Endocrine function over time in patients with myotonic dystrophy type 1

Dahlqvist, Julia R.; Ørngreen, Mette Cathrine; Witting, Nanna; Vissing, John

doi:10.1111/ene.12542

Cited by 35 publications

(16 citation statements)

References 23 publications

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“…Other studies of patients with DM also report a one in four to one in five prevalence of hypercalcaemia, a slightly lower incidence compared with our findings . However, these studies differ as to the cause, with vitamin D deficiency being seen in more than 80% of patients, a finding not replicated in our study, suggesting significant heterogeneity in calcium metabolism in patients with DM …”

Section: Discussioncontrasting

confidence: 94%

Dysregulation of calcium metabolism in type 1 myotonic dystrophy

Hlaing

Scott

Jackson

2019

Internal Medicine Journal

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Background Patients with type 1 myotonic dystrophy (DM1) have a higher incidence of hypercalcaemia compared with the general population. The nature and effects of dysregulated calcium metabolism underpinning this phenomenon have not been fully characterised. Aims To determine the characteristics of dysregulated calcium metabolism in patients with DM1 and its association with bone mineral density. Methods A retrospective review of medical records of patients with DM1 attending a DM clinic at Logan Hospital, Brisbane, Queensland, between 2005 and 2018 and who had concurrent serum assays performed of corrected serum calcium, 25 hydroxyvitamin D, parathyroid hormone (PTH) and phosphate and for whom results were available for estimated glomerular filtration rate, bone mineral densitometry tests and urinary calcium clearance to creatinine clearance ratio (UCCR). Results Forty‐four patients with DM1 (22 females, 22 males) were reviewed of whom 14 (32%) had elevated corrected serum calcium and inappropriate PTH. Another 10 patients (23%) had raised PTH with normocalcaemia. Eighteen of 19 (94.7%) patients with hypercalcaemia or high PTH level completed 24‐h urinary calcium. All had UCCR ≤0.02. Twelve patients had UCCR <0.01. Seven of 44 (16%) had low 25 hydroxy vitamin D. All patients had normal estimated glomerular filtration rate. None was osteoporotic. Conclusions One in three patients with DM1 was hypercalcaemic with unsuppressed PTH. Their clinical features and biochemical pictures resemble those of familial hypocalciuric hypercalcaemia (FHH) and raises the possibility that impaired activity of calcium‐sensing receptors, due to abnormal splicing of the calcium‐sensing receptor messenger RNA in DM1, causes a FHH‐like syndrome (‘pseudo‐FHH of DM1’).

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Section: Discussioncontrasting

confidence: 94%

Dysregulation of calcium metabolism in type 1 myotonic dystrophy

Hlaing

Scott

Jackson

2019

Internal Medicine Journal

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“…About a 2-fold increased cancer susceptibility has been reported in myotonic dystrophy with endometrial, brain, ovarian, and colon cancers carrying the highest risk compared to the general population [81]. Endocrine dysfunction may include primary hypogonadism, hyperinsulinism usually without frank diabetes and likely related to insulin resistance, and frontal balding, apparent in at least half of patients and increases during aging [82].…”

Section: Other Systemic Involvementmentioning

confidence: 99%

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

2018

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Myotonic dystrophy is an autosomal dominant muscular dystrophy not only associated with muscle weakness, atrophy, and myotonia but also prominent multisystem involvement. There are 2 similar, but distinct, forms of myotonic dystrophy; type 1 is caused by a CTG repeat expansion in the DMPK gene, and type 2 is caused by a CCTG repeat expansion in the CNBP gene. Type 1 is associated with distal limb, neck flexor, and bulbar weakness and results in different phenotypic subtypes with variable onset from congenital to very late-onset as well as variable signs and symptoms. The classically described adult-onset form is the most common. In contrast, myotonic dystrophy type 2 is adult-onset or late-onset, has proximal predominant muscle weakness, and generally has less severe multisystem involvement. In both forms of myotonic dystrophy, the best characterized disease mechanism is a RNA toxic gain-of-function during which RNA repeats form nuclear foci resulting in sequestration of RNA-binding proteins and, therefore, dysregulated splicing of premessenger RNA. There are currently no disease-modifying therapies, but clinical surveillance, preventative measures, and supportive treatments are used to reduce the impact of muscular impairment and other systemic involvement including cataracts, cardiac conduction abnormalities, fatigue, central nervous system dysfunction, respiratory weakness, dysphagia, and endocrine dysfunction. Exciting preclinical progress has been made in identifying a number of potential strategies including genome editing, small molecule therapeutics, and antisense oligonucleotide-based therapies to target the pathogenesis of type 1 and type 2 myotonic dystrophies at the DNA, RNA, or downstream target level.

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“…S7g-i), mimicking the wide variations observed in patients. 61 Although adult DSMD-QKO SC mice did not show major heart arrhythmias, they exhibited the overt functional defects and histological abnormalities in heart (Supplementary information, Fig. S7j-k).…”

Section: Mice Carrying Quadruple Mutations Show Typical Symptoms In Cmentioning

confidence: 99%

Dosage effect of multiple genes accounts for multisystem disorder of myotonic dystrophy type 1

Yin

Wang

et al. 2019

Cell Res

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Multisystem manifestations in myotonic dystrophy type 1 (DM1) may be due to dosage reduction in multiple genes induced by aberrant expansion of CTG repeats in DMPK, including DMPK, its neighboring genes (SIX5 or DMWD) and downstream MBNL1. However, direct evidence is lacking. Here, we develop a new strategy to generate mice carrying multigene heterozygous mutations to mimic dosage reduction in one step by injection of haploid embryonic stem cells with mutant Dmpk, Six5 and Mbnl1 into oocytes. The triple heterozygous mutant mice exhibit adult-onset DM1 phenotypes. With the additional mutation in Dmwd, the quadruple heterozygous mutant mice recapitulate many major manifestations in congenital DM1. Moreover, muscle stem cells in both models display reduced stemness, providing a unique model for screening small molecules for treatment of DM1. Our results suggest that the complex symptoms of DM1 result from the reduced dosage of multiple genes.

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Endocrine function over time in patients with myotonic dystrophy type 1

Abstract: Our findings show that endocrine abnormalities amongst patients with DM1 increase over time. Based on these findings it is suggested that correctable endocrine abnormalities should be monitored periodically in this patient group.

Cited by 35 publications

References 23 publications

Dysregulation of calcium metabolism in type 1 myotonic dystrophy

Dysregulation of calcium metabolism in type 1 myotonic dystrophy

Myotonic Dystrophies: Targeting Therapies for Multisystem Disease

Dosage effect of multiple genes accounts for multisystem disorder of myotonic dystrophy type 1

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