Loss of TMEM106B leads to myelination deficits: implications for frontotemporal dementia treatment strategies.

Brain. 2020 Jun 05;:

Authors: Zhou X, Nicholson AM, Ren Y, Brooks M, Jiang P, Zuberi A, Phuoc HN, Perkerson RB, Matchett B, Parsons TM, Finch NA, Lin W, Qiao W, Castanedes-Casey M, Phillips V, Librero AL, Asmann Y, Bu G, Murray ME, Lutz C, Dickson DW, Rademakers R

Abstract
Genetic variants that define two distinct haplotypes at the TMEM106B locus have been implicated in multiple neurodegenerative diseases and in healthy brain ageing. In frontotemporal dementia (FTD), the high expressing TMEM106B risk haplotype was shown to increase susceptibility for FTD with TDP-43 inclusions (FTD-TDP) and to modify disease penetrance in progranulin mutation carriers (FTD-GRN). To elucidate the biological function of TMEM106B and determine whether lowering TMEM106B may be a viable therapeutic strategy, we performed brain transcriptomic analyses in 8-month-old animals from our recently developed Tmem106b-/- mouse model. We included 10 Tmem106b+/+ (wild-type), 10 Tmem106b+/- and 10 Tmem106-/- mice. The most differentially expressed genes (153 downregulated and 60 upregulated) were identified between Tmem106b-/- and wild-type animals, with an enrichment for genes implicated in myelination-related cellular processes including axon ensheathment and oligodendrocyte differentiation. Co-expression analysis also revealed that the most downregulated group of correlated genes was enriched for myelination-related processes. We further detected a significant loss of OLIG2-positive cells in the corpus callosum of Tmem106b-/- mice, which was present already in young animals (21 days) and persisted until old age (23 months), without worsening. Quantitative polymerase chain reaction revealed a reduction of differentiated but not undifferentiated oligodendrocytes cellular markers. While no obvious changes in myelin were observed at the ultrastructure levels in unchallenged animals, treatment with cuprizone revealed that Tmem106b-/- mice are more susceptible to cuprizone-induced demyelination and have a reduced capacity to remyelinate, a finding which we were able to replicate in a newly generated Tmem106b CRISPR/cas9 knock-out mouse model. Finally, using a TMEM106B HeLa knock-out cell line and primary cultured oligodendrocytes, we determined that loss of TMEM106B leads to abnormalities in the distribution of lysosomes and PLP1. Together these findings reveal an important function for TMEM106B in myelination with possible consequences for therapeutic strategies aimed at lowering TMEM106B levels.

PMID: 32504082 [PubMed - as supplied by publisher]

COST Actions: fostering collaborative research for rare diseases.

Lancet Neurol. 2019 11;18(11):989-991

Authors: Desviat LR, Mallebrera CJ, Vallejo-Illarramendi A, Mayán MD, Nogales-Gadea G, Arechavala-Gomeza V

PMID: 31609208 [PubMed - indexed for MEDLINE]

Two novel homozygous mutations in NPHP1 lead to late onset end-stage renal disease: a case report of an adult nephronophthisis in a Chinese intermarriage family.

BMC Nephrol. 2019 05 16;20(1):173

Authors: Wang Y, Chen F, Wang J, Zhao Y, Liu F

Abstract
BACKGROUND: Nephronophthisis (NPHP) is an autosomal recessive hereditary disease with highly variable clinical characteristics for which 20 genes (NPHP1-20) have been identified. NPHP1 is the major subtype leading to pediatric end-stage renal disease (ESRD). Reports of adult NPHP1 are rare.
CASE PRESENTATION: Here, we report a 27-year-old male from a Chinese intermarriage family who was diagnosed as NPHP from clinical presentations and molecular genetic analysis by whole-exome sequencing. The genetic investigation revealed a novel homozygous nonsense mutation, p. E697X,37 and a novel homozygous missense mutation, p. F691 L, in the NPHP1 gene. His parents and fraternal twin harbored heterozygous mutations of the two loci and had no renal symptoms. His elder sister developed ESRD and died at 23 years of age.
CONCLUSIONS: The report indicated that adult NPHP should be taken into consideration for adults with ESRD of uncertain cause. The genotype-phenotype correlation requires further investigation.

PMID: 31096956 [PubMed - indexed for MEDLINE]

10 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 2020/06/05

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.

Malta (MYH9 Associated Elastin Aggregation) Syndrome: Germline Variants in MYH9 Cause Rare Sweat Duct Proliferations and Irregular Elastin Aggregations.

