Multiple sulfatase deficiency (Mucosulfatidosis): Impaired degradation of labeled sulfated compounds in cultured skin fibroblasts in vivo

Skin fibroblasts from a Japanese patient with multiple sulfatase deficiency (MSD) (Mucosulfatidosis) were studied with regard to metabolism of various sulfated compounds in vivo. Several sulfatase activities (arylsulfatases A,B and C, cholesterol sulfatase, heparin N-sulfatase) were deficient in skin fibroblasts grown in F-10 CO₂ medium. The accumulation and degradation of ³⁵S-sulfatide, ³⁵S-mucopolysaccharides, ¹⁴C-cholesterol sulfate by MSD cells were also studied, comparing them to control, Hunter and metachromatic leukodystrophy cells. MSD fibroblasts accumulated and failed to degrade these compounds in vivo. Cholesterol sulfate was also incorporated into the control and pathological cells, and MSD cells were unable to hydrolyze cholesterol sulfate, though cholesterol sulfate is known to be hydrolyzed in the non-lysosomal subfraction. From these data it is clear that multiple enzyme deficiencies in MSD fibroblasts can be demonstrated in vivo.Supported by grants Nanbyo from a Ministry of Education, 1979     

Genetic deficiency of medium-chain acyl coenzyme A dehydrogenase: studies in cultured skin fibroblasts and peripheral mononuclear leukocytes

Medium-chain acyl coenzyme A (CoA) dehydrogenase deficiency was demonstrated in fibroblasts and/or mononuclear leukocytes from 14 patients, most of whom initially presented early in childhood with a Reye-like syndrome associated with hypoketotic hypoglycemia, dicarboxylic aciduria, and low levels of plasma carnitine. Parents of these patients had intermediate levels of medium-chain acyl CoA dehydrogenase activity, consistent with their being heterozygous for an autosomal recessive trait. All patients had normal levels of long-chain acyl CoA dehydrogenase activity, but had reduced short-chain acyl CoA dehydrogenase activity. Fatty acid oxidation was examined in cultured fibroblasts from five of the patients, using a series of 14C-labeled fatty acids of different chain length (palmitic, octanoic, and butyric). Oxidation of [1-14C]-octanoic acid was less than 20% of control levels: [1-14C], [6-14C]-, [16(14)C]-, and [14C(U)]-palmitic acid oxidation rates were 88, 51, 13, and 42% of control rates, respectively. [1-14C]-butyric acid was oxidized normally. These data extend our previous findings of medium-chain acyl CoA dehydrogenase deficiency in liver tissue from three of these patients. They demonstrate the value of cultured fibroblasts and leukocytes in the diagnosis and evaluation of inherited disorders of fatty acid oxidation.     

Corneal crystals, myopathy and nephropathy: a new syndrome?

A case with ocular (corneal crystals and retinal pigment epithelial mottling), muscle (oropharyngeal and hand weakness and atrophy), and renal (proteinuria and hypertension) abnormalities is described. We believe that this represents a previously unrecognized syndrome.     

Adrenoleukodystrophy: impaired oxidation of very long chain fatty acids in white blood cells, cultured skin fibroblasts, and amniocytes

We compared the formation of 14CO2 from [I-14C]fatty acids in homogenates of cultured skin fibroblasts and white blood cells from 25 patients with adrenoleukodystrophy (ALD) and from 24 controls. The ALD group included 16 boys with childhood ALD, five men with adrenomyeloneuropathy (AMN), and two boys and two girls with neonatal ALD. The substrates were unbranched saturated fatty acids ranging in chain length from 16-26 carbons. From C24:0, the radioactive CO2 production by homogenates of ALD fibroblasts and white blood cells was 17% and 37% of control, respectively, and from C26:0 it was 17% of control in ALD fibroblasts. The CO2 evolution from palmitate (C16:0) in the ALD was identical to the control group; for C18:0, the value for ALD cells was 76% of control, and fatty acids with chain lengths between C18:0 and C24:0 gave intermediate results. Results for childhood ALD patients were similar to those for the AMN patients. More limited studies with cultured amniocytes of fetuses with childhood ALD gave results similar to those obtained with cultured skin fibroblasts, and results with neonatal ALD patients appeared to be the same as for childhood ALD and AMN. Studies of three women who were carriers for childhood ALD gave values intermediate between ALD and control. The total C26:0 levels in ALD cultured skin fibroblasts and white blood cells were 4-6 times that of control; the total C24:0 levels were increased 10-30%, whereas the C22:0 levels were unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)     

A novel mutation and unusual clinical features in a patient with immune dysregulation,polyendocrinopathy, enteropathy,X-linked (IPEX) syndrome

