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1.  OSBPL2 encodes a protein of inner and outer hair cell stereocilia and is mutated in autosomal dominant hearing loss (DFNA67) 
Background
Early-onset hearing loss is mostly of genetic origin. The complexity of the hearing process is reflected by its extensive genetic heterogeneity, with probably many causative genes remaining to be identified. Here, we aimed at identifying the genetic basis for autosomal dominant non-syndromic hearing loss (ADNSHL) in a large German family.
Methods
A panel of 66 known deafness genes was analyzed for mutations by next-generation sequencing (NGS) in the index patient. We then conducted genome-wide linkage analysis, and whole-exome sequencing was carried out with samples of two patients. Expression of Osbpl2 in the mouse cochlea was determined by immunohistochemistry. Because Osbpl2 has been proposed as a target of miR-96, we investigated homozygous Mir96 mutant mice for its upregulation.
Results
Onset of hearing loss in the investigated ADNSHL family is in childhood, initially affecting the high frequencies and progressing to profound deafness in adulthood. However, there is considerable intrafamilial variability. We mapped a novel ADNSHL locus, DFNA67, to chromosome 20q13.2-q13.33, and subsequently identified a co-segregating heterozygous frameshift mutation, c.141_142delTG (p.Arg50Alafs*103), in OSBPL2, encoding a protein known to interact with the DFNA1 protein, DIAPH1. In mice, Osbpl2 was prominently expressed in stereocilia of cochlear outer and inner hair cells. We found no significant Osbpl2 upregulation at the mRNA level in homozygous Mir96 mutant mice.
Conclusion
The function of OSBPL2 in the hearing process remains to be determined. Our study and the recent description of another frameshift mutation in a Chinese ADNSHL family identify OSBPL2 as a novel gene for progressive deafness.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-015-0238-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-015-0238-5
PMCID: PMC4334766
OSBPL2; DFNA67; Autosomal dominant hearing loss
2.  New spastic paraplegia phenotype associated to mutation of NFU1 
Recently an early onset lethal encephalopathy has been described in relation to mutations of NFU1, one of the genes involved in iron-sulfur cluster metabolism. We report a new NFU1 mutated patient presenting with a milder phenotype characterized by a later onset, a slowly progressive spastic paraparesis with relapsing-remitting episodes, mild cognitive impairment and a long survival. The early white matter abnormalities observed on MRI was combined with a mixed sensory-motor neuropathy in the third decade. Our case clearly suggests the importance of considering NFU1 mutation in slowly evolving leukoencephalopathy with high glycine concentration.
doi:10.1186/s13023-015-0237-6
PMCID: PMC4333890
Irons sulfur clusters; Leukoencephalopathy; Spastic paraplegia; NFU1
3.  A nationwide survey of hereditary angioedema due to C1 inhibitor deficiency in Italy 
Introduction
Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE type I) or dysfunction (C1-INH-HAE type II) is a rare disease characterized by recurrent episodes of edema with an estimated frequency of 1:50,000 in the global population without racial or gender differences. In this study we present the results of a nationwide survey of C1-INH-HAE patients referring to 17 Italian centers, the Italian network for C1-INH-HAE, ITACA.
Methods
Italian patients diagnosed with C1-INH-HAE from 1973 to 2013 were included in the study. Diagnosis of C1-INH-HAE was based on family and/or personal history of recurrent angioedema without urticaria and on antigenic and/or functional C1-INH deficiency.
Results
983 patients (53% female) from 376 unrelated families were included in this survey. Since 1973, 63 (6%) patients diagnosed with C1-INH-HAE died and data from 3 patients were missing when analysis was performed. Accordingly, the minimum prevalence of HAE in Italy in 2013 is 920:59,394,000 inhabitants, equivalent to 1:64,935. Compared to the general population, patients are less represented in the early and late decades of life: men start reducing after the 5th decade and women after the 6th. Median age of patients is 45 (IQ 28-57), median age at diagnosis is 26 years (IQ 13-41). C1-INH-HAE type 1 are 87%, with median age at diagnosis of 25 (13-40); type 2 are 13% with median age at diagnosis of 31 (IQ 16-49). Functional C1INH is ≤50% in 99% of patients. Antigen C1INH is ≤50% in 99% of type 1. C4 is ≤50% in 96% of patients. The chance of having C1-INH-HAE with C4 plasma levels >50% is < 0.05.
Conclusion
This nationwide survey of C1-INH-HAE provides for Italy a prevalence of 1:64,935. C1-INH-HAE patients listed in our database have a shorter life expectancy than the general population. An increased awareness of the disease is needed to reduce this discrepancy. Measurement of C4 antigen can exclude diagnosis of C1-INH-HAE with an accuracy > 95%. This parameter should be therefore considered for initial screening in differential diagnosis of angioedema.
doi:10.1186/s13023-015-0233-x
PMCID: PMC4333895
Hereditary angioedema; C1 inhibitor; C4
4.  Cost effective assay choice for rare disease study designs 
High throughput assays tend to be expensive per subject. Often studies are limited not so much by the number of subjects available as by assay costs, making assay choice a critical issue. We have developed a framework for assay choice that maximises the number of true disease causing mechanisms ‘seen’, given limited resources. Although straightforward, some of the ramifications of our methodology run counter to received wisdom on study design. We illustrate our methodology with examples, and have built a website allowing calculation of quantities of interest to those designing rare disease studies.
doi:10.1186/s13023-015-0226-9
PMCID: PMC4334400  PMID: 25648394
WES; WGS; High-throughput assay; Rare disease; Study design
5.  Vitamin D and skeletal health in autoimmune bullous skin diseases: a case control study 
Background
The presence of hypovitaminosis D in patients with autoimmune bullous skin diseases, such as pemphigus vulgaris (PV) and bullous pemphigoid (BP), is debated. In a previous study we found an increased prevalence of vertebral fractures (VFx) and hypovitaminosis D in PV and BP patients. The present study extends the sample size of the previous one, for investigating the 25-hydroxyvitamin D (25OHVitD) levels in relation with the skeletal health and disease intensity in these patients.
