Outcomes of patients with Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia caused by pathogenic SMAD4 variants in a pan-Scotland cohort.

Constitutional loss of SMAD4 function results in Juvenile Polyposis-Hereditary Haemorrhagic Telangiectasia Overlap Syndrome (JP-HHT). A retrospective multi-centre case-note review identified 28 patients with a pathogenic SMAD4 variant from 13 families across all Scottish Clinical Genetics Centres. This provided a complete clinical picture of the Scottish JP-HHT cohort. Colonic polyps were identified in 87% (23/28) and gastric polyps in 67% (12/18) of screened patients. Complication rates were high: 43% (10/23) of patients with polyps required a colectomy and 42% (5/12) required a gastrectomy. Colorectal cancer occurred in 25% (7/28) of patients, at a median age of 33 years. Pulmonary arteriovenous malformations were identified in 42% (8/19) of screened patients. 88% (23/26) and 81% (17/21) of patients exhibited JP and HHT features respectively, with 70% (14/20) demonstrating features of both conditions. We have shown that individuals with a pathogenic SMAD4 variant are all at high risk of both gastrointestinal neoplasia and HHT-related vascular complications, requiring a comprehensive screening programme.

Interactions between anti-EGFR therapies and cytotoxic chemotherapy in oesophageal squamous cell carcinoma: why clinical trials might have failed and how they could succeed.

PURPOSE: Oesophageal squamous cell carcinoma (ESCC) has a poor prognosis. Advanced tumours are treated with fluoropyrimidine/platinum chemotherapy followed by irinotecan or taxane monotherapy, but resistance is common and new treatments are needed. Approximately 20% of ESCCs carry copy number gain (CNG) of the epidermal growth factor receptor (EGFR) gene. Previous trials show that while anti-EGFR monotherapy benefits biomarker-selected patients with EGFR CNG and/or high EGFR expression, combining anti-EGFR therapies with platinum fluoropyrimidine chemotherapies is not effective, and uncertainty remains regarding the optimal cytotoxic chemotherapy partner for anti-EGFR therapies in ESCC. METHODS: The effects of EGFR CNG on fluoropyrimidine/platinum chemotherapy sensitivity in a cohort of gastroesophageal cancer patients (n = 302) was evaluated. Drug combination studies using the EGFR inhibitor gefitinib with cytotoxic chemotherapies, docetaxel, cisplatin, oxaliplatin and irinotecan, on cell proliferation and cell death of EGFR CNG ESCC cell lines were assessed. RESULTS: EGFR CNG in gastroesophageal cancer patients was associated with improved overall survival following fluoropyrimidine/platinum chemotherapy. However, co-administration of gefitinib and oxaliplatin or cisplatin was frequently antagonistic in cell-based assays in EGFR CNG ESCC, whereas the combination of gefitinib with docetaxel or irinotecan was more efficacious. Co-administration of gefitinib/docetaxel and sequential administration of docetaxel before gefitinib showed synergy, but docetaxel given after gefitinib was antagonistic. CONCLUSION: Gefitinib/platinum co-administration demonstrated antagonism suggesting a possible explanation for the lack of benefit from addition of anti-EGFR therapies to fluoropyrimidine/platinum chemotherapy in trials. Gefitinib/docetaxel co-administration demonstrated synergy suggesting taxanes could be the most effective cytotoxic partner for anti-EGFR therapies in EGFR CNG-positive ESCC, but careful consideration of drug scheduling is required.

Cost effectiveness of cascade testing for familial hypercholesterolaemia, based on data from familial hypercholesterolaemia services in the UK.

