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1.  Huntington disease in the South African population occurs on diverse and ethnically distinct genetic haplotypes 
European Journal of Human Genetics  2013;21(10):1120-1127.
Huntington disease (HD) is a neurodegenerative disorder resulting from the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. Worldwide prevalence varies geographically with the highest figures reported in populations of European ancestry. HD in South Africa has been reported in Caucasian, black and mixed subpopulations, with similar estimated prevalence in the Caucasian and mixed groups and a lower estimate in the black subpopulation. Recent studies have associated specific HTT haplotypes with HD in distinct populations. Expanded HD alleles in Europe occur predominantly on haplogroup A (specifically high-risk variants A1/A2), whereas in East Asian populations, HD alleles are associated with haplogroup C. Whether specific HTT haplotypes associate with HD in black Africans and how these compare with haplotypes found in European and East Asian populations remains unknown. The current study genotyped the HTT region in unaffected individuals and HD patients from each of the South African subpopulations, and haplotypes were constructed. CAG repeat sizes were determined and phased to haplotype. Results indicate that HD alleles from Caucasian and mixed patients are predominantly associated with haplogroup A, signifying a similar European origin for HD. However, in black patients, HD occurs predominantly on haplogroup B, suggesting several distinct origins of the mutation in South Africa. The absence of high-risk variants (A1/A2) in the black subpopulation may also explain the reported low prevalence of HD. Identification of haplotypes associated with HD-expanded alleles is particularly relevant to the development of population-specific therapeutic targets for selective suppression of the expanded HTT transcript.
doi:10.1038/ejhg.2013.2
PMCID: PMC3778359  PMID: 23463025
Huntington disease; South Africa; haplotypes; haplogroups; prevalence; CAG expansion
2.  SHORT COMMUNICATION: Hyperphagia among patients with Bardet-Biedl syndrome 
Pediatric obesity  2013;8(5):e64-e67.
Summary
Background
The importance of hyperphagia as a cause for energy imbalance in humans with Bardet-Biedl syndrome (BBS) has not been established. We therefore compared hyperphagic symptoms in patients with BBS versus controls.
Methods
We studied 13 patients with BBS and 23 nonsyndromic controls with similar age, sex, and BMI z-score. A 13-item hyperphagia questionnaire was completed by patients’ parents/guardians.
Results
Total hyperphagia questionnaire score was higher in BBS than controls (27.6±9.0 vs. 19.1±7.9, p=0.005). Behavior and drive sub-scales were higher for BBS than controls (12.5±4.1 vs. 7.8±3.2, p=0.001, and 11.2±4.1 vs. 8.3±3.8, p=0.04, respectively); severity was not significantly different between groups (3.8±1.5 vs. 3.0±1.3, p=0.072). After adjustment for demographic variables and BMI-Z score, total and behavior subscale scores remained significantly different between groups, suggesting food-seeking activity, rather than preoccupation with food may be the main hyperphagic feature among patients with BBS.
Conclusion
Appetite dysregulation may contribute to obesity in BBS.
doi:10.1111/j.2047-6310.2013.00182.x
PMCID: PMC3901011  PMID: 23776152
hyperphagia; obesity; Bardet-Biedl syndrome; obesity syndromes; polyphagia; energy intake; questionnaire; child; adolescent
3.  Mutation Spectrum in the Large GTPase Dynamin 2, and Genotype–Phenotype Correlation in Autosomal Dominant Centronuclear Myopathy 
Human mutation  2012;33(6):949-959.
Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype–phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot–Marie–Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT.
doi:10.1002/humu.22067
PMCID: PMC3374402  PMID: 22396310
centronuclear myopathy; congenital myopathy; Charcot–Marie–Tooth neuropathy; DNM2; ADCNM; CMTD1B; DI-CMTB; CMT2M; hereditary motor and sensory neuropathy type II; HMSNII; MTM1; myotubular myopathy; BIN1; RYR1; endocytosis
4.  Novel and recurrent non-truncating mutations of the MITF basic domain: genotypic and phenotypic variations in Waardenburg and Tietz syndromes 
The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor, which regulates melanocyte development and the biosynthetic melanin pathway. A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss. Twelve patients with new or recurrent non-truncating mutations of the MITF basic domain from six families were enrolled in this study. We observed a wide range of phenotypes and some unexpected features. All the patients had blue irides and pigmentation abnormalities that ranged from diffuse hypopigmentation to Waardenburg-like patches. In addition, they showed congenital complete hearing loss, diffuse hypopigmentation of the skin, freckling and ocular abnormalities, more frequently than patients with MITF mutations outside the basic domain. In conclusion, the non-truncating mutations of the basic domain do not always lead to Tietz syndrome but rather to a large range of phenotypes. Sun-exposed freckles are interestingly observed more frequently in Asian populations. This variability argues for the possible interaction with modifier loci.