Methods
The previous study was performed in 13 PV and 15 BP patients and 28 controls. Data from 39 additional patients (22 PV and 17 BP) were now added. Eventually, we studied 67 patients (35 PV, 32 BP, 51 females), aged 64.7 ± 16.9 years and 67 age- gender- and body mass index-matched controls. In all subjects, serum 25OHVitD, calcium and alkaline phosphatase (ALP) levels were measured, bone mineral density (BMD) was evaluated by Dual-energy X-ray. Absorptiometry at lumbar spine (LS) and femoral neck (FN) and the presence of VFx were ascertained by visual assessment from spinal radiographs. In patients, the disease intensity was evaluated by the autoimmune bullous skin disorder intensity score (ABSIS).
Results
As compared with controls, both PV and BP patients showed lower 25OHVitD (22.2 ± 11.1 vs 13.9 ± 8.3 ng/mL, p < 0.001 and 22.4 ± 14.9 vs 9.5 ± 7.7 ng/mL, p < 0.0001, respectively) and higher prevalence of severe hypovitaminosis D (22.9 vs 48.6%, p < 0.02 and 31.1 vs 75.0%, p < 0.0001, respectively) and VFx (28.6 vs 57.1%, p = 0.03 and 34.4 vs 62.5%, P = 0.02, respectively). In both PV and BP patients, LS and FN BMD did not differ from controls. In the whole patients’ group, ABSIS score was inversely associated with 25OHVitD levels (R = −0.36, p < 0.005), regardless of age (β = −3.2, P = 0.009).
Conclusions
PV and BP patients have an increased prevalence of hypovitaminosis D and VFx. The extended study shows, for the first time, that the 25OHVitD levels are inversely associated with disease intensity and that VFx occur in spite of a not reduced BMD.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-015-0230-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-015-0230-0
PMCID: PMC4323030  PMID: 25644263
Vitamin D; Autoimmune bullous skin diseases; Vertebral fractures
6.  Gene panel sequencing in heritable thoracic aortic disorders and related entities – results of comprehensive testing in a cohort of 264 patients 
Background
Heritable Thoracic Aortic Disorders (H-TAD) may present clinically as part of a syndromic entity or as an isolated (nonsyndromic) manifestation. About one dozen genes are now available for clinical molecular testing. Targeted single gene testing is hampered by significant clinical overlap between syndromic H-TAD entities and the absence of discriminating features in isolated cases. Therefore panel testing of multiple genes has now emerged as the preferred approach. So far, no data on mutation detection rate with this technique have been reported.
Methods
We performed Next Generation Sequencing (NGS) based screening of the seven currently most prevalent H-TAD-associated genes (FBN1, TGFBR1/2, TGFB2, SMAD3, ACTA2 and COL3A1) on 264 samples from unrelated probands referred for H-TAD and related entities. Patients fulfilling the criteria for Marfan syndrome (MFS) were only included if targeted FBN1 sequencing and MLPA analysis were negative.
Results
A mutation was identified in 34 patients (13%): 12 FBN1, one TGFBR1, two TGFBR2, three TGFB2, nine SMAD3, four ACTA2 and three COL3A1 mutations. We found mutations in FBN1 (N = 3), TGFBR2 (N = 1) and COL3A1 (N = 2) in patients without characteristic clinical features of syndromal H-TAD. Six TAD patients harboring a mutation in SMAD3 and one TAD patient with a TGFB2 mutation fulfilled the diagnostic criteria for MFS.
Conclusion
NGS based H-TAD panel testing efficiently reveals a mutation in 13% of patients. Our observations emphasize the clinical overlap between patients harboring mutations in syndromic and nonsyndromic H-TAD related genes as well as within syndromic H-TAD entities, justifying a widespread application of this technique.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-014-0221-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-014-0221-6
PMCID: PMC4326194  PMID: 25644172
Heritable Thoracic Aortic Disorders – next generation sequencing – Aneurysm; Dissecting/genetics – mutation detection rate
7.  New biomarkers for early diagnosis of Lesch-Nyhan disease revealed by metabolic analysis on a large cohort of patients 
Background
Lesch-Nyhan disease is a rare X-linked neurodevelopemental metabolic disorder caused by a wide variety of mutations in the HPRT1 gene leading to a deficiency of the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt). The residual HGprt activity correlates with the various phenotypes of Lesch-Nyhan (LN) patients and in particular with the different degree of neurobehavioral disturbances. The prevalence of this disease is considered to be underestimated due to large heterogeneity of its clinical symptoms and the difficulty of diagnosing of the less severe forms of the disease. We therefore searched for metabolic changes that would facilitate an early diagnosis and give potential clues on the disease pathogenesis and potential therapeutic approaches.
Methods
Lesch-Nyhan patients were diagnosed using HGprt enzymatic assay in red blood cells and identification of the causal HPRT1 gene mutations. These patients were subsequently classified into the three main phenotypic subgroups ranging from patients with only hyperuricemia to individuals presenting motor dysfunction, cognitive disability and self-injurious behavior. Metabolites from the three classes of patients were analyzed and quantified by High Performance Ionic Chromatography and biomarkers of HGprt deficiency were then validated by statistical analyses.
Results
A cohort of 139 patients, from 112 families, diagnosed using HGprt enzymatic assay in red blood cells, was studied. 98 displayed LN full phenotype (86 families) and 41 (26 families) had attenuated clinical phenotypes. Genotype/phenotype correlations show that LN full phenotype was correlated to genetic alterations resulting in null enzyme function, while variant phenotypes are often associated with missense mutations allowing some residual HGprt activity. Analysis of metabolites extracted from red blood cells from 56 LN patients revealed strong variations specific to HGprt deficiency for six metabolites (AICAR mono- and tri-phosphate, nicotinamide, nicotinic acid, ATP and Succinyl-AMP) as compared to controls including hyperuricemic patients without HGprt deficiency.
