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Congenital heart defects and left ventricular non-compaction in males with loss-of-function variants in NONO

23 Aug, 16 | by hqqu

Changes in an X chromosome gene called NONO have been shown to cause delayed development and intellectual disability in males.  In this article we describe three males with changes in NONO who have the delayed development and intellectual disability previously described but also have heart defects and/or abnormal heart muscles.  This suggest that changes in NONO may put males at risk for developing heart problems.   We also found that males with changes in NONO often have large heads and sometime have changes in the nerve fibers that connect the right and left sides of the brain. (By Dr. Daryl A. Scott, )

Survival and causes of death in patients with von Hippel-Lindau disease

23 Aug, 16 | by hqqu

von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition causing life-long risk of tumor development in multiple organs. In a national research project including all known vHL families in Denmark, we found that the survival of vHL patients has improved over the last 100 years, and is getting closer to that of their siblings without vHL and the general population. Survival is influenced by a patient’s birth year, sex, and type of mutation in the VHL gene. The estimated mean life expectancy of vHL patients born in 2000 was 67 years for men and 60 years for women. (By Dr. Marie Louise Binderup, )

Amelogenesis imperfecta in familial hypomagnesaemia and hypercalciuria with nephrocalcinosis caused by CLDN19 gene mutations

16 Aug, 16 | by hqqu

Amelogenesis Imperfecta (AI) is a genetic condition characterized by tooth enamel quantitative or qualitative defects. The defects affect the enamel appearance, which can be chalky, discolored, thinner, pitted or grooved. Usually, a combination of different defects can be found within the same patient. In the last decade, studies have shown that AI may be associated with some inherited kidney diseases. In our study, we demonstrated that patients with Familial Hypomagnesemia and Hypecalciuria with Nephrocalcinosis may present AI. This study reinforces the importance of the dental exam of kidney diseases patients and the importance of nephrologic investigation of patients with AI. (By Dr. Ana Carolina Acevedo, )

Phenotypic spectrum of POLR3B mutations: isolated hypogonadotropic hypogonadism without neurological or dental anomalies

11 Aug, 16 | by hqqu

The gene POLR3B is associated with 4H leukodystrophy, a syndrome that includes reproductive failure (in the form of idiopathic hypogonadotropic hypogonadism (IHH)), neurologic disease (often in the form of ataxia), and hypodontia. To date, most patients reported to carry biallelic variants in POLR3B begin to show neurologic symptoms in early childhood, often before they are 3 years old. In our cohort of 565 patients with IHH, we identified four individuals with two variants in POLR3B; however, these patients were not found to have any signs of neurodegeneration or ataxia when evaluated in their early 30s. Our finding broadens the understanding of the spectrum of reproductive and neurologic disorders associated with POLR3B mutations. (By Mary Richards, )

New insights in the molecular signature of advanced medullary thyroid cancer: evidence of a bad outcome of cases with double RET mutations

28 Jul, 16 | by hqqu

Advanced sporadic MTC are characterized by a high prevalence of RET somatic mutations. In particular the M918T is the most frequent mutation but also small deletions/insertions (complex mutations can be present. In some cases more than one RET mutation can occur. K- or H-RAS mutations are also present even if at a lower frequency. RET and RAS mutations are mutually exclusive. Cases with multiple or complex mutations have a worse outcome. (By Drs. Rossella Elisei and Cristina Romei, )

Reader’s letter: comments on “Salbutamol increases SMN mRNA and protein levels in spinal muscular atrophy cells”

14 Jul, 16 | by hqqu

Salbutamol increases SMN mRNA and protein levels in spinal muscular atrophy cells
C Angelozzi, F Borgo, F D Tiziano, A Martella, G Neri, C Brahe