doi:10.1038/ejhg.2011.234
PMCID: PMC3330215  PMID: 22258527
Waardenburg syndrome; Tietz syndrome; MITF; freckles; pigmentation
5.  Novel and recurrent non-truncating mutations of the MITF basic domain: genotypic and phenotypic variations in Waardenburg and Tietz syndromes 
The microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor which regulates melanocyte development and the biosynthetic melanin pathway. A notable relationship has been described between non-truncating mutations of its basic domain and Tietz syndrome, which is characterized by albinoid-like hypopigmentation of the skin and hair, rather than the patchy depigmentation seen in Waardenburg syndrome, and severe hearing loss. Twelve patients with new or recurrent non-truncating mutations of the MITF basic domain from six families were enrolled in this study. We observed a wide range of phenotypes and some unexpected features. The patients all had blue irides and pigmentation abnormalities that ranged from diffuse hypopigmentation to Waardenburg-like patches. In addition, they showed congenital complete hearing loss, diffuse hypopigmentation of the skin, freckling and ocular abnormalities, more frequently than patients with MITF mutations outside the basic domain. In conclusion, the non-truncating mutations of the basic domain do not always lead to Tietz syndrome but rather to a large range of phenotypes. Sun-exposed freckles are interestingly observed more frequently in Asian populations. This variability argues for the possible interaction with modifier loci.
doi:10.1038/ejhg.2011.234
PMCID: PMC3330215  PMID: 22258527
Waardenburg syndrome; Tietz syndrome; MITF; Freckles; Pigmentation
6.  Mutations in TMEM216 perturb ciliogenesis and cause Joubert, Meckel and related syndromes 
Nature genetics  2010;42(7):619-625.
Joubert syndrome (JBTS), related disorders (JSRD) and Meckel syndrome (MKS) are ciliopathies. We now report that MKS2 and JBTS2 loci are allelic and due to mutations in TMEM216, encoding an uncharacterized tetraspan transmembrane protein. JBTS2 patients displayed frequent nephronophthisis and polydactytly, and two cases conformed to the Oro-Facio-Digital type VI phenotype, whereas skeletal dysplasia was common in MKS fetuses. A single p.R73L mutation was identified in all patients of Ashkenazi Jewish descent (n=10). TMEM216 localized to the base of primary cilia, and loss of TMEM216 in patient fibroblasts or following siRNA knockdown caused defective ciliogenesis and centrosomal docking, with concomitant hyperactivation of RhoA and Dishevelled. TMEM216 complexed with Meckelin, encoded by a gene also mutated in JSRD and MKS. Abrogation of tmem216 expression in zebrafish led to gastrulation defects that overlap with other ciliary morphants. The data implicate a new family of proteins in the ciliopathies, and further support allelism between ciliopathy disorders.
doi:10.1038/ng.594
PMCID: PMC2894012  PMID: 20512146
7.  Efavirenz use during pregnancy and for women of child-bearing potential 
Background
Efavirenz is the preferred non-nucleoside reverse transcriptase inhibitor for first-line antiretroviral treatment in many countries. For women of childbearing potential, advantages of efavirenz are balanced by concerns that it is teratogenic. This paper reviews evidence of efavirenz teratogenicity and considers implications in common clinical scenarios.
Findings
Concerns of efavirenz-induced fetal effects stem from animal studies, although the predictive value of animal data for humans is unknown. Four retrospective cases of central nervous system birth defects in infants with first trimester exposure to efavirenz have been interpreted as being consistent with animal data. In a prospective pregnancy registry, which is subject to fewer potential biases, no increase was detected in overall risk of birth defects following exposure to efavirenz in the first-trimester.
Discussion
For women planning a pregnancy or not using contraception, efavirenz should be avoided if alternatives are available. According to WHO guidelines for resource-constrained settings, benefits of efavirenz are likely to outweigh risks for women using contraception. Women who become pregnant while receiving efavirenz often consider drug substitution or temporarily suspending treatment. Both options have substantial risks for maternal and fetal health which, we argue, appear unjustified after the critical period of organogenesis (3–8 weeks post-conception). Efavirenz-based triple regimens, initiated after the first trimester of pregnancy and discontinued after childbirth, are potentially an important alternative for reducing mother-to-child transmission in pregnant women who do not yet require antiretroviral treatment.
Conclusion
Current recommendations for care for women who become pregnant while receiving efavirenz may need to be re-considered, particularly in settings with limited alternative drugs and laboratory monitoring. With current data limitations, additional adequately powered prospective studies are needed.
doi:10.1186/1742-6405-3-11
PMCID: PMC1468418  PMID: 16603057

Results 1-8 (8)