A genomic approach to mutation analysis of holocarboxylase synthetase gene in three Chinese patients with late-onset holocarboxylase synthetase deficiency

OBJECTIVE: Multiple carboxylase deficiency (MCD, MIM:253270) is a common organic aciduria and caused by deficiency of either biotinidase or holocarboxylase synthetase (HLCS; EC 6.3.4.10). Patients commonly present during early infancy with acute metabolic derangements and severe metabolic acidosis. Recently, a late onset form of HLCS deficiency was also described. The different phenotypes (early and late presenting) may be related to a spectrum of mutations in HLCS gene. Applications of mutation analysis in HLCS had been limited previously by the requirement of cDNA from living tissue for study. We described here a genomic approach for molecular diagnosis of HLCS deficiency which we have used to detect mutations in Chinese patients who had the late-onset form of HLCS deficiency. In addition, a fibroblast cell line with MCD from Coriell Cell repositories was also studied. DESIGN AND METHODS: Three Chinese patients with late onset HLCS deficiency were studied. The genomic sequence of HLCS was retrieved and newly designed primers were used to cover all coding sequences of the gene. PCR products were analyzed by direct sequencing. Population allelic frequencies of mutations detected were determined by genotyping of control samples by restriction fragment length polymorphism. RESULTS: We found a recurrent mutation, R508W, in the three unrelated Chinese patients. Two were homozygous for this mutation. The other patient was a compound heterozygote of R508W and a novel mutation, D634N. The results suggest that R508W may be an important and relatively prevalent disease-causing mutation in Chinese MCD patients. A fibroblast cell-line from an African patient revealed an additional novel mutation, R565X and a known mutation, V550M. CONCLUSION: R508W is a recurrent mutation in Chinese MCD patients which is associated with the late onset phenotype. This new genomic approach for mutation analysis of HLCS gene provides new opportunities in studies of MCD.     

Gingival overgrowth caused by vitamin C deficiency associated with metabolic syndrome and severe periodontal infection: a case report

It has been suggested that vitamin C deficiency/scurvy is associated with gingival inflammatory changes; however, the disorder is very infrequently encountered in the modern era. Here, we report a case of extensive gingival overgrowth caused by vitamin C deficiency associated with metabolic syndrome and severe periodontal infection.     

Severe Iron Deficiency Anemia and Lice Infestation

Background

Lice infestation is a commonly encountered disorder in emergency medicine. The louse survives from a blood meal from its host; hence, iron deficiency anemia is a theoretic possibility. A limited number of reports of severe iron deficiency anemia have appeared in the veterinary literature, but a thorough review of the medical literature did not reveal a single instance in human beings.

Objective

We report a small case series of patients with heavy louse infestation and profound iron deficiency anemia.

Case report

The index case along with two other cases discovered from an exhaustive search of 4 years of the institution’s Emergency Department records all had heavy infestation with head and body lice. Laboratory evaluation revealed serum hemoglobin levels under 6 gm/dL, low serum ferritin levels, and microcytic red blood cell indices. All patients were admitted to the hospital, received transfusions, and had evaluation of their anemia. No patient had evidence of gastrointestinal blood loss or alternative explanation for their anemia.

Conclusions

Although cause and effect cannot be established from this case series, to the best of our knowledge, this is the first published evidence of a provocative association of louse infestation and severe iron deficiency anemia in humans.     

Dominantly inherited hyperinsulinism caused by a mutation in the sulfonylurea receptor type 1

ATP-sensitive potassium channels play a major role in linking metabolic signals to the exocytosis of insulin in the pancreatic beta cell. These channels consist of two types of protein subunit: the sulfonylurea receptor SUR1 and the inward rectifying potassium channel Kir6.2. Mutations in the genes encoding these proteins are the most common cause of congenital hyperinsulinism (CHI). Since 1973, we have followed up 38 pediatric CHI patients in Finland. We reported previously that a loss-of-function mutation in SUR1 (V187D) is responsible for CHI of the most severe cases. We have now identified a missense mutation, E1506K, within the second nucleotide binding fold of SUR1, found heterozygous in seven related patients with CHI and in their mothers. All patients have a mild form of CHI that usually can be managed by long-term diazoxide treatment. This clinical finding is in agreement with the results of heterologous coexpression studies of recombinant Kir6.2 and SUR1 carrying the E1506K mutation. Mutant K(ATP) channels were insensitive to metabolic inhibition, but a partial response to diazoxide was retained. Five of the six mothers, two of whom suffered from hypoglycemia in infancy, have developed gestational or permanent diabetes. Linkage and haplotype analysis supported a dominant pattern of inheritance in a large pedigree. In conclusion, we describe the first dominantly inherited SUR1 mutation that causes CHI in early life and predisposes to later insulin deficiency.     

