Uniparental Disomy as a Mechanism for Combined Oxidative Phosphorylation Deficiency Associated with MRPS34 Gene.

INTRODUCTION: Mitochondrial oxidative phosphorylation (OXPHOS) is a cellular process that generates most of the cellular energy required by the body. Disorders affecting OXPHOS are multisystem diseases caused by pathogenic variants in more than 50 genes. In 2017, biallelic variants in the MRPS34 gene were shown to cause combined oxidative phosphorylation deficiency type 32 (COPD32) (OMIM#617664); however, only 7 patients have been reported in the literature up to this moment. COPD32 is characterized mainly by a severe Leigh-like syndrome. METHODS: Whole-exome sequencing identified a homozygous pathogenic variant in the MRPS34 gene, c.322-10G>A. Only the mother was heterozygous for this variant. SNP-array analysis was performed, which revealed a region of absence of heterozygosity in variant 16q with 9.8Mb, compatible with maternal uniparental disomy. RESULTS/CASE REPORT: We report the case of an 18-year-old female with unremarkable family history. The pregnancy was complicated by oligohydramnios, and the neonatal period was unremarkable. She evolved with low weight, mild-moderate developmental delay/intellectual disability, and hypogonadotropic hypogonadism. On examination, she had slender habitus, joint laxity, and kyphoscoliosis. The cardiac evaluation was normal, and the head MRI showed bilateral olivary nucleus degeneration that was not confirmed subsequently. Extensive metabolic studies documented only mild lactate and pyruvate elevation, and the chromosomal microarray was normal. CONCLUSION: We have reported the case of the first patient with COPD32 due to partial maternal uniparental disomy of chromosome 16, being first in Portugal and seventh in the literature. Contrarily to previous patients, who died in the first months of life or survived with severe DD/ID, and had a Leigh-like syndrome, this case is significantly milder, contributing to a better characterization of the phenotypic spectrum. Recurrence risk is unexpectedly low in this instance. This case illustrates the importance of segregation analysis in patients with homozygous recessive mutations.

Vosoritide Therapy in Children with Achondroplasia: Early Experience and Practical Considerations for Clinical Practice.

INTRODUCTION: Vosoritide is the first precision medical therapy approved to increase growth velocity in children with achondroplasia. Sharing early prescribing experiences across different regions could provide a framework for developing practical guidance for the real-world use of vosoritide. METHODS: Two meetings were held to gather insight and early experience from experts in Europe, the Middle East, and the USA. The group comprised geneticists, pediatric endocrinologists, pediatricians, and orthopedic surgeons. Current practices and considerations for vosoritide were discussed, including administration practicalities, assessments, and how to manage expectations. RESULTS: A crucial step in the management of achondroplasia is to determine if adequate multidisciplinary support is in place. Training for families is essential, including practical information on administration of vosoritide, and how to recognize and manage injection-site reactions. Advocated techniques include establishing a routine, empowering patients by allowing them to choose injection sites, and managing pain. Patients may discontinue vosoritide if they cannot tolerate daily injections or are invited to participate in a clinical trial. Clinicians in Europe and the Middle East emphasized the importance of assessing adherence to daily injections, as non-adherence may impact response and reimbursement. Protocols for monitoring patients receiving vosoritide may be influenced by regional differences in reimbursement and healthcare systems. Core assessments may include pubertal staging, anthropometry, radiography to confirm open physes, the review of adverse events, and discussion of concomitant or new medications-but timing of these assessments may also differ regionally and vary across institutions. Patients and families should be informed that response to vosoritide can vary in both magnitude and timing. Keeping families informed regarding vosoritide clinical trial data is encouraged. CONCLUSION: The early real-world experience with vosoritide is generally positive. Sharing these insights is important to increase understanding of the practicalities of treatment with vosoritide in the clinical setting.

Characterization of three adults and an adolescent with Osteogenesis Imperfecta type VI and a novel founder SERPINF1 variant.

