MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement.

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

Modelling dispersal of radioactive contaminants in Arctic waters as a result of potential recovery operations on the dumped submarine K-27.

Of the wide variety of dumped objects containing radioactive materials in the Arctic seas, the submarine K-27 constitutes a major risk due to the large amount of highly enriched uranium onboard and its location in shallow waters. As the matter of potential operations involving raising of the submarine have entered the public arena, a priori assessment of the contamination in the Arctic marine environment that could result after a possible accident during such operations is a matter of some interest. The dispersion of contaminants within the Arctic has been assessed using a large scale hydrodynamic model for a series of plausible accident scenarios and locations under different oceanographic regimes. Results indicate that, depending primarily on the nature of a release (i.e. instantaneous or continuous), large areas of the Arctic marine environment will exhibit contamination to varying degrees.

Impacts on the marine environment in the case of a hypothetical accident involving the recovery of the dumped Russian submarine K-27, based on dispersion of 137Cs.

There is increasing concern regarding the issue of dumped nuclear waste in the Arctic Seas and in particular dumped objects with Spent Nuclear Fuel (SNF). Amongst dumped objects in the Arctic, the dumped Russian submarine K-27 has received great attention as it contains two reactors with highly enriched fuel and lies at a depth of about 30 m under water. To address these concerns a health and environmental impact assessment has been undertaken. Marine dispersion of potentially released radionuclides as a consequence of different hypothetical accident scenarios was modelled using the model NAOSIM. The outputs from the dispersion modelling have been used as inputs to food-chain transfer and environmental dosimetry models. The annual effective doses for subsistence fishing communities of the Barents-Kara seas region do not exceed 0.6 mSv for hypothetical accidents located at Stepovogo fjord or the Barents Sea. For high rate consumers of fish in Norway, following a potential accident at the Gremikha Bay, annual effects doses would be at around 0.15 mSv. Accumulated doses (over 90 days) for various organisms and for all release scenarios considered were never in excess of 150 µGy. The levels of 137Cs derived for marine organism in areas close to Norway were not values that would likely cause concern from a regulatory perspective although for subsistence fishing communities close to the considered accident locations, it is not inconceivable that some restrictions on fishing etc. would need to be introduced.

Derivation of risk indices and analysis of variablility for the management of incidents involving the transport of nuclear materials in the Northern Seas.

The transport of nuclear or radioactive materials and the presence of nuclear powered vessels pose risks to the Northern Seas in terms of potential impacts to man and environment as well socio-economic impacts. Management of incidents involving actual or potential releases to the marine environment are potentially difficult due to the complexity of the environment into which the release may occur and difficulties in quantifying risk to both man and environment. In order to address this, a state of the art oceanographic model was used to characterize the underlying variability for a specific radionuclide release scenario. The resultant probabilistic data were used as inputs to transfer and dose models providing an indication of potential impacts for man and environment This characterization was then employed to facilitate a rapid means of quantifying risk to man and the environment that included and addressed this variability. The radionuclide specific risk indices derived can be applied by simply multiplying the reported values by the magnitude of the source term and thereafter summing over all radionuclides to provide an indication of total risk.

Clinical and genetic complexity of Mitchell-Riley/Martinez-Frias syndrome.

Mitchell-Riley syndrome/Martinez-Frias syndrome (MRS/MFS) is a rare, autosomal recessive disorder with multisystem involvement and poor prognosis. Most reported cases have been associated with homozygous or compound heterozygous mutations in the RFX6 gene, a transcriptional regulatory factor for pancreatic morphogenesis. Given the limited number of reported cases, the syndrome may be under-recognized. When the particular phenotype of MFS includes a mutation on the RFX6 gene and neonatal diabetes, it has been called Mitchell-Riley syndrome. Because of this, we propose that MFS/MRS is a symptom continuum or an RFX6 malformation complex. We report an infant with all of the key clinical features of MRS/MFS without a definable mutation in RFX6 gene, supporting the consideration of these features as a symptom complex, and raising the question of genetic heterogeneity.

