metabolism. The transmission mechanism of the disease is discussed. Lastly, a preventive and therapeutic approach is proposed.