J Invest Dermatol. 2019 10;139(10):2238-2241.e6

Authors: Fewings E, Ziemer M, Hörtnagel K, Reicherter K, Larionov A, Redman J, Goldgraben MA, Pepler A, Hearn T, Firth H, Ha T, Schaller J, Adams DJ, Rytina E, van Steensel M, Tischkowitz M

PMID: 31125547 [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 2020/06/02

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 2020/06/02

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.

Solitary fibrous tumor of the scrotum: a case report and review of the literature.

BMC Urol. 2019 Dec 30;19(1):138

Authors: Chang TH, Chen M, Lee CC

Abstract
BACKGROUND: Solitary fibrous tumor (SFT) is a rare soft tissue tumor originally reported in the pleura. Although it has been reported in various extra-pleural sites, the occurrence of SFT in the scrotum is extremely rare. Herein, we present a 48-year-old man who had scrotal SFT. There are very few reported cases of genitourinary SFTs, this is only the fifth report of SFT of the scrotum in the English medical literature.
CASE PRESENTATION: In this study, we report on a 48-year-old man who presented with a 5 × 8 cm scrotal mass between his testes. Physical examination revealed a 4.7 × 8.5 cm lobulated tumor mass located between his testicles. Surgical excision of the tumor with scrotal approach was done and pathology reported a SFT. The patient was alive without tumor recurrence or distant metastasis during ongoing follow-up for 9 months post-operatively..
CONCLUSION: Scrotal SFTs are very rare and only five cases have been reported in English literature to date. Treatment often involves surgical resection, and a definite diagnosis is made with the help of immunohistochemistry. The current general consensus for the management of SFTs is long-term follow-up after surgical excision of the tumor.

PMID: 31888599 [PubMed - indexed for MEDLINE]

A rare hereditary and metastatic paraganglioma involved in both spermatic cord and testis.

Endocrine. 2019 07;65(1):217-218

Authors: Luo S, Liu Z, Zhou Z

PMID: 30798430 [PubMed - indexed for MEDLINE]

Eisenmenger Syndrome: A Multisystem Disorder-Do Not Destabilize the Balanced but Fragile Physiology.

Can J Cardiol. 2019 Dec;35(12):1664-1674

Authors: Chaix MA, Gatzoulis MA, Diller GP, Khairy P, Oechslin EN

Abstract
Eisenmenger syndrome is the most severe and extreme phenotype of pulmonary arterial hypertension associated with congenital heart disease. A large nonrestrictive systemic left-to-right shunt triggers the development of pulmonary vascular disease, progressive pulmonary arterial hypertension, and increasing pulmonary vascular resistance at the systemic level, which ultimately results in shunt reversal. Herein, we review the changing epidemiological patterns and pathophysiology of Eisenmenger syndrome. Multiorgan disease is an integral manifestation of Eisenmenger syndrome and includes involvement of the cardiac, hematological, neurological, respiratory, gastrointestinal, urinary, immunological, musculoskeletal, and endocrinological systems. Standardized practical guidelines for the assessment, management, risk stratification, and follow-up of this very fragile and vulnerable population are discussed. Multidisciplinary care is the best clinical practice. An approach to the prevention and management of a broad spectrum of complications is provided. Relevant therapeutic questions are discussed, including anticoagulation, noncardiac surgery, physical activity, transplantation, and advanced-care planning (palliative care). Advanced pulmonary arterial hypertension therapies are indicated in patients with Eisenmenger syndrome and World Health Organization functional class II or higher symptoms to improve functional capacity, quality of life, and-less well documented-survival. Specific recommendations regarding monotherapy or combination therapy are provided according to functional class and clinical response. The ultimate challenge for all care providers remains early detection and management of intracardiac and extracardiac shunts, considering that Eisenmenger syndrome is a preventable condition.

PMID: 31813503 [PubMed - indexed for MEDLINE]

Protein-Losing Enteropathy Following Fontan Palliation.

