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The first Tanzania Liver Cancer Conference (TLCC2023) took place on 17-18 March 2023 in Dar es Salaam, Tanzania with the aim of raising awareness among healthcare providers on the problem that liver cancer poses to the Tanzanian population and the urgent need to address this important issue. The conference focused on the following agenda items: 1) to build awareness among local healthcare providers on the status of liver cancer in Tanzania and the available diagnostic and management options, 2) to update Tanzanian healthcare providers on the current standard of care for liver cancer provided in developed countries and recent advancements in liver cancer care and 3) to promote an inclusive and multidisciplinary approach in research and the clinical care of patients with liver cancer in Tanzania. TLCC2023 was preceded by community-facing pre-conference activities, including screening 684 community members for hepatitis B virus free of charge. The conference was attended by 161 healthcare professionals from varying disciplines across Tanzania and abroad. TLCC2023 featured over 30 speakers from Tanzania, Kenya, Egypt, India and the United States that comprehensively covered a wide range of topics related to research and clinical care of liver cancer patients. A holistic and unified approach integrating both private and public sectors is vital in improving care for patients with liver cancer, and this was a common theme ingrained in the majority of presentations. Overall, the conference was well-received by attendees and knowledge assessment scores improved from 50% pre-conference to 75% post-conference (p < 0.001), demonstrating its educational value. As Tanzania's first conference on the subject, TLCC2023 marked an important milestone in a united fight against liver cancer in the country and beyond.

PURPOSE Comprehensive breast cancer control programs are needed to decrease breast cancer mortality, but few tools exist to assist stakeholders in limited-resource settings. The Knowledge Summaries for Comprehensive Breast Cancer Control (KSBCs) are a series of evidence-based publications intended to support cancer control planning at various resource levels. The goals of this evaluation research study were to learn about the extent to which the KSBCs could be useful to policymakers, health care providers, and breast cancer advocates in Kenya, and whether introducing the KSBCs led to their uptake, and if so, how they were used. METHODS This study used one-on-one interviews, focus groups, and self-administered online surveys. Policymakers were recruited from the Ministry of Health. Providers were recruited from four hospitals in two cities, Nairobi and Eldoret, and one rural municipality, Kijabe. Advocates were recruited from cancer advocacy organizations. RESULTS Twenty individuals participated in the research. They found the KSBCs to be educational reference tools that create a shared planning-related knowledge base among diverse stakeholders. The KSBCs were seen to be applicable to a variety of contexts and stakeholders. CONCLUSION This study found that the KSBCs can be useful as both an educational tool and a convening tool for multistakeholder engagement in breast cancer prevention and control in a variety of settings. Additional engagement with users of the KSBCs can provide more knowledge about how the KSBCs are used and how they contribute to building collaborations across stakeholder groups to strengthen breast cancer prevention and control in low-resource settings.

Genetic polymorphisms within the IFNL3/IFNL4 genomic region, which encodes type III interferons, have been strongly associated with clearance of hepatitis C virus. We hypothesized that type III interferons might be important for the immune response to other pathogens as well. In a cohort of 914 Malian children, we genotyped functional variants IFNL4-rs368234815, IFNL4-rs117648444, and IFNL3-rs4803217 and analyzed episodes of malaria, gastrointestinal, and respiratory infections recorded at 30,626 clinic visits from birth up to 5 years of age. Compared to children with the rs368234815-TT/TT genotype (IFN-λ4-Null), rs368234815-dG allele was most strongly associated with an earlier time-to-first episode of gastrointestinal infections (p = 0.003). The risk of experiencing an infection episode during the follow-up was also significantly increased with rs368234815-dG allele, with OR = 1.53, 95%CI (1.13–2.07), p = 0.005 for gastrointestinal infections and OR = 1.30, 95%CI (1.02–1.65), p = 0.033 for malaria. All the associations for the moderately linked rs4803217 (r2 = 0.78 in this set) were weaker and lost significance after adjusting for rs368234815. We also analyzed all outcomes in relation to IFN-λ4-P70S groups. Our results implicate IFN-λ4 and not IFN-λ3 as the primary functional cause of genetic associations with increased overall risk and younger age at first clinical episodes but not with recurrence or intensity of several common pediatric infections.

