Gene Variants Determine Placental Transfer of Perfluoroalkyl Substances (PFAS), Mercury (Hg) and Lead (Pb), and Birth Outcome: Findings From the UmMuKi Bratislava-Vienna Study.

Prenatal exposure to perfluoroalkyl substances (PFAS), bisphenol A (BPA), lead (Pb), total mercury (THg), and methylmercury (MeHg) can affect fetal development. Factors influencing placental transfer rate of these toxins are poorly investigated. Whether prenatal exposure to pollutants has an effect on birth weight is incompletely understood. We therefore aimed (1) to determine placental transfer rates of PFAS, BPA, Pb, THg, and MeHg, (2) to analyze relationships between fetal exposure and birth outcome and (3) to analyze gene variants as mediators of placental transfer rates and birth outcome. Two hundred healthy pregnant women and their newborns participated in the study. BPA, 16 PFAS, THg, MeHg, and Pb were determined using HPLCMS/MS (BPA, PFAS), HPLC-CV-ICPMS (MeHg), CV-AFS (THg), and GF-AAS (Pb). Questionnaires and medical records were used to survey exposure sources and birth outcome. 20 single nucleotide polymorphisms and two deletion polymorphisms were determined by real-time PCR from both maternal and newborn blood. Genotype-phenotype associations were analyzed by categorical regression and logistic regression analysis. Specific gene variants were associated with altered placental transfer of PFAS (ALAD Lys59Asn, ABCG2 Gln141Lys), THg (UGT Tyr85Asp, GSTT1del, ABCC1 rs246221) and Pb (GSTP1 Ala114Val). A certain combination of three gene polymorphisms (ABCC1 rs246221, GCLM rs41303970, HFE His63Asp) was over-represented in newborns small for gestational age. 36% of Austrian and 75% of Slovakian mothers had levels exceeding the HBM guidance value I (2 µg/L) of the German HBM Commission for PFOA. 13% of newborns and 39% of women had Ery-Pb levels above 24 µg/kg, an approximation for the BMDL01 of 12 µg/L set by the European Food Safety Authority (EFSA). Our findings point to the need to minimize perinatal exposures to protect fetal health, especially those genetically predisposed to increased transplacental exposure.

Report of a Second Lebanese Family with Basel-Vanagaite-Smirin-Yosef Syndrome: Possible Founder Mutation.

Basel-Vanagaite-Smirin-Yosef syndrome (OMIM 616449) is a rare autosomal recessive genetic disorder characterized by severe developmental delay and variable craniofacial, neurological, cardiac, and ocular anomalies in the presence of variants in the MED25 gene. So far, only a handful of patients have been reported with this condition globally. Here, we report an additional Lebanese family with 2 affected siblings presenting with severely delayed psychomotor and language development as well as craniofacial anomalies. By whole-exome sequencing (WES), a homozygous variant was found in the MED25 gene, c.518T>C, predicted to result in a p.Ile173Thr change in the MED25 protein. This change has recently been reported in another Lebanese family. Review of the literature, the importance of this mutation in the Lebanese population, and the possibility that this condition may be underdiagnosed and only effectively detected using molecular techniques such as WES are discussed.

The Lebanese Allele in the PET100 Gene: Report on Two New Families with Cytochrome c Oxidase Deficiency.

Cytochrome c oxidase deficiency is caused by mutations in any of at least 30 mitochondrial and nuclear genes involved in mitochondrial complex IV biogenesis and structure, including the recently identified PET100 gene. Here, we report two families, of which one is consanguineous, with two affected siblings each. In one family, the siblings presented with developmental delay, seizures, lactic acidosis, abnormal brain magnetic resonance imaging, and low muscle mitochondrial complex IV activity at 30%. In the other family, the two siblings, now deceased, had a history of global developmental delay, failure to thrive, muscular hypotonia, seizures, developmental regression, respiratory insufficiency, and lactic acidosis. By whole exome sequencing, a missense mutation in exon 1 of the PET100 gene (c.3G > C; [p.Met1?]) was identified in both families. A review of the clinical description and literature is discussed, highlighting the importance of this variant in the Lebanese population.

A novel nonsense autosomal dominant mutation in the GLRA1 gene causing hyperekplexia.

We present a family with two members affected by hyperekplexia and two unaffected members. All exons in the glycine receptor alpha 1 subunit gene (GLRA1) were sequenced in all four family members. Our index patient harbored a novel nonsense mutation (p.Trp314*; rs867618642) in the transmembrane domain three of the GLRA1 and a novel missense variant in the NH2-terminal part (p.Val67Met; rs142888296). After development of tolerance for the effective treatment with clobazam a drug holiday led to a sustained restoration of the treatment response.