Can J Cardiol. 2019 Dec;35(12):1857-1860

Authors: Al Balushi A, Mackie AS

Abstract
Protein-losing enteropathy (PLE) is a chronic condition involving multiple organ systems that may develop any time following Fontan completion. The pathogenesis of PLE is complex and multifactorial. Chronic venous hypertension, low cardiac output, and abnormal lymphatics may all play a role in the pathogenesis of PLE. Common signs and symptoms include chronic diarrhea, abdominal pain, and ascites. Diagnosis is based on the presence of signs and symptoms in addition to hypoalbuminemia and elevated stool alpha 1 antitrypsin. Early identification and a comprehensive approach to evaluation and treatment are important, as they may affect survival. The initial evaluation should include cardiac catheterization for hemodynamic assessment. Although an evidence base for treatment is lacking, various medical, interventional, and surgical approaches have been described with variable degrees of success. Commonly used therapies include nutritional support, diuretics, subcutaneous unfractionated heparin, budesonide, and sildenafil. Limited data exist for Fontan conversion or takedown. Assessment for heart transplantation should be considered. PLE mortality is high-approximately 50%-but may be mitigated by aggressive investigation and management. The evolving understanding of the role of lymphatics in the pathophysiology of PLE and the emerging role of interventional lymphatic procedures may further improve outcomes in this patient population.

PMID: 31711823 [PubMed - indexed for MEDLINE]

Rare case of simultaneous manifestation of pigmented paravenous retinochoroidal atrophy and retinitis pigmentosa in contralateral eye.

Indian J Ophthalmol. 2019 11;67(11):1875-1876

Authors: Mehrotra N, Khandelwal J, Nagpal M

PMID: 31638054 [PubMed - indexed for MEDLINE]

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 2020/05/28

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 2020/05/28

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 2020/05/27

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 2020/05/27

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.

The role of sodium channels in sudden unexpected death in pediatrics.

Mol Genet Genomic Med. 2020 May 25;:e1309

Authors: Rochtus AM, Goldstein RD, Holm IA, Brownstein CA, Pérez-Palma E, Haynes R, Lal D, Poduri AH

Abstract
BACKGROUND: Sudden Unexpected Death in Pediatrics (SUDP) is a tragic event, likely caused by the complex interaction of multiple factors. The presence of hippocampal abnormalities in many children with SUDP suggests that epilepsy-related mechanisms may contribute to death, similar to Sudden Unexplained Death in Epilepsy. Because of known associations between the genes SCN1A and SCN5A and sudden death, and shared mechanisms and patterns of expression in genes encoding many voltage-gated sodium channels (VGSCs), we hypothesized that individuals dying from SUDP have pathogenic variants across the entire family of cardiac arrhythmia- and epilepsy-associated VGSC genes.
METHODS: To address this hypothesis, we evaluated whole-exome sequencing data from infants and children with SUDP for variants in VGSC genes, reviewed the literature for all SUDP-associated variants in VGSCs, applied a novel paralog analysis to all variants, and evaluated all variants according to American College of Medical Genetics and Genomics (ACMG) guidelines.
RESULTS: In our cohort of 73 cases of SUDP, we assessed 11 variants as pathogenic in SCN1A, SCN1B, and SCN10A, genes with long-standing disease associations, and in SCN3A, SCN4A, and SCN9A, VGSC gene paralogs with more recent disease associations. From the literature, we identified 82 VGSC variants in SUDP cases. Pathogenic variants clustered at conserved amino acid sites intolerant to variation across the VGSC genes, which is unlikely to occur in the general population (p < .0001). For 54% of variants previously reported in literature, we identified conflicting evidence regarding pathogenicity when applying ACMG criteria and modern population data.
CONCLUSION: We report variants in several VGSC genes in cases with SUDP, involving both arrhythmia- and epilepsy-associated genes. Accurate variant assessment as well as future studies are essential for an improved understanding of the contribution of sodium channel-related variants to SUDP.

PMID: 32449611 [PubMed - as supplied by publisher]

A rare case of type 1 unilateral 'peripheral' Peters' anomaly.

Indian J Ophthalmol. 2019 10;67(10):1702-1703

Authors: Shah C, Sen P, Mohan A, Chandra K, Jain E

PMID: 31546519 [PubMed - indexed for MEDLINE]

From the Editors Desk: Angela Zawacki-Downing Writing to Professor Illana Gozes, Editor-in-Chief Journal of Molecular Neuroscience-Speaking from a Mother's Heart, AD's ADNP Syndrome.

J Mol Neurosci. 2019 08;68(4):511-514

Authors: Zawacki-Downing A

PMID: 31201656 [PubMed - indexed for MEDLINE]

Perioperative Management of Left Atrial Dissection After Mitral Valve Repair: Navigating the Challenges and Conundrums With a Rare Complication.

J Cardiothorac Vasc Anesth. 2019 Jul;33(7):2046-2052

Authors: Fernando RJ, Zhou E, Patel PA, Garner C, Feinman JW, Ha B, Johnson SD, Weiss SJ, Goeddel LA, Augoustides JG

PMID: 30914215 [PubMed - indexed for MEDLINE]