Genetic polymorphisms within the IFNL3/IFNL4 genomic region, which encodes type III interferons, have been strongly associated with impaired clearance of hepatitis C virus (HCV) infection. We hypothesized that type III interferons might be important for the immune response to other pathogens as well. In a cohort of 914 Malian children, we analyzed episodes of malaria, gastrointestinal and respiratory infections using information for 30,626 clinic visits from birth through up to 5 years of follow-up. Genetic polymorphisms IFNL4-rs368234815 and IFNL3-rs4803217 that functionally affect type III interferons were genotyped with TaqMan assays. For both genetic variants and each infection, we evaluated time-to-first episode and calculated odds ratios (ORs) for the risk of an infection episode during follow-up, controlling for relevant covariates. Compared to children with the rs368234815-TT/TT genotype (IFN-λ4-Null), each copy of the rs368234815-dG allele was associated with an earlier first episode of a gastrointestinal infection (p=0.003) and respiratory infection (p=0.045). The risk of experiencing an infection episode during the follow-up was also significantly increased with each copy of the rs368234815-dG allele – for gastrointestinal infections (OR=1.53, 95%CI (1.13-2.07), p=0.005) and malaria (OR=1.30, 95%CI (1.02-1.65), p=0.033). IFNL4-rs368234815 and IFNL3-rs4803217 were in moderate linkage disequilibrium in this population (r2=0.78), and all the associations for rs4803217 were weaker and lost significance after adjusting for rs368234815, implicating IFN-λ4 and not IFN-λ3 as the primary cause of these associations. We conclude that the ability to produce IFN-λ4 may have broad health-related implications by negatively affecting the immune response and clinical outcomes of several common infections.

Purpose Histology and cytopathology services are necessary for cancer diagnosis and treatment. However, the current capacity of Kenya’s pathology laboratories is unknown. A national survey was conducted among public sector pathology laboratories to assess their capacity to perform histology, fine-needle aspiration, and bone marrow aspiration. Methods Between April and June 2017, we identified all public hospitals that provide pathology services in Kenya. In total, two national and 13 county referral hospitals met the inclusion criteria and were sent a standardized, pretested, self-administered questionnaire. Results A total of 11 hospitals (73%) completed the survey. The reported total caseload of histology, fine-needle aspiration, and bone marrow aspiration for 2016 was 26,472. All of the facilities staffed a pathologist and were providing cancer-related diagnostic services. Nine (82%) of the hospitals maintain a register of diagnosed cancer cases, but only one (11%) of those uses an electronic system. Six (55%) of the surveyed hospitals were able to perform histology with a median turnaround time of 14 days. Six (55%) laboratories regularly referred some specimens elsewhere for interpretation, but three of these centers relied on patients for transportation of the specimen to the referral institution. No laboratories were accredited by an external organization; however, 10 (91%) of the laboratories were working toward achieving accreditation, but only for clinical pathology services. Conclusion This study describes the current status of histology and cytopathology capacity in Kenya’s public sector hospitals. It provides useful baseline information needed by the Ministry of Health to develop necessary capacity building and referral-strengthening interventions. A high proportion of hospitals are working to achieve accreditation points toward their commitment to providing quality services to the Kenyan public.

Background Delays to cancer diagnosis exist, resulting in worse survival outcomes for many cancers. Interventions targeting delays and barriers to cancer diagnosis and treatment have been investigated, but mostly in high-income countries. We conducted a systematic literature review to identify and characterize the interventions studied across cancers, within low- and middle-income countries (LMICs). Methods This systematic review forms part two of a wider study examining solutions to delays and barriers in cancer early diagnosis in LMICs. A comprehensive literature search was conducted on November 27, 2017, encompassing published studies from the preceding 15 years. We extracted study design, population, and intervention, and reported outcome measures from each study. Results were presented by target of interventions (general vs. health care professionals). A narrative synthesis was used to summarize intervention efficacy. Results Of 10,193 abstracts returned, 25 were included, consisting of studies across World Health Organization geographical regions, examining breast, cervix, childhood, prostate, head and neck, and gastric cancers. Altogether, 11 intervention studies targeted the general population, 12 targeted health care professionals, and 2 targeted both. The majority (17/25) of studies reported interventions focusing on patient and diagnosis-related barriers early in the cancer care pathway. Most studies reported knowledge score as primary outcome measure (17/25); few (6/25) reported on clinically relevant measures such as reducing disease stage at presentation or diagnostic time interval. Effectiveness of interventions was demonstrated for some cancers only. Conclusion More interventions reporting clinically relevant measures and using standardized methods and outcomes are required to improve our ability to effectively improve cancer early diagnosis in LMICs. Implications for Practice Prior to this study, the extent of intervention literature in cancer early diagnosis in low- and middle-income countries had not been characterized. This study aimed to outline and characterize interventions across all cancer types and across all countries. This systematic review demonstrated that interventions have been investigated targeting both the general population and health care professionals. Furthermore, this review demonstrates that the majority of studies report knowledge as an outcome measure, rather than clinically significant measures that improve cancer-related outcomes, such as delay intervals or downstaging of disease. Future interventions should address clinically relevant measures to better assess efficacy of interventions.