Refinement of the Region for Split Hand/Foot Malformation 5 on 2q31.1.

Background: Deletions that encompass 2q31.1 have been proposed as a microdeletion syndrome with common clinical features, including intellectual disability/developmental delay, microcephaly, cleft palate, growth delay, and hand/foot anomalies. In addition, several genes within this region have been proposed as candidates for split hand-foot malformation 5 (SHFM5). Methods: To delineate the genotype-phenotype correlation between deletions of this region, we identified 14 individuals with deletions at 2q31.1 detected by microarray analysis for physical and developmental disabilities. Results: All subjects for whom detailed clinical records were available had neurological deficits of varying degree. Seven subjects with deletions encompassing the HOXD cluster had hand/foot anomalies of varying severity, including syndactyly, brachydactyly, and ectrodactyly. Of 7 subjects with deletions proximal to the HOXD cluster, 5 of which encompassed DLX1/DLX2, none had clinically significant hand/foot anomalies. In contrast to previous reports, the individuals in our study did not display a characteristic gestalt of dysmorphic facial features. Conclusion: The absence of hand/foot anomalies in any of the individuals with deletions of DLX1/DLX2 but not the HOXD cluster supports the hypothesis that haploinsufficiency of the HOXD cluster, rather than DLX1/DLX2, accounts for the skeletal abnormalities in subjects with 2q31.1 microdeletions.

Phenotypic variability in 49 cases of ESCO2 mutations, including novel missense and codon deletion in the acetyltransferase domain, correlates with ESCO2 expression and establishes the clinical criteria for Roberts syndrome.

BACKGROUND: Roberts syndrome (RBS) and SC phocomelia are caused by mutations in ESCO2, which codes for an acetyltransferase involved in the regulation of sister chromatid cohesion. Of 26 mutations described to date, only one missense mutation has been reported and all others are predicted to be truncating mutations. Genotype-phenotype analysis has been hampered by limited numbers of patients with clinical information available. OBJECTIVE: To provide unpublished clinical data for 31 patients with proven ESCO2 mutations and combine this series with previously reported clinical and mutation data on 18 cases. Methods Genotype-phenotype correlations and functional effects of two novel ESCO2 mutations were analysed. In situ hybridisation on human embryos at Carnegie stages 14, 17 and 21 was performed to study ESCO2 expression during development. RESULTS AND CONCLUSIONS: Using the cohort of 49 patients, the clinical criteria for RBS were delineated to include: growth retardation; symmetric mesomelic shortening of the limbs in which the upper limbs are more commonly and severely affected than the lower limbs; characteristic facies with microcephaly. The severity of malformations of the facies correlates with the severity of limb reduction. The occurrence of corneal opacities may be associated with specific mutations. Two new mutations, both in the ESCO2 acetyltransferase domain, are described and their acetylation effects in vitro demonstrated. In situ hybridisation on human embryos showed ESCO2 expression in the brain, face, limb, kidney and gonads, which corresponds to the structures affected in RBS.

Discordant PKU phenotype in one family due to disparate genotypes and a novel mutation.

Classical phenylketonuria (PKU) and mild hyperphenylalaninaemia (MHP) are two ends of the broad diagnostic spectrum in phenylalanine hydroxylase (PAH) deficiency. We have analysed a family in which classical PKU, MHP and a normal phenotype occurred in family members with different mutations. Sequence analysis revealed three mutations segregating in the family. The individual with classical PKU had two previously reported deleterious mutations. A third novel mutation was identified in the other two individuals. This report demonstrates that when discordant phenotypes occur in a family, without protein loading or phenylalanine tolerance test, complete analysis of the PAH gene may be performed in order to support the diagnosis and assist in accurate genetic counselling and patient management.

Detection of anthropogenic climate change in the world's oceans.