Conclusions
A highly significant correlation between six metabolites and the HGprt deficiency was established, each of them providing an easily measurable marker of the disease. Their combination strongly increases the probability of an early and reliable diagnosis for HGprt deficiency.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-014-0219-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-014-0219-0
PMCID: PMC4320826  PMID: 25612837
HGprt; Hypoxanthine-guanine phosphoribosyltransferase; Deficiency; Genotype; Metabolome; Lesch-Nyhan disease; Variants; AICAR
8.  Prognostic and predictive role of CXCR4, IGF-1R and Ezrin expression in localized synovial sarcoma: is chemotaxis important to tumor response? 
Background
Synovial sarcoma (SS) is a rare tumor, with dismal survival when metastatic. The role of adjuvant chemotherapy is debated. New prognostic and predictive factors are needed.
Methods
We reviewed patients with localized SS; SS18-SSX fusion transcript presence was confirmed by FISH and RT-PCR. Expression of CXCR4, IGF-1R and Ezrin were evaluated by immunohistochemistry.
Results
Tumor samples from 88 SS patients (45 female; 43 male) with median age 37 years (range 11–63) were selected. The size of the lesion was > 5 cm in 68% of patients and 34% of cases presented biphasic histotype. All patients underwent surgery, 56% adjuvant radiotherapy (RT), 65% adjuvant chemotherapy. A positive stain for IGF-1R was detected in 55 patients, with nucleus expression in 21 patients. CXCR4 was expressed in 74 patients, nuclear pattern in 31 patients. 80 SS were positive to Ezrin, 48 had cytoplasmatic location, 32 membrane location. With a median follow-up of 6 years (1–30 years), the 5-year overall survival (OS) was 70% (95% CI 60–81). 5-year OS was 63% (95% CI 41-85%) for patients with positive IGF-1R/nuclear expression, and 73% (95% CI 61-85%; P = 0.05) in negative patients. 5-year OS was 47% (95% CI 27-66%) in patients with positive CXCR4/nuclear staining, and 86% (95% CI 76-96%, P = 0.0003) in negative cases. No survival difference was found according to Ezrin expression. By multivariate analysis, nuclear expression of CXCR4 and IGF-1R was confirmed independent adverse prognostic factor for SS patient survival linked to the use of chemotherapy.
Conclusions
Our findings have important potential implications demonstrating that together with clinical prognostic factors such as radiotherapy and age, CXCR4 and IGF-1R negatively influences survival in patients with localized SS. We believe that further studies addressed to the effects of CXCR4 and IGF-1R inhibitors on cell viability and function are needed to plan new and more appropriate SS treatments.
doi:10.1186/s13023-014-0222-5
PMCID: PMC4320838  PMID: 25613038
CXCR4; IGFR1; Ezrin; Synovial sarcoma; Prognostic factors; Predictive factors
9.  A comprehensive database of Duchenne and Becker muscular dystrophy patients (0–18 years old) in East China 
Background
Currently, there is no cure for Duchenne and Becker muscular dystrophies (DMD/BMD). However, clinical trials with new therapeutic strategies are being conducted or considered. A comprehensive database is critical for patient recruitment and efficacy evaluation. China has the largest population, yet, no comprehensive database for DMD/BMD is available. Our study registered the data of the DMD/BMD patients in East China.
Methods
A modified registry form of Remudy (http://www.remudy.jp/) was applied to Chinese DMD/BMD patients through the outpatient clinic at Children’s Hospital of Fudan University, Shanghai during the period of August 2011 to December 2013. The data included geographic distribution of patients, age at diagnosis, clinical manifestation, genetic analysis and treatment status.
Results
194 DMD and 35 BMD patients were registered. Most patients lived in East China, namely Jiangsu province, Anhui province, Zhejiang province, Jiangxi province, Shanghai, Fujian province and Shandong province. All individuals aged less than 18 years (age limit to a children’s hospital). Diagnosis was made for a majority of patients during the age of 3–4 (16.6%) and 7–8 (14.8%) years old. Exon deletion was the most frequent genetic mutations (65.5% and 74.3%) followed by point mutations (14.4% and 11.4%), duplications (9.8% and 8.6%) and small insertion/deletion (9.3% and 2.9%) for DMD and BMD, respectively. 82.5% of DMD registrants were ambulatory, and all the BMD registrants were able to walk. 26.3% of DMD registrants have been treated with steroids. Cardiac functions were examined for 46.4% DMD boys and 45.7% BMD boys and respiratory functions were examined for 18.6% DMD boys and 14.3% BMD boys. Four boys with abnormal cardiac function were prescribed for treatment with cardiac medicine. 33.2% of DMD patients are eligible for exon skipping therapy, and among them 9.2% and 4.3% patients are eligible for skipping exon 51 and 53, respectively.
Conclusions
The database is the first linking accurate genetic diagnosis with clinical manifestation and treatment status of dystrophinopathy patients in East China. It provides comprehensive information essential for further patient management, especially for promotion of international cooperation in developing experimental therapies such as exon skipping and read-through of nonsense mutations targeting a subgroup of DMD patient population.
doi:10.1186/s13023-014-0220-7
PMCID: PMC4323212  PMID: 25612904
Duchenne and Becker muscular dystrophy; The CHFU database; Patient management
10.  Molecular and clinical analysis of TRPC6 and AGTR1 genes in patients with pulmonary arterial hypertension 
Background
Pulmonary arterial hypertension (PAH) is a rare and progressive vascular disorder characterized by increased pulmonary vascular resistance and right heart failure. The aim of this study was to analyze 5′UTR region in canonical transient receptor potential isoform 6 (TRPC6) and 3′UTR region in Angiotensin II type I receptor (AGTR1) genes in patients with idiopathic and associated PAH. Correlation among mutations and clinical and functional parameters was further analyzed.
Methods
Analysis of TRPC6 and AGTR1 genes was performed by polymerase chain reaction (PCR) and direct sequencing. We used a non-parametric test to determine if significant differences were found between the groups studied and chi-square test to compare clinical and hemodynamic variables among genotypes.
