Audit Sampling Case Memo Essay Example | Topics and Well Written Essays - 1250 words

Audit Sampling Case Memo - Essay Example : (1) the existence of the inventory; (2) the rights or obligations of inventory; (3) the completeness of the inventory as stated in the balance sheet; (4) the valuation of inventory on hand, and whether it is presented according to GAAP along with (5) the presentation or disclosure of inventories in the financial statements (Whittington & Pany, 2006). RF= the reliability factor for the specified risk of incorrect acceptance. This is taken from figure 13-5 in Boynton & Johnson (2010), and for a risk of incorrect acceptance of 37% as listed, the reliability factor is 1.0. EF= the expansion factor for anticipated misstatement. This is obtained from figure 13-6 in Boynton & Johnson (2010). With a risk of incorrect acceptance at 37%, the expansion factor is given as 1.15. In Boynton & Johnson (2010), the risk of incorrect acceptance is listed at 37%. There are scenarios that would explain why 37% is chosen instead of higher or lower percentages. An important element mentioned by Whittington & Pany (2006) is the level of overall audit risk. Audit risk is based on the following formula: Audit risk (AR) is the overall allowable audit risk that a material misstatement will remain undetected. Inherent risk (IR) is a risk of a material misstatement in the financial statements, assuming a company had no internal controls. Control risk (CR) is the risk that a material misstatement could occur in an assertion and will not be detected by internal control. Detection risk (DR) is the risk that the auditors’ substantive testing will not find a material misstatement (Whittington & Pany, 2006). The setting of the risk of incorrect acceptance at 37% is not an exact science. If circumstances arise where auditors place inherent risk and control risk at high levels, and do not engage in other tests of the balance assertion, then the risk of incorrect acceptance would have to be set at a low level. However if a decrease in inherent risk or control risk occurs, then a

Design in a Changing World Case Study Example | Topics and Well Written Essays - 500 words

Design in a Changing World - Case Study Example This feedback can be audible or visual. Feedback gives the user a feeling as well as a sense of confirmation that a system is functioning correctly and responsive. Consistency; User interfaces will be designed for consistency in appearance and function. Information will be organized on forms; the shape and size of icons, the arrangement and names of menu items, and the order followed to perform tasks will be consistent throughout the system (Satzinger, Jackson & Burd, 2012). Shortcuts; User interfaces, as well as dialogs designed for novices, are usually an impediment and annoyance to the productivity of experienced users. Users that frequently work with an application or for a long time want shortcuts for regularly used functions so as to cut down on the number of mouse clicks, keystrokes and menu selections needed to complete the task (Satzinger, Jackson & Burd, 2012). The system will have shortcuts such as voice commands and shortcut keys, like Windows keyboard sequences Ctrl+V for paste. Easy Reversal of Actions; Users should explore options as well as take actions that can be reversed or canceled with ease. This is also known as experimenting whereby users learn about the system. It is as well a way to avoid errors; since users can cancel the action once they realize that they had done a mistake (Satzinger, Jackson & Burd, 2012). Additionally, the design will include cancel buttons on every dialog box as well as allow users to go step backward at any time. Lastly, the system will ask the user to verify the action when he/she deletes something important like a record, a file or a transaction, if possible, the system will delay implementing that action.