Large-scale increases in the heat content of the world's oceans have been observed to occur over the last 45 years. The horizontal and temporal character of these changes has been closely replicated by the state-of-the-art Parallel Climate Model (PCM) forced by observed and estimated anthropogenic gases. Application of optimal detection methodology shows that the model-produced signals are indistinguishable from the observations at the 0.05 confidence level. Further, the chances of either the anthropogenic or observed signals being produced by the PCM as a result of natural, internal forcing alone are less than 5%. This suggests that the observed ocean heat-content changes are consistent with those expected from anthropogenic forcing, which broadens the basis for claims that an anthropogenic signal has been detected in the global climate system. Additionally, the requirement that modeled ocean heat uptakes match observations puts a strong, new constraint on anthropogenically forced climate models. It is unknown if the current generation of climate models, other than the PCM, meet this constraint.

Quantifying the uncertainty in forecasts of anthropogenic climate change

Forecasts of climate change are inevitably uncertain. It is therefore essential to quantify the risk of significant departures from the predicted response to a given emission scenario. Previous analyses of this risk have been based either on expert opinion, perturbation analysis of simplified climate models or the comparison of predictions from general circulation models. Recent observed changes that appear to be attributable to human influence provide a powerful constraint on the uncertainties in multi-decadal forecasts. Here we assess the range of warming rates over the coming 50 years that are consistent with the observed near-surface temperature record as well as with the overall patterns of response predicted by several general circulation models. We expect global mean temperatures in the decade 2036-46 to be 1-2.5 K warmer than in pre-industrial times under a 'business as usual' emission scenario. This range is relatively robust to errors in the models' climate sensitivity, rate of oceanic heat uptake or global response to sulphate aerosols as long as these errors are persistent over time. Substantial changes in the current balance of greenhouse warming and sulphate aerosol cooling would, however, increase the uncertainty. Unlike 50-year warming rates, the final equilibrium warming after the atmospheric composition stabilizes remains very uncertain, despite the evidence provided by the emerging signal.

Partial paternal uniparental disomy of chromosome 6 in an infant with neonatal diabetes, macroglossia, and craniofacial abnormalities.

Neonatal diabetes, which can be transient or permanent, is defined as hyperglycemia that presents within the first month of life and requires insulin therapy. Transient neonatal diabetes mellitus has been associated with abnormalities of the paternally inherited copy of chromosome 6, including duplications of a portion of the long arm of chromosome 6 and uniparental disomy, implicating overexpression of an imprinted gene in this disorder. To date, all patients with transient neonatal diabetes mellitus and uniparental disomy have had complete paternal isodisomy. We describe a patient with neonatal diabetes, macroglossia, and craniofacial abnormalities, with partial paternal uniparental disomy of chromosome 6 involving the distal portion of 6q, from 6q24-qter. This observation demonstrates that mitotic recombination of chromosome 6 can also give rise to uniparental disomy and neonatal diabetes, a situation similar to that observed in Beckwith-Wiedemann syndrome, another imprinted disorder. This finding has clinical implications, since somatic mosaicism for uniparental disomy of chromosome 6 should also be considered in patients with transient neonatal diabetes mellitus.

Duchenne/Becker muscular dystrophy: correlation of phenotype by electroretinography with sites of dystrophin mutations.

The dark-adapted electroretinogram (ERG) of patients with Duchenne and Becker muscular dystrophy (DMD/BMD) shows a marked reduction in b-wave amplitude. Genotype-phenotype studies of mouse models for DMD show position-specific effects of the mutations upon the phenotype: mice with 5' defects of dystrophin have normal ERGs, those with defects in the central region have a normal b-wave amplitude associated with prolonged implicit times for both the b-wave and oscillatory potentials, and mice with 3' defects have a phenotype similar to that seen in DMD/BMD patients. The mouse studies suggest a key role for the carboxyl terminal dystrophin isoform, Dp260, in retinal electrophysiology. We have undertaken a systematic evaluation of DMD/BMD patients through clinical examination and review of the literature in order to determine whether the position-specific effects of mutations noted in the mouse are present in man. We have found that, in man, a wider variation of DMD defects correlate with reductions in the b-wave amplitude. Individuals with normal ERGs have mutations predominantly located 5' of the transcript initiation site of Dp260. Our results suggest that the most important determinant in the ERG b-wave phenotype is the mutation position, rather than muscle disease severity. Forty-six per cent of patients with mutations 5' of the Dp260 transcript start site have abnormal ERGs, as opposed to 94% with more distal mutations. The human genotype-phenotype correlations are consistent with a role for Dp260 in normal retinal electrophysiology and may also reflect the expression of other C-terminal dystrophin isoforms and their contributions to retinal signal transmission.