Results
Fifty five patients and fifty two controls were included in this study. We found statistically significant differences for c.1-361A > T (p = 0.0077), c.1-254C > G (p < 0.0001) and c.1-218C > T (p = 0.0021) in TRPC6 gene and c.1166A > C (p < 0.001) in AGTR1 gene, between patients and controls. Idiopathic PAH patients (IPAH) and controls presented significant differences for all 3 TRPC6 polymorphisms (p = 0.020), (p = 0.002) and (p = 0.008) respectively, and also showed differences for AGTR1 gene (p < 0.001). In associated PAH (APAH) patients we found statistical differences for c.1-254C > G (p < 0.001) and c.1-218C > T (p = 0.001) in TRPC6 gene and c.1166A > C (p = 0.001) in AGTR1 gene. Several clinical and hemodynamic parameters showed significant differences between carriers and non-carriers of these single nucleotide polymorphisms (SNPs). Nineteen patients were carriers of all 3 SNPs in TRPC6 gene and presented a more severe phenotype with differences in mean pulmonary arterial pressure (p = 0.016), systolic pulmonary arterial pressure (p = 0.040), cardiac index (p < 0.001) and 6 minute walking test (p = 0.049). 16 of these patients harbored the SNP in AGTR1 gene. These patients showed differences in age at diagnosis (p = 0.049), mean pulmonary arterial pressure (p = 0.033), cardiac index (p = 0.002) and 6 minute walking test (p = 0.039).
Conclusions
PAH is a rare disease with pulmonary vascular remodeling caused in part by a heterogeneous constellation of genetic arrangements. This study seems to suggest that c.1-361A > T, c.1-254C > G and c.1-218C > T polymorphisms in TRPC6 gene and c.1166A > C polymorphism in AGTR1 could have a role in the development of this disease.
doi:10.1186/s13023-014-0216-3
PMCID: PMC4307182  PMID: 25603901
Pulmonary Arterial Hypertension; TRPC6; AGTR1; Polymorphism; Correlation genotype/phenotype
11.  Diagnosis and treatment of congenital abdominal aortic aneurysm: a systematic review of reported cases 
Background
Congenital abdominal aortic aneurysm (AAA) is distinctly rare in infants and children and carries a high mortality rate. Our objective was to summarize the experience of the diagnosis and treatment in patients with congenital AAA.
Methods
Reported cases of congenital AAA published prior to November 8, 2014, were identified through PubMed, EMBASE, Web of Science, and reference lists. All selected cases were evaluated for main clinical characteristics.
Results
Twenty-six cases of congenital AAA were identified in the English language literature. Congenital AAA occurred primarily in children under three years old, but it was also found in young adults and fetuses. With regards to the localization, the great majority of congenital AAA was infrarenal AAA. The majority of the AAA patients lacked specific symptoms, and a painless pulsatile abdominal mass was the most common clinical presentation. The diagnosis of AAA was based on ultrasound scanning in twenty-five cases, multi-slice spiral computed tomography angiography (MSCTA) in sixteen cases, and magnetic resonance angiography (MRA) in nine cases. Histopathological analyses were available in seven cases. Seven patients received conservative management. Surgical treatment was performed in seventeen cases, and open repair with an artificial graft was the main surgical intervention. The mortality associated with congenital AAA was high (30.76%). Ruptured aneurysm and renal failure were the main causes of death.
Conclusions
Good outcomes can be achieved in children with early identification of congenital AAA and individualized surgical repair with grafts.
doi:10.1186/s13023-015-0225-x
PMCID: PMC4307982  PMID: 25608574
Aortic aneurysms; Abdominal; Congenital; Ultrasonography; Surgical repair; Children
12.  Elevated risk of thrombophilia in agenesis of the vena cava as a factor for deep vein thrombosis 
Background
Congenital absence of the inferior vena cava (AIVC) is a rare malformation which may be associated with an increased risk for deep vein thrombosis (DVT). However, the role of thrombophilia in AIVC and DVT is unknown.
Methods
Between 1982 and 2013 41 patients (12 female, 29 male, mean age 28 S.D. 11 years) were detected at the University of Düsseldorf, Germany, with AIVC. Based on medical history, clinical examination, imaging and coagulation studies, we performed on this collective a risk characterisation. Extensive literature research added further 123 published cases during 1993 and 2013. AIVC-patients were compared with iliocaval DVT-patients without AIVC (n = 168) treated during the same period in our clinic (90 female, 78 male, mean age 38 S.D. 17 years).
Results
In contrast to classical DVT younger men were more often affected. Factor-V-Leiden-mutation, 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism and hyperhomocysteinemia individually are associated with an increased risk of DVT in patients with AIVC. Aplasia/hypoplasia of the right or left kidney is also associated with IVCA.
Conclusions
AIVC should be considered in young patients who present with DVT involving the vena cava. Analysis of publications with AIVC and our patients yielded a typical spectrum of AIVC-associated DVT characteristics: AIVC occurs in young male adults, is revealed by proximal DVT, not necessarily accused by precipitating factors like immobilisation, and is mostly located bilateral. Hereditary coagulation abnormalities seem to be more often a contributing factor for DVT in AIVC.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-014-0223-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-014-0223-4
PMCID: PMC4308084  PMID: 25604085
Vena cava anomaly; Agenesis; Deep venous thrombosis; Thrombophilia
13.  Low penetrance in facioscapulohumeral muscular dystrophy type 1 with large pathological D4Z4 alleles: a cross-sectional multicenter study 
Background
Facioscapulohumeral muscular dystrophy type 1(FSHD1) is an autosomal dominant disorder associated with the contraction of D4Z4 less than 11 repeat units (RUs) on chromosome 4q35. Penetrance in the range of the largest alleles is poorly known. Our objective was to study the penetrance of FSHD1 in patients carrying alleles ranging between 6 to10 RUs and to evaluate the influence of sex, age, and several environmental factors on clinical expression of the disease.
Methods
A cross-sectional multicenter study was conducted in six French and one Swiss neuromuscular centers. 65 FSHD1 affected patients carrying a 4qA allele of 6–10 RUs were identified as index cases (IC) and their 119 at-risk relatives were included. The age of onset was recorded for IC only. Medical history, neurological examination and manual muscle testing were performed for each subject. Genetic testing determined the allele size (number of RUs) and the 4qA/4qB allelic variant. The clinical status of relatives was established blindly to their genetic testing results. The main outcome was the penetrance defined as the ratio between the number of clinically affected carriers and the total number of carriers.