J Med Genet 2008; 45: 29-31

eLetter ID: jmedgenet_el;2828
Article ID: 45/1/29
Article Date: 1 January 2008

I just read the articles on SMA1, SMA2, SMA3. I felt it important to tell you of my son, born 1/26/70. When I took him to his first checkup at 3 months old, I voiced my concern for his floppy head. Again at 6 months old, when he couldn’t sit up, roll over, kick against resistance. Finally, the Pediatrician agreed to get an appointment with Yale Hospital in CT at 8 mos. The biopsy was shown to be SMA 1. We weren’t given any chance of survival. He was subsequently re-diagnosed at 3 years old, and again the results were, SMA1. He is now 46 years old. Graduated UCONN with honors and is still living in Litchfield CT. He is not on a ventilator but uses a bi-pap, 6 to 8% lung capacity. We have been told over and over there is no medication and there is no trials he could be involved with. However, with the social media being his way to communicate with the mass population he has discovered the Salbutamol available now through a client with SMA2. She has given us hope that this new drug will give him even the slightest increase in strength to keep the two fingers he uses to control his fiber optic wheelchair. Unfortunately it’s too expensive. It is heartbreaking to come so close to possibly gaining enough strength to stay mobile. If there is any possible way he could be helpful to your programs via computer please let us know.

Respectfully, June Lajoie Strada

Conflict of Interest:

None declared

The clinical, biochemical and genetic features associated with RMND1-related mitochondrial disease

13 Jul, 16 | by hqqu

Recessive mutations in the RMND1 gene, encoding the Required for Meiotic Nuclear Division protein 1, can cause defects in mitochondrial translation and oxidative phosphorylation, resulting in multi-system mitochondrial disease. In this multi-centre international study, we identified 14 new cases from 11 pedigrees with recessive RMND1 mutations including six novel, pathogenic variants.  Hypotonia, developmental delay, congenital sensorineural deafness and lactic acidaemia are common clinical features with disease onset under two years. Progressive kidney disease manifesting with electrolyte imbalance, normocytic anaemia, dysplastic kidney and hypertension was evident in two-third of patients, and good clinical outcome was demonstrated in four recipients of kidney transplant. (By Dr. Yi Shiau Ng, )

De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy

29 Jun, 16 | by hqqu

Pathogenic variants in the X-linked KIAA2022 gene are known to cause severe intellectual disability in males. Until now, all reported related female carriers of these KIAA2022 disruptions were unaffected and only 3 affected female patients have been described so far. We now report 14 female patients with heterozygous de novo loss of function mutations of KIAA2022. Twelve patients had epilepsy and 13 had mild to severe intellectual disability. This article provides an extensive clinical description of the affected females, providing clinicians with useful information for genetic counseling. Our data strongly suggest that pathogenic KIAA2022 variants can lead to a phenotype not only in males, but also in females. (By Iris de Lange, )

Figure 1. Genomic organization of KIAA2022 and location of mutations

Specifying the ovarian cancer risk threshold of ‘premenopausal risk-reducing salpingo-oophorectomy’ for ovarian cancer prevention: a cost-effectiveness analysis

29 Jun, 16 | by hqqu

Risk-reducing surgery to prevent ovarian cancer involves removal of tubes and ovaries. This has traditionally been performed in women at high risk (>1-in-10 chance) of getting ovarian cancer (e.g. BRCA1/BRCA2 carriers). However, the ovarian cancer risk level at which surgical prevention should be offered has not been previously defined. We undertook a health economic analysis comparing surgical prevention with no surgery at different ovarian cancer risk levels of 2%, 4%, 5%, 6%, 8% and 10% in pre-menopausal women >40 years. We found that surgical prevention is highly cost-effective in women at the ≥4% lifetime risk of ovarian cancer, leading to increased life-expectancy for an incremental cost-effectiveness ratio =£19536/QALY. Current surgical prevention guidelines should be re-evaluated to reduce the ovarian cancer risk threshold to benefit a number of at-risk women who presently cannot access risk-reducing surgery. (By Dr Ranjit Manchanda, )

Identification of bi-allelicLRRK1mutations inosteosclerotic metaphyseal dysplasiaand evidence for locus heterogeneity

22 Jun, 16 | by hqqu

Osteosclerotic metaphyseal dysplasia is a unique form of osteopetrosis characterized by dysplasiaof metaphyses of tubular bones with increased bone density. By exome sequencing, we found a homozygous mutation, c.5938_5944del[p.E1980Afs*66]in LRRK1 (Leucin-rich repeat kinase 1). LRRK1 was highly expressed in differentiated osteoclast. The patient’s phenotype was very similar to that of Lrrk1 knockout mice that we previously reported. In vitro transfection rescue experiments using osteoclasts from the knockout mice showed that the deletion caused a loss of bone-resorbing function of osteoclast. LRRK1 can be afascinating new drug target ofosteoporosis, like RANKL and sclerostin. (By Dr. Aritoshi Iida, )

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