In vitro microbiological characterization of novel cyclic homopentapeptides, CP-101,680 and CP-163,234, for animal health use.

Two cyclic homopentapeptides, CP-101,680 and CP-163,234 [6a-(3',4'-dichlorophenylamino) analogs of viomycin and capreomycin, respectively], were identified as novel antibacterial agents for the treatment of animal disease, especially for livestock respiratory disease. The in vitro microbiological characterization of both CP-101,680 and CP-163,234 was carried out using their parent compounds, viomycin and capreomycin, as controls. This characterization included antibacterial spectrum, influence of media, inoculum size, pH, EDTA, polymixin B nonapeptide (PMBN), serum, cell-free protein synthesis inhibition, and time-kill kinetics. Our results indicated that the capreomycin analog, CP-163,234, showed slightly improved in vitro potency over the viomycin analog, CP-101,680. Both analogs showed very potent cell-free protein synthesis inhibition activity and were bactericidal against Pasteurella haemolytica, P. multocida and Actinobacillus pleuropneumoniae at the level of 4 times and 8 times MICs. CP-163,234 was bactericidal at the level of 4x and 8x MIC against E. coli, but re-growth was observed after 24 hours incubation at both concentrations of CP-101,680.

Hemifacial microsomia in a newborn with hypoplastic skin lesions, an eyelid skin tag, and microphthalmia: an unusual presentation of Delleman syndrome.

Delleman syndrome (oculocerebrocutaneous syndrome) is characterized by orbital cysts, periorbital skin appendages, and focal cutaneous hypoplasia. We describe a male infant with findings associated with this condition, including an eyelid appendage, discrete hypoplastic skin lesions, unilateral microphthalmia, and hydrocephalus. In addition, he had striking unilateral mandibular hypoplasia and microtia, features often present in the oculoauriculovertebral (OAV) spectrum. However, hypoplastic skin lesions and eyelid appendages are not features of the OAV spectrum. The marked degree of hemifacial microsomia present in this child has not been previously noted in Delleman syndrome. Two patients with Delleman syndrome have been previously described who have features typically present in the OAV spectrum. This case demonstrates that characteristics of both Delleman syndrome and the OAV spectrum may be present in one individual.

OA1 mutations and deletions in X-linked ocular albinism.

X-linked ocular albinism (OA1), Nettleship-Falls type, is characterized by decreased ocular pigmentation, foveal hypoplasia, nystagmus, photodysphoria, and reduced visual acuity. Affected males usually demonstrate melanin macroglobules on skin biopsy. We now report results of deletion and mutation screening of the full-length OA1 gene in 29 unrelated North American and Australian X-linked ocular albinism (OA) probands, including five with additional, nonocular phenotypic abnormalities (Schnur et al. 1994). We detected 13 intragenic gene deletions, including 3 of exon 1, 2 of exon 2, 2 of exon 4, and 6 others, which span exons 2-8. Eight new missense mutations were identified, which cluster within exons 1, 2, 3, and 6 in conserved and/or putative transmembrane domains of the protein. There was also a splice acceptor-site mutation, a nonsense mutation, a single base deletion, and a previously reported 17-bp exon 1 deletion. All patients with nonocular phenotypic abnormalities had detectable mutations. In summary, 26 (approximately 90%) of 29 probands had detectable alterations of OA1, thus confirming that OA1 is the major locus for X-linked OA.

Neuropathological findings in eight children with cerebro-oculo-facio-skeletal (COFS) syndrome.