This review outlines causes of delays in diagnosis and barriers to early diagnosis of cancer in patients in low‐ and middle‐income countries., Background. Advanced stage presentation of patients with is common in low‐ and middle‐income countries (LMICs). A comprehensive analysis of existing delays and barriers in LMICs has not been previously reported. We conducted a systematic literature review to comprehensively outline delays and barriers to identify targets for future interventions and provide recommendations for future research in this field. Materials and Methods. Multiple electronic databases were searched using a standardized search strategy. Eligible articles were of any language, from LMICs, and published between January 1, 2002, and November 27, 2017. Included studies reported cancer care intervals or barriers encountered. Intervals and associated barriers were summarized by cancer type and geographical region. Results. This review included 316 study populations from 57 LMICs: 142 (44.9%) studies addressed time intervals, whereas 214 (67.7%) studies described barriers to cancer diagnosis. The median intervals were similar in the following three stages of early diagnosis: (a) access (1.2 months), (b) diagnostic (0.9 months), and (c) treatment (0.8 months). Studies from low‐income countries had significantly longer access intervals (median, 6.5 months) compared with other country income groups. Patients with breast cancer had longer delay intervals than patients with childhood cancer. No significant variation existed between geographic regions. Low health literacy was reported most frequently in studies describing barriers to cancer diagnosis and was associated with lower education level, no formal employment, lower income, and rural residence. Conclusion. Early diagnosis strategies should address barriers during all three intervals contributing to late presentation in LMICs. Standardization in studying and reporting delay intervals in LMICs is needed to monitor progress and facilitate comparisons across settings. Implications for Practice. This review draws the attention of cancer implementation scientists globally. The findings highlight the significant delays that occur throughout the cancer care continuum in low‐ and middle‐income countries and describe common barriers that cause them. This review will help shape the global research agenda by proposing metrics and implementation studies. By demonstrating the importance of standardized reporting metrics, this report sets forth additional research and evidence needed to inform cancer control policies.

PURPOSE In 2017, the Kenya Ministry of Health launched the National Cancer Control Strategy 2017 to 2022. A scoping review of oncology research in Kenya was conducted to understand the scope of—and gaps in—existing research and inform the development of the national cancer research agenda. METHODS We searched PubMed/MEDLINE, Embase, Scopus, and Global Health databases using controlled vocabulary and keywords to identify oncology research with a study site in Kenya, published in English, from 2007 to 2017. Fifteen journals and additional gray literature sources were hand searched. Screening of titles, abstracts, and full text was completed by pairs of 2 reviewers, with a third reviewer reconciling discrepancies. From included studies, data were extracted and coded using Google Forms. Microsoft Excel was used for descriptive statistics. RESULTS Of the 284 included articles, a majority were analytic observational studies (66.9%). The top 5 cancers studied were cervical cancer (n = 106; 35.9%), breast cancer (n = 25; 11.9%), Burkitt lymphoma (n = 23; 8.5%), esophageal cancer (n = 15; 5.1%), and pediatric cancers (n = 12; 4.1%). Primary focus areas were early detection, diagnosis, and prognosis and cancer control, survivorship, and outcomes research. Kenyatta National Hospital, Moi Teaching and Referral Hospital, and University of Nairobi were most often cited as research host institutions. One hundred twenty-three unique funding sources were reported, with the most prevalent study funding sources by region being North America (48%), Europe (28.8%), and Middle East/Africa (17.6%). The US National Institutes of Health was cited as the leading funding source of cancer research in Kenya. CONCLUSION This scoping review provides an overview of the published literature on cancer research conducted in Kenya. It highlights cancer research by cancer type, location, and focus area. It also focuses attention on research gaps, as well as the need for rigorous, well-conducted population-based studies, longitudinal studies, and randomized controlled trials aligned with the cancer burden in Kenya.