PMM2‐CDG and nephrotic syndrome: A case report

Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, characterized by a defect in the protein glycosylation process. Enzymes involved in this metabolic mechanism have ubiquitous distribution; thus, their alteration can cause systemic involvement and considerable phenotypic variability. Nephrotic syndrome (NS) is a clinical condition characterized by edema, hypoalbuminemia, hyperlipidemia, and proteinuria. We hereby report the case of a girl with central hypotonia, epilepsy, and severe psychomotor delay diagnosed with phosphomannomutase 2 deficiency (PMM2‐CDG) after presenting with nephrotic syndrome at age 4 years.     

A high prevalence of prediabetes and vitamin D deficiency are more closely associated in women: results of a cross-sectional study

ObjectiveMany studies have shown that vitamin D deficiency is associated with insulin resistance and metabolic syndrome. However, few studies have shown independent associations between vitamin D deficiency and the metabolic characteristics of prediabetes. We aimed to evaluate the relationship between serum vitamin D concentration and metabolic risk factors in adults with prediabetes.MethodsWe enrolled 161 patients aged 25 to 75 years in a cross-sectional study and collected clinical and biochemical data, including 25-hydroxyvitamin D (25[OH]D) status and fasting glucose concentration. Vitamin D status was defined as follows: deficiency (25[OH]D <49.9 ng/mL), insufficiency (49.9 to 74.9 nmol/L) or sufficiency (>74.9 nmol/L). Prediabetes was defined using fasting plasma glucose concentrations of 5.55 to 6.49 mmol/L.ResultsThe prevalences of vitamin D deficiency and insufficiency were 49.7% and 24.8%, respectively. Participants with vitamin D deficiency had a higher prevalence of prediabetes than those without (53.8% vs. 32.1%), and there was a significant relationship between female sex and vitamin D status (odds ratio: 1.382; 95% confidence interval: 0.335–5.693).ConclusionVitamin D deficiency is more closely associated with a high prevalence of prediabetes in women than in men. Further studies are needed to elucidate the explanation for this association.     

Adult presentation of MCAD deficiency revealed by coma and severe arrythmias

We report the case of a 33-year-old man who presented with headaches and vomiting. Soon after admission he became drowsy and agitated, developed ventricular tachycardia and his neurological state worsened (Glasgow coma score 6). Blood analysis showed respiratory alkalosis, hyperlactacidemia (8 mmol/l), hyperammonemia (390 µmol/l) and hypoglycaemia (2.4 mmol/l). Subsequently, he developed supraventricular tachycardia, ventricular tachycardia and ultimately ventricular fibrillation resulting in cardiac arrest, which was successfully treated. A CT scan of the head revealed cerebral oedema. Whilst in the intensive care unit, he developed renal failure and rhabdomyolysis. The metabolic abnormalities seen at the time of admission normalised within 48 h with IV glucose infusion. Biological investigations, including urinary organic acids and plasma acylcarnitines, showed results compatible with MCAD deficiency. Mutation analysis revealed the patient was homozygous for the classical mutation A985G. This is one of only a few reports of severe cardiac arrhythmia in an adult due to MCAD deficiency. This condition is probably under-diagnosed in adult patients with acute neurological and/or cardiac presentations.     

The effect of potassium chloride and organic potassium salts on the acid-base equilibrium in normo and hypokalemic rats]

The effects of intravenous infusions of potassium chloride, potassium acetate, potassium aspartate and potassium malate on plasma electrolytes and acid-base balance were investigated in normokalemic or hypokalemic alkalotic rats. Animals who obtained equal volumes of isotonic sodium chloride solution served as controls. All of these potassium solutions increased the plasma potassium concentrations to the same extent. Potassium chloride shifted the acid-base balance to acidotic values in normal rats or corrected metabolic alkalosis in hypokalemic rats. The potassium salts of organic acids, however, caused an increase in alkalosis, acetate acting stronger than aspartate and malate. In potassium deficiency combined with metabolic alkalosis the administration of potassium chloride is preferable to the organic potassium salts since it corrects both the electrolyte disturbances at the same time.     

