Early onset hearing loss in autosomal recessive hypophosphatemic rickets caused by loss of function mutation in ENPP1

2015 ◽  
Vol 28 (7-8) ◽  
Author(s):  
Elisabeth Steichen-Gersdorf ◽  
Bettina Lorenz-Depiereux ◽  
Tim Matthias Strom ◽  
Nicholas J. Shaw
Keyword(s):  
Hearing Loss ◽  
Early Onset ◽  
Autosomal Recessive ◽  
Hypophosphatemic Rickets ◽  
Loss Of Function ◽  
Rare Form ◽  
Nucleotide Pyrophosphatase ◽  
Renal Tubular ◽  
Autosomal Recessive Hypophosphatemic Rickets

AbstractAutosomal recessive hypophosphatemic rickets 2 (ARHR2) is a rare form of renal tubular phosphate wasting disorder. Loss of function mutations of the ecto-nucleotide pyrophosphatase/pyrophosphodiesterase 1 gene (

VITAMIN D DEPENDENCY: AN INHERITED POSTNATAL SYNDROME WITH SECONDARY HYPERPARATHYROIDISM

PEDIATRICS ◽  
1970 ◽  
Vol 46 (6) ◽  
pp. 871-880
Author(s):  
C. Arnaud ◽  
R. Maijer ◽  
T. Reade ◽  
C. R. Scriver ◽  
D. T. Whelan
Keyword(s):  
Vitamin D ◽  
Autosomal Recessive ◽  
Hypophosphatemic Rickets ◽  
First Year ◽  
Tubular Dysfunction ◽  
Renal Tubular Dysfunction ◽  
Recessive Trait ◽  
Daily Allowance ◽  
Renal Tubular ◽  
First Year Of Life

Three French-Canadian children in a large inbred pedigree each developed hypocalcemic, hypophosphatemic rickets in the latter half of their first year of life; there were also manifestations of generalized renal tubular dysfunction. These abnormalities, which mimic advanced Vitamin D deficiency, disappeared only when Vitamin D2 or D3 was given at about 100 times the recommended daily allowance; this indicated the diagnosis of Vitamin D dependency. Enamel hypoplasia was a prominent clinical finding; only those teeth which calcify postnatally were affected, indicating that the condition found does not affect Vitamin D-dependent nutrition in utero. The level of parathyroid hormone was elevated in serum before treatment; it fell to normal either after treatment with Vitamin D, or during intravenous infusion with a calcium solution sufficient to produce hypercalcemia. Vitamin D dependency appeared to be inherited as an autosomal recessive trait in this pedigree, but we could observe no phenotypic signs in presumably obligate heterozygotes. One of the three cases in the pedigree arose from outbreeding, suggesting that the mutant allele is probably not particularly rare in the population under our surveillance.

scholarly journals Van der Knaap disease

2019 ◽  
Vol 7 (10) ◽  
pp. 3917
Author(s):  
Manoj Kumar Mahata ◽  
Saikat Ghosh ◽  
K. C. Ghosh ◽  
R. Bhattacharya ◽  
G. P. Mondal
Keyword(s):  
Cognitive Impairment ◽  
Early Onset ◽  
Autosomal Recessive ◽  
Rare Form ◽  
Temporal Lobes ◽  
Mri Brain ◽  
Early Onset Ataxia ◽  
Subcortical Cysts

Van der Knaap disease is a rare form of leukodystrophy, phenotypically characterized by megalencephaly, early-onset ataxia, pyramidal features, cognitive impairment, with an autosomal recessive inheritence. MRI Brain shows T1 and FLAIR hypointense subcortical cysts in mostly temporal lobes and in fronto-parietal subcortical areas. Authors report a 20 yr. girl with typical features.

scholarly journals Novel Loss-of-Function Mutations in COCH Cause Autosomal Recessive Nonsyndromic Deafness

2020 ◽  
Author(s):  
Kevin T Booth ◽  
Amama Ghaffar ◽  
Muhammad Rashid ◽  
Luke T Hovey ◽  
Mureed Hussain ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Rna Splicing ◽  
Autosomal Recessive ◽  
Dominant Negative ◽  
Nonsyndromic Hearing Loss ◽  
Loss Of Function ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Exon Splicing ◽  
Coding Variants