Purpose The goal of this study was to describe the pathologic findings and early follow-up experience of patients who underwent a sentinel lymph node biopsy (SLNB) at Aga Khan University Hospital (AKUH) between 2008 and 2017. Patients and Methods We performed a retrospective analysis of women with breast cancer who underwent an SLNB at AKUH between 2008 and 2017. The SLNB was performed on patients with stage I and stage II breast cancer, and identification of the sentinel lymph node was made by radioactive tracer, blue dye, or both, per availability and surgeon preference. Demographic, surgical, and pathologic data, including immunohistochemistry of the surgical sample for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, were abstracted from the patient records. Follow-up data were available for a subset of patients. Results Between 2008 and 2017, six surgeons performed SLNBs on 138 women, 129 of whom had complete records and were included in the study. Thirty-one of 129 (24%) had a positive SLNB, including 10 of 73 (14%) with stage I and 21 of 56 (38%) with stage II disease. Seventy-eight patients (60%) received systemic adjuvant chemotherapy and 79 (62%) received radiation therapy, and of the 102 patients who were estrogen receptor positive, 86 (85%) received endocrine therapy. Seventy-nine patients were observed for > 2 years, and, of these, four (5.1%) had a regional recurrence. Conclusion The SLNB positivity rates were similar to those of high-income country (HIC) cohorts. However, preliminary data suggest that recurrence rates are elevated at AKUH as compared with those of HIC cohorts, perhaps because of a lower use of radiotherapy and chemotherapy at AKUH compared with HIC cohorts or because of differences in the characteristics of the primary tumor in patients at AKUH as compared with those in HICs.

Interferon lambda 4 (IFN-λ4) is a novel type-III interferon that can be generated only in individuals carrying a ΔG frame-shift allele of an exonic genetic variant (rs368234815-ΔG/TT). The rs368234815-ΔG allele is strongly associated with decreased clearance of hepatitis C virus (HCV) infection. Here, we further explored the biological function of IFN-λ4 expressed in human hepatic cells-a hepatoma cell line HepG2 and fresh primary human hepatocytes (PHHs). We performed live confocal imaging, cell death and proliferation assays, mRNA expression profiling, protein detection, and antibody blocking assays using transient and inducible stable in vitro systems. Not only did we observe significant intracellular retention of IFN-λ4 but also detected secreted IFN-λ4 in the culture media of expressing cells. Secreted IFN-λ4 induced strong activation of the interferon-stimulated genes (ISGs) in IFN-λ4-expressing and surrounding cells in transwell assays. Specifically, in PHHs, secreted IFN-λ4 induced expression of the CXCL10 transcript and a corresponding pro-inflammatory chemokine, IP-10. In IFN-λ4-expressing HepG2 cells, we also observed decreased proliferation and increased cell death. All IFN-λ4-induced phenotypes--activation of ISGs, decreased proliferation, and increased cell death--could be inhibited by an anti-IFN-λ4-specific antibody. Our study offers new insights into biology of IFN-λ4 and its possible role in HCV clearance.

Summary Insufficient awareness of the centrality of pathology and laboratory medicine (PALM) to a functioning health-care system at policy and governmental level, with the resultant inadequate investment, has meant that efforts to enhance PALM in low-income and middle-income countries have been local, fragmented, and mostly unsustainable. Responding to the four major barriers in PALM service delivery that were identified in the first paper of this Series (workforce, infrastructure, education and training, and quality assurance), this second paper identifies potential solutions that can be applied in low-income and middle-income countries (LMICs). Increasing and retaining a quality PALM workforce requires access to mentorship and continuing professional development, task sharing, and the development of short-term visitor programmes. Opportunities to enhance the training of pathologists and allied PALM personnel by increasing and improving education provision must be explored and implemented. PALM infrastructure must be strengthened by addressing supply chain barriers, and ensuring laboratory information systems are in place. New technologies, including telepathology and point-of-care testing, can have a substantial role in PALM service delivery, if used appropriately. We emphasise the crucial importance of maintaining PALM quality and posit that all laboratories in LMICs should participate in quality assurance and accreditation programmes. A potential role for public-private partnerships in filling PALM services gaps should also be investigated. Finally, to deliver these solutions and ensure equitable access to essential services in LMICs, we propose a PALM package focused on these countries, integrated within a nationally tiered laboratory system, as part of an overarching national laboratory strategic plan.