Results
Among the relatives, 59 carried the D4Z4 contraction. At the clinical level, 34 relatives carriers were clinically affected and 25 unaffected. Therefore, the calculated penetrance was 57% in the range of 6–10 RUs. Penetrance was estimated at 62% in the range of 6–8 RUs, and at 47% in the range of 9–10 RUs. Moreover, penetrance was lower in women than men. There was no effect of drugs, anesthesia, surgery or traumatisms on the penetrance.
Conclusions
Penetrance of FSHD1 is low for largest alleles in the range of 9–10 RUs, and lower in women than men. This is of crucial importance for genetic counseling and clinical management of patients and families.
doi:10.1186/s13023-014-0218-1
PMCID: PMC4320820  PMID: 25603992
Facioscapulohumeral muscular dystrophy; Penetrance; FSHD1; D4Z4
14.  Sneddon’s syndrome: a comprehensive review of the literature 
Sneddon’s syndrome (SS) is a rare non-inflammatory thrombotic vasculopathy characterized by the combination of cerebrovascular disease with livedo racemosa(LR). The Orpha number for SS is ORPHA820. It has been estimated that the incidence of SS is 4 per 1 million per annum in general population and generally occurs in women between the ages of 20 and 42 years. LR may precede the onset of stroke by years and the trunk and/or buttocks are involved in nearly all patients. The cerebrovascular manifestations are mostly secondary to ischemia (transient ischemic attacks and cerebral infarct). Other neurological symptoms range from headache, cerebral hemorrhage, seizures, cognitive and psychiatric disturbances. The involved internal organs include heart, kidney, and eyes. Histological findings of skin are characteristic and the involved vessels are small to medium-sized arteries at the border of dermis to subcutis with a distinct histopathological time course. The main diagnostic criteria are general LR with typical histopathological findings on skin biopsy and focal neurological deficits. The pathogenesis is related to hypercoagulable state and intrinsic small-vessel vasculopathy. The optimal management remains an unsolved problem and long-term anticoagulation have been recommended for cerebral ischemic events based on the presumed pathogenesis. There are controversial results in treatment of SS with immunomodulatory agents. The aim of this review is to comprehensively discuss this disease.
doi:10.1186/s13023-014-0215-4
PMCID: PMC4302600  PMID: 25551694
Sneddon’s syndrome; Skin disease; Stroke; Systematic review
15.  Severity score for hereditary hemorrhagic telangiectasia 
Background
A disease severity score in hereditary hemorrhagic telangiectasia (HHT) would be a useful tool for assessing burden of disease and for designing clinical trials. Here, we propose the first known HHT severity score, the HHT-score.
Methods
Demographics and disease characteristics were collected for the first 525 HHT patients recruited to the HHT Project of the Brain Vascular Malformation Consortium (BVMC). HHT-score was calculated based on presence of: organ arteriovenous malformations (maximum 3 points); chronic bleeding (maximum 2 points); and severe organ involvement (maximum 2 points). Points were summed and patients categorized as having mild (0–2), moderate (3–4) or severe (5–7) disease. The occurrence of “any adverse outcome” was evaluated for association with HHT-score categories.
Results
The frequency of “any adverse outcome” was significantly different across the three groups (49.6% in mild, 65.8% in moderate and 89.5% in severe, p < 0.001). Adjusting for age and gender, the risk of “any adverse outcome” was higher in the moderate (OR = 1.84, 95% CI: 1.15-2.95, p = 0.011) and severe groups (OR = 9.16, 95% CI: 1.99-42.09, p = 0.004) compared to the mild.
Conclusions
We have taken the first steps toward creating a global measure of disease severity in HHT. While the initial results are promising, further validation of the HHT-score is still required.
doi:10.1186/s13023-014-0188-3
PMCID: PMC4302697
Hereditary Hemorrhagic Telangiectasia (HHT); Osler-Weber-Rendu; Arteriovenous Malformation (AVM); Bleeding; Disease severity; Severity score
16.  Thymectomy for non-thymomatous myasthenia gravis: a propensity score matched study 
Background
The efficacy of thymectomy in patients with non-thymomatous Myasthenia Gravis (MG) is still unclear. Main limitations have been variable outcome definitions, lack of a control group and adjustment for confounding.
Objective
To study the efficacy of thymectomy in achieving remission or minimal manifestation (R/MM) status in patients with non-thymomatous MG.
Methods
Patients with generalized MG and minimum follow-up of 6 months were included. Demographic data and treatments were recorded, as well as the MGFA post-intervention status at the last visit. Propensity scores were used to create a matched cohort of treated and untreated patients. Standard and Bayesian Cox models were used to study treatment effects.
Results
Of 395 patients included, 183(46%) had a thymectomy. Thymectomy patients were younger (p < 0.001), with more females (p < 0.001) and more patients in MGFA classes 4–5 at diagnosis (p = 0.01). A matched cohort of thymectomized patients and controls (n = 98) was created. The hazard ratio (HR) for the matched cohort was 1.9 (CI:1.6-2.3), favoring thymectomy. The predicted R/MM rate was 21% in treated and 6% in controls at 5 years (Absolute difference:15%). A Bayesian Cox model for the matched cohort had an estimated probability of thymectomy efficacy (HR > 1) of 96% using a non-informative prior, and 79% using a skeptical prior.
Discussion
When controlling for potential confounders, thymectomized patients had a higher probability of achieving R/MM status through time compared to controls. This study provides class III evidence of the efficacy of thymectomy in non-thymomatous myasthenia gravis.
doi:10.1186/s13023-014-0214-5
PMCID: PMC4296689  PMID: 25539860
Myasthenia Gravis; Thymectomy; Propensity Score; Bayesian
17.  Functional and molecular characterization of inherited platelet disorders in the Iberian Peninsula: results from a collaborative study 
Background
The diagnostic evaluation of inherited platelet disorders (IPDs) is complicated and time-consuming, resulting in a relevant number of undiagnosed and incorrectly classified patients. In order to evaluate the spectrum of IPDs in individuals with clinical suspicion of these disorders, and to provide a diagnostic tool to centers not having access to specific platelets studies, we established the project “Functional and Molecular Characterization of Patients with Inherited Platelet Disorders” under the scientific sponsorship of the Spanish Society of Thrombosis and Haemostasis.