Business Intelligence Research Paper Example | Topics and Well Written Essays - 1250 words

Business Intelligence - Research Paper Example mpares and contrasts IBM and Tableau business intelligence software while evaluating how large companies handle BI implementation; the role of BI in competitive advantage and organizational strategy; organizational management of change during new information system implementation; and a summary of a case study of a company that implemented BI Solution. Large enterprises using Cognos gain from using elements such as reports, analysis, scorecards, and dashboards for monitoring the performance of their businesses, analyzing trends, and measuring results. This way, businesses have the capability and information needed to make better decisions and approach their services with a service-oriented architecture that has both ease of management and deployment. Other benefits of Cognos business intelligence are mobile BI, collaborative BI, and real time monitoring. In terms of trend analysis and results measurement using Cognos BI, large businesses benefit from the software’s capability to be used with relational and multidimensional data sources from different vendors. For instance, Cognos BI products can integrate with NCR Teradata, Oracle, Microsoft, and SAP, to present web-based service oriented architecture (SOA). Though IBM Cognos is designed for large companies, Cognos Express is meant for mid-sized companies to allow companies to take advantage of features such as budgeting, forecasting, and planning functions. Furthermore, Cognos 10, integrates with Lotus Connect and SPSS predictive analysis, and mobile capability that allows users to access to full version of Cognos from their smartphones and tablets (Lodestar, 2013). However, IBM Cognos is known for very slow performance in preparing active reports with large datasets and one is required to only use small data sets, and apply query filters to return only the values of interest. Secondly, Cognos BI does not drill through functionality when applied in active reports viewed off line. Thirdly, active reports do not

Dissertation outline(please help me think of a title related to CSR Outline

Dissertation (please help me think of a title related to CSR with extractive industries) - Outline Example companies that are engaged in the business process of extracting materials, minerals and metals from the surface of the earth for further processing and commercial use. It has been observed under the review of literature that the extraction companies are mostly listed in the Canada and there has been an increase in the investments of these companies in both the domestic as well as the overseas markets. In recent years, the multination investment in the extraction industries like oil and gas, mining, etc. have increased at an average rate in the US and UK. On the other hand, the multinational investments in the countries of Asia and Africa as well as the developing economies have increased multiple folds. While this represe4nts a win-win situation for the multinational investors in the extraction sector and the economies that are rich in the mineral and resources as their primary industrial sector, there is a gap in the literature which suggests that the multinational companies invest ing in the extraction industries have often faced complex situation and challenges in running their business in the extraction sector (Abdel-Fatau, 2002, p.16). The review of literature suggests the Canadian financial market are the largest sources of equity capital for the mining and exploration industry and the expenditure of the Canadian based extraction industry accounts for almost 43% of the total expenditures by the companies in the extraction industry all over the globe. However, with the increasing performance of the extractive industries, the multinational investments have started flow into the developing countries. Although the extraction industries have been playing a major role in stimulating the growth of the host countries, there are several social and environmental challenges faced in their course of operations. It has been found that the extraction industries have performed the role of CSR on an increasing trend while operating in the overseas markets. In order to

CFD Assignment Coursework Example | Topics and Well Written Essays - 2750 words

CFD Assignment - Coursework Example Please note that the University enforces a penalty of zero percent for work submitted after the published deadline without valid extenuating circumstances (see University student handbook on the portal for details). Intended outcomes – By the end of this coursework, you should be able to: Carry out a CFD simulation using ANSYS Workbench/CFX, demonstrating ability to import geometry, produce a mesh, set up and solve a simulation and effectively post-process results. Evaluate grid-dependency of a solution and demonstrate the process of finding a grid-independent solution. Demonstrate ability to compare CFD results with published experimental data, and critically evaluate results with reference to relevant literature. Recognise capabilities and limitations of a CFD analysis in a particular application. Present results of a CFD analysis clearly and concisely, with appropriate output from CFD-Post. Aim To use ANSYS CFX to simulate the flow around a two-dimensional NACA 642-015 aero foil section at a 5o angle of attack and to assess the accuracy of the simulation. Problem specification It is important to understand the lift and drag characteristics of aerofoil sections when designing devices such as aircraft (wings and tails) or yachts (rudders and keels). Traditionally, foil theory has been used to give performance estimates, along with extensive experimental testing. More recently, CFD has become another possible option when investigating foil performance. In reality, foils exhibit three-dimensional performance, because flow around the tip of the foil affects lift and drag. However, it is useful to determine performance of a two-dimensional foil – that is one that is so long (approaching infinite length) that the effects of flow around the tip are negligible. You are going to use CFD to simulate a 2-d foil, and compare your results to those obtained experimentally in a wind tunnel, detailed in a NACA paper from 1945. Instructions You will not be writin g a formal report for this project. Instead, you will work through this document (using it as a template), adding content and answering questions as instructed. You will then submit the completed document for assessment. Note that answers/images, etc. do not have to fit into the space provided – insert extra space as necessary, but