Osteogenesis imperfecta (OI) type VI is an extremely rare form of OI caused by biallelic variants in the SERPINF1 gene, which codes for the pigment-epithelium derived factor (PEDF). We report on four patients (three adults and one adolescent) with a severe deforming form of OI. All patients presented no abnormalities at birth, frequent long bone and vertebrae fractures (mainly during childhood), marked short stature, severe bone deformities, chronic mild to moderate pain, and severe limitation of mobility, with three being completely wheelchair bound. Blue sclera and dentinogenesis imperfecta were absent, although some patients presented tooth, ophthalmological, and/or cardiac features. Radiographic findings included, among others, thin diaphysis and popcorn calcifications, both of which are non-specific to this type of OI. The novel homozygous variants c.816_819del (p.Met272Ilefs*8) and c.283+2T > G in SERPINF1 were identified in three and one patient, respectively. The three patients carrying the frameshift variant were born in nearby regions suggesting a founder effect. Describing the long-term outcomes of four patients with OI type VI, this cohort adds relevant data on the clinical features and prognosis of this type of OI.

Precocious puberty and anal stenosis in an African patient with Rothmund-Thomson syndrome.

Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by a rash that progresses to poikiloderma. Other common features include sparse hair, eyelashes and eyebrows, short stature, variable skeletal abnormalities, dental defects, cataracts, hypogonadism, and an increased risk for cancer, especially osteosarcoma and skin cancer. RTS is caused by biallelic pathogenic variants in ANAPC1 (Type 1 RTS) or RECQL4 (Type 2 RTS). We present an African girl with Type 2 RTS caused by a nonsense variant and an intronic variant in RECQL4. The patient presented precocious puberty, which has not been previously reported in RTS and that was treated with a GnRH analog, and anal stenosis, which has only been reported once. This case highlights the need to consider deep intronic variants in patients with RTS when pathogenic variants in the coding regions and exon/intron boundaries are not identified and expands the phenotypic spectrum of this disorder.

High prevalence of variants in skeletal dysplasia associated genes in individuals with short stature and minor skeletal anomalies.

OBJECTIVE: Next generation sequencing (NGS) has expanded the diagnostic paradigm turning the focus to the growth plate. The aim of the study was to determine the prevalence of variants in genes implicated in skeletal dysplasias in probands with short stature and mild skeletal anomalies. DESIGN: Clinical and radiological data were collected from 108 probands with short stature and mild skeletal anomalies. METHODS: A customized skeletal dysplasia NGS panel was performed. Variants were classified using ACMG recommendations and Sherloc. Anthropometric measurements and skeletal anomalies were subsequently compared in those with or without an identified genetic defect. RESULTS: Heterozygous variants were identified in 21/108 probands (19.4%). Variants were most frequently identified in ACAN (n = 10) and IHH (n = 7) whilst one variant was detected in COL2A1, CREBBP, EXT1, and PTPN11. Statistically significant differences (P < 0.05) were observed for sitting height/height (SH/H) ratio, SH/H ratio standard deviation score (SDS), and the SH/H ratio SDS >1 in those with an identified variant compared to those without. CONCLUSIONS: A molecular defect was elucidated in a fifth of patients. Thus, the prevalence of mild forms of skeletal dysplasias is relatively high in individuals with short stature and mild skeletal anomalies, with variants in ACAN and IHH accounting for 81% of the cases. An elevated SH/H ratio appears to be associated with a greater probability in detecting a variant, but no other clinical or radiological feature has been found determinant to finding a genetic cause. Currently, we cannot perform extensive molecular studies in all short stature individuals so detailed clinical and radiological phenotyping may orientate which are the candidate patients to obtain worthwhile results. In addition, detailed phenotyping of probands and family members will often aid variant classification.

Spondyloepiphyseal dysplasia type Stanescu: Expanding the clinical and molecular spectrum of a very rare type II collagenopathy.