Patients/methods
Subjects were patients from a prospective cohort of individuals referred for clinical suspicion of IPDs as well as healthy controls. Functional studies included light transmission aggregation, flow cytometry, and when indicated, Western-blot analysis of platelet glycoproteins, and clot retraction analysis. Genetic analysis was mainly performed by sequencing of coding regions and proximal regulatory regions of the genes of interest.
Results
Of the 70 cases referred for study, we functionally and molecularly characterized 12 patients with Glanzmann Thrombasthenia, 8 patients with Bernard Soulier syndrome, and 8 with other forms of IPDs. Twelve novel mutations were identified among these patients. The systematic study of patients revealed that almost one-third of patients had been previously misdiagnosed.
Conclusions
Our study provides a global picture of the current limitations and access to the diagnosis of IPDs, identifies and confirms new genetic variants that cause these disorders, and emphasizes the need of creating reference centers that can help health care providers in the recognition of these defects.
doi:10.1186/s13023-014-0213-6
PMCID: PMC4302577  PMID: 25539746
Bernard Soulier syndrome; Glanzmann thrombasthenia; Inherited platelet disorders; Chediak-Higashi syndrome; Hermansky Pudlak syndrome; ANKRD26; Congenital amegakaryocytic thrombocytopenia
18.  Follow-up of folinic acid supplementation for patients with cerebral folate deficiency and Kearns-Sayre syndrome 
Background
Kearns-Sayre syndrome (KSS) is a mitochondrial DNA deletion syndrome that presents with profound cerebral folate deficiency and other features. Preliminary data support the notion that folinic acid therapy might be useful in the treatment of KSS patients. Our aim was to assess the clinical and neuroimaging outcomes of KSS patients receiving folinic acid therapy.
Methods
Patients: We recruited eight patients with diagnoses of KSS. Four cases were treated at 12 de Octubre Hospital, and the other two cases were treated at Sant Joan de Déu Hospital. Two patients refused to participate in the treatment protocol.
Methods: Clinical, biochemical and neuroimaging data (magnetic resonance imaging or computed tomography scan) were collected in baseline conditions and at different time points after the initiation of therapy. Cerebrospinal fluid 5-methyltetrahydrofolate levels were analysed with HPLC and fluorescence detection. Large-scale mitochondrial DNA deletions were analysed by Southern blot.
Treatment protocol: The follow-up periods ranged from one to eight years. Cases 1–4 received oral folinic acid at a dose of 1 mg/kg/day, and cases 6 and 8 received 3 mg/kg/day.
Results
No adverse effects of folinic acid treatment were observed. Cerebral 5-methyltetrahydrofolate deficiencies were observed in all cases in the baseline conditions. Moreover, all three patients who accepted lumbar puncture after folinic acid therapy exhibited complete recoveries of their decreased basal cerebrospinal fluid 5-methyltetrahydrofolate levels to normal values. Two cases neurologically improved after folinic therapy. Disease worsened in the other patients.
Post-treatment neuroimaging was performed for the 6 cases that received folinic acid therapy. One patient exhibited improvements in white matter abnormalities. The remaining patients displayed progressions in subcortical cerebral white matter, the cerebellum and cerebral atrophy.
Conclusions
Four patients exhibited clinical and radiological progression of the disease following folinic acid treatment. Only one patient who was treated in an early stage of the disease exhibited both neurological and radiological improvements following elevated doses of folinic acid, and an additional patient experienced neurological improvement. Early treatment with high-dose folinic acid therapy seems to be advisable for the treatment of KSS.
Trial registration
EudracT2007-00-6748-23
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-014-0217-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-014-0217-2
PMCID: PMC4302586  PMID: 25539952
Kearns-Sayre syndrome; Mitochondrial DNA deletion; Cerebral folate deficiency; Folinic acid treatment; Neuroimaging
19.  Skin fibroblasts from individuals with Chediak-Higashi Syndrome (CHS) exhibit hyposensitive immunogenic response 
Background
Chediak-Higashi Syndrome (CHS) is a rare autosomal recessive disease characterized by immunodeficiency, oculocutaneous albinism, neurological dysfunction, and early death. Individuals with CHS present with increased susceptibility to infections of the skin, upper-respiratory tract, gastrointestinal tract, and oral tissues. Classical CHS is caused by mutations in the gene encoding lysosomal trafficking regulator (LYST). Although defects in cytotoxic T cell lytic secretory granule secretion and neutrophil phagocytosis are suggested to contribute to the immunodeficiency in CHS, the underlying molecular mechanisms are unknown. We hypothesized that skin fibroblasts from CHS subjects exhibit impaired immune response due to defective trafficking of inflammatory factors.
Methods and results
Primary skin fibroblasts from CHS subjects or healthy controls were assessed for genes encoding inflammatory response factors using PCR array. At baseline, we found CD14, IL1R1 and TLR-1 were down-regulated significantly (≥2 fold change) and the genes encoding TLR-3, IL-1β and IL-6 were up-regulated in CHS cells compared to control cells. When challenged with E. coli lipopolysaccharide (LPS), CHS cells were less responsive than control cells, with only 8 genes significantly up-regulated (3–68 fold change) compared to baseline values, whereas 28 genes in control cells were significantly up-regulated at a much higher magnitude (3–4,629 fold change). In addition, 50% of the genes significantly up-regulated in LPS-treated control cells were significantly lower in LPS-treated CHS cells. IL-6, a fibroblast-derived proinflammatory cytokine essential for fighting infections was significantly lower in culture media of CHS cells with or without LPS. Furthermore, Western blot and immunofluorescent staining revealed that TLR-2 and TLR-4 were diminished on cell membranes of CHS cells and dissociated from Rab11a.