某地区新生儿葡萄糖-6-磷酸脱氢酶筛查结果分析

目的了解广西地区新生儿葡萄糖-6-磷酸脱氢酶(G6PD)缺乏症的发病情况,为患该病新生儿的防治提供参考依据。方法采用荧光法对本筛查中心的30 556例新生儿进行G6PD筛查检测,对可疑患儿召回并用G6PD/6PGD比值法进行确诊。结果所有被检测的新生儿中G6PD缺乏症的初筛阳性率是7.36%,其中男性为10.89%,女性为2.86%;对民族进行分组,汉族G6PD缺乏症的初筛阳性率是5.29%,壮族为9.54%,其他少数民族为5.42%。对可疑患儿召回确诊发现荧光法与G6PD/6PGD比值法的符合率为97%,重度G6PD缺陷者符合率达100%。结论荧光法准确性高、简便、快捷、费用低廉,广西壮族自治区作为G6PD缺乏症的高发区,应常规开展新生儿葡萄糖-6-磷酸脱氢酶缺乏症的筛查工作,使G6PD缺乏症患者能够及时采取预防性措施。     

儿童缺铁性贫血危险因素及影响贫血程度的相关因素分析

目的对儿童缺铁性贫血(IDA)危险因素及影响贫血程度的相关因素进行分析。方法回顾性分析该院2010年1月至2015年12月收治并明确诊断为IDA的280例1~5岁患儿临床资料(IDA组),并根据其外周血血红蛋白(Hb)水平将贫血程度分为轻度、中度、重度及极重度。同时选取同期280例非贫血患儿为对照组。对可能的儿童IDA危险因素进行多因素Logistic回归分析,筛选儿童IDA的危险因素及影响贫血程度的相关因素。结果 280例IDA患儿轻度贫血者134例,占47.8%,中度贫血者122例,占43.6%,重度及极重度贫血者24例,占8.6%。家庭人均月收入、母亲孕期贫血、母亲未接受育儿指导、母亲文化程度、儿童既往病史及喂养方式是导致患儿发生IDA的危险因素。年龄、病程、母亲文化程度、孕周、出生体质量、喂养方式、儿童既往病史、母亲孕期贫血、母亲未接受育儿指导与贫血严重程度有关(P0.05)。年龄、孕周、出生体质量、儿童既往病史是影响IDA患儿贫血程度的相关因素。结论对于儿童IDA应着重以预防为主,应加大儿童营养保健知识宣教普及力度,定期培训基层儿童保健医护人员,同时制订符合我国儿童饮食特点及含铁丰富食物饮食方案,以降低儿童IDA发病率。     

Fatal metabolic acidosis caused by thiamine deficiency

Acute thiamine deficiency, an uncommon cause of hemodynamic instability in Western countries, may be manifested by acute heart failure and neurological deficits. Severe metabolic acidosis is one of its least recognized features. We present a report of foreign workers who complained of weakness and lower limb edema and were found to have acute thiamine deficiency. One died of refractory metabolic acidosis and shock, and the diagnosis was reached post mortem. Thiamine deficiency should be considered in every case of severe lactic acidosis without an obvious cause, especially in high-risk populations (malnourished, alcoholics, Far-East workers, etc). Whenever it is suspected, empiric treatment with thiamine should be initiated immediately. Physicians who care for populations at risk should be familiar with the clinical spectrum of nutritional deficits, and monitor the nutritional habits of these patients carefully. The treatment is inexpensive and devoid of adverse effects. Moreover, delaying thiamine administration in patients with deficiency may cause severe life-threatening metabolic acidosis and affect recovery. The prophylactic use of thiamine in a high-risk population, even before blood levels are received, may be cost effective.     

Successful treatment of fetal hemolytic disease due to glucose phosphate isomerase deficiency (GPI) using repeated intrauterine transfusions: a case report

Hemolytic anemia due to GPI deficiency can be severe and life threatening during fetal life. When parents decline invasive testing, ultrasound monitoring of fetuses at risk is feasible. Intrauterine transfusion can be effective for the treatment of severe fetal anemia due to GPI deficiency.     