Background In response to a growing cancer burden and need for improved coordination among stakeholders in Kenya, the US National Cancer Institute and the Kenya Ministry of Health collaboratively hosted a stakeholder meeting in 2014 which identified four priority areas of need (research capacity building, pathology and cancer registries, cancer awareness and education, and health system strengthening) and developed corresponding action plans. Methods Surveys were conducted with participants to collect input on the progress and impact of the 2014 stakeholder meeting. Findings Of 69 eligible participants, 45 responded from academia, healthcare institutions, civil society, government, and international agencies. Of the four technical focus areas, three have continued to conduct working group meetings and two have conducted in-person meetings to review and update their respective action plans. Accomplishments linked to or enhanced by the meeting include: Kenyan and international support for expansion of population-based cancer registries, increased availability of prioritized diagnostic tests in selected regional referral hospitals, a greater focus on development of a national cancer research agenda, strategic planning for a community education strategy for cancer awareness, and improved coordination of partners through in-country technical assistance. Interpretation The Stakeholder Program has successfully united individuals and organizations to improve cancer control planning in Kenya, and has enhanced existing efforts and programs across the country. This model of partners working in parallel on prioritized track activities has supported development of long term coordination of cancer research and control activities sustainable by the Kenyan government and Kenyan institutions.

Chronic infection with hepatitis C virus (HCV) is a common cause of liver cirrhosis and cancer. We performed RNA sequencing in primary human hepatocytes activated with synthetic double-stranded RNA to mimic HCV infection. Upstream of IFNL3 (IL28B) on chromosome 19q13.13, we discovered a new transiently induced region that harbors a dinucleotide variant ss469415590 (TT or ΔG), which is in high linkage disequilibrium with rs12979860, a genetic marker strongly associated with HCV clearance. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designated IFNL4, encoding the interferon-λ4 protein (IFNL4), which is moderately similar to IFNL3. Compared to rs12979860, ss469415590 is more strongly associated with HCV clearance in individuals of African ancestry, although it provides comparable information in Europeans and Asians. Transient overexpression of IFNL4 in a hepatoma cell line induced STAT1 and STAT2 phosphorylation and the expression of interferon-stimulated genes. Our findings provide new insights into the genetic regulation of HCV clearance and its clinical management.

Lactic acidosis (LA) is a marker for mortality in severe malaria, but the mechanisms that lead to LA in the different types of severe malaria and the extent to which LA-associated mortality differs by type of severe malaria are not well described. We assessed the frequency of LA in children admitted to Mulago Hospital, Kampala, Uganda with cerebral malaria (CM, n = 193) or severe malarial anemia (SMA, n = 216). LA was compared to mortality and measures of parasite biomass and sequestration (P. falciparum histidine-rich protein-2 (PfHRP2) concentration, platelet count), and to a measure of systemic tissue oxygen delivery (hemoglobin level). LA was more frequent in children with SMA than CM (SMA, 47.7%, CM, 34.2%, P = 0.006), but mortality was higher in children with CM (13.0%) than SMA (0.5%, P

A Sephardi Jewish family is reported in which the two brothers had mental retardation, lower limb spasticity and bilateral clasped thumbs anomaly. This X-linked recessive disorder has only been reported twice. We believe this syndrome comprises a distinct entity among the X-linked mental retardation syndromes.