Cochlear Implantation in Siblings With Refsum's Disease.

OBJECTIVES: Whether the origin of severe hearing loss in Refsum's syndrome is caused by cochlear impairment or retrocochlear degeneration remains unclear. This case report aims to investigate hearing performance before and after cochlear implantation to shed light on this question. Also, identification of new mutations causing Refsum's syndrome would be helpful in generating additional means of diagnosis. METHODS: A family of 4 individuals was subjected to genetic testing. Two siblings (56 and 61 years old) suffered from severe hearing and vision loss and received bilateral cochlear implants. Genetic analysis, audiological outcome, and clinical examinations were performed. RESULTS: One new mutation in the PHYH gene (c.768del63bp) causing Refsum's disease was found. Preoperative distortion product otoacoustic emissions (DPAOEs) were absent. Postoperative speech perception in Freiburger speech test was 100% for bisyllabic words and 85% (patient No. 1) and 65% (patient No. 2), respectively, for monosyllabic words. Five years after implantation, speech perception remained stable for bisyllabic words but showed decreasing capabilities for monosyllabic words. DISCUSSION: A new mutation causing Refsum's disease is presented. Cochlear implantation in case of severe hearing loss leads to an improvement in speech perception and should be recommended for patients with Refsum's disease, especially when the hearing loss is combined with a severe loss of vision. Decrease of speech perception in the long-term follow-up could indicate an additional retrocochlear degeneration.

Hereditary Neuropathy with Liability to Pressure Palsies Masked by Previous Gunshots and Tuberculosis.

Objectives. Although hereditary neuropathy with liability to pressure palsies (HNPP) presents with a distinct phenotype on history, clinical exam, and nerve conduction studies, it may be masked if diagnostic work-up suggests other causes. Case Report. In a 37-year-old male with pseudoradicular lumbar pain, neurological exam revealed sore neck muscles, peripheral facial nerve palsy, right anacusis and left hypoacusis, hemihypesthesia of the right face, mild distal quadriparesis, diffuse wasting, and generally reduced tendon reflexes. He had a history of skull fracture due to a gunshot behind the right ear and tuberculosis for which he had received adequate treatment for 3 years; MRI revealed a disc prolapse at C6/7 and Th11/12. Nerve conduction studies were indicative of demyelinating polyneuropathy with conduction blocks. Despite elevated antinuclear antibodies and elevated CSF-protein, HNPP was diagnosed genetically after having excluded vasculitis, CIDP, radiculopathy, and the side effects of antituberculous treatment. Conclusions. HNPP may manifest with mild, painless, distal quadriparesis. The diagnosis of HNPP may be blurred by a history of tuberculosis, tuberculostatic treatment, hepatitis, and the presence of elevated CSF-protein.

Syncope and hyperCKemia as minimal manifestations of short CTG repeat expansions in myotonic dystrophy type 1.

INTRODUCTION: Syncope and palpitations as the only initial manifestations of myotonic dystrophy type 1 (MD1) due to a CTG expansion of 50-100 repeats have not been reported. CASE REPORT: In a 55-year-old female with a family history of MD1 and a personal history of a single syncope, palpitations, and hyperCKemia, 70 CTG repeats were detected in the DMPK gene. Her brother had presented atypical clinical, electromyographic, and muscle biopsy features since the age of 35 but had been diagnosed with MD1 after he later developed typical distal myotonia. He died suddenly during an episode of syncope at the age of 53. A sister with clinical myotonia died suddenly during sleep at the age of 45 and a second sister with quadriparesis died from complications of intestinal rupture at age 52. A third sister committed suicide at age 40 after developing recurrent syncopes, while a fourth sister had hyperCKemia and foot-extensor weakness. The mother of these five affected children died suddenly from myocardial rupture. CONCLUSIONS: MD1 with <100 CTG repeats may exclusively manifest cardiologically. Family screening for MD1 is important even in asymptomatic patients. MD1 may initially manifest without typical features, while muscle biopsy may be misleading and indicate glycogenosis. Close cardiac follow-up is important if MD1 manifests cardiologically to prevent syncope or sudden cardiac death.

Recurrent takotsubo syndrome in a patient with myotonic dystrophy 1.

