Barriers to effective health care for patients who have smell or taste disorders.

OBJECTIVES: Smell/taste disturbances are a common but underrated, under-researched and under treated sensory loss and an independent risk factor for reduced longevity. This study aimed to characterise the experience of patients with these disorders in seeking help. DESIGN: The study was designed by patients together with clinicians through a dedicated workshop and conducted as a cross-sectional survey to capture experiences in public and private healthcare settings internationally. SETTING: Primary, secondary and tertiary care. PARTICIPANTS: Any members of the public self-reporting a smell/taste disorder were invited to participate. MAIN OUTCOME MEASURES: The survey captured information including experience of getting consultations and referrals to medical professionals, treatments offered, costs incurred and related problems with mental health. RESULTS: Of 673 participants; 510 female, 160 male, three not stated, self-reported aetiology included sinonasal disease (24%), idiopathic (24%) and post-viral olfactory dysfunction (22%); true gustatory disorders were typically rare. Failure of medical professionals to recognise the problem was a key concern - 64%, 76% and 47% of GPs, ENT specialists and Neurologists acknowledged, respectively. Other issues included repeated ineffective treatments, difficulties getting referrals to secondary/tertiary care, mental health problems (60%) and a mean personal cost of £421 to seeking advice and treatment. Whilst the participants were self-selecting, however, they do represent those who are seeking help and intervention for their disorders. CONCLUSION: There is an unmet need for these patients in accessing health care including a clear need to improve education of and engagement with the medical profession in Otorhinolaryngology, General Practice and other specialties, in order to remove the current barriers they face.

STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility.

SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release. Co-immunoprecipitation of STAC3 with CaV 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV 1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of CaV 1.1 sarcolemma mislocalization or impaired STAC3-CaV 1.1 interaction.

Successful pregnancies and reduced treatment requirement while breast feeding in a patient with congenital hypoparathyroidism due to homozygous c.68C>A null parathyroid hormone gene mutation.

A female patient with consanguineous parents presented at the age of 4 with isolated hypoparathyroidism due to a parathyroid hormone (PTH) gene mutation. She was managed with alfacalcidol and calcium supplements, and developed normally. Her consanguineous parents described symptoms suggestive of hypocalcaemia but had normal serum calcium and low normal PTH levels. A molecular diagnosis obtained in her adulthood revealed the presence of homozygous point mutation (c.68C>A) in exon 2 introducing a premature stop codon resulting in a non-functional precursor protein. This mutation has been reported only once before. Our patient remained on stable doses of alfacalcidol during pregnancy, but stopped all supplementation while breast feeding. This case confirms that alternative mechanisms (likely breast-derived parathyroid hormone-related protein) contribute to calcium homeostasis during breast feeding. Heterozygotes for the c.68C>A mutation may have latent hypoparathyroidism and maintain calcium homeostasis except during prolonged hypocalcaemia. This would suggest incomplete dominance, or a dose effect of the wild-type PTH allele.

Mutations in NOTCH1 cause Adams-Oliver syndrome.

Notch signaling determines and reinforces cell fate in bilaterally symmetric multicellular eukaryotes. Despite the involvement of Notch in many key developmental systems, human mutations in Notch signaling components have mainly been described in disorders with vascular and bone effects. Here, we report five heterozygous NOTCH1 variants in unrelated individuals with Adams-Oliver syndrome (AOS), a rare disease with major features of aplasia cutis of the scalp and terminal transverse limb defects. Using whole-genome sequencing in a cohort of 11 families lacking mutations in the four genes with known roles in AOS pathology (ARHGAP31, RBPJ, DOCK6, and EOGT), we found a heterozygous de novo 85 kb deletion spanning the NOTCH1 5' region and three coding variants (c.1285T>C [p.Cys429Arg], c.4487G>A [p.Cys1496Tyr], and c.5965G>A [p.Asp1989Asn]), two of which are de novo, in four unrelated probands. In a fifth family, we identified a heterozygous canonical splice-site variant (c.743-1 G>T) in an affected father and daughter. These variants were not present in 5,077 in-house control genomes or in public databases. In keeping with the prominent developmental role described for Notch1 in mouse vasculature, we observed cardiac and multiple vascular defects in four of the five families. We propose that the limb and scalp defects might also be due to a vasculopathy in NOTCH1-related AOS. Our results suggest that mutations in NOTCH1 are the most common cause of AOS and add to a growing list of human diseases that have a vascular and/or bony component and are caused by alterations in the Notch signaling pathway.

FAN1 mutations cause karyomegalic interstitial nephritis, linking chronic kidney failure to defective DNA damage repair.

Chronic kidney disease (CKD) represents a major health burden. Its central feature of renal fibrosis is not well understood. By exome sequencing, we identified mutations in FAN1 as a cause of karyomegalic interstitial nephritis (KIN), a disorder that serves as a model for renal fibrosis. Renal histology in KIN is indistinguishable from that of nephronophthisis, except for the presence of karyomegaly. The FAN1 protein has nuclease activity and acts in DNA interstrand cross-link (ICL) repair within the Fanconi anemia DNA damage response (DDR) pathway. We show that cells from individuals with FAN1 mutations have sensitivity to the ICL-inducing agent mitomycin C but do not exhibit chromosome breakage or cell cycle arrest after diepoxybutane treatment, unlike cells from individuals with Fanconi anemia. We complemented ICL sensitivity with wild-type FAN1 but not with cDNA having mutations found in individuals with KIN. Depletion of fan1 in zebrafish caused increased DDR, apoptosis and kidney cysts. Our findings implicate susceptibility to environmental genotoxins and inadequate DNA repair as novel mechanisms contributing to renal fibrosis and CKD.

Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database.

Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal-dominant disorder characterized by ocular and renal malformations. Mutations in the paired-box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus-specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl/PAX2. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed.

Floating-Harbor syndrome complicated by tethered cord: a new association and potential contribution from growth hormone therapy.

Floating-Harbor syndrome is a rare syndrome with short stature, severely delayed bone age, typical facies and delay in expressive speech. Structural malformations are uncommon, and tethered cord or other forms of spinal dysraphism have not previously been reported. We report on a case of Floating-Harbor syndrome, complicated by tethered cord and discuss the possibility that growth hormone therapy may contribute to the development of symptoms of this malformation.