keep answers concise. Carry out the steps as follows: Carry out a basic CFD simulation (named â€Å"Run_1†) of a NACA 642-015 foil noting the following: The foil geometry has been created in SolidWorks for you – the file aerofoil_CW_2011.SLDPRT can be found on the DSGN313 Tulip site under CFD Coursework. The file Aerofoil_Instructions_2011.doc (also on the portal) explains how to modify the geometry parameters using SolidWorks. Note that it is down to you to modify dimensions to set the extents of your domain in all directions, and to set your foil chord and angle of attack – don’t just run with the dimensions given to y ou. Your simulation should be for a 5o angle of attack, and a 24 inch chord length (for comparison against the NACA experimental data). You should run your simulation at a Reynolds number of 6x106. Note that the length scale used in the Reynolds number is the chord length of the airfoil section in the model. Use ‘Water’ as the fluid and assume that the flow is incompressible, steady, isothermal and turbulent. Use the k-? turbulence model. Run_1 should be a coarse, unrefined mesh purely to get your simulation working (you

Legal, Social, and Economic Environments of Business Essay Example for Free

Legal, Social, and Economic Environments of Business Essay There are several categories that a small business can fall into. Within these businesses there are legal, social and economic environments that effect how the business is run and whether the business is a success or failure. From the cost to run to how the tax return is filed; all three have their advantages and disadvantages. All three also can produce a lucrative income for the right person or people. It is imperative to the business for the owner(s) to choose which path is the best way to go while taking in consideration the pros and cons of each type. Legal, Social, and Economic Environments of Business The idea of a three pronged cord came to me when I noticed how many cords have burned up on my appliances. The third prong on the cord would distribute the current better. My goal is to manufacture and sell my product. Small businesses are what formed our country. From the forming of our governments to starting computer companies in our garages business decisions had to be made. There are three main organizations of small businesses: Sole Proprietor, Partnership, and Corporation.  When opening a business the owner or owners need to know how each organization operates and which would be the best for them. Each has its own advantages and disadvantages, but every business falls into one category or another. Business Organizations Sole Proprietor: A sole proprietor is a single individual who makes all the decisions in the business. There is no one to run to and ask â€Å"What do you think about this? † It is the most simple of the three types because there are almost no legal requirements. As a sole proprietor there is more freedom to do what the individual wants which makes it much easier to run. Also, the individual can get a tax benefit and there is a lower cost to start (Tavassoli, 2013. Slide 9) Almost anyone can have a small business as a sole proprietor. Although saving some money on the start up and from tax exemptions are a plus, there are some things one has to take into consideration. One is the limited resources because there is no one else around to bounce ideas off of and most people don’t have the business sense to run their own company from the start, unless they’ve had previous experience and knowledge in that field (Tavassoli, 2013. Another is the difficulty of borrowing money. Most banks or investors are hesitant to lend funds to one person because their financial resources are limited. Finally, all the liability of the business is put directly on the individual (Tavassoli, 2013. Slide 9). Whatever happens in the business is solely on the owner and there usually isn’t anyone to fall back on for help. Partnership: The second type of business is a partnership. There is more room for growth in this type of business because now we have an added talent or experience (Tavassoli, 2013). You automatically have someone to get insight on ideas and bring more ideas to the table. There is a better opportunity to borrow money. Now instead of one persons income and assets there are two. Someone is more likely to help finance a partnership than an individual person (Tavassoli, 2013, Slide 10). In addition, the business return flows into the individual/joint return. Just as a sole proprietor, a partnership has unlimited liability. The only difference is now there is more than one person involved so burden is split. In a partnership the owners are responsible for all the debt and expenses of the business (Ebert Griffin, 2005). Something else to consider is the difficulty to sell a business owned by a partnership. Why is it difficult? Consent is always needed from the other partner. No decision can be legally made without the other partner agreeing. Corporation: The third decision is a Corporation. Companies like Apple, Ford, and Microsoft all fall into corporations. One good thing about a corporation is the stockholders of a corporation have limited liability which means they are only liable for the amount they invested (Tavassoli, 2013. Slide 11) When there are law suits or debts only the corporation loses money. Lenders and investors are most like to provide funding for a legitimate corporation before others. Another thing is there is a better chance to find talent and pool ideas. The opportunity to create more jobs is another plus for being a corporation. With the good comes the bad. In a corporation there are multiple stockholders that have to be answered to when it comes to business decisions (Tavassoli, 2013. ) Theses owners will have their own opinions on how things should be done and which ideas to be taken into action. A corporation can be easily taken over if it is agreed upon by the majority of the owners. The financial reporting requirements are more extensive. Finally, at the corporate level businesses are double taxes not only as a corporation but on the paid dividends to its stockholders (Ebert Griffin, 2005). After careful consideration I feel a limited partnership is the best choice for my business. A Limited Partnership would allow us to obtain financing in the future, rather than trying to get financing on my own as a sole proprietor. Also, the amount of liability is reduced because we are only liable for the amount of our individual investments. This allows my partner not to have to take an active role in the partnership. A limited partnership agreement is not required but will be put in place to protect each partner (CEC, 2010).

