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SERAC1 deficiency causes complicated HSP: evidence from a novel splice mutation in a large family

15 Sep, 17 | by hqqu

“Methylglutaconic aciduria, Deafness, Encephalopathy, Leigh-like” syndrome (MEGDEL syndrome) is a genetic disease caused by mutations in a gene named SERAC1, which is involved in the metabolism of specific lipids, so-called phosphatidylglycerols. MEGDEL syndrome typically presents with progressive deafness, motor symptoms (i. e. dystonia) and additional features (e. g. neonatal sepsis and liver failure) with onset in early childhood. In our study, we now show that this classic infantile phenotype represents only ONE far-end of what is actually a broad continuum of SERAC1 disease. This spectrum includes, on the other end, also much later, oligosymptomatic presentations of teenage-onset complex hereditary spastic paraplegia (cHSP). Our findings thus unfold a SERAC1 disease spectrum of variable disease severity and add SERAC1 to the increasing list of cHSP genes due to disturbances in lipid metabolism pathways. (By Dr. Benjamin Röben, http://jmg.bmj.com/content/early/2017/09/15/jmedgenet-2017-104622 )

the now unfolding clinical disease spectrum of SERAC1 mutations

Hypothesis: lobe A (COG1–4)-CDG causes a more severe phenotype than lobe B (COG5–8)-CDG

28 Aug, 17 | by hqqu

Some cellular components may be more equal than others.  In this study we used the frequency gap – underreporting of a certain phenomenon – to determine the relative importance of both A and B lobes for the functioning of a protein complex called “the COG complex”.  Two observations suggest that the consequences of lobe A dysfunction is more severe. First, patients with bi-allelic lobe A defects are underreported compared to lobe B defects. Second, deleterious variants in healthy adults are underreported in lobe A genes compared to lobe B genes. Much like driving a car is more hampered by a defective motor than by a defective gear case, comparable molecular defects are more detrimental in lobe A COG-CDG than in lobe B COG-CDG. (By Hanneke A. Haijes-Siepel and Dr. Peter M. van Hasselt, http://jmg.bmj.com/content/early/2017/08/27/jmedgenet-2017-104586 )

CTCF deletion syndrome: clinical features and epigenetic delineation

28 Aug, 17 | by hqqu

CTCF has multiple function in epigenetics including X-chromosome inactivation, genomic imprinting and genome organization. Mutations in CTCF are known to cause intellectual disability, however mechanism underlying the disease remains unknown. In this study, we reported two patients with a deletion including CTCF and proposed CTCF deletion syndrome because they showed distinct clinical characteristics icluding intellectual disability. Surprisingly, X-chromosome inactivation and DNA methylation at imprinted loci were normal, while genome-wide DNA hypermethylation only at CTCF binding sites were demonstrated and two candidate genes, PRKCZ and FGFR2, were identified, suggesting the underlying mechanism of the syndrome. (By Drs. Ikumi Hori and Shinji Saitoh, http://jmg.bmj.com/content/early/2017/08/28/jmedgenet-2017-104854 )

Genetic Severity Score predicts clinical phenotype in NF2

28 Aug, 17 | by hqqu

Individuals affected with Neurofibromatosis type 2 (NF2) typically develop multiple brain and spine tumours, and often lose hearing in young adulthood. The disease course can vary amongst patients and their severity is linked to genetic variations. The NF2 genetic severity score presented here, groups patients using genetic test results. The score separated patients according to 10 different outcomes, including age at diagnosis and number of interventions. This score will allow genetic information to be routinely incorporated in studies delineating the natural history of NF2, and in future studies assessing NF2 treatment response. (By Dorothy Halliday, http://jmg.bmj.com/content/early/2017/08/28/jmedgenet-2017-104519 )

 

Fabry disease: characterisation of the plasma proteome pre- and post-enzyme replacement therapy

24 Aug, 17 | by hqqu

Fabry disease (FD) is characterized by the progressive accumulation of globotriaosylceramide (Gb3). Enzyme replacement therapy (ERT) clears this accumulation. We analyzed plasma proteome profiles before and after ERT to characterize its molecular pathology. After ERT, the levels of proteins involved in inflammation, oxidative and ischemic injury, or complement activation were reduced significantly. In particular, we found out that inactivated complement C3b (iC3b) was significantly elevated in pre-ERT FD plasma and it gradually decreased along ERT, comparable to the changes of Gb3.Our study indicates that C3-mediated complement activation might be altered in FD and ERT might promote its stabilization. (By Dr. Beom Hee Lee, http://jmg.bmj.com/content/early/2017/08/23/jmedgenet-2017-104704 )

Autosomal recessive chondrodysplasia with severe short stature caused by a biallelic COL10A1 variant

24 Aug, 17 | by hqqu

Individuals carrying single mutated copies of Collagen 10 alpha-1, (COL10A1) suffer from Metaphyseal chondrodysplasia, Schmid type, (MCDS), involving mild to moderate short stature and skeletal deformities of the limbs. We describe individuals with two mutated copies of COL10A1, exhibiting extreme short stature and severe lower limb deformities. However, individuals with single mutated copies had below average heights and no apparent skeletal defects. This mutation was located in the NC2 domain, in which no pathogenic variants have been described before. This is the first report of a COL10A1 variant with autosomal recessive skeletal dysplasia and suggests that some COL10A1 alleles may be involved in isolated short stature. (By Dr. Sadaf Naz, http://jmg.bmj.com/content/early/2017/08/22/jmedgenet-2017-104885 )

Their loss is our gain: regressive evolution in vertebrates provides genomic models for uncovering human disease loci

16 Aug, 17 | by hqqu

What can an armadillo tell us about blindness and an anteater about dental disorders? Many animals have evolved traits that are similar to human genetic diseases, although for these animals the traits are adaptive, not disease-causing. Intriguingly, when animals possess these disease-mimicking traits, they frequently have disabling mutations in the same genes underlying the human genetic disorders. Here we show how medical geneticists can leverage the genomes of these disease-mimicking animals, which range from blue whales to sloths and pangolins to naked mole-rats, to corroborate and discover novel gene-disease associations for diseases related to vision, teeth and other organs. (By Dr. Christopher A Emerling, http://jmg.bmj.com/content/early/2017/08/16/jmedgenet-2017-104837 )

Mutations in SCAPER cause autosomal recessive retinitis pigmentosa with intellectual disability

9 Aug, 17 | by hqqu

Retinitis pigmentosa (RP) is a hereditary eye disease marked by progressive degeneration of the retina – the part of the eye that is home to the photosensitive cells. RP can occur by itself or in combination with other impairments. The latter cases are known as syndromic RP. We identified mutations in a gene named SCAPER in four patients from Israel and Spain, affected by RP and intellectual disability. This gene was not previously associated with a human disease. Our findings place SCAPER as a gene necessary for normal function of both the retina and the brain. (By Dr. Tamar Ben-Yosef, http://jmg.bmj.com/content/early/2017/08/09/jmedgenet-2017-104632 )

SCAPER expression pattern in the mouse retina. (A) Sagittal sections of adult mouse retina were immunostained with an anti-SCAPER antibody (red); (B) DAPI nuclear staining (blue); (C) merge of images A and B. SCAPER expression was observed in the retinal pigment epithelium (RPE), in photoreceptor outer segments (OS) and inner segments, including the outer nuclear layer (ONL), in the inner plexiform layer (IPL) and in the ganglion cell layer (GCL). OS, outer segments; INL, inner nuclear layer. Scale bar, 20µm.

Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia: from attention deficit to severe dystonia and intellectual disability

9 Aug, 17 | by hqqu

Hyperphenylalaninemia is one of the most common inherited metabolic diseases diagnosed in the newborn screening and until now follow-up investigation included differential diagnosis of phenylketonuria (PKU) and tetrahydrobiopterin (BH4) deficiency. With the description of patients with biallelic variants in co-chaperone DNAJC12 (van Spronsen et al 2017), the paradigm of hyperphenylalaninemia needs reconsideration. DNAJC12-deficient patients may present initially without any symptoms, with only mild attention deficit or with a severe intellectual disability, and need immediate and appropriate treatment (BH4, l-dopa/Carbidopa and 5-hydroxytryptophan). Thus, every newborn with hyperphenylalaninemia, in which PKU and BH4 deficiency were excluded need to be tested for DNAJC12 variants. (By Prof. Dr. Beat Thöny, http://jmg.bmj.com/content/early/2017/08/09/jmedgenet-2017-104875 )

A common SLC26A4-linked haplotype underlying non-syndromic hearing loss with enlargement of the vestibular aqueduct

5 Aug, 17 | by hqqu

Two mutated copies of the SLC26A4 gene are associated with Pendred syndrome, comprised of bilateral hearing loss with enlargement of the vestibular aqueduct (EVA) and thyroid goiter.  Other EVA patients have a normal thyroid gland and only one mutated copy of SLC26A4.  Our study identified the same combination, or haplotype, of noncoding sequence variants upstream of the non-mutated copy of SLC26A4 in most of these nonsydromic EVA patients.  This haplotype defines the most common allele associated with hereditary hearing loss in Caucasians.  Testing for this haplotype will facilitate the genetic and prognostic counseling of many patients with EVA. (By Dr. Andrew J Griffith, http://jmg.bmj.com/content/early/2017/08/05/jmedgenet-2017-104721 )

(Source: https://www.nidcd.nih.gov/health/enlarged-vestibular-aqueducts-and-childhood-hearing-loss )

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