Hanne Jensen

Ophthalmic manifestations of congenital disorder of glycosylation type 1a.

Purpose: To present the ophthalmic manifestations of patients with congenital disorder of glycosylation type Ia (CDG-Ia) due to the frequent R141H/F119L PMM2 genotype. Methods: Ophthalmic records of 23 patients (age: 10 months to 20 years) were evaluated. They had had at least one ophthalmic reexamination. Results: Measurements of refractive error showed that 18 patients were myopic, two were hypermetropic, and three could not be measured. Serial measurements in 12 patients indicated a progression towards myopia of 0.80 diopters (D) per year. Congenital esotropia and delayed visual maturation (DVM) were consistent findings. Two children developed good visual acuity (VA), 16 had low vision, and five were legally blind. Pallor of the optic disc was noted in five patients. Electroretinography (ERG) performed in nine patients showed reduced rod responses, while cone responses were only slightly reduced. Conclusions: The present study illustrates the difficulties in examining severely disabled children. Consistent ophthalmic manifestations of CDG-Ia patients due to the R141H/F119L genotype were congenital esotropia, DVM, and a reduced rod response in ERG-examined patients.The vast majority of patients had reduced VA and developed myopia.We speculate that there is a relationship between the glycosylation defect in CDGIa and the development of myopia. We recommend that CDG-Ia patients be followed annually by an ophthalmologist.

A novel nonsense mutation in MYO6 is associated with progressive nonsyndromic hearing loss in a Danish DFNA22 family

Autosomal dominant inheritance is described in about 20% of all nonsyndromic hearing loss with currently 54 distinct loci (DFNA1‐54), and >20 different genes identified. Seven different unconventional myosin genes are involved in ten different types of syndromic and nonsyndromic hearing loss with different patterns of inheritance: MYO7A in DFNA11/DFNB2/USH1B, MYH9 in DFNA17, MYH14 in DFNA4, MYO6 in DFNA22/DFNB37, MYO3A in DFNB30, MYO1A in DFNA48, and MYO15A in DFNB3. Two missense mutations in MYO6 (p.C442Y and p.H246R) have been characterized in families of Italian and American Caucasian extraction with autosomal dominant hearing loss, respectively, and the latter was associated with cardiomyopathy in some patients. Three Pakistani families had homozygosity for three MYO6 mutations (c.36insT, p.R1166X, and p.E216V, respectively), and was in one instance associated with retinal degeneration. In the present study, we linked autosomal dominant hearing loss in a large Danish family to a 38.9 Mb interval overlapping with the DFNA22/DFNB37 locus on chromosome 6q13. A novel nonsense mutation in MYO6 exon 25 (c.2545Cu2009>u2009T; p.R849X) was identified in the family. The mutation co‐segregated with the disease and the mutant allele is predicted to encode a truncated protein lacking the coiled‐coil and globular tail domains. These domains are hypothesized to be essential for targeting myosin VI to its cellular compartments. No other system was involved indicating nonsyndromic loss. In conclusion, a novel nonsense MYO6 mutation causes post‐lingual, slowly progressive autosomal dominant nonsyndromic moderate to severe hearing loss in a Danish family.

A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia

Anomalies of eye development can lead to the rare eye malformations microphthalmia and anophthalmia (small or absent ocular globes), which are genetically very heterogeneous. Several genes have been associated with microphthalmia and anophthalmia, and exome sequencing has contributed to the identification of new genes. Very recently, homozygous variations within ALDH1A3 have been associated with autosomal recessive microphthalmia with or without cysts or coloboma, and with variable subphenotypes of developmental delay/autism spectrum disorder in eight families. In a consanguineous family where three of the five siblings were affected with microphthalmia/coloboma, we identified a novel homozygous missense mutation in ALDH1A3 using exome sequencing. Of the three affected siblings, one had intellectual disability and one had intellectual disability and autism, while the last one presented with normal development. This study contributes further to the description of the clinical spectrum associated with ALDH1A3 mutations, and illustrates the interfamilial clinical variation observed in individuals with ALDH1A3 mutations.

Validity and Agreement between the 28-Joint Disease Activity Score Based on C-Reactive Protein and Erythrocyte Sedimentation Rate in Patients with Rheumatoid Arthritis.

Objective. To validate the agreement between the 28-joint disease activity score based on erythrocyte sedimentation rate (DAS28-ESR) and the 28-joint disease activity score based on C-reactive protein (DAS28-CRP) in a group of Danish patients with rheumatoid arthritis (RA). Methods. Data from 109 Danish RA patients initiating biologic treatment were analysed at baseline and following one year of treatment. Participants were retrospectively enrolled from a previous cohort study and were considered eligible for this project if CRP and ESR were measured at baseline and at the follow-up visit. To assess the extent of agreement between the two DAS28 definitions, the “European League Against Rheumatism” (EULAR) response criteria based on each definition were calculated with cross-classification. Weighted Kappa (κ) coefficients were calculated, and Bland-Altman plots were used to illustrate degree of agreement between DAS28 definitions. Results. The 75 eligible patients were classified as EULAR good, moderate, and nonresponders with good agreement (61/75; 81%) between DAS28-CRP and DAS28-ESR (κ = 0.75 (95% CI: 0.63 to 0.88)). Conclusions. According to our findings, DAS28-CRP and DAS28-ESR are interchangeable when assessing RA patients and the two versions of DAS28 are comparable between studies.

