Ptosis as an associated finding in maternally inherited diabetes and deafness

Purpose: To report ptosis as an associated finding in 2 patients with maternally inherited diabetes and deafness (MIDD). Methods: Two unrelated female patients with genetically proven MIDD are described. A complete ophthalmological examination included evaluation of levator muscle function, vertical fissure height and upper lid crease position measurements, the ice pack test and extensive imaging. In addition, pathology of the levator muscle was performed in 1 patient. Results: The first patient had an asymmetric ptosis at presentation. Levator muscle function was initially normal and decreased 3 years after, suggestive of a myogenic ptosis. Fundus examination revealed a macular pattern dystrophy. The second MIDD patient was referred for bilateral pigment alterations at the posterior pole. Gradually bilateral ptosis developed over a 3-year period. In both patients, ocular motility testing revealed a reduced upgaze. Conclusions: Myogenic ptosis has been described in association with several of the phenotypes caused by the m.3243A > G mutation, but up to now it had not been described as a finding in MIDD. MIDD has pleomorphic manifestations, and myogenic ptosis should be added to the list of associated clinical features. The additional symmetric elevation deficit in both patients may be an early sign of chronic progressive external ophthalmoplegia (CPEO). The results provide further evidence to suggest that MIDD represents only a part of a continuous spectrum of disease related to the m.3243A > G point mutation in the tRNA<SULeu</SU gene

Role of mitochondria in kainate-induced fast Ca(2+) transients in cultured spinal motor neurons

Motor neuron death in amyotrophic lateral sclerosis (ALS) has been linked to selective vulnerability towards AMPA receptor-mediated excitotoxicity. We investigated intracellular mechanisms leading to impairment of motor neuron Ca(2+) homeostasis with near physiological AMPA receptor activation. Using fast solution exchange on patch-clamped cultured neurons, kainate (KA) was applied for 2s. This induced a transient increase in the cytosolic Ca(2+) concentration ([Ca(2+)](c)) for seconds. Inhibition of the mitochondrial uniporter by RU-360 abolished the decay of the Ca(2+) transient and caused immediate [Ca(2+)](c) overload. Repetitive short KA stimulation caused a slowing of the decay of the Ca(2+) transient and a gradual increase in peak and baseline [Ca(2+)](c) in motor neurons, but not in other neurons, indicating saturation of the mitochondrial buffer. Furthermore, mitochondrial density was lower in motor neurons and, in a network of neurons with physiological synaptic AMPA receptor input, RU-360 acutely induced an increase in Ca(2+) transients. We conclude that motor neurons have an insufficient mitochondrial capacity to buffer large Ca(2+) elevations which is partly due to a reduced mitochondrial density per volume compared to non-motor neurons. This may exert deleterious effects in motor neuron disease where mitochondrial function is thought to be compromised.status: publishe

Recurrent Mutation in the First Zinc Finger of the Orphan Nuclear Receptor NR2E3 Causes Autosomal Dominant Retinitis Pigmentosa

“Autosomal dominant retinitis pigmentosa” (adRP) refers to a genetically heterogeneous group of retinal dystrophies, in which 54% of all cases can be attributed to 17 disease loci. Here, we describe the localization and identification of the photoreceptor cell-specific nuclear receptor gene NR2E3 as a novel disease locus and gene for adRP. A heterozygous mutation c.166G→A (p.Gly56Arg) was identified in the first zinc finger of NR2E3 in a large Belgian family affected with adRP. Overall, this missense mutation was found in 3 families affected with adRP among 87 unrelated families with potentially dominant retinal dystrophies (3.4%), of which 47 were affected with RP (6.4%). Interestingly, affected members of these families display a novel recognizable NR2E3-related clinical subtype of adRP. Other mutations of NR2E3 have previously been shown to cause autosomal recessive enhanced S-cone syndrome, a specific retinal phenotype. We propose a different pathogenetic mechanism for these distinct dominant and recessive phenotypes, which may be attributed to the dual key role of NR2E3 in the regulation of photoreceptor-specific genes during rod development and maintenance

The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder

A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/?FTD from five European cohorts (total n=1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n=434) and controls (n=856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/?FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/?FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P&lt;10?8). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe