Mitochondrial serine protease HTRA2 p.G399S in a kindred with essential tremor and Parkinson disease

Essential tremor is one of the most frequent movement disorders of humans and can be associated with substantial disability. Some but not all persons with essential tremor develop signs of Parkinson disease, and the relationship between the conditions has not been clear. In a six-generation consanguineous Turkish kindred with both essential tremor and Parkinson disease, we carried out whole exome sequencing and pedigree analysis, identifying HTRA2 p.G399S as the allele likely responsible for both conditions. Essential tremor was present in persons either heterozygous or homozygous for this allele. Homozygosity was associated with earlier age at onset of tremor (P < 0.0001), more severe postural tremor (P < 0.0001), and more severe kinetic tremor (P = 0.0019). Homozygotes, but not heterozygotes, developed Parkinson signs in the middle age. Among population controls from the same Anatolian region as the family, frequency of HTRA2 p.G399S was 0.0027, slightly lower than other populations. HTRA2 encodes a mitochondrial serine protease. Loss of function of HtrA2 was previously shown to lead to parkinsonian features in motor neuron degeneration (mnd2) mice. HTRA2 p.G399S was previously shown to lead to mitochondrial dysfunction, altered mitochondrial morphology, and decreased protease activity, but epidemiologic studies of an association between HTRA2 and Parkinson disease yielded conflicting results. Our results suggest that in some families, HTRA2 p.G399S is responsible for hereditary essential tremor and that homozygotes for this allele develop Parkinson disease. This hypothesis has implications for understanding the pathogenesis of essential tremor and its relationship to Parkinson disease.Essential tremor is one of the most frequent movement disorders in humans (1). It is characterized primarily by postural or kinetic tremor of the arms and hands, but head, legs, voice, and other regions of the body may also be affected (2). The worldwide prevalence is 0.9%, increasing to more than 4% in elderly populations (1). Familial essential tremor is genetically heterogeneous. Genetic linkage studies of multiply affected families revealed three genomic regions segregating with the condition, on chromosomes 3q13 [ETM1; Online Mendelian Inheritance in Man (OMIM) 190300], 2p22-24 (ETM2; OMIM 602134), and 6p23 (ETM3; OMIM 611456) (3–5). No clearly causal mutations have been identified in these regions, although the common variant DRD3 p.S9G in the ETM1 region has been proposed as a risk factor and HS1BP3 p.A265G in the ETM2 region appeared in two multiply affected families (6, 7). Genomewide association studies of essential tremor reported associations with common variants in an intron of LINGO1 and in an intron of SLC1A2 (8–10). Recently, DNAJC13 p.N855S, which had been identified in Parkinson disease patients, was also found in two unrelated patients with essential tremor (11). Nonsense mutation p.Q290X in the RNA-binding protein FUS was identified by whole exome sequencing in a large family with essential tremor (ETM4; OMIM 614782) (12). Screening other subjects with essential tremor for FUS revealed two rare missense variants, suggesting that mutations in FUS explain a subset of cases with the condition (13, 14).In this study, we examined a six-generation family segregating essential tremor, and in multiple relatives, essential tremor as a feature of Parkinson disease. We carried out whole exome sequencing of genomic DNA from three severely affected family members and subsequent pedigree analysis to identify the genetic basis of essential tremor and Parkinson disease in the family.     

Macroglossia and Generalized Edema not Due to Hypothyroidism

We present a 69-year-old male patient with the macroglossia, dysphagia and generalized edema. He was seen previously by other physicians and diagnosed as hypothyroidism. With thyroid stimulating hormone in normal range, tongue biopsy revealed primary systemic amyloidosis. Amyloidosis is the most common cause of macroglossia. Primary systemic amyloidosis should be suspected when laboratory does not support hypothyroidism especially if the enlarged tongue is firm and additional findings are present.     

Speaker Abstracts

Narcolepsy is a rare disorder characterised by sleep disturbances, cataplexy, sleep paralysis and hypnagogic, hypnopompic hallucinations. Although several treatment modalities, such as tricyclic antidepressants or selective serotonin reuptake inhibitors, have been used to treat different symptoms, there is no definite treatment for narcolepsy. Modafinil or amphetamine-like stimulants, such as dexamphetamine or methylphenidate, are used to treat sleepiness. Our case was a 58-year-old woman who was diagnosed as narcolepsy cataplexy syndrome. Her Epworth Sleepiness Scale (ESS) score was 14 and Beck Depression Inventory (BDI) score was 29 in the first evaluation. Imipramine and modafinil were begun for the treatment, but there was no improvement in her symptoms. Subsequently, bupropion was started at 150 mg/day and then dosage was increased to 300 mg/day. She was asymptomatic at the end of 3 months. To our knowledge, this is the second depressive narcoleptic patient who has responded to 300 mg/day of bupropion.     

