Treatment of hypophosphatasia.

Wien Med Wochenschr. 2020 Apr;170(5-6):112-115

Authors: Simon S, Resch H

Abstract
Hypophosphatasia (HPP) is a rare disorder with perinatal, infantile, childhood, and adult presentations. Severe forms are autosomal recessive with an early onset, whereas milder forms have a later onset. The underlying cause of the disease is a mutation based on a genetic disorder of the tissue non-specific alkaline phosphatase (TNSALP) gene, leading on the one hand to decreased activity of the TNSALP enzyme, and on the other hand to accumulation of TNSALP substrates. Symptoms like non-traumatic and non-healing fractures, musculoskeletal pain, chondrocalcinosis, seizures, premature loss of fully rooted teeth or delayed development of milk teeth, respiratory insufficiency, and calcinosis in muscles, kidneys, and joints occur. Supportive treatment is important for HPP patients, including mechanical ventilation, accurate fracture treatment, physical therapy, dental monitoring, and follow-up care to avoid subsequent problems. A causal enzyme therapy replacement with asfotase-alfa was approved by the Food and Drug Administration (FDA) in 2015. Asfotase-alfa improves respiratory insufficiency, bone mineralization, and long-term survival, and has a very good safety profile.

PMID: 32072352 [PubMed - indexed for MEDLINE]

Multidisciplinary patient care in X-linked hypophosphatemic rickets: one challenge, many perspectives.

Wien Med Wochenschr. 2020 Apr;170(5-6):116-123

Authors: Raimann A, Mindler GT, Kocijan R, Bekes K, Zwerina J, Haeusler G, Ganger R

Abstract
X‑linked hypophosphatemic rickets (XLH, OMIM #307800) is a rare genetic metabolic disorder caused by dysregulation of fibroblast-like growth factor 23 (FGF23) leading to profound reduction in renal phosphate reabsorption. Impaired growth, severe rickets and complex skeletal deformities are direct consequences of hypophosphatemia representing major symptoms of XLH during childhood. In adults, secondary complications including early development of osteoarthritis substantially impair quality of life and cause significant clinical burden. With the global approval of the monoclonal FGF23 antibody burosumab, a targeted treatment with promising results in phase III studies is available for children with XLH. Nevertheless, complete phenotypic rescue is rarely achieved and remaining multisystemic symptoms demand multidisciplinary specialist care. Coordination of patient management within the major medical disciplines is a mainstay to optimize treatment and reduce disease burden. This review aims to depict different perspectives in XLH patient care in the setting of a multidisciplinary centre of expertise for rare bone diseases.

PMID: 31993875 [PubMed - indexed for MEDLINE]

An Endotracheal Plasmablastic Lymphoma.

Respiration. 2019;98(6):546-550

Authors: Bots EMT, Opperman J, Bassa F, Koegelenberg CFN

Abstract
We describe an exceptionally rare case of a male patient with newly diagnosed advanced human immunodeficiency virus (HIV) infection, who presented with a plasmablastic lymphoma involving the right maxillary alveolar ridge with associated cervical lymphadenopathy. On a staging positron emission tomography computed tomography (PET-CT) scan, he was incidentally found to have an endotracheal tumour involving the anterolateral aspect of the mid-trachea. The tumour appeared to be well-vascularised at bronchoscopy and was confirmed as well-differentiated plasmablastic lymphoma. Plasmablastic lymphoma is a rare form of non-Hodgkin lymphoma and is associated with HIV. Tracheal involvement to the extent seen in our patient is exceptionally rare, and, to the best of our knowledge, has never been described.

PMID: 31634891 [PubMed - indexed for MEDLINE]

RNA delivery biomaterials for the treatment of genetic and rare diseases.

Biomaterials. 2019 10;217:119291

Authors: Zhao W, Hou X, Vick OG, Dong Y

Abstract
Genetic and rare diseases (GARDs) affect more than 350 million patients worldwide and remain a significant challenge in the clinic. Hence, continuous efforts have been made to bridge the significant gap between the supply and demand of effective treatments for GARDs. Recent decades have witnessed the impressive progress in the fight against GARDs, with an improved understanding of the genetic origins of rare diseases and the rapid development in gene therapy providing a new avenue for GARD therapy. RNA-based therapeutics, such as RNA interference (RNAi), messenger RNA (mRNA) and RNA-involved genome editing technologies, demonstrate great potential as a therapy tool for treating genetic associated rare diseases. In the meantime, a variety of RNA delivery vehicles were established for boosting the widespread applications of RNA therapeutics. Among all the RNA delivery platforms which enable the systemic applications of RNAs, non-viral RNA delivery biomaterials display superior properties and a few biomaterials have been successfully exploited for achieving the RNA-based gene therapies on GARDs. In this review article, we focus on recent advances in the development of novel biomaterials for delivery of RNA-based therapeutics and highlight their applications to treat GARDs.