AIMS: Familial hypercholesterolaemia (FH) is a vastly under-diagnosed genetic disorder, associated with early development of coronary heart disease and premature mortality which can be substantially reduced by effective treatment. Patents have recently expired on high-intensity statins, reducing FH treatment costs. We build a model using UK data to estimate the cost effectiveness of DNA testing of relatives of those with monogenic FH. METHODS AND RESULTS: A Markov model was used to estimate the cost effectiveness of cascade testing, using data from UK cascade services. The estimated incremental cost effectiveness ratio (ICER) was £5806 and the net marginal lifetime cost per relative tested was £2781. More than 80% of lifetime costs were diagnosis-related and incurred in the 1st year. In UK services, 23% of 6396 index cases were mutation-positive. For each mutation-positive index case, 1.33 relatives were tested, resulting overall in a rate of 0.31 tested relatives per tested index case. If the number of relatives tested per tested index case rose to 3.2 (projected by National Institute for Health and Care Excellence in 2008) the ICER would reduce to £2280 and lifetime costs to £1092. CONCLUSION: Cascade testing of relatives of those with suspected FH is highly cost effective. The current Europe-wide high levels of undiagnosed FH, and associated morbidity and mortality, mean adoption of cascade services should yield substantial quality of life and survival gains.

Health Care Delivery Practices in Huntington's Disease Specialty Clinics: An International Survey.

BACKGROUND: Little is known about the organization of clinical services for Huntington's disease (HD). OBJECTIVE: To describe how health care services are organized and delivered in HD-clinics taking part in or eligible for the Enroll-HD study. METHODS: In 2014, a 69-item survey was administered to sites taking part in or eligible for the Enroll-HD study. RESULTS: Of 231 sites surveyed, 121 (52.2%) sites in Europe, North America, Latin America, and Oceania responded. Most sites in the sample serve large populations, with 61.1% serving more than 1.5 million people, and a further 33% serving >500,000. Almost all (86.0%) centers see patients from outside their region. The majority of centers (59.7%) follow 50-199 patients, 21.9% care for more than 200. Most centers provide care in all stages of HD, and nearly all review pre-symptomatic cases. Multidisciplinary case reviews are offered in 54.5% of sites, with outreach clinics offered by 48.1%. Videoconferencing and telemedicine are used by 23.6%. Separate consultations for caregivers are offered in more than half of the centers. Most centers (70.4%) report following published guidelines or local care pathways for HD. CONCLUSIONS: Most centers serve a large population and use a multidisciplinary approach. The survey gives insight into factors underpinning HD service delivery globally. There is a need for more in-depth studies of clinical practice to understand how services are organized and how such features may be associated with quality of care.

Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification.

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41% of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.

ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency.

Multiple acyl-CoA dehydrogenation deficiency (MADD) is a disorder of fatty acid, amino acid and choline metabolism that can result from defects in two flavoproteins, electron transfer flavoprotein (ETF) or ETF: ubiquinone oxidoreductase (ETF:QO). Some patients respond to pharmacological doses of riboflavin. It is unknown whether these patients have defects in the flavoproteins themselves or defects in the formation of the cofactor, FAD, from riboflavin. We report 15 patients from 11 pedigrees. All the index cases presented with encephalopathy or muscle weakness or a combination of these symptoms; several had previously suffered cyclical vomiting. Urine organic acid and plasma acyl-carnitine profiles indicated MADD. Clinical and biochemical parameters were either totally or partly corrected after riboflavin treatment. All patients had mutations in the gene for ETF:QO. In one patient, we show that the ETF:QO mutations are associated with a riboflavin-sensitive impairment of ETF:QO activity. This patient also had partial deficiencies of flavin-dependent acyl-CoA dehydrogenases and respiratory chain complexes, most of which were restored to control levels after riboflavin treatment. Low activities of mitochondrial flavoproteins or respiratory chain complexes have been reported previously in two of our patients with ETF:QO mutations. We postulate that riboflavin-responsive MADD may result from defects of ETF:QO combined with general mitochondrial dysfunction. This is the largest collection of riboflavin-responsive MADD patients ever reported, and the first demonstration of the molecular genetic basis for the disorder.