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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, )

Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head

21 Jun, 16 | by hqqu

Osteonecrosis of the femoral head is a painful and debilitating bone disease that causes bone death at the hip leading to its collapse and subsequent end-stage osteoarthritis.  The disease is poorly understood limiting treatment options to invasive surgical procedures such as total hip replacement. We have identified a Canadian family of Greek origin with osteonecrosis of the femoral head in four out of six siblings with no risk factors for the disease. Genetic analysis discovered a mutation of the TRPV4 gene found only in the four affected siblings. Measurements of the mutant protein’s function found that its activity was higher than the normal protein. TRPV4-associated phenotypes involve a large spectrum of skeletal dyscrasias and neuropathies. Our findings broaden the spectrum of phenotypes caused by TRPV4 mutations and highlight the relevance of this ion channel in the physiopathology of osteonecrosis. (By Dr Chantal Séguin, )


Dr Chantal Séguin

Mutations in TUBB8 cause a multiplicity of phenotypes in human oocytes and early embryos

6 Jun, 16 | by hqqu

An essential feature of successful mammalian reproduction is the fusion of a sperm with a mature oocyte. We previously found that heterozygous mutations in TUBB8 caused oocyte maturation arrest. In this study, we identified novel heterozygous and homozygous mutations in TUBB8 that cause variability in the corresponding phenotypes of human oocytes and early embryos. For example, oocyte with some mutations can exclude the first polar body and be fertilized, although the ensuing embryos became developmentally arrested. Our data substantially expand the range of dysfunctional oocyte phenotypes incurred by mutation in TUBB8, extend the class of genetic diseases known as the tubulinopathies, and provide new criteria for the qualitative evaluation of MII oocytes for IVF. (By Dr. Lei Wang, )


Genes associated with common variable immunodeficiency: one diagnosis to rule them all?

1 Jun, 16 | by hqqu

Common variable immunodeficiency (CVID) is an immune disorder characterized by low antibody levels and an increased susceptibility to infections and immune-related complications. It is a heterogeneous disorder with a variable clinical presentation and severity. Thus far, single gene defects have been identified in about 2-10% of patients. As more disease genes are being identified, it is becoming clear that CVID is an umbrella diagnosis and that many of these genetic defects cause separate disease entities. Moreover, it is thought that, in at least a subgroup of CVID patients, a single genetic defect does not suffice to develop the disease, meaning that additional genetic and/or environmental factors are involved. This review provides an overview of disease genes implicated in CVID and discusses current evidence on a possible multifactorial origin of this disorder. (Delfien Bogaert on behalf of all authors, )

A Splicing Mutation in VPS4B Causes Dentin Dysplasia I

31 May, 16 | by hqqu

Dentin dysplasia I (DDI) is an autosomal dominant disorder characterized by rootless teeth with abnormal pulpal morphology. The etiology of DDI still remains largely unclear. Here, we identified VPS4B as a disease-causing gene for DDI by linkage analysis followed by deep sequencing of the candidate genes in a large Chinese family with DDI. A splicing mutation (IVS7+46C>G) in VPS4B gene was found, which resulted in the aberrant transcripts with a 15-amino acid insertion and loss of function. We showed that VPS4B was identified to be linked to Wnt/beta-catenin signaling and other genes involved in odontogenesis by a functional study. (By Prof. Fu Xiong, )

GATOR1 complex: the common genetic actor in focal epilepsies

19 May, 16 | by hqqu

mTOR is a critical effector of cell signaling, playing a pivotal role in regulating physiology of the whole body, including the brain. Mutations in genes encoding GATOR1 complex, an inhibitor of mTOR activity, have been recently implicated in the pathogenesis of a wide spectrum of focal epilepsies (FEs), occasionally associated with malformations of cortical development. Loss of mTOR inhibitor activity is the hypothesized mechanism underlying epilepsy. In this review, the authors summarize the current knowledge about GATOR1 mutations in FEs, and discuss the future therapeutic opportunities for patients. (By Sara Baldassari, )

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