Abstract —In a previous report by Freedman et al ( J Clin Invest. 1996;97:979–987), plasma from 2 brothers with stroke or transient ischemic attack inactivated the antiplatelet effects of nitric oxide (NO), and this effect was found to be a consequence of a deficiency of plasma glutathione peroxidase (GSH-Px). In this study, we attempted to define the generalizability of this deficiency by studying NO-mediated antiplatelet effects in 7 families with familial childhood stroke. Seven families with familial childhood stroke that consecutively presented to a large referral center were included in the study. We monitored ADP-induced aggregation of normal gel-filtered platelets (GFP) in platelet-poor plasma (PPP) from normal individuals and from patients in the presence or absence of an NO donor (S-nitroso–glutathione). Surface P-selectin expression of normal GFP in patients’ PPP was analyzed by flow cytometry after incubation with a P-selectin–specific monoclonal antibody in the presence or absence of the NO donor. We also measured GSH-Px activity in plasmas from family members and normal controls using standard methods. In 6 of 7 families, NO failed to inhibit platelet P-selectin expression and platelet aggregation in PPP from the affected family members and some of their relatives. Of 4 families studied, 3 probands and their corresponding affected parent had 50% decrease in plasma GSH-Px activity. In some patients with childhood stroke, impaired metabolism of reactive oxygen species as a result of reduced GSH-Px activity results in NO insufficiency that affects normal platelet inhibitory mechanisms and predisposes to arterial thrombosis.

Background Cerebral malaria (CM) and severe malarial anemia (SMA) account for a substantial proportion of malaria-related deaths in sub-Saharan Africa. However, postdischarge morbidity in children with CM or SMA has not been well established. Methods Children 18 months to 12 years of age, enrolled on admission to Mulago National Referral Hospital in Kampala, Uganda (CM, n = 162; SMA, n = 138), and healthy children recruited from the community (CC) (n = 133) were followed up for 6 months. The incidences of hospitalizations and outpatient clinic visits for illness during the follow-up period were compared between children with CM or SMA and the CC. Results After adjustment for age, sex, and nutritional status, children with SMA had a higher incidence rate ratio (IRR) than CC for hospitalization (95% confidence interval [CI], 20.81 [2.48-174.68]), hospitalization with malaria (17.29 [95% CI, 2.02-148.35]), and clinic visits for any illness (95% CI, 2.35 [1.22-4.51]). Adjusted IRRs for children with CM were also increased for all measures compared with those for CC, but they achieved statistical significance only for clinic visits for any illness (2.24 [95% CI, 1.20-4.15]). In both groups, the primary reason for the clinic visits and hospitalizations was malaria. Conclusions In the 6 months after initial hospitalization, children with SMA have an increased risk of repeated hospitalization, and children with CM or SMA have an increased risk of outpatient illness. Malaria is the main cause of inpatient and outpatient morbidity. Malaria prophylaxis has the potential to decrease postdischarge morbidity rates in children with SMA or CM.

Phenylketonuria (PKU) and benign hyperphenylalaninaemia (HPA) result from a variety of mutations in the gene for the hepatic enzyme phenylalanine hydroxylase. PKU has been found in the Israeli population in two variants, classical and atypical. The two are clinically indistinguishable and require treatment with low phenylalanine diet to prevent mental retardation, but show differences in serum phenylalanine levels and in tolerance to this amino acid. Maternal PKU is a syndrome of congenital anomalies and mental retardation that appears in offspring of PKU mothers as a result of fetal exposure to the high phenylalanine level in the maternal blood. We studied a family in which two children with severe, classical PKU and their unaffected brother showed mild signs of maternal PKU. Their mother had no clinical signs of PKU, but the phenylalanine concentration in her serum reached a level that usually characterises PKU patients. This woman represents a rare phenotype, benign atypical PKU. Such 'hidden' PKU in women may lead to maternal PKU in the offspring, similar to overt PKU. Special attention should therefore be paid to women having children with any of the clinical hallmarks of maternal PKU, and to children born to women known to have benign HPA. The mother was also found to be homozygous for a missense mutation at the phenylalanine hydroxylase locus, R261Q, which does not abolish enzymatic activity completely. In two other families, homozygosity for this mutation resulted in atypical PKU in four children. This observation suggests that mutations that do not completely destroy phenylalanine hydroxylase activity may exhibit variable phenotypic expression which is unpredictable. Compound heterozygosity for R261Q and other mutations led in other patients either to classical PKU or to mild benign HPA.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a progressive inherited neurological disorder characterized by macrocephaly, deterioration in motor functions and cerebellar ataxia. In Israel the disease is found in an increased frequency among Libyan Jews. The disease is caused by mutations in the MLC1 gene, which encodes a putative CNS membrane transporter. We describe three novel mutations (p.G59E, p.P92S, and 134_136insC) in seven MLC families. One of these mutations, p.G59E, was found in the vast majority of MLC patients in Israel. Screening of 200 normal Libyan Jewish individuals for the p.G59E mutation, revealed a carrier rate of 1/40 compared with an expected carrier rate of 1/81. Several explanations could account for this difference the most likely one is an admixture of the Libyan Jewish population.