Natural history of potassium-deficiency myopathy in the dog: role of adrenocorticosteroid in rhabdomyolysis

Potassium deficiency occurs in several conditions and is reported to cause muscle weakness and rhabdomyolysis. The mechanisms by which potassium deficiency cause muscle disease remain unknown, but the primary purpose of the present study was to determine whether abnormal muscle glycogen metabolism causes muscle weakness, as suggested by previous work. We monitored the natural history of potassium deficiency in two groups of dogs, one of which also received deoxycorticosterone acetate (DOCA), an agent commonly used in other studies to accelerate potassium loss. Group I dogs on potassium-free diet alone showed a 41% decrease in muscle potassium, no change in serum CO2, creatine kinase (CK), or muscle phosphorylase activity and only mild histopathologic abnormalities before death, after 198 +/- 42 days on the diet (mean +/- S.D.). In contrast, group II dogs on the same diet plus DOCA developed clinically similar severe weakness and died more rapidly than group I, 37 +/- 7 days (p less than 0.03). DOCA dogs showed a more rapid decrease in muscle potassium to the same level as group I, a 37% increase in serum CO2, an increase in serum CK to 1060 to 2775 IU/ml, a 23% decrease in muscle phosphorylase activity, and severe muscle histopathology, including rhabdomyolysis. Neither group showed any change in body weight, electromyogram (EMG), muscle glycogen concentration, glycogen synthetase activity, serum or muscle magnesium or phosphorus, or serum T3 or T4. In conclusion, dietary potassium deficiency in dogs causes severe weakness and death without causing rhabdomyolysis or abnormal muscle glycogen metabolism. Adding DOCA to the potassium-free diet creates a different model characterized by rapid clinical deterioration and rhabdomyolysis.     

新生儿G6PD缺乏症并发高胆红素血症的临床分析

目的：回顾性分析新生儿GBPD缺乏症并发新生儿高胆红素血症的临床特点,探讨G6PD缺乏症在新生儿期发病的诱因、临床进程及诊治效果。方法：2007—10—201206收治的12例新生儿G6PD缺乏症并发高胆红素血症患儿,对其病因、临床表现及转归进行分析。结果：黄疸高峰出现在生后第2～7天,血清总胆红素（STB）峰值为（417．38±154．73）μmol／L,STB〉342μmol／L占66．7％。血红蛋白（Hb）为52～164g／L,平均为（123．37±34．54）g／L,Hb〈140g／L占66．7％;血网织红细胞（Ret）为1．31％～4．22％,均值（2．50±0．94）％。G6PD／6PGD比值平均为（0．44±0．18）。回归分析显示STB与G6PD／6PGD比值、HB和Ret均无明显相关性（r=-0．175,-0．180,0．272;P=0．587,0．576,0．393）。合并疾病及并发症：感染4例,窒息缺氧1例,ABO溶血病2例,核黄疸2例。结论：G6PD缺乏所致新生儿高胆红素血症发病早,黄疸进展快而严重,大多数患儿无明显诱因;G6PD活性和Hb水平不能完全反映黄疸的严重性或溶血程度。对新生儿早期重度黄疸应提高对本病的认识,常规行G6PD活性的检查,并给予积极治疗能有效预防胆红素脑病的发生。     

Coronary artery stenosis treatment in aging patients with inherited Factor VII deficiency: Where do we stand?

Aging with rare bleeding disorders such as factor VII (FVII) deficiency poses several challenges to treatment because of the occurrence of cerebral and cardiovascular age-related comorbidities and high bleeding risks. We report a case of long-term treatment with antiplatelet agents and contemporary prophylaxis of bleeding in a woman affected by severe FVII deficiency diagnosed with symptomatic coronary artery stenosis. Information on the management of antithrombotic treatment in rare bleeding disorders is lacking and mainly limited to anecdotal reports or side effects secondary to replacement therapy. We also briefly reviewed available data on the treatment of arterial thrombosis in FVII deficiency.     

Complementation analysis of fatty acid oxidation disorders.