Spondyloepiphyseal dysplasia type Stanescu (SED-S) is a very rare type II collagenopathy. We describe an 8-year-old boy who presented with short trunk, C2-C3 vertebral fusion, hand, foot, leg and thigh pain, stiffness and limited joint mobility, and waddling gait. Radiographs showed platyspondyly with anterior wedging and endplate irregularities, broad femoral necks, and large epiphyses and epiphyseal equivalents. Differential diagnosis included progressive pseudorheumatoid dysplasia and SED-S. A skeletal dysplasia custom-designed NGS panel was performed and the heterozygous pathogenic variant c.620G>A; p.(Gly207Glu) in COL2A1 was detected, establishing the diagnosis of SED-S. Vertebral fusions, observed in our patient, have not been previously described in this dysplasia. This variant has not been previously associated with SED-S, but was reported in two other families with spondyloepiphyseal dysplasia. Thus, this case expands the clinical and mutational spectrum of SED-S and demonstrates that SED-S significantly overlaps with other skeletal dysplasias.

Clinical and Molecular Description of 16 Families With Heterozygous IHH Variants.

CONTEXT: Heterozygous variants in the Indian hedgehog gene (IHH) have been reported to cause brachydactyly type A1 and mild hand and feet skeletal anomalies with short stature. Genetic screening in individuals with short stature and mild skeletal anomalies has been increasing over recent years, allowing us to broaden the clinical spectrum of skeletal dysplasias. OBJECTIVE: The objective of this article is to describe the genotype and phenotype of 16 probands with heterozygous variants in IHH. PATIENTS AND METHODS: Targeted next-generation sequencing or Sanger sequencing was performed in patients with short stature and/or brachydactyly for which the genetic cause was unknown. RESULTS: Fifteen different heterozygous IHH variants were detected, one of which is the first reported complete deletion of IHH. None of the patients showed the classical phenotype of brachydactyly type A1. The most frequently observed clinical characteristics were mild to moderate short stature as well as shortening of the middle phalanx on the fifth finger. The identified IHH variants were demonstrated to cosegregate with the short stature and/or brachydactyly in the 13 probands whose family members were available. However, clinical heterogeneity was observed: Two short-statured probands showed no hand radiological anomalies, whereas another 5 were of normal height but had brachydactyly. CONCLUSIONS: Short stature and/or mild skeletal hand defects can be caused by IHH variants. Defects in this gene should be considered in individuals with these findings, especially when there is an autosomal dominant pattern of inheritance. Although no genotype-phenotype correlation was observed, cosegregation studies should be performed and where possible functional characterization before concluding that a variant is causative.

Upper limb phocomelia: A prenatal case of thrombocytopenia-absent radius (TAR) syndrome illustrating the importance of chromosomal microarray in limb reduction defects.

OBJECTIVE: To describe the ultrasonographic, pathologic and molecular findings in a fetus with TAR syndrome, and to illustrate the contribution of chromosomal microarray analysis (CMA) to the etiological investigation of fetal upper limb reduction defects. CASE REPORT: A 35-year-old woman was referred for Genetic Counseling after pregnancy termination for severe upper limb bilateral phocomelia detected in the second trimester. Fetal autopsy showed severe shortening of the arms and forearms. The fetal skeletal survey confirmed the absence of the radii, ulnae and humeri. CMA revealed an interstitial deletion in 1q21 including the RBM8A gene. Subsequent Sanger sequencing of this gene identified a hypomorphic mutant allele, c.-21G > A, confirming the diagnosis of TAR syndrome. CONCLUSION: The differential diagnosis of upper limb defects is broad. Identification of their cause is essential for adequate genetic counseling including prognosis and recurrence risk estimation. CMA should be considered in fetuses with upper limb reduction defects, especially when the thumbs are present.

Reporting and methodological quality of clinical trials on exercise therapy for Parkinson's disease.

BACKGROUND: Exercise therapy is becoming extremely relevant as a new efficacious intervention in multiple medical fields. Although several clinical trials have reported benefits of exercise therapy for Parkinson's disease (PD), recommendations and prescriptions for its use in clinical practice remain limited. OBJECTIVES: To evaluate the methodological quality and publication rate of clinical trials on exercise therapy for PD. METHODS: We analyzed all clinical trials assessing exercise therapy for PD registered in the WHO International Clinical Trials Registry Platform and the ClinicalTrials.gov registries, from 2000 to 2017. We evaluated the methodological quality of trials using the Cochrane Risk of Bias criteria. RESULTS: A total of 236 clinical trials were identified. Only 70 (29.7%) trials reported their findings, and 61 (25.8%) had results published in scientific journals. Most trials had an unclear risk of bias concerning incomplete and selective outcome reporting and lacked data on the randomization process, allocation concealment, blinding of participants and personnel, and outcomes assessors. Aerobic capacity was the most frequent type of exercise intervention. CONCLUSIONS: Although a large number of trials on exercise are registered in international portals, the quality of reporting remains suboptimal and only a quarter of trials have their results published in scientific journals. These two factors, in addition to the heterogeneity of the interventions tested and the unsatisfactory reported methodological quality of most trials, compromise the interpretation of study results. Therefore, higher quality clinical trials reports are needed to establish exercise as part of the PD armamentarium.