PMID: 31255978 [PubMed - indexed for MEDLINE]

Polymicrogyria is associated with pathogenic variants in PTEN.

Ann Neurol. 2020 Sep 22;:

Authors: Shao DD, Achkar CM, Lai A, Srivastava S, Doan RN, Rodan LH, Chen AY, Poduri A, Yang E, Walsh CA, Brain Development Genetics Study Group

Abstract
OBJECTIVE: Congenital structural brain malformations have been described in patients with pathogenic PTEN variants, but the frequency of cortical malformations in PTEN variants and their impact on clinical phenotype are not well understood. Our goal was to systematically characterize brain malformations in patients with PTEN variants and assess the relevance of their brain malformations to clinical presentation.
METHODS: We systematically searched a local radiology database for patients with pathogenic PTEN variants who had available brain magnetic resonance imaging (MRI). MRIs were reviewed systematically for cortical abnormalities. We reviewed EEG data and evaluated the electronic medical record to for evidence of epilepsy and developmental delay.
RESULTS: In total we identified 22 patients with PTEN pathogenic variants for which brain MRIs were available (age range 0.4 years - 17 years). Twelve among these 22 (54%) had polymicrogyria (PMG). Variants associated with PMG or atypical gyration encoded regions of the phosphatase or C2 domains of PTEN. Interestingly, epilepsy was present in only 2 of the 12 patients with PMG. We found a trend toward higher rates of GDD, ID, and motor delay in individuals with cortical abnormalities, though cohort size limited statistical significance.
INTERPRETATION: Malformations of cortical development, PMG in particular, represent an underrecognized phenotype associated with PTEN pathogenic variants and may have an association with cognitive and motor delays. Epilepsy was infrequent compared to the high risk of epilepsy in patients with PMG reported previously. This article is protected by copyright. All rights reserved.

PMID: 32959437 [PubMed - as supplied by publisher]

SARS-CoV-2 disrupts clinical research: the role of a rare disease-specific trial network.

Eur Respir J. 2020 09;56(3):

Authors: van Koningsbruggen-Rietschel S, Dunlevy F, Bulteel V, Downey DG, Dupont L

PMID: 32764115 [PubMed - indexed for MEDLINE]

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/09/22

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

9 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/09/22

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Netherton syndrome: Temporary response to dupilumab.

Pediatr Dermatol. 2020 Sep 19;:

Authors: Aktas M, Salman A, Apti Sengun O, Comert Ozer E, Hosgoren Tekin S, Akin Cakici O, Demir G, Ergun T

Abstract
Netherton syndrome (NS) is an orphan disease characterized by congenital ichthyosis, hair abnormalities, and atopy, with limited treatment options. We achieved temporary improvement only during the initial 6 weeks of treatment with dupilumab, which differs from the sustained improvement observed in 2 other recently published cases. Although the clinical presentation of atopy and increased pre-allergic cytokines in NS patients suggest that dupilumab may be beneficial, larger studies are required.

PMID: 32951242 [PubMed - as supplied by publisher]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/09/20

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"Rare Diseases"[Mesh] OR "orphan disease"

These pubmed results were generated on 2020/09/20

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

[Methods for quality of life assessment in children with orphanic diseases].

Probl Sotsialnoi Gig Zdravookhranenniiai Istor Med. 2020 Aug;28(Special Issue):778-784

Authors: Makarova EV, Krysanov IS, Vasilyeva TP, Alexandrova OY, Malachova AR

Abstract
Orphan (rare) diseases include congenital or acquired diseases, the frequency of occurrence of which does not exceed a certain number established by the laws of various countries. Despite its rarity, the orphan diseases make a significant contribution to the structure of population disability and most of them have no specific treatment. One of the main clinical challenges in these patients is to ensure their high quality of life (QOL). The review describes basic non-specific and specific questionnaires for assessing QOL in children with orphan diseases. An ideal questionnaire for assessing QOL in children with orphan disease should be sufficiently reliable, valid, sensitive and specific, fill out by a child or adolescents on their own, include questions covering as much as possible all areas of life and health aspects - especially those associated with the main decease. The questionnaire should not be too huge and complicated for the patient. From the side of the researcher, the simplicity of the tool in calculating and the ability to use the results for subsequent analysis are important.

PMID: 32856825 [PubMed - indexed for MEDLINE]

[Socio-economic burden of pulmonary hypertension: relevance of assessment in Russia and the world].