Conclusions
For the first time, results from our study indicate defective trafficking of TLR-2 and TLR-4 contributes to the hyposensitive response of CHS skin fibroblasts to immunogenic challenge, providing a potential therapeutic target for clinical intervention in CHS.
doi:10.1186/s13023-014-0212-7
PMCID: PMC4296684  PMID: 25528552
Lysosome trafficking regulator; Intracellular vesicle trafficking; Immunodeficiency; Toll-like receptors
20.  Oxidative stress and mitochondrial dysfunction in Kindler syndrome 
Background
Kindler Syndrome (KS) is an autosomal recessive skin disorder characterized by skin blistering, photosensitivity, premature aging, and propensity to skin cancer. In spite of the knowledge underlying cause of this disease involving mutations of FERMT1 (fermitin family member 1), and efforts to characterize genotype-phenotype correlations, the clinical variability of this genodermatosis is still poorly understood. In addition, several pathognomonic features of KS, not related to skin fragility such as aging, inflammation and cancer predisposition have been strongly associated with oxidative stress. Alterations of the cellular redox status have not been previously studied in KS. Here we explored the role of oxidative stress in the pathogenesis of this rare cutaneous disease.
Methods
Patient-derived keratinocytes and their respective controls were cultured and classified according to their different mutations by PCR and western blot, the oxidative stress biomarkers were analyzed by spectrophotometry and qPCR and additionally redox biosensors experiments were also performed. The mitochondrial structure and functionality were analyzed by confocal microscopy and electron microscopy.
Results
Patient-derived keratinocytes showed altered levels of several oxidative stress biomarkers including MDA (malondialdehyde), GSSG/GSH ratio (oxidized and reduced glutathione) and GCL (gamma-glutamyl cysteine ligase) subunits. Electron microscopy analysis of both, KS skin biopsies and keratinocytes showed marked morphological mitochondrial abnormalities. Consistently, confocal microscopy studies of mitochondrial fluorescent probes confirmed the mitochondrial derangement. Imbalance of oxidative stress biomarkers together with abnormalities in the mitochondrial network and function are consistent with a pro-oxidant state.
Conclusions
This is the first study to describe mitochondrial dysfunction and oxidative stress involvement in KS.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-014-0211-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-014-0211-8
PMCID: PMC4302591  PMID: 25528446
Kindlin1; Oxidative stress; Mitochondria; Keratinocytes; Genodermatosis
21.  Relapsing polychondritis: clinical presentations, disease activity and outcomes 
Background
Relapsing polychondritis is a rare disease characterised by inflammation of cartilaginous and proteoglycan rich structures. As there are only a few published single centre case series from all across the world, we describe our experience with 26 patients at a tertiary centre in north India.
Methods
A retrospective study with all patients meeting Damiani and Levine’s modification of McAdam’s diagnostic criteria. Clinical details, investigations, disease activity assessment [(Relapsing Polychondritis Disease Activity Index (RPDAI)], treatment and outcomes were recorded.
Results
Ten men and sixteen women (median age 45 years) met the diagnostic criteria. Auricular chondritis (96%), arthritis (54%), hearing impairment (42%), ocular (42%), dermal (26%), cardiovascular (11%) and laryngotracheal involvement (11%) characterized the clinical presentations. The median RPDAI was 31 (range 9-66). Two patients died during observation. Overall survival was 92.3% (median survival 13.5 years).
Conclusions
Apart from reduced laryngotracheal involvement, RP in India was clinically similar to recorded patterns elsewhere.
doi:10.1186/s13023-014-0198-1
PMCID: PMC4302515  PMID: 25527201
Relapsing polychondritis; RPADAI; Auricular chondritis; MAGIC syndrome; Survival
22.  Ventricular septal defect 
Background
Ventricular septal defects are the commonest congenital cardiac malformations. They can exist in isolation, but are also found as integral components of other cardiac anomalies, such as tetralogy of Fallot, double outlet right ventricle, or common arterial trunk. As yet, there is no agreement on how best to classify such defects, nor even on the curved surface that is taken to represent the defect.
Methods
Based on our previous pathological and clinical experiences, we have reviewed the history of classification of holes between the ventricles. We proposed that the defects are best defined as representing the area of deficient ventricular septation. This then permits the recognition of clinically significant variants according to the anatomic borders, and the way the curved surface representing the area of deficient septation opens into the morphologically right ventricle.
Results
Clinical manifestation depends on the size of the defect, and on the relationship between systemic and pulmonary vascular resistances. Symptoms include failure to thrive, along with the manifestations of the increase in flow of blood to the lungs. Diagnosis can be made by physical examination, but is confirmed by echocardiographic interrogation, which delineates the precise anatomy, and also provides the physiologic information required for optimal clinical decision-making. Cardiac catheterization offers additional information regarding hemodynamics, particularly if there is a concern regarding an increase in pulmonary vascular resistance. Hemodynamic assessment is rarely necessary to make decisions regarding management, although it can be helpful if assessing symptomatic adults with hemodynamically restrictive defects. In infants with defects producing large shunts, surgical closure is now recommended in most instances as soon as symptoms manifest. Only in rare cases is palliative banding of the pulmonary trunk now recommended. Closure with devices inserted on catheters is now the preferred approach for many patients with muscular defects, often using a hybrid procedure. Therapeutic closure should now be anticipated with virtually zero mortality, and with excellent anticipated long-term survival.
Conclusion
Ventricular septal defects are best defined as representing the borders of the area of deficient ventricular septation. An approach on this basis permits recognition of the clinically significant phenotypic variants.
doi:10.1186/s13023-014-0144-2
PMCID: PMC4316658  PMID: 25523232
Classification; Terminology; Perimembranous; Conoventricular; Conduction tissues
23.  Comparative cost of illness analysis and assessment of health care burden of Duchenne and Becker muscular dystrophies in Germany 
Background
Our study aimed to determine the burden of illness in dystrophinopathy type Duchenne (DMD) and Becker (BMD), both leading to progressive disability, reduced working capacity and high health care utilization.
Methods
A micro-costing method was used to examine the direct, indirect and informal care costs measuring the economic burden of DMD in comparison to BMD on patients, relatives, payers and society in Germany and to determine the health care burden of these diseases. Standardized questionnaires were developed based on predefined structured interview guidelines to obtain data directly from patients and caregivers using the German dystrophinopathy patient registry. The health-related quality of life (HRQOL) was analyzed using PedsQL™ Measurement Model.
