Edition of 19 May 2009

The recently-held Sixth European Haemophilia Consortium Round Table meeting focused on Health Technology Assessments (HTAs) and their value for haemophilia treatment. But the observations and concerns voiced by stakeholders could be relevant to any rare disorder. HTAs are supposed to evaluate the medical, social, economic and ethical information of medicinal products in order to contribute useful information that enables countries to develop health policies and budgets. With no EU-level standardised practice for HTAs, comparison between countries is currently not possible. Indeed, some governments rely more on evidence from the biopharmaceutical industry, while others source clinicians or patients for determining the HTA of a product. Using haemophilia prophylaxis as an example, speakers at the meeting evoked both their economic savings and improvement to quality of life. One speaker asserted that HTAs “must answer to the relation between the effects of the treatment with the associated costs to it”. The validity of the QALY (quality-adjusted life year) tool was called into question and experts gave examples of how QALY is not satisfactory for determining the value of haemophilia products. The case of haemophilia care in Romania was evoked, where a lack of adequate treatment translates into over 70% of young haemophiliac patients with locomotor disabilities and thus a poor quality of life. However, HTA can help underscore the fact that though existing care for haemophilia may be expensive, a lack of treatment is ultimately more costly. The meeting concluded with a set of resolutions to further efforts to develop sector-specific HTAs for rare diseases that take these factors into account, are based on enhanced cooperation between industry, clinicians, patient groups and policy makers, and which are more easily accessible between different Member States.
Read the summary report

Network of excellence for rare inherited neuromuscular diseases Treat-NMD, the Association Française contre les Myopathies and the Institut de Myologie together organised a round-table event recently with representatives from Russian clinical and research centres and also patient organisations. Aimed at facilitating collaborative efforts, the meeting gave participants the opportunity to learn about research, training, patient diagnosis and current treatment and care in Russia while exploring “training and education opportunities for Russian scientists and clinicians, grant submissions for joint EU-Russia calls, experience sharing between Russian patient organisations and the AFM, and opportunities for integration of Russian centres into TREAT-NMD activities, in particular the patient registries and care and trial sites initiatives.” Follow up joint actions will include training fellowships for Russian and Belarusian physicians and scientists, particularly in the field of non-invasive outcome measures of skeletal muscle in clinical trials, as well as travel grants for participation in the Myology summer school, the organisation of seminars in Russia and Belarus, an active support to fund-raising initiatives in Russia, and collaboration on medical imaging with the Belarusian Academy of Science. Furthermore, Russian and Belarusian patient registries for spinal muscular atrophy and Duchenne muscular dystrophy will be established and feed into the TREAT-NMD patient registries initiative, and Russian and Belarusian clinical centres will join the TREAT-NMD care and trial sites network to improve dissemination of care standards and work towards possible future clinical trials in neuromuscular diseases. In a separate initiative, it is hoped that TREAT-NMD participation in the international neuromuscular conference in the Ukraine on 21-23 May will extend this collaboration to include Ukrainian clinicians with an interest in neuromuscular diseases. The overarching goal of these activities is to establish strong links with a number of Russian, Belarusian and possibly Ukrainian teams and develop joint clinical as well as pre-clinical research protocols in the field of neuro-muscular disorders.

The authors identified a consanguineous Pakistani family in which oligodontia, the lack of more than six permanent teeth, is inherited along with short stature in an autosomal-recessive fashion. Increased bone density was present in the spine and at the base of the skull. They identified a homozygous nonsense mutation within LTBP3, the gene for the latent TGF-beta binding protein 3, an extracellular matrix protein believed to be required for osteoclast function.
Read the PubMed abstract

Distal myopathies represent a heterogeneous group of inherited skeletal muscle disorders. One type of adult-onset, progressive autosomal-dominant distal myopathy is frequently associated with dysphagia and dysphonia (vocal cord and pharyngeal weakness with distal myopathy). The authors identified in two families a point mutation in the gene MATR3, expressed in skeletal muscle and encoding matrin 3, a component of the nuclear matrix.
Read the PubMed abstract