Vacuolating megalencephalic leucoencephalopathy with subcortical cysts (VL) is a newly described, inherited leucodystrophy (MIM 604004). Clinically, the disease is characterised by accelerated head growth beginning in the first year of life and resulting in extreme macrocephaly and mild delays in gross motor milestones. In most cases, these early manifestations are followed by evolution of pyramidal symptoms and signs, cerebellar ataxia, epilepsy, and in older patients dystonia and athetosis.1 Cognitive function is relatively spared in most patients. Brain imaging with computed tomography (CT) or magnetic resonance imaging (MRI) shows diffuse cerebral white matter swelling with progressive cystic-like changes, prominent in the frontotemporal regions, with preservation of grey matter structures.1,2 Pathological specimens from VL patients showed splitting of the myelin sheaths between the lamellae consistent with an oedematous process, with sparing of the exons.3 Although progressive in nature, VL is characterised by a relatively mild clinical course compared to the severity of the neuroradiological findings.4,5 About 70 cases of the disease have been described in different ethnic groups. The molecular basis of this disorder remains unknown. The inheritance is autosomal recessive and the disease gene was recently mapped to a 3 cM interval between D22S1161 and the telomere of chromosome 22q.6 Linkage was established in a group of 13 Turkish families all originating from rural areas of central and south eastern Anatolia. No shared alleles or shared haplotypes were detected between the Turkish families. Six of the seven families included in this study (fig 1) have been described in detail by Ben Zeev et al .7 Families 1, 2, 4, and 6 are of Libyan Jewish origin and family 3 is of Turkish Jewish origin. …

We have identified a novel human interferon, designated as interferon-λ4 (IFN-λ4) (Prokunina-Olsson et al., Nature Genetics, 2013). Inducible expression of IFNL4 , along with three related genes ( IFNL1 , IFNL2 and IFNL3 ) located on chromosome 19q13.13 and encoding other interferon-λ proteins, IFN-λ1, IFN-λ2 and IFN-λ3, was revealed by RNA-sequencing in primary human hepatocytes treated with polyI:C. In humans, IFN-λ4 is fully genetically controlled – it is produced only by mRNA transcripts with a frameshift dG allele of a genetic variant ss469415590 (TT/dG) within the first exon of the gene, while transcripts with the TT allele can generate only unrelated proteins or protein fragments. We characterized IFN-λ4 as a class-2 cytokine based on its protein homology with IFN-λ3 (29% amino acid identity), the ability to cause STAT1 and STAT2 phosphorylation, activation of an ISRE-Luc reporter, induction of ISGs and antiviral response in HepG2 cells transiently transfected with an IFNL4-expressing construct. IFN-λ4 signaling is decreased by a JAK inhibitor, siRNA-silencing of IFN-λR1, and blocking of IL10R2. However, HepG2 cells did not respond to treatment with purified recombinant IFN-λ4 protein. Protein expression of IFN-λ4 is detectable in cells transfected with an IFNL4-expressing construct but not in the culture supernatants. It remains unclear whether IFN-λ4 is an unusual intracellular interferon, which signals through yet unknown intracellular partners or it is released at low levels through secretion or other mechanisms. Individuals homozygous for the derived human-specific ss469415590-TT allele (90% of Asians, 50% of Europeans and 10% of individuals of African ancestry) are genetically unable to produce IFN-λ4. This pattern suggests strong positive selection for elimination of IFN-λ4, which might be caused by current or historic infectious diseases. Individuals who are unable to produce IFN-λ4 are more likely to clear hepatitis C virus (HCV) either spontaneously or after treatment with IFN-α and ribavirin.