Vasodilators in acute heart failure - evidence based on new studies.

Acute heart failure (AHF) contributes largely to the worldwide burden of heart failure (HF) and is associated with high mortality, poor prognosis and high rehospitalization rate. The pharmacologic therapy of AHF includes diuretics and vasodilators, which are a keystone when fluid overload and congestion are present. However, vasodilators are mainly focused on controlling symptoms, and drugs that also improve long-term mortality and morbidity seem to be in high demand. In this review, we summarize the existing evidence on mortality benefits of IV vasodilators in AHF. There is lack of evidence on the mortality benefits of IV vasodilators in AHF, as well as well-designed and large-scale trials for some of them. The existing trials on nitrates have conflicting results and are insufficient to establish definitive conclusions. Other vasodilators, such as enalaprilat, clevidipine, carperitide, and ularitide, have been evaluated only in a few trials assessing mortality. Levosimendan, nesititide and carperitide are approved by some regulatory agencies; however, data regarding mortality are also conflicting and large-scale post-marketing studies would be important. Serelaxin is a recent therapy with a novel mechanism of action and seemed to be promising; although serelaxin was safe and well tolerated in earlier trials, the results of a larger phase III trial failed to meet the primary endpoints of reduction in cardiovascular death at day 180 and reduction of worsening heart failure at day 5. The absence of definitive mortality benefits and high-quality and large-scale data not allow firm conclusions to be drawn about the role of IV vasodilators in AHF. Well-designed studies are needed to clarify the role of these drugs in the long-term outcome of AHF, as well as new therapies entering the clinical investigation.

Fifteen Years of Clinical Trials in Huntington's Disease: A Very Low Clinical Drug Development Success Rate.

BACKGROUND: Drug development in Huntington's disease (HD) is particularly challenging, and only two compounds are approved by the FDA. It is therefore essential to appraise drug development programs in order to understand the reasons for their failure during the early stages of development. OBJECTIVES: To describe the landscape of HD therapeutic development and critically explore the causes of compound attrition in the different stages of drug development, from phase 1 to phase 4. METHODS: All HD clinical trials registered in the WHO International Clinical Trials Search Portal, from inception to May 2017, were analyzed. Two independent authors selected and extracted data. Success rate in a trial phase was calculated as the number of compounds that progressed to the next trial phase divided by the number of compounds in that phase. The overall success rate was calculated as the ratio between the number of compounds that receive regulatory approval and the total number of compounds. RESULTS: Ninety-nine trials assessing 41 compounds and eleven non-pharmacological interventions (devices and cell therapies) were identified. Twenty-four (24.2%) were phase 1 trials, 46 (46.5%) phase 2, 20 (20.2%) phase 3, and two (2.0%) phase 4. Sixty trials (60.6%) received industry sponsorship. The most frequently studied compounds were creatine, latrepirdine and pridopidine. The mean number of participants enrolled was 92.0 and the length of treatment was 262.9 days, and both increased from phase 1 to phase 3 trials. The success rate was 25.0% from phase 1 to phase 2, 19.4% from phase 2 to phase 3, and 14.3% from phase 3 to approval. The overall success rate was 3.5%. CONCLUSIONS: Although HD is a rare condition, 99 HD trials were identified in a comprehensive clinical trial registry. We found a low success rate at earlier phases of drug-development and a very low trial success rate at later phases. There is a significant gap between drug discovery and development success rates that warrants careful appraisal and improvement.