Multifactorial intervention to prevent cardiovascular disease in patients with early rheumatoid arthritis: protocol for a multicentre randomised controlled trial

Introduction Cardiovascular morbidity is a major burden in patients with rheumatoid arthritis (RA). In this study, we compare the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment of modifiable risk factors for cardiovascular disease (CVD) in patients with early RA fulfilling the 2010 American College of Rheumatology European League Against Rheumatism (ACR/EULAR) criteria. Methods and analysis The study is a prospective, randomised, open label trial with blinded end point assessment and balanced randomisation (1:1) conducted in 10 outpatient clinics in Denmark. The primary end point after 5u2005years of follow-up is a composite of death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke and cardiac revascularisation. Secondary outcomes are: the proportion of patients achieving low-density lipoprotein cholesterol <2.5u2005mmol/L, glycated haemoglobin <48u2005mmol/mol, blood pressure <140/90u2005mmu2005 Hg for patients without diabetes and <130/80u2005mmu2005Hg for patients with diabetes and normoalbuminuria (urinary albumin creatinine ratio <30u2005mg/g) after 1u2005year of follow-up and the proportion of patients in each treatment group achieving low RA disease activity after 1u2005year, defined as a disease activity score C-reactive protein (DAS28-CRP) <3.2 and a DAS28-CRP score <2.6 after 12, 24 and 60u2005months. Furthermore, all hospitalisations for acute and elective reasons will be adjudicated by the event committee after 12, 24 and 60u2005months. Three hundred treatment-naive patients with early RA will be randomly assigned (1:1) to receive either conventional treatment administered and monitored by their general practitioner according to national guidelines (control group) or a stepwise implementation administered and monitored in a quarterly rheumatological nurse-administered set-up of behaviour modification and pharmacological therapy targeting (1) hyperlipidaemia, (2) hypertension, (3) hyperglycaemia and (4) microalbuminuria (intervention group). Ethics and dissemination This protocol is approved by the local ethics committee (DK-S-2014007) and The Danish Health and Medicines Authority. Dissemination will occur through presentations at National and International conferences and publications in international peer-reviewed journals. Trial registration number NCT02246257

Congenital Microphthalmia, Anophthalmia and Coloboma among Live Births in Denmark

ABSTRACT Purpose: This study aims to quantify the occurrence of the congenital eye malformations anophthalmia (AO), microphthalmia (MO) and coloboma among liveborn infants in Denmark, and to estimate the rate of chromosomal abnormalities in this group of patients. Methods: A cohort of patients born in 1995–2012 with diagnoses of MO/AO or coloboma was identified from the Danish National Patient Registry (DNPR), and their ocular and extra-ocular diagnoses were reviewed. In order to assess the occurrence of chromosomal abnormalities in the cohort, the data were cross-referenced with the Danish Cytogenetic Central Registry (DCCR). Results: We identified 415 patients with MO/AO/coloboma in the DNPR. The total number of live births from 1995–2012 was 1,174,299, and the average birth prevalence of MO/AO/coloboma was 3.6/10,000 live births and of MO/AO was 1.2/10,000 live births. Extra-ocular abnormalities were observed in 32.1% of MO/AO cases and 21.7% of coloboma cases. Chromosome analysis was performed in 36.1% of the cohort, and 14.7% of cases had an abnormal karyotype. In 8.7% of the cohort, a chromosome microarray analysis was performed, and in 44.4% of cases, a possibly pathogenic copy number variation was observed. Conclusion: The birth prevalence of MO/AO/coloboma in Denmark has been steady at 3.6/10,000 live births during the last 17 years. The rate of syndromic cases was lower compared to other studies. A relatively high rate of pathogenic chromosomal aberrations was observed, suggesting an important role for cytogenetic analysis in this group of patients.

Usher syndrome in Denmark: mutation spectrum and some clinical observations

Usher syndrome (USH) is a genetically heterogeneous deafness‐blindness syndrome, divided into three clinical subtypes: USH1, USH2 and USH3.

Case report: a novel KERA mutation associated with cornea plana and its predicted effect on protein function

BackgroundCornea plana (CNA) is a hereditary congenital abnormality of the cornea characterized by reduced corneal curvature, extreme hypermetropia, corneal clouding and hazy corneal limbus. The recessive form, CNA2, is associated with homozygous or compound heterozygous mutations of the keratocan gene (KERA) on chromosome 12q22. To date, only nine different disease-associated KERA mutations, including four missense mutations, have been described.Case presentationIn this report, we present clinical data from a Turkish family with autosomal recessive cornea plana. In some of the affected individuals, hypotrichosis was found. KERA was screened for mutations using Sanger sequencing. We detected a novel KERA variant, p.(Ile225Thr), that segregates with the disease in the homozygous form. The three-dimensional structure of keratocan protein was modelled, and we showed that this missense variation is predicted to destabilize the structure of keratocan, leading to the classical ocular phenotype in the affected individuals. All the four known missense mutations, including the variation found in this family, affect the conserved residues of the leucine rich repeat domain of keratocan. These mutations are predicted to result in destabilization of the protein.ConclusionWe present the 10th pathogenic KERA mutation identified so far. Protein modelling is a useful tool in predicting the effect of missense mutations. This case underline the importance of the leucin rich repeat domain for the protein function, and this knowledge will ease the interpretation of future findings of mutations in these areas in other families with cornea plana.

Unilateral Ocular Duplication

Purpose: To present a boy with unilateral duplication of the eye. Method: The case history is described from the first visit at birth to the age of 14 years. Results: A review of the literature shows that this malformation is compatible with life although malformations of the brain and epilepsy have been reported in all cases where a paediatric exam was described. We show that the malformation can appear as a synophthalmic eye in a single orbit or as two separate unilateral eyes in a separate orbit. Conclusion: We find the denomination, triophthalmia insufficient to differentiate between the two types and suggest a differentiation between unilateral synophthalmia and ipsilateral ocular duplication.