OBJECTIVES: Stress-induced cardiomyopathy (takotsubo-syndrome, TTS) and its recurrence have not been described in myotonic dystrophy-1. CASE REPORT: The patient was a 47-year-old female who was suspected to suffer from myotonic dystrophy-1 at 20 years of age, upon the typical clinical presentation and the electrophysiological findings. During weaning from general anesthesia for resectioning of a pelvic tumour she developed ventricular fibrillation, but was successfully resuscitated. During coronary angiography two days later she experienced recurrent QT-prolongation, torsades de pointes, and ventricular fibrillation, but was successfully resuscitated again each time. Echocardiography and electrocardiography were indicative of TTS, which was confirmed by normal findings on echocardiography and electrocardiography two months later. Ten months after the first TTS she developed dyspnea, leg edema, and anginal chest pain. Recurrence of TTS was diagnosed upon a typical electrocardiography and echocardiography findings. Shortly after onset of the second TTS, she unexpectedly died from sepsis. CONCLUSIONS: TTS may also occur in patients with myotonic dystrophy-1 induced by stress from surgery, respiratory insufficiency, or infection. In patients with myotonic dystrophy-1, takotsubo-syndrome may recur and may represent a previously unreported feature of cardiac involvement in myotonic dystrophy-1.

Somatic mosaicism in trichorhinophalangeal syndrome: a lesson for genetic counseling.

Trichorhinophalangeal syndrome type I (TRPSI) is a genetic disorder characterized by sparse hair, a bulbous nasal tip, short stature with severe generalized shortening of all phalanges, metacarpal and metatarsal bones and cone-shaped epiphyses. This syndrome is caused by autosomal dominant mutations in the TRPS1 gene. However, because recurrence has been observed in siblings from healthy parents, an autosomal recessive mode of inheritance has also been suggested. We report on a male patient, born to healthy unrelated parents, with TRPSI. Using Sanger sequencing, we identified a mutation in the TRPS1 gene (c.2735 G>A, P.Cys912Tyr). The same mutation was detected as a 10% mosaic mutation by Pyrosequencing in blood-derived DNA from his healthy mother. To our knowledge, this is the first time that somatic mosaicism has been identified in TRPSI. This data combined with the observations of recurrences in siblings from healthy parents modifies the genetic counseling for TRPSI, which should discuss a 5-10 percent recurrence risk for healthy parents with an affected child because of the possibility of germinal mosaicism.

First IKBKG gene mutation study in Serbian incontinentia pigmenti patients.

INTRODUCTION: Incontinentia pigmenti (IP) is a rare X-linked dominant genodermatosis. Mutations of the IKBKG gene are the only known cause of IP. The presence or other than skin changes is important in the diagnosis of atypical IP cases when skin changes are discrete. OBJECTIVE: The study was designed to analyze clinical manifestation, family histories and the frequency of IKBKG gene mutation in IP patients in Serbia for the first time and to compare them with other reported findings. METHODS: Two Serbian unrelated families with eight female subjects were investigated. Blood samples were used for IKBKG exon 4-10 deletion testing using modified PCR protocol. For probands pathohistological and ultrastructural analyses of skin biopsies were done. RESULTS: Positive clinical diagnosis according to IP criteria was present in seven cases. In six of them, including probands, positive molecular gene testing for IKBKG exon 4-10 deletion was present. CONCLUSION: This is the first report of genetically confirmed IP in two Serbian families. The IP patients presented a common IKBKG exon 4-10 deletion. The frequency and type of IKBKG mutation found in investigated IP patients in Serbia were similar to results of other studies. Various clinical features of investigated patients have allowed us to demonstrate that molecular genetic testing which specifically detects the common IKBKG mutations, the only known cause of IP, is useful in diagnosing IP especially in mild or atypical cases. The molecular genetic testing of the IKBKG mutations may be helpful for rapid confirmation of IP diagnosis, prenatal diagnosis and carrier detection.

Dental and oral anomalies in incontinentia pigmenti: a systematic review.

OBJECTIVES: Incontinentia pigmenti (IP) is an X-linked genodermatosis caused by a mutation of the IKBKG gene. The objective of this study was to present a systematic review of the dental and oral types of anomalies, to determine the total number and sex distribution of the anomalies, and to analyze possible therapies. MATERIALS AND METHODS: We analyzed the literature data from 1,286 IP cases from the period 1993-2010. RESULTS: Dental and/or oral anomalies were diagnosed for 54.38% of the investigated IP patients. Most of the anomaly types were dental, and the most frequent of these were dental shape anomalies, hypodontia, and delayed dentition. The most frequent oral anomaly types were cleft palate and high arched palate. IKBKG exon 4-10 deletion was present in 86.36% of genetically confirmed IP patients. CONCLUSIONS: According to the frequency, dental and/or oral anomalies represent the most frequent and important IP minor criteria. The most frequent mutation was IKBKG exon 4-10 deletion. The majority of dental anomalies and some of the oral anomalies could be corrected. CLINICAL RELEVANCE: Because of the presence of cleft palate and high arched palate in IP patients, these two anomalies may be considered as diagnostic IP minor criteria as well.