Ter Arkh. 2020 Apr 27;92(3):125-131

Authors: Zakiev VD, Gvozdeva AD, Martynyuk TV

Abstract
Pulmonary hypertension (PH) is a progressive disease which is characterized with the increase of pulmonary artery pressure and pulmonary vascular resistance. Such condition leads to right ventricular heart failure and premature death of patients. Pulmonary arterial hypertension (PAH) has the status of an orphan disease. However in Russia only idiopathic PH is included in the list of 24 life-threatening and chronic progressive rare diseases, while other forms of PH are not in it. Inclusion in this list guarantees drug provision for patients at the expense of the regional budget, while patients with other forms of PH can rely on free medication only if they have a disability. The lack of criteria for revising this list as well as the imperfection of legal regulation in the field of drug support for orphan diseases leads to high disability, a significant decrease in the duration and quality of life of patients with PH. As part of a multicriteria approach, a clinical and economic analysis of the disease burden can be one of the tools for policy development and decision-making on the distribution of funding in the healthcare. The article provides a review of the economic burden of various forms of PH in the world.

PMID: 32598804 [PubMed - indexed for MEDLINE]

Natural history of incidental sporadic and tuberous sclerosis complex associated lymphangioleiomyomatosis.

Respir Med. 2020 07;168:105993

Authors: Di Marco F, Terraneo S, Dias OM, Imeri G, Centanni S, Rinaldo RF, Giuliani L, Lesma E, Palumbo G, Wanderley M, Ribeiro Carvalho CR, Guedes Baldi B

Abstract
Lymphangioleiomyiomatosis (LAM) is a rare disease affecting women in childbearing age. A sporadic form (S-LAM) affecting previously healthy women, and a form associated with Tuberous Sclerosis Complex (TSC-LAM) are described. Some data suggested that TSC-LAM could be a milder disease compared to S-LAM. To investigate whether the different disease behavior is real or due to overdiagnosis of screened TSC women, we compared the natural history of S-LAM and TSC-LAM in patients with incidental diagnosis. Clinical, and functional data from 52 patients (23 with S-LAM and 29 with TSC-LAM) were analysed. At diagnosis functional impairment was mild without differences between groups [FEV1 % pred was 97% (88-105) and 94% (82-106) in TSC-LAM and S-LAM, respectively, p = 0.125]. Patients with S-LAM had less renal angiomyolipoma, and lower VEGF-D serum levels than TSC-LAM. There was no difference in the baseline extent of pulmonary cysts on CT scan and no difference in yearly rate of functional decline between TSC-LAM, and S-LAM patients [e.g. yearly rate of decline of FEV1 % pred was -0.51 (-1.59-2.24) and -0.90 (-1.92--0.42) in TSC-LAM and S-LAM, respectively, p = 0.265]. In conclusion, the natural history of TSC-LAM and S-LAM, when a potential selection bias due to screening in the latter group is balanced, is similar. Our study suggests that the prevalence of S-LAM can be significantly underestimated due to a tendency to diagnosis more frequently patients with more severe impairment, without identifying several ones with asymptomatic disease.

PMID: 32469709 [PubMed - indexed for MEDLINE]

A superior vena cava aneurysm discovered by chance at regular physical examination.

Respir Investig. 2020 Jul;58(4):291-294

Authors: Nakajima Y, Minami T, Ishigaki H, Sakai E, Takahashi R, Yokoi T, Kuribayashi K, Kijima T

Abstract
A superior vena cava (SVC) aneurysm is a rare disease that can be confused with upper mediastinal tumor. A 57-year-old female visited our hospital regarding an abnormal shadow in her mediastinum on a chest X-ray. Upon closer examinations, which included three-dimensional computed tomography, we diagnosed it as a SVC aneurysm. Since her SVC aneurysm was regarded as fusiform type at low risk of rupture and thrombosis, she has been managed conservatively and is free from any complications to date. Thus, it is important to keep SVC aneurysms in mind during routine examinations.

PMID: 32089406 [PubMed - indexed for MEDLINE]

Association or causation: Symptoms and rare disease.

J Inherit Metab Dis. 2019 09;42(5):729

Authors: Wilcken B

PMID: 31250462 [PubMed - indexed for MEDLINE]

[Posterior cortical atrophy-plus syndrome. A case report].

Fortschr Neurol Psychiatr. 2020 Aug;88(8):528-531

Authors: Saleh C, Seidl U, Stegentritt K, Schumacher F, Fehrenbach RA

Abstract
Posterior cortical atrophy (PCA) is a rare neurodegenerative disease, which manifests with complex visual disturbances. PCA can present in isolation ('PCA-pure') or in association with other neurodegenerative disorders ('PCA-plus'). Diagnosis is nevertheless frequently delayed, as PCA is a less known disease entity and initially a primary ocular disease is taken into consideration.