AbstractCOCH is the most abundantly expressed gene in the cochlea. Unsurprisingly, mutations in COCH underly deafness in mice and humans. Two forms of deafness are linked to mutations in COCH, the well-established autosomal dominant nonsyndromic hearing loss, with or without vestibular dysfunction (DFNA9) via a gain-of-function/dominant-negative mechanism, and more recently autosomal recessive nonsyndromic hearing loss (DFNB110) via nonsense variants. Using a combination of targeted gene panels, exome sequencing and functional studies, we identified four novel pathogenic variants (two nonsense variants, one missense and one inframe deletion) in COCH as the cause of autosomal recessive hearing loss in a multi-ethnic cohort. To investigate whether the non-truncating variants exert their effect via a loss-of-function mechanism, we used mini-gene splicing assays. Our data showed both the missense and inframe deletion variants altered RNA-splicing by creating an exon splicing silencer and abolishing an exon splicing enhancer, respectively. Both variants create frameshifts and are predicted to result in a null allele. This study confirms the involvement of loss-of-function mutations in COCH in autosomal recessive nonsyndromic hearing loss, expands the mutational landscape of DFNB110 to include coding variants that alter RNA-splicing, and highlights the need to investigate the effect of coding variants on RNA-splicing.

scholarly journals Mineralizing Enthesopathy Is a Common Feature of Renal Phosphate-Wasting Disorders Attributed to FGF23 and Is Exacerbated by Standard Therapy in Hyp Mice

Endocrinology ◽  
2012 ◽  
Vol 153 (12) ◽  
pp. 5906-5917 ◽  
Author(s):  
Andrew C. Karaplis ◽  
Xiuying Bai ◽  
Jean-Pierre Falet ◽  
Carolyn M. Macica
Keyword(s):  
Standard Therapy ◽  
Autosomal Recessive ◽  
Fibroblast Growth Factor 23 ◽  
Hypophosphatemic Rickets ◽  
Phex Gene ◽  
Dentin Matrix ◽  
Insertion Sites ◽  
Autosomal Recessive Hypophosphatemic Rickets ◽  
The Impact ◽  
Inactivating Mutations

Abstract We have previously confirmed a paradoxical mineralizing enthesopathy as a hallmark of X-linked hypophosphatemia. X-linked hypophosphatemia is the most common of the phosphate-wasting disorders mediated by elevated fibroblast growth factor 23 (FGF23) and occurs as a consequence of inactivating mutations of the PHEX gene product. Despite childhood management of the disease, these complications of tendon and ligament insertion sites account for a great deal of the disease's morbidity into adulthood. It is unclear whether the enthesopathy occurs in other forms of renal phosphate-wasting disorders attributable to high FGF23 levels. Here we describe two patients with autosomal recessive hypophosphatemic rickets due to the Met1Val mutation in dentin matrix acidic phosphoprotein 1 (DMP1). In addition to the biochemical and skeletal features of long-standing rickets with elevated FGF23 levels, these individuals exhibited severe, debilitating, generalized mineralized enthesopathy. These data suggest that enthesophytes are a feature common to FGF23-mediated phosphate-wasting disorders. To address this possibility, we examined a murine model of FGF23 overexpression using a transgene encoding the secreted form of human FGF23 (R176Q) cDNA (FGF23-TG mice). We report that FGF23-TG mice display a similar mineralizing enthesopathy of the Achilles and plantar facial insertions. In addition, we examined the impact of standard therapy for phosphate-wasting disorders on enthesophyte progression. We report that fibrochondrocyte hyperplasia persisted in Hyp mice treated with oral phosphate and calcitriol. In addition, treatment had the untoward effect of further exacerbating the mineralization of fibrochondrocytes that define the bone spur of the Achilles insertion. These studies support the need for newer interventions targeted at limiting the actions of FGF23 and minimizing both the toxicities and potential morbidities associated with standard therapy.

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