We assayed [9,10(n)-3H]palmitate oxidation by fibroblast monolayers from patients with fatty acid oxidation disorders. Activities in the different disorders were (percent control): short-chain acyl-coenzyme A (CoA) dehydrogenase deficiency (115%), medium chain acyl-CoA dehydrogenase deficiency (18%), long-chain acyl-CoA dehydrogenase deficiency (28%), multiple acyl-CoA dehydrogenation disorder, mild and severe variants (49% and 7%), and palmityl-carnitine transferase deficiency (4%). Multiple acyl-CoA dehydrogenation disorder, medium chain acyl-CoA dehydrogenase-deficient lines, and long-chain acyl-CoA dehydrogenase-deficient lines all complemented one another after polyethylene glycol fusion, with average activity increases of 31-83%. We detected two complementation groups in the severe multiple acyl-CoA dehydrogenation disorder lines, consistent with deficiencies of either electron transfer flavoprotein or electron transfer flavoprotein:ubiquinone oxidoreductase. The metabolic block in the latter cell lines is threefold more severe than in the former (P less than 0.001). No intragenic complementation was observed within either group. We assigned two patients with previously unreported severe multiple acyl-CoA dehydrogenation disorder to the electron transfer flavoprotein:ubiquinone oxido-reductase-deficient group.     

应用荧光斑点法筛查葡萄糖6-磷酸脱氢酶缺乏

目的：建立适于葡萄糖6－磷酸脱酸酶（G6PD）缺乏新生儿筛查的检测方法。方法：用荧光斑点法（FST）对新生儿筛查滤纸干血片标本进行检测,对阳性者召回,抽静脉血以G6PD／6PGD比值法进行确诊,结果：用FST测定11437份新生儿筛查滤纸干血片标本的G6PD活性,其筛查阳性率4．2％,确诊检出率3．7％。与G6PD／6PGD比值法的符合率为86．8％,重度G6PD缺陷者符合率达100％,具有高敏感性和特异性,结论：FST准确性高,简便、快捷、费用低廉,可以滤纸干血片标本进行大规模的筛查检测, 适宜在高发区开展G6PD缺乏的新生儿筛查和早期诊断及防治工作中应用。     

乳酸亚铁片治疗妊娠合并缺铁性贫血52例报告

目的:探讨乳酸亚铁片治疗妊娠合并缺铁性贫血的疗效和安全性。方法:52例妊娠合并缺铁性贫血患者,轻度贫血患者予乳酸亚铁片0.1 bid,饭后口服,中度贫血予乳酸亚铁片0.2bid或tid饭后口服治疗。连续治疗4周后复查血常规。结果:50例患者均有不同程度的症状改善,例无效。结论:乳酸亚铁片治疗妊娠合并缺铁性贫血疗效良好,药物不良反应小。     

Pneumonia

Abstract

The porphyrias are a group of metabolic diseases caused by inherited or acquired enzymatic deficiency in the metabolic pathway of heme biosynthesis. Simplistically, they can be considered as storage diseases, because the partial enzymatic defect gives rise to a metabolic “bottleneck” in the biosynthetic pathway and hence to an accumulation of different metabolic intermediates, potentially toxic and responsible for the various (cutaneous or neurovisceral) clinical manifestations observed in these diseases. In the acute porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and the very rare delta-aminolevulinic acid dehydratase ALAD-d porphyria), the characteristic severe neurovisceral involvement is mainly ascribed to a tissue accumulation of delta-aminolevulinic acid, a neurotoxic nonporphyrin precursor. Many different factors, both endogenous and exogenous, may favor the accumulation of this precursor in patients who are carriers of an enzymatic defect consistent with an acute porphyria, thus contributing to trigger the serious (and potentially fatal) clinical manifestations of the disease (acute porphyric attacks). To date, many different drugs are known to be able to precipitate an acute porphyric attack, so that the acute porphyrias are also considered as pharmacogenetic or toxygenetic diseases. This article reviews the different biochemical mechanisms underlying the capacity of many drugs to precipitate a porphyric acute attack (drug porphyrogenicity) in carriers of genetic mutations responsible for acute porphyrias, and addresses the issue of prescribing drugs for patients affected by these rare, but extremely complex, diseases.     

Syndromes with focal femoral deficiency: strengths and weaknesses of prenatal sonography.

OBJECTIVE: To further characterize the prenatal diagnosis of proximal focal femoral deficiency and to contrast this entity with a variety of other "syndromes" in which the femur may be deficient. METHODS: We report 2 cases of proximal focal femoral deficiency and a case of femoral-facial syndrome. RESULTS: A series of 3 women whose fetuses had deficiency of 1 or both femurs were carefully analyzed for severity and for similarities and differences with other syndromes in which the femur may be deficient, as well as syndromes showing global skeletal abnormalities. CONCLUSIONS: Prenatal sonography is a valuable tool both for detecting cases of proximal focal femoral deficiency, separating them from syndromes showing global skeletal abnormalities, and for stratifying them according to severity.