3-Methylglutaconic Aciduria Research

3-Methylglutaconic Aciduria Research A distinct type of 3-methylglutaconic aciduria due to a mutation in the Translocase of Inner Mitochondrial Membrane 50 (TIMM50) gene Abstract BACKGROUND: 3-methylglutaconic aciduria biochemically characterized by increased urinary excretion of 3-methylglutaconic acid result from defective leucine metabolism and disorders affecting mitochondrial function though in many cases the cause remains unknown. Recently mutations in mitochondrial TIMM50 gene has been reported in four patients from two unrelated families. We report additional mutations in TIMM50 gene in 6 individuals from two unrelated consanguineous families with a distinctive type of 3-methylglutaconic aciduria. METHODS:Â  We report on three patients of South Asian ancestry with intractable epilepsy, microcephaly, developmental delay, visual deficit spastic quadriplegia and three Caucasian patients of eastern European origin with intellectual disability with or without seizure. Metabolic testing revealed mild lactic acidosis and excretion of large amount of 3-methylglutaconic acid in urine in all patients. Full exome sequencing was performed using genomic DNA isolated from one surviving patient, two healthy siblings and both parents of South Asian family. Exome sequencing was also performed for Caucasian patients of eastern European origin. RESULTS:Â  Exome sequencing identified two homozygous mutation Gly372Ser and Iso392Thr mutations in the gene TIMM50. There were no other candidate alterations in exome that could explain the phenotype in the proband. The mutations are located in the conserved C-terminal domain of the Tim50 protein that interacts with the N-terminal domain of the Tim23 protein in the intermembrane space and regulates mitochondrial protein import of presequence-containing polypeptides Both parents are heterozygous. CONCLUSION: Given the phenotypic similarilty of the patients from two unrelated families and an earlier report of mutations in additional family, we conclude that TIMM50 gene mutation results in a novel mitochondrial disorder with 3-methyl glutaconic aciduria. INTRODUCTION 3-methylglutaconic aciduria (MGCA), an increase in urinary 3-methylglutaconic acid or 3-methylglutaric acid, can be a nonspecific finding in mitochondrial disorders, organic aciduria, urea cycles disease, neuromuscular disorders. but is a consistent abnormality of 3-methylglutaconyl-CoA hydratase deficiency and patients with mutations in TAZ, SERAC1, OPA3, DNAJC19 and TMEM70 gene1. These genes all encode mitochondrial membrane or membrane related proteins. In 3-methylglutaconyl-CoA hydratase deficiency due to mutation in AUH gene , 3-methylglutaconic acid derives from 3-methylglutaconyl CoA (3MG CoA), an intermediate in leucine catabolism1. It has been proposed that in other disorders, 3-methylglutaconic acid derives from aberrant isoprenoid shunting from cytosol to mitochondria via mevalonate pathway or redirection of mitochondrial acetyl CoA toward production of 3MGA due to an increase in the intra-mitochondrial NADH/NAD+ ratio resulting from mutation induced impairment in electron transport chain or Kreb cycle function 2. Examples of mitochondrial include Barth syndrome, a cardioskeletal myopathy with neutropenia, abnormal mitochondria and MGCA. Barth syndrome is caused by X-linked recessive mutations in the TAZ gene which encodes the mitochondrial membrane localized transacylase involved in the maturation of cardiolipin. Autosomal recessive mutations in the OPA3 gene (OMIM: 606580), the mouse ortholog of which encodes a mitochondrial inner membrane protein of unknown function, cause MGCA3 (OMIM: 258501), a neuroopthalmologic syndrome characterized by early-onset bilateral optic atrophy and later-onset spasticity, extrapyramidal dysfunction and cognitive deficit. MGCA5 (OMIM: 610198) is yet another form of MGCA caused by autosomal recessive mutations in the DNAJC19 gene (OMIM: 608977) and in addition to increased urinary excretion of 3-methylglutaconic acid, patients present with infancy or childhood onset dilated cardiomyopathy, microcytic anemia, mild muscle weakness and ataxia. Many patients die of cardiac failure. The DNAJC19 gene encodes the human homolog of the yeast Tim14 which is a part of the Tim23 mitochondrial protein import machinery and hasbeen shown to interact with the mtHsp70 in an ATP-dependent