Mutations and polymorphisms at the phenylalanine hydroxylase (PAH) gene were used to study the genetic diversity of the Jewish and Palestinian Arab populations in Israel. PAH mutations are responsible for a large variety of hyperphenylalaninemias (HPAs), ranging from the autosomal recessive disease phenylketonuria to various degrees of nonclinical HPA. Seventy-two Jewish and 36 Palestinian Arab families with various HPAs, containing 115 affected genotypes, were studied by haplotype analysis, screening for previously known PAH lesions and a search for novel mutations. Forty-one PAH haplotypes were observed in this sample. Four mutations previously identified in Europe (IVS10nt546, R261Q, R408W and R158Q) were found, and were associated with the same haplotypes as in Europe, indicating possible gene flow from European populations into the Jewish and Palestinian gene pools. Of particular interest is a PAH allele with the IVS10nt546 mutation and haplotype 6, that might have originated in Italy more than 3,000 years ago and spread during the expansion of the Roman Empire. These results, together with previous identification of three PAH mutations unique to Palestinian Arabs [IVSnt2, Edel(197-205) and R270S], indicate that the relatively high genetic diversity of the Jewish and Palestinian populations reflects, in addition to genetic events unique to these communities, some gene flow from neighboring and conquering populations.

An eight-year-old boy developed acute parkinsonism four days after open-heart surgery for repair of a ventriculo-septal defect. During the procedure he experienced a hypotensive episode which required administration of positive-inotropic agents. Complementing the clinical signs of parkinsonism, CT scan showed symmetrical hypodensities in the basal ganglia, and decreased regional cerebral blood flow was demonstrated using 99mTc HMPAO SPECT. These findings were suggestive of a hypoxic-ischaemic insult to the basal ganglia. The child was treated with levodopa/carbidopa and subsequently completely recovered within a follow-up period of eight months. CT scan appearances and cerebral blood flow findings returned to normal. Parkinsonism secondary to a hypoxic-ischaemic insult to basal ganglia in children is a rare but reversible disorder, in contrast to its progressive course which results in severe disability in adults.

The combination of microcephaly, spasticity, and profound mental retardation is usually found in children with severe perinatal asphyxia or congenital infection. These children are commonly diagnosed as having cerebral palsy. However, in some children there is no evidence of a perinatal insult and there may be familial recurrence.1 The London Dysmorphology Database2 offers 104 genetic syndromes that include these features. However, most of them also show dysmorphism and other organ involvement. Twenty-three of these syndromes are the result of an identified inborn error of metabolism. In some genetic syndromes the microcephaly may be progressive and brain neuroimaging may show cortical or cerebellar atrophy.3 Cerebellar atrophy can be associated with spasticity and profound mental retardation in pontocerebellar hypoplasia type 2 (PCH 2). We describe seven patients from six non-consanguineous Sephardi Jewish families with a previously undescribed syndrome of profound mental retardation, progressive microcephaly, and severe spasticity. Radiologically, repeat magnetic resonance imaging showed progressive cerebellar atrophy followed by cerebral atrophy involving both white and grey matter. An extensive metabolic evaluation was normal. Table 1 shows seven patients (five female), identified in two paediatric neurology clinics in Israel, with a similar clinical picture of profound mental retardation, progressive microcephaly, and severe spasticity. All had the same radiological features consistent with progressive cerebellar atrophy and cerebral atrophy involving both white and grey matter. View this table: Table 1 Patient characteristics Five patients were isolated cases and two were sisters. All families were non-consanguineous Sephardi Jews of either Moroccan or Iraqi origin. All the parents and unaffected sibs were healthy and neurologically intact. Age range was 18 months to 19 years. All patients were the product of a normal pregnancy and delivery. Head circumference was normal at birth. Progressive microcephaly became evident during the first year of life, ranging from 2 to 5 SD below the norm. …

Generalized epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by the presence of febrile and afebrile seizures. The first gene, GEFS1, was mapped to chromosome 19q and was identified as the sodium-channel beta1-subunit, SCN1B. A second locus on chromosome 2q, GEFS2, was recently identified as the sodium-channel alpha1-subunit, SCN1A. Single-stranded conformation analysis (SSCA) of SCN1A was performed in 53 unrelated index cases to estimate the frequency of mutations in patients with GEFS+. No mutations were found in 17 isolated cases of GEFS+. Three novel SCN1A mutations-D188V, V1353L, and I1656M-were found in 36 familial cases; of the remaining 33 families, 3 had mutations in SCN1B. On the basis of SSCA, the combined frequency of SCN1A and SCN1B mutations in familial cases of GEFS+ was found to be 17%.