Rapidly progressive phenotype of Lafora disease associated with a novel NHLRC1 mutation.

Lafora disease is a fatal, autosomal recessive form of progressive myoclonus epilepsy. Patients characteristically exhibit myoclonic and tonic-clonic seizures and cognitive impairment, beginning in their second decade. Alterations in two genes were identified as the cause of the disease. Mutations in the NHL repeat containing 1 (NHLRC1) gene were described in association with a more benign clinical course and later age of death, compared with epilepsy progressive myoclonus type 2A (EPM2A) mutations. We describe a rapidly progressive phenotype of Lafora disease in an adolescent patient with a novel NHLRC1 mutation. He developed severe disability and dementia less than 2 years after the onset of signs.

The relevance of the individual genetic background for the toxicokinetics of two significant neurodevelopmental toxicants: mercury and lead.

The heavy metals mercury and lead are well-known and significant developmental neurotoxicants. This review summarizes the genetic factors that modify their toxicokinetics. Understanding toxicokinetics (uptake, biotransformation, distribution, and elimination processes) is a key precondition to understanding the individual health risks associated with exposure. We selected candidate susceptibility genes when evidence was available for (1) genes/proteins playing a significant role in mercury and lead toxicokinetics, (2) gene expression/protein activity being induced by these metals, and (3) mercury and lead toxicokinetics being affected by gene knockout/knockdown or (4) by functional gene polymorphisms. The genetic background is far better known for mercury than for lead toxicokinetics. Involved are genes encoding L-type amino acid transporters, organic anion transporters, glutathione (GSH)-related enzymes, metallothioneins, and transporters of the ABC family. Certain gene variants can influence mercury toxicokinetics, potentially explaining part of the variable susceptibility to mercury toxicity. Delta-aminolevulinic acid dehydratase (ALAD), vitamin D receptor (VDR) and hemochromatosis (HFE) gene variants are the only well-established susceptibility markers of lead toxicity in humans. Many gaps remain in our knowledge about the functional genomics of this issue. This calls for studies to detect functional gene polymorphisms related to mercury- and lead-associated disease phenotypes, to demonstrate the impact of functional polymorphisms and gene knockout/knockdown in relation to toxicity, to confirm the in vivo relevance of genetic variation, and to examine gene-gene interactions on the respective toxicokinetics. Another crucial aspect is knowledge on the maternal-fetal genetic background, which modulates fetal exposure to these neurotoxicants. To completely define the genetically susceptible risk groups, research is also needed on the genes/proteins involved in the toxicodynamics, i.e., in the mechanisms causing adverse effects in the brain. Studies relating the toxicogenetics to neurodevelopmental disorders are lacking (mercury) or very scarce (lead). Thus, the extent of variability in susceptibility to heavy metal-associated neurological outcomes is poorly characterized.

Genetic background of lead and mercury metabolism in a group of medical students in Austria.

BACKGROUND: Information on the impact of genetic predisposition on metal toxicokinetics in the human body is limited. There is increasing evidence that certain genetic polymorphisms modify lead and mercury toxicokinetics. This called for analysis of further candidate genes. OBJECTIVES: Medical students (N=324) were examined in order to detect potential associations between lead exposure and polymorphisms in HFE, VDR, ALAD, and MT genes, as well as between mercury exposure and GSTT1, GSTM1, GSTA1, GSTP1, GCLC, and MT polymorphisms. METHODS: The levels of lead and mercury exposure of students were determined by blood, urine, and hair analyses (ICP-MS, CV-AAS). Genotyping of common polymorphisms was examined by MALDI-TOF MS and the TaqMan methodology. Associations between lead and mercury exposures and genetic background were examined by bivariate analysis, and by categorical regression analysis (CATREG) controlled by metal- and matrix-specific variables. RESULTS: Lead and mercury levels in urine, blood, and hair indicated low exposures. VDR polymorphism and joint presence of VDR/ALAD polymorphisms were significantly and independently associated with urine lead concentrations (CATREG P<0.05). Polymorphisms in GSTP1-114 and MT4 genes as well as dual gene combinations including GSTP1, GCLC, GSTT1, and GSTM1 polymorphisms were independent variables related to mercury body burdens (CATREG P<0.05). GSTP1-114/GSTT1 and GSTP1-105/GCLC combinations showed synergistic effects on hair mercury levels compared to single-gene variants. CONCLUSIONS: We found evidence that certain genetic backgrounds were associated with lead and mercury metabolism, suggesting gene-environment and gene-gene-environment interactions. The modes of interaction remain to be evaluated.