manner to regulate Tim23 function (Davey, 2006). WE report a distinct type of 3-methylglutaconic aciduria resulting from a mutation in mitochondrial TIMM50 gene in 3 sibs from a consanguineous family. We initially reported these xases in abstract form. Recently two different mutations in mitochondrial TIMM50 gene have been reported in four patients with 3 methylglutaconic aciduria, epilepsy, severe intellectual disability and lactic acidosis. Subjects Family 1 Family 1 has three affected sibs of South Asian ancestry with intractable epilepsy, microcephaly, developmental delay, visual deficit spastic quadriplegia. Two affected sibs died unexpectedly when they were visiting families in a remote area of a South Asian country. Metabolic testing had revealed large amount of 3-methylglutaconic acid in urine in all three affected sibs. The patients have a healthy brother and a healthy sister. Mother and father are first cousins. Detailed clinical history, imaging, EEG and metabolic testing were obtained for all affected persons. Full exome sequencing was performed using genomic DNA isolated from one surviving patient, two healthy siblings and both parents. Patient IV-1. Patient IV-1 was the first born child of the parents and was born at 36 weeks gestation after a normal pregnancy and delivery. Her weight at birth was 1.99 kg. Her weight, height and head circumference were always below 5th centile. She also had asthma and frequent episodes of pneumonia presumably due to aspiration, but the family refused G-tube placement. She was severely delayed. She never sat, stand or spoke. She has poor head control, truncal hypotonia but very brisk tendon jerks and sustained clonus. Funduscopy revealed bilateral optic atrophy. She developed seizures at 1 year of age. EEG revealed multifocal spikes arising from both hemispheres. She was treated with phenobarbital and Zonegran but family was noncompliant with medications. She continued to have daily myoclonic jerks. MRI at 2.5 and 5 years of age showed increased T2 signal in basal ganglia and periventricular white matter, brain atrophy, prominent ventricle, increased extraxial fluid. Normal liver en zymes and blood count, normal blood and CSF glucose and a serum ammonia of 21. Several serum lactate levels were mildly elevated. Lactate 2.8, 4.5 (Pyruvate 0.23), 5.4 (normal 0.7 to 2.1) Lactate to pyruvate ratio 20:1. Urine organic acid analysis revealed very high lactic acid, 3-methylglutaconic acid, and 3-methylglutaric acid. Muscle biopsy revealed only scattered atrophic muscle fibers on electron microscopy. Respiratory chain enzyme activities were within normal limits. She died at 7.5 years of age apparently due to complications from an infection while she was visiting families in a remote area of a South Asian country. Patient IV-4 was twin A born at 36 weeks gestation after an uncomplicated twin pregnancy. Her weight, height and head circumference were always below 5th centile. She was severely delayed. She never sat, stand or spoke. She has poor head control, truncal hypotonia but very increased reflexes and spasticity in the limbs. At nine-month-of age, she started to experience several episodes of eye fluttering and body jerking. Her EEG reved slow background, poor sleep architecture and frequent multifocal spike and sharp wave activities coming from both the left and right hemispheres. Her seizures were treated with Zonegran and was poorly controlled but parents refused more aggressive treatment of seizures. Metabolic testing revealed mild elevation of lactate and moderate increase of 3 methylglutaconic, 3 methylglutaric acids in urine. A brain MRI at 11-month-of age revealed diffuse volume loss supratentorially with prominent sulci and extraaxial fluid spaces, mild enlargement of the ventricl es and patchy signal abnormalities in the basal ganglia bilaterally, especially involving the caudate nuclei and putamen. On spectroscopy with voxel placed in the right basal ganglia with short and long TE, there was a lactate peak which inverted on long TE spectrum. Also, the NAA peak was low with NAA to creatinine being 1.15 on short echo and 1.29 on long echo spectrum. Also, the choline was elevated with choline/creatine ratio being 1.00 on short echo and 1.41 on long echo images. She died at 1.5 years of age apparently due to complications of an infection while she was visiting families in a remote area of a South Asian country. Patient IV-5 is a 13 year old female of South Asian ancestry, with 3-methylglutaconic aciduria intractable epilepsy, microcephaly, developmental delay, visual deficit and spastic quadriplegia. She was born at 36 weeks gestation after an uncomplicated twin pregnancy. She was twin B and stayed in NICU for 18 days for feeding issues. Her weight was 1.4 kg and she was not intubated. Patient first presented with seizures at 3 months of age with eyelid fluter and jerking of extremities. Her initial EEG revealed multifoal spikes. Initial biochemical evaluation revealed normal serum and CSF glucose, normal ammonia and liver enzymes. Serum lactate and CSF lactate 4.24 mmol were mildly elevated . Lactate was 2.7. Ammonia 25. Serum amino increased alanine 43.6 micromol/dl (9.9-34.5). Csf lactate 4.24 mmol. CSF alanine 7 micromol/dl (0.6 -4.7). There were also mild elevations of serum and CSF valine, leucine, isoleucine and alanine and lysine. Urine organic analysis revealed moderate increase of 3 methylglutaconic, 3 methylglutaric, glutaric, adipic, suberic, and sebacic acids. MRI of brain at 11 months of age revealed severe atrophic changes involving gray and white matter, predominantly of the cerebrum. Grossly abnormal signal is seen in the basal ganglia, particularly the caudate nucleus and the putamen with relative sparing of the globus pallidus and thalamus. A recent MRI (at age 13 years) reveals severe but stable atrophic changes of the gray and white matter of the supra and infratentorial brain, stable white matter changes of the putamen, caudate nucleus and periventricular white matter, Scattered diffusion restriction in the retrotrigonal white matter, compatible with active demyelination and atrophic changes of the optic nerves. Her seizures were treated with with Keppra, Lamictal, Zonegran and Onfi. She also receives carnitine. She continues to have brief episodes of whole body stiffening each week, but the family was also not very compliant with medications. He r current EEG shows slow background for age, poorly formed sleep spindles indicatvie of diffuse neuronal dysfunction, frequent multifocal interictal spike and wave suggests increased risk of seizures arising from multiple foci and hypsarrhythmia in sleep . She has failure to thrive despite G-tube feeding. At 12 years of age, G-tube was placed due to history of aspirations. Height, weight and head circumference below 5th centile. She is severely delayed. She is nonverbal and never learned to sit independently, stand or walk. She recognizes family members, responds to their voice and looks and smiles at them. Her fundoscopy shows mild optic atrophy. She has bilateral esotropia and dysconjugate gaze. She has poor head control and truncal hypotonia, but her limbs are spastic and her tendon reflexes are very brisk. Family 2 Patient V:1 was the first son of Caucasian consanguineous parents (IV:4 and IV:5) of Eastern European origin. Within the context of an organic acid and amino acid study in young and adult subjects with non-syndromic developmental delay and intellectual disability, he was investigated at the age of 17 years and presented with a developmental language disorder (involving semantic, syntactic, and pragmatic components of the linguistic system), emotional and communicative problems (fearful, aggressive, and loner), and hyperactivity. On neuropsychological testing he showed a short attention span. The child was born at term after an uneventful pregnancy and his birth weight was 2.9 kg. At 4 months of age he was affected by myoclonic jerks that were controlled by administration of valproic acid and lamotrigine. Developmental delay was observed starting from the middle of the first year of life, accompanied by decreased muscle tone. He could walk without support only at 6 years. At last medi cal exam, the patient showed a reduced muscle mass (height 148 cm, Z-score 3.43; weight 38 kg, Z-score 4.21; BMI 17.1 kg/m2, Z-score 2.02) and a head circumference of 51 cm (Z-score 2.76). Due to refusal of parents, no brain imaging studies could be performed. Fundoscopic examination was normal. Laboratory tests, including creatine phosphokinase (CPK), liver enzymes and plasma amino acids, were normal. The profile of urinary organic acids showed a large peak of 3-methylglutaconic acid (113 mmol/mol creatine) and a slightly increased level of 3-methylglutaric acid (17 mmol/mol creatinine). Patient V:3 was the younger brother of V:1, the third child of IV:4 and IV:5. He was investigated at the age of 11 years and presented with a clinical phenotype (developmental delay and intellectual and behavioral disorder) similar to that of his brother. The pregnancy and early postnatal course was unremarkable and birth weight was 3.1 kg. At 3 months he received valproic acid and lamotrigine to control tonic seizures with sudden stiffening movements of arms and legs. The boy walked independently at 4 years. When he was 9 years, his growing parameters were: height 119 cm (Z-score 2.47), weight 22 kg (Z-score 1.91), BMI 15.5 kg/m2 (Z-score 0.38), and head circumference 48 cm (Z-score 3.52). Neuropsychological exam revealed mental retardation and impaired communicative skills, including poor language abilities (few repetitive words with no sentences). Occasionally, the patient is aggressive. Ophthalmologic examination revealed left esotropia. High levels of 3-methylglutaconic acid (15 5 mmol/mol creatine) were identified in urine, together with smaller amounts of 3-methylglutaric acid (22 mmol/mol creatinine). Patient V:5 was the second son of consanguineous parents (IV:9 and IV:10) related to those of patients V:1 and V:3. The girl was delivered by cesarean section because of growth arrest at 37 week. The neonate showed no external malformations. Birth weight was 2.1 kg. In the following years, the clinical phenotype was characterized by delayed developmental milestones, nocturnal enuresis, severe cognitive impairment, speech retardation, and lack of communicative skills. Results of the electroencephalogram were normal. No brain imaging data are available. On a few occasions, levels of ammonia and lactic acid were found to be slightly elevated, but these results could not be confirmed by repeated blood analyses. Plasma levels of amino acids are within normal range. Fundoscopic examination was normal up to 7 years, but since then there is evidence of mild bilateral optic atrophy. Urine levels of of 3-methylglutaconic acid and 3-methylglutaric acid were 176 mmol/mol creatine and 29 mmol/mol creatinine, respectively. DISCUSSION Deleterious Nature of the TIMM50 gene alteration: TIMM50 NM_001001563 c.1114G>A p.G372S The p.G372S variant (also known as c.1114G>A), located in coding exon 9 of the TIMM50 gene, results from a G to A substitution at nucleotide position 1114. The glycine at codon 372 is replaced by serine, an amino acid with somewhat similar properties. The alteration is not observed in healthy cohorts: Based on data from the NHLBI Exome Sequencing Project (ESP), the TIMM50 c.1114G>A alteration was not observed among 6,503 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). Though some variants may appear to be rare due to database-specific ethnic underrepresentation, rare missense alleles commonly exhibit a deleterious effect on protein function (Kryukov, 2007; Tennessen, 2012). The altered amino acid is conserved throughout evolution: The G372 amino acid position is completely conserved in eukaryotes all th e way from the yeast Saccharomyces cerevisiae to humans (Mokranjac, 2003). The alteration is predicted deleterious by in silico models: The p.G372S alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. The amino acid is located in a functionally important protein domain: The p.G372S alteration is located in the conserved C-terminal domain of the Tim50 protein that interacts with the N-terminal domain of the Tim23 protein in the inter membrane space and regulates mitochondrial protein import of presequence-containing polypeptides (Geissler, 2002; Yamamoto, 2002; Guo, 2004). The alteration cosegregated with disease in the family herein: Co-segregation analysis revealed that this alteration is present in a heterozygous form in the mother, father and brother, and absent in the sister. Based on the available evidence, the TIMM50 c.1114G>A (p.G372S) alteration is classified as a likely pathogenic mutation. The TIMM50 gene is not currently known to underlie Mendelian disease (aka clinically novel). The TIMM50 gene function is consistent with the probands clinical presentation: The Translocase of Inner Mitochondrial Membrane 50 (TIMM50) gene (OMIM: 607381) is located on human chromosome 19q13.2 and consists of 11 exons. It encodes the Tim50 protein, a 353 amino acid 40 kDA homolog of the yeast Tim50 