Results
In total, 363 patients with genetically confirmed dystrophinopathies were enrolled. Estimated annual disease burden including direct medical/non-medical, indirect and informal care costs of DMD added up to € 78,913 while total costs in BMD were € 39,060. Informal care costs, indirect costs caused by loss of productivity and absenteeism of patients and caregivers as well as medical costs of rehabilitation services and medical aids were identified as the most important cost drivers. Total costs notably increased with disease progression and were consistent with the clinical severity; however, patients’ HRQOL declined with disease progression.
Conclusion
In conclusion, early assessments of economic aspects and the disease burden are essential to gain extensive knowledge of a distinct disease and above all play an important role in funding drug development programs for rare diseases. Therefore, our results may help to accelerate payer negotiations such as the pricing and reimbursement of new therapies, and will hopefully contribute to facilitating the efficient translation of innovations from clinical research over marketing authorization to patient access to a causative treatment.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-014-0210-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-014-0210-9
PMCID: PMC4302713  PMID: 25519771
Duchenne muscular dystrophy; Becker muscular dystrophy; Direct costs; Indirect costs; Informal care costs; Cost of illness (COI); Burden of illness; Health care burden; Health-related quality of life (HRQOL); Socio-economic evaluation
24.  An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A 
Background
Charcot-Marie-Tooth type 1A disease (CMT1A) is a rare orphan inherited neuropathy caused by an autosomal dominant duplication of a gene encoding for the structural myelin protein PMP22, which induces abnormal Schwann cell differentiation and dysmyelination, eventually leading to axonal suffering then loss and muscle wasting. We favour the idea that diseases can be more efficiently treated when targeting multiple disease-relevant pathways. In CMT1A patients, we therefore tested the potential of PXT3003, a low-dose combination of three already approved compounds (baclofen, naltrexone and sorbitol). Our study conceptually builds on preclinical experiments highlighting a pleiotropic mechanism of action that includes downregulation of PMP22. The primary objective was to assess safety and tolerability of PXT3003. The secondary objective aimed at an exploratory analysis of efficacy of PXT3003 in CMT1A, to be used for designing next clinical development stages (Phase 2b/3).
Methods
80 adult patients with mild-to-moderate CMT1A received in double-blind for 1 year Placebo or one of the three increasing doses of PXT3003 tested, in four equal groups. Safety and tolerability were assessed with the incidence of related adverse events. Efficacy was assessed using the Charcot-Marie-Tooth Neuropathy Score (CMTNS) and the Overall Neuropathy Limitations Scale (ONLS) as main endpoints, as well as various clinical and electrophysiological outcomes.
Results
This trial confirmed the safety and tolerability of PXT3003. The highest dose (HD) showed consistent evidence of improvement beyond stabilization. CMTNS and ONLS, with a significant improvement of respectively of 8% (0.4% - 16.2%) and 12.1% (2% - 23.2%) in the HD group versus the pool of all other groups, appear to be the most sensitive clinical endpoints to treatment despite their quasi-stability over one year under Placebo. Patients who did not deteriorate over one year were significantly more frequent in the HD group.
Conclusions
These results confirm that PXT3003 deserves further investigation in adults and could greatly benefit CMT1A-diagnosed children, usually less affected than adults.
Trial registration
EudraCT Number: 2010-023097-40. ClinicalTrials.gov Identifier: NCT01401257. The Committee for Orphan Medicinal Products issued in February 2014 a positive opinion on the application for orphan designation for PXT3003 (EMA/OD/193/13).
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-014-0199-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-014-0199-0
PMCID: PMC4311411  PMID: 25519680
Charcot-Marie-Tooth; CMT1A; Clinical trial; Phase 2; Repurposing; Combination therapy
25.  Extensive clinical, hormonal and genetic screening in a large consecutive series of 46,XY neonates and infants with atypical sexual development 
Background
One in 4500 children is born with ambiguous genitalia, milder phenotypes occur in one in 300 newborns. Conventional time-consuming hormonal and genetic work-up provides a genetic diagnosis in around 20-40% of 46,XY cases with ambiguous genitalia. All others remain without a definitive diagnosis. The investigation of milder cases, as suggested by recent reports remains controversial.
Methods
Integrated clinical, hormonal and genetic screening was performed in a sequential series of 46, XY children, sex-assigned male, who were referred to our pediatric endocrine service for atypical genitalia (2007–2013).
Results
A consecutive cohort of undervirilized 46,XY children with external masculinization score (EMS) 2–12, was extensively investigated. In four patients, a clinical diagnosis of Kallmann syndrome or Mowat-Wilson syndrome was made and genetically supported in 2/3 and 1/1 cases respectively. Hormonal data were suggestive of a (dihydro)testosterone biosynthesis disorder in four cases, however no HSD17B3 or SRD5A2 mutations were found. Array-CGH revealed a causal structural variation in 2/6 syndromic patients. In addition, three novel NR5A1 mutations were found in non-syndromic patients. Interestingly, one mutation was present in a fertile male, underlining the inter- and intrafamilial phenotypic variability of NR5A1-associated phenotypes. No AR, SRY or WT1 mutations were identified.
Conclusion
Overall, a genetic diagnosis could be established in 19% of non-syndromic and 33% of syndromic cases. There is no difference in diagnostic yield between patients with more or less pronounced phenotypes, as expressed by the external masculinisation score (EMS). The clinical utility of array-CGH is high in syndromic cases. Finally, a sequential gene-by-gene approach is time-consuming, expensive and inefficient. Given the low yield and high expense of Sanger sequencing, we anticipate that massively parallel sequencing of gene panels and whole exome sequencing hold promise for genetic diagnosis of 46,XY DSD boys with an undervirilized phenotype.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-014-0209-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-014-0209-2
PMCID: PMC4271496  PMID: 25497574
46,XY DSD; Undervirilization; Integrated screening; Diagnosis; Array-CGH; MLPA; NR5A1 mutations

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