Ichthyosis follicularis with atrichia and photophobia (IFAP syndrome) is a rare X-linked, oculocutaneous human disorder. The authors provide evidence that missense mutations in the gene MBTPS2 exchanging highly conserved amino acids of membrane-bound transcription factor protease are associated with this phenotype. The degree of diminished activity correlated with clinical severity. These findings indicate that the phenotypic expression of IFAP syndrome is quantitatively related to a reduced function of a key cellular regulatory system affecting cholesterol homeostasis and ability to cope with ER stress.
Read the PubMed abstract

Idiopathic Ventricular Fibrillation (IVF) is defined as spontaneous VF without any known structural or electrical heart disease. A family history is present in up to 20% of probands with the disorder, suggesting that at least a subset of IVF is hereditary. A genome-wide haplotype-sharing analysis was performed for identification of the responsible gene in three distantly related families in which multiple individuals died suddenly or were successfully resuscitated at young age. The authors identified a haplotype, on chromosome 7q36, that was conserved in these three families and was also shared by 7 of 42 independent IVF patients. The shared chromosomal segment harbours part of the DPP6 gene, which encodes a putative component of the transient outward current in the heart. A 20-fold increase in DPP6 mRNA levels in the myocardium was found in carriers as compared to controls.
Read the PubMed abstract

Segmental duplications at breakpoints (BP4-BP5) of chromosome 15q13.2q13.3 mediate a recurrent genomic imbalance syndrome associated with intellectual deficit, epilepsy, and/or electroencephalogram (EEG) abnormalities. The authors describe ten new patients with a spectrum of neuropsychiatric impairments that include autism spectrum disorder, attention deficit hyperactivity disorder, anxiety disorder, and mood disorder. Cognitive impairment varied from moderate intellectual deficit to normal IQ with learning disability. However, none had epilepsy and two had a normal EEG.
Read the PubMed abstract

Huntington disease (HD) is a fatal hereditary neurodegenerative disorder characterised by motor, cognitive, and behavioural disturbances. In this study, the authors found that hypothalamic-pituitary-adrenal (HPA) axis dysfunction hyperactivity is an early feature of HD and may contribute to some signs and symptoms in patients.
Read the PubMed abstract

A pilot open label, single dose trial of fenobam, an mGluR5 antagonist, was conducted to provide an initial evaluation of safety and pharmacokinetics in adult males and females with fragile X syndrome (FXS). Clinically significant adverse effects were not identified across the range of dosages utilised. The positive effects seen in animal models of FXS treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS.
Read the PubMed abstract

The prevalence of scoliosis in children with Prader-Willi syndrome (PWS) is 30%-80%, depending on age. Although reports about effects of GH treatment on scoliosis in children with PWS are limited, scoliosis is generally considered a contraindication for GH treatment. The authors studied the effects of GH treatment on the onset of scoliosis and curve progression in children with PWS via a multicenter, randomised, controlled GH study in infants and prepubertal and pubertal children. They found that GH-treated children had similar onset of scoliosis and curve progression as randomised controls. The authors conclude that scoliosis should no longer be considered a contraindication for GH treatment in children with PWS.
Read the PubMed abstract

To determine whether inhibition of Syk would be useful in FcgammaR-dependent cytopenias such as immune thrombocytopenic purpura (ITP) or autoimmune hemolytic anemia, sixteen adults with chronic ITP were entered into an open-label, single-arm cohort dose-escalation trial beginning with 75 mg and escalating as high as 175 mg twice daily. Toxicity was primarily GI-related with diarrhea (urgency) and vomiting; 2 patients had transaminitis. Inhibition of Syk was an efficacious means of increasing and maintaining the platelet count in half the patients with chronic refractory ITP.
Read the PubMed abstract