protein that functions as an integral part of the mitochondrial Tim23 protein import machinery by linking protein translocation across the outer and inner mitochondrial membranes. This interaction was confirmed by the coprecipitation of Tim50 with an antibody against Tim23 (Geissler, 2002; Yamamoto, 2002; Guo, 2004). The authors further confirmed that the C-terminal domain of Tim50 is located in the inter-membrane space (IMS) where it stably binds to the segment of Tim23 that spans the IMS and regulates its function. Nuclear encoded mitochondrial proteins are synthesized in the cytosol and subsequently imported into the mitochondria through the function of translocators, the TOM complex of the outer mitochondrial membrane (OMM), and the Tim23 and Tim22 complexes of the inner mitochondrial membrane (IMM) (Jensen, 2002). While the Tim22 complex is involved in the transport and insertion of proteins lacking the presequence into the inner membrane, the Tim23 complex is required to process and insert presequence-containing precursor proteins. The IMM generates a proton motive force that is critical for cellular energy synthesis (Stock, 2000) and the permeability barrier of the IMM needs to be maintained during the transport of proteins through the pore-forming Tim23 protein associated with other IMM proteins such as Tim14 (human DNAJC19), Tim17, Tim21, Tim44 and Tim50. Using various yeast IMM protein mutants, Meinecke et al. (2006) demonstrated that tim17 and tim21 mutant mitochondria displayed membra ne potential values that were comparable to wild type mitochondria, whereas tim50 mutant mitochondria showed a drastic reduction of the membrane potential. Further functional studies revealed that the Tim23 channel is tightly regulated by Tim50 in its inactive state to maintain the IMM permeability barrier and is opened only when presequence-containing polypeptide chains need to be translocated into the mitochondrial matrix or the inter membrane space (IMS). Loss of Tim50 function in yeast led to cellular growth arrest and reduced cell viability (Mokranjac, 2003). Knockdown to Tim50 expression in cultured human cells using RNA mediated interference resulted in an increase in the release of cytochrome c and apoptosis in response to cell death stimuli (Guo, 2004). A 50 kDa isoform of the human mitochondrial TIM50, TIM50a, consisting of 456 amino acids has been found to localize in nuclear speckles, specifically in the Cajal bodies, and interact with small nuclear ribonuclear proteins (snRNPs), the coilin protein and the Survival of Motor Neurons (SMN) protein (Xu, 2005) which has been implicated in Spinal Muscular Atrophy (SMA). The protein sequences of the mitochondrial TIM50 and the nuclear TIM50a are identical with the exception of additional 103 amino acids at the N-terminal of TIM50a that are the result of an alternative translational start sequence. This additional N-terminal sequence in TIM50a is thought to contain a putative nuclear localization sequence that allows the Tim50a isoform to display a nucleus specific localization. Based on their results, Xu et al. hypothesized that Tim50a might be involved in the regulation of snRNP biogenesis and possibly the function of the nuclear SMN protein encoded by the SMN1 gene. One of our patien ts had mulsle biopsy. Although there were atrophic changes, no neuropthic pattern was seen. Reference List (1) Wortmann SB, Kluijtmans LA, Rodenburg RJ et al. 3-Methylglutaconic acidurialessons from 50 genes and 977 patients. J Inherit Metab Dis 2013;36:913-921. (2) Ikon N, Ryan RO. On the origin of 3-methylglutaconic acid in disorders of mitochondrial energy metabolism. J Inherit Metab Dis 2016;39:749-756. Legends Legend to Figure 1 Five-generations pedigree of the family with mild 3-methylglutaconic aciduria in which the TIMM50 p.(Ile293Thr) was identified. Subjects V:1, V:3, and V:5 (filled symbols) are patients suffering from intellectual disability and increased urinary excretion of 3-methylglutaconic acid. They are born to consanguineous parents and homozygous for the TIMM50 c.1011T>C mutation predicting the replacement of isoleucine 293 with threonine in the encoded protein. The mutation was inherited by a common ancestor (either I:1 or I:2) and has been identified in the heterozygous state in the clinically and biochemically unaffected subjects III:3, III:4, III:9, IV:2, IV:4; IV:5; IV:9, IV:10, and V:2.