Management of open apices in thirteen traumatized permanent incisors using mineral trioxide aggregate: Case series

AimThe partial pulpotomy can offer a successful outcome for the treatment of traumatic complicated crown fractures. The aim of this clinical report was to evaluate the effect of mineral trioxide aggregate (MTA) in apexogenesis of traumatized immature permanent incisors with pulp exposure.Case reportAccording to clinical and radiological examinations complicated crown fractures and open apices were identified in 13 permanent upper incisors in ten patients (age range 7–10 years). Partial pulpotomy procedures were performed and the teeth were treated with MTA. In this report, periodic clinical and radiological follow-ups were performed. At recall examinations, all teeth were asymptomatic, and clinical and radiological investigations revealed excellent healing patterns with continued apexogenesis.ConclusionRegular examination of immature traumatized permanent teeth is critical for vitality and apexification. In this report, clinical and radiological findings confirm that partial pulpotomy with MTA is a reliable and effective treatment approach in apexogenesis of traumatized immature permanent incisors with pulp exposure.     

Regio- and diastereoselective synthesis of spiropyrroloquinoxaline grafted indole heterocyclic hybrids and evaluation of their anti-Mycobacterium tuberculosis activity

An efficient and eco compatible approach for the regio- and stereoselective synthesis of structurally diverse novel hybrid heterocycles comprising spiropyrrolidine, indenoquinoxaline and indole structural units in excellent yields, has been achieved through a one-pot multicomponent process involving 1,3-dipolar cycloaddition as a key step. The 1,3-dipolar component is the azomethine ylide generated in situ from indenoquinoxaline and l-tryptophan and reacts with various substituted β-nitrostyrenes affording the spiroheterocyclic hybrids. The ring system thus created possesses two C–C and three C–N bonds and four adjacent stereogenic carbons, one of which is quaternary and the reaction proceeded with full diastereomeric control. All the synthesized compounds were assayed for their in vitro activity against Mycobacterium tuberculosis H37Rv using MABA assay. Interestingly, the compound bearing a 2-fluoro substituent on the aryl ring displayed an equipotent activity (MIC 1.56 μg mL⁻¹) to ethambutol against Mycobacterium tuberculosis H37Rv.

An efficient and eco compatible approach for the regio- and stereoselective synthesis of structurally diverse novel spiropyrrolidine tethered indole hybrids in excellent yields employing a one-pot multicomponent 1,3-dipolar cycloaddition strategy.     

Acute Renal Failure and Mortality After Open-Heart Surgery in Infants

Acute renal failure (ARF) is a major complication in infants who undergo cardiac surgery. The aim of this investigation was to identify possible risk factors for ARF and mortality in this patients group. Out of 64 patients, 21 (32.8%) cases developed acute renal failure and overall mortality rate was 25%. The mortality rate was higher in the infants who developed ARF than those who did not (66.7% and 4.7%, respectively, p < 0.05). Also, ARF was positively correlated with mortality (r:0.70, p < 0.0001). The nonsurvivors had lower mean serum albumin than did the survivors (p < 0.05), and serum albumin level was negatively correlated with mortality (r = ? 0.34, p < 0.05). For the patients with serum albumin level < 3.5 g/dL, the unadjusted odds ratio for mortality was 4.3 (CI 95%:1.05 ? 17.86). Total bypass time and aorta clamping time were significantly longer in the nonsurvivor group than in the survivor group (p < 0.05 for both). In conclusion, the significant risk factors for mortality in these patients were development of ARF, low serum albumin level, and long total bypass and aorta clamping times, which may be predictive of poor prognosis.     

Two discrete masses of leiomyomatosis in a patient, one extending to the right atrium

Leiomyomatosis extending to the right side of the heart through the inferior vena cava (IVC) is an extremely rare neoplasm. Although it is pathologically classified as a benign neoplastic formation, its growth and recurrence rate makes its extirpation mandatory. In this case report, we describe a 57-year-old woman who presented with leiomyotosis extending from the IVC to the right atrium (RA). This patient had presented with uterine leiomyoma three years previously. The patient died in the operating theatre from hemostatic problems after surgical complications arising from the unexpected presence of a second tumor.