Cerebro-oculo-facial-skeletal (COFS) syndrome is a rare autosomal recessive disorder with microcephaly, severe mental retardation, and death in childhood. The pathogenesis is unknown. Neuropathological features of 8 children with COFS syndrome are presented. Seven of the children, ranging in age from 36 weeks gestation to 5 years 8 months, are of North American aboriginal background from Manitoba, Canada. The eight child is a 3-year-old Caucasian male. In all children there was severe microencephaly and mild ventriculomegaly. Cerebral myelination appeared to be delayed in one infantile case. Swollen ubiquitinated granular cells appeared in the white matter shortly after birth. Older children displayed cortical neuron loss, patchy or diffuse absence of myelin and gliosis in the white matter, and pericapillary and parenchymal mineralization in the globus pallidus and to a lesser extent the putamen and cerebral cortex. The cerebellum of older children exhibited severe degenerative changes involving the internal granular layer and Purkinje cell layer. The neuropathological changes, previously not well documented, suggest that COFS syndrome is associated with a degenerative process that begins in utero and affects many brain cell types. Similarities to Cockayne syndrome are discussed.

Acute lymphoblastic leukemia in a child with the CHIME neuroectodermal dysplasia syndrome.

The "CHIME" syndrome (MIM#280000) is a rare neuroectodermal disorder comprised of Colobomas of the eye, Heart defects, Ichthyosiform dermatosis, Mental retardation, and Ear defects. We report on the sixth child with this syndrome and the first of these to develop acute lymphoblastic leukemia at age 4 1/2 years. Her major problems included a migratory ichthyosiform dermatosis, multiple skin infections and infestations, bilateral retinal coloboma, developmental delay, seizures, infantile macrosomia, facial anomalies, a duplicated renal collecting system, and conductive hearing loss. Histologic examination of the skin demonstrated findings of an epidermal nevus with deep rete pegs, hyperkeratosis, and a markedly increased granular layer. The cause of the CHIME syndrome is unknown, but the disorder is easily recognized because of the striking phenotype. The diagnosis is important to make because of the potential for associated congenital heart disease, neurologic compromise, possible autosomal recessive inheritance, and possible association with malignancy.

Magnetization transfer in the investigation of patients with tuberous sclerosis.

We examined 21 patients aged 5 months to 19 years, on a 1.5 T magnet. T1-weighted spin-echo images, proton density and T2-weighted images with spin-echo and turbo spin-echo sequences, and contrast-enhanced magnetization transfer (MT) T1-weighted images were obtained in all cases. MT T1-weighted images were performed before injection in 9 patients. Subependymal nodules were found in 14, and cortical and subcortical tubers in 20 of the 21 patients. MT T1-weighted images showed tubers and subependymal nodules as higher signal than normal gray matter and revealed more tubers than conventional sequences in 11 cases. High signal intensity lesions of the white matter were found in 19 patients but were seen only on MT images in 9 cases. When MT images both before and after injection were available, tubers and white matter lesions were more easily recognised on unenhanced MT images because of their higher contrast.

Utility of linked markers in genetic counseling: estimation of carrier risks in X-linked ocular albinism.

We apply a method proposed by Rogatko et al. [1995: Am J Med Genet 59:24-32] to estimate carrier risks using genetic linkage data. The method is illustrated for X-linked ocular albinism. Linkage data from pedigrees were combined with genome mapping data to compute carrier risks for individuals with unknown carrier status based on pedigree data alone. We considered two situations. First, a linkage map with some ambiguity in the gene order was considered. This analysis allows us to examine the effect of incomplete genetic map information on risk computations. Second, published physical and meiotic mapping information was used to derive a linkage map that could be assumed known without ambiguity. In both situations, the mean and median estimate of carrier risk differed significantly from that obtained using pedigree relationships only, in that the computed risk was significantly different from the a priori value of 0.5. The 95% CI's associated with point estimates of risk made using the known map or an map with ambiguity did not overlap in some cases. These results suggest that the risk estimate and the confidence with which a risk estimate can be imparted may depend on the genetic map and marker data used in the risk estimation procedure. We conclude that the method presented here can be used to estimate genetic risk under a variety of analytical conditions.