PMID: 32634845 [PubMed - indexed for MEDLINE]

KBTBD13 is an actin-binding protein that modulates muscle kinetics.

J Clin Invest. 2020 02 03;130(2):754-767

Authors: de Winter JM, Molenaar JP, Yuen M, van der Pijl R, Shen S, Conijn S, van de Locht M, Willigenburg M, Bogaards SJ, van Kleef ES, Lassche S, Persson M, Rassier DE, Sztal TE, Ruparelia AA, Oorschot V, Ramm G, Hall TE, Xiong Z, Johnson CN, Li F, Kiss B, Lozano-Vidal N, Boon RA, Marabita M, Nogara L, Blaauw B, Rodenburg RJ, Küsters B, Doorduin J, Beggs AH, Granzier H, Campbell K, Ma W, Irving T, Malfatti E, Romero NB, Bryson-Richardson RJ, van Engelen BG, Voermans NC, Ottenheijm CA

Abstract
The mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy caused by mutations in KBTBD13 (NEM6). In addition to weakness, NEM6 patients have slow muscle relaxation, compromising contractility and daily life activities. The role of KBTBD13 in muscle is unknown, and the pathomechanism underlying NEM6 is undetermined. A combination of transcranial magnetic stimulation-induced muscle relaxation, muscle fiber- and sarcomere-contractility assays, low-angle x-ray diffraction, and superresolution microscopy revealed that the impaired muscle-relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure. Using homology modeling and binding and contractility assays with recombinant KBTBD13, Kbtbd13-knockout and Kbtbd13R408C-knockin mouse models, and a GFP-labeled Kbtbd13-transgenic zebrafish model, we discovered that KBTBD13 binds to actin - a major constituent of the thin filament - and that mutations in KBTBD13 cause structural changes impairing muscle-relaxation kinetics. We propose that this actin-based impaired relaxation is central to NEM6 pathology.

PMID: 31671076 [PubMed - indexed for MEDLINE]

Hemophagocytic syndrome, a diagnostic challenge in Gastroenterology.

Rev Esp Enferm Dig. 2019 10;111(10):816

Authors: Jiménez Rosales R, Martín-Rodríguez MDM, Redondo-Cerezo E

Abstract
Hemophagocytic lymphohistiocytosis is a syndrome of severe immune activation with macrophage and T- cell infiltration resulting in multi organ damage. We report the case of a patient successfully treated for a haemophagocytic syndrome triggered by a metastatic neoplasm of the rectum. A 57 years old man is initially presented with fever without focus. Despite of wide spectrum antibiotics he developed a multi-organ dysfunction. A bone marrow aspirate showed histiocytes that had phagocytosed hematic cells. Hemophagocytic syndrome was suspected and specific treatment was administered. The patient's condition improved remarkably and he was discharged. Nevertheles, finally, the patient died due to a bad response to chemotherapy. Malignancies are a well known triggering of hemophagocytic lymphohistiocytosis being hematological the most commun malignancy associated. However, solid tumors are anecdotic and, to our knowledge, this case is the first one documented due only to rectal carcinoma.

PMID: 31545066 [PubMed - indexed for MEDLINE]

Striated preferentially expressed protein kinase (SPEG)-deficient skeletal muscles display fewer satellite cells with reduced proliferation and delayed differentiation.

Am J Pathol. 2020 Sep 10;:

Authors: Li Q, Lin J, Rosen SM, Zhang T, Kazerounian S, Luo S, Agrawal PB

Abstract
Centronuclear myopathies (CNMs) are a subtype of congenital myopathies characterized by skeletal muscle weakness and an increase in the number of central myonuclei. SPEG (striated preferentially expressed protein kinase) has been identified as the sixth gene associated with CNM, and it has been shown that striated muscle-specific Speg-knockout (KO) mice have defective triad formation, abnormal excitation-contraction coupling and calcium mishandling. The impact of SPEG deficiency on the survival and function of myogenic cells remains to be deciphered. In this study, we examined the overall population, proliferation, and differentiation of myogenic cells obtained from striated-muscle specific Speg-KO mice and compared them with wild-type (WT) controls. SPEG-deficient skeletal muscles contained fewer myogenic cells, which on further study demonstrated reduced proliferation and delayed differentiation compared to those from WT. Regenerative response to skeletal muscle injury in Speg-KO was compared to that of WT, leading to the identification of similar abnormalities including fewer satellite cells, fewer dividing cells, and an increase in apoptotic cells in KO mice. Overall, these results reveal specific abnormalities in myogenic cell number and behavior associated with SPEG deficiency. Similar SC defects have been reported in mouse models of MTM1- and DNM2-associated CNM, suggestive of shared underlying pathways.

PMID: 32919980 [PubMed - as supplied by publisher]