We report a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome with a novel splicing mutation of the FOXP3 gene. The patient is a boy, born at 39 + 2 weeks gestation with a birth weight of 3,280 g. The family history was unremarkable. He was well until 11 months of age, when he was diagnosed with type 1 diabetes mellitus. The level of urine C-peptide was 0.58 μg/day (normal range, 44–116 μg/day). Glutamic acid decarboxylase autoantibody was not detected, but a high level of anti-insulin antibody (50 IU/mL; normal range, <5 IU/mL) was noted. This patient presented with unusual clinical features, including pure red cell aplasia, membranous glomerulopathy, and posterior reversible encephalopathy syndrome after a vaccination against influenza A H1N1 virus. The diagnosis of IPEX was made when the patient was 11 years old, which is quite late compared with typical cases. Conclusion: Although IPEX syndrome is usually a disease of infancy, it should not be ruled out solely on the basis of age. IPEX presentation is so variable that it should be suspected in a male child with one or more autoimmune disorders and severe infections.     

Fluorescence imaging of mitochondria in cultured skin fibroblasts: a useful method for the detection of oxidative phosphorylation defects

Background:Protons are pumped from the mitochondrial matrix via oxidative phosphorylation (OXPHOS) into the intermembrane space, creating an electric membrane potential (ΔΨ) that is used for adenosine triphosphate (ATP) production. Defects in one or more of the OXPHOS complexes are associated with a variety of clinical symptoms, often making it difficult to pinpoint the causal mutation.Methods:In this article, a microscopic method for the quantitative evaluation of ΔΨ in cultured skin fibroblasts is described. The method using 5,5',6,6'-tetraethylbenzimidazolyl-carbocyanine iodide (JC-1) fluorescence staining was tested in a selection of OXPHOS-deficient cell lines.Results:A significant reduction of ΔΨ was found in the cell lines of patients with either an isolated defect in complex I, II, or IV or a combined defect (complex I + complex IV). ΔΨ was not reduced in the fibroblasts of two patients with severe complex V deficiency. Addition of the complex I inhibitor rotenone induced a significant reduction of ΔΨ and perinuclear relocalization of the mitochondria. In cells with a heteroplasmic mitochondrial DNA (mtDNA) defect, a more heterogeneous reduction of ΔΨ was detected.Conclusion:Our data show that imaging of ΔΨ in cultured skin fibroblasts is a useful method for the evaluation of OXPHOS functioning in cultured cell lines.     

Barth综合征1例临床及基因突变分析

目的探讨Barth综合征(BTHS)的临床表现及遗传学特征。方法回顾分析1例BTHS患儿的临床资料。结果患儿,男,10月龄,以左室增大,爆发性心肌炎,心力衰竭,肌无力,单核细胞增多,低血糖,乳酸性酸中毒,腹泻,面部异常等为主要表现。基因测序显示TAZ基因存在一个错义突变(c.406CT,p.Cys136Arg),突变来自患儿母亲。结论扩充了中国BTHS的基因突变谱及临床特征。     

Acquired immune deficiency syndrome (AIDS) and neoplasia

The acquired immune deficiency syndrome (AIDS) is a novel epidemic form of immunodeficiency that has been widely recognized within the last six years. AIDS is characterized by Kaposi's sarcoma, B cell lymphoma, and/or life-threatening opportunistic infections superimposed on an immune deficiency state which consists of lymphopenia with a selective depletion of the CD4 T cells. In addition, lymphocytes from AIDS patients show decreased responses to antigen or mitogen stimulation in vitro. Although the secondary infections and malignancies seen in these patients may be successfully treated, the underlying immune defect persists, leaving the patient susceptible to further complications.     

Kearns' syndrome: a case study (author's transl)

An anatomoclinical study of a case of Kearns' syndrome is reported. Neuro-ophthalmic symptoms appeared when the child was 13 year-old. Two and a half years later occurred an episode of paroxystic atrioventricular block, after which the triad characterising the syndrome was completed: retinitis pigmentosa, ophthalmoplegia, disorder of heart conduction. The course was unfavorable despite pacemaker insertion. Study of the central nervous system showed spongiosis of the subcortical white substance, of the basal ganglia and of the cranial nerve nuclei. The specialized heart conduction tissue was the site of apparently primary degeneration. The extension of the visceral involvement is discussed in the light of published data.     

Primary intestinal myopathy, a cause of chronic idiopathic intestinal pseudoobstruction syndrome (CIPS): clinicopathological studies of seven cases in children

Clinicopathological data on seven instances of primary intestinal myopathy in children are reported. The ages of the patients ranged from eleven months to thirteen years. A persistent intestinal obstruction was the main and constant clinical feature. An ineffective intestinal propulsion was documented on manometric studies. Various urological abnormalities were present in three cases. One patient died and six survive but are dependent on enteral and parenteral nutrition. The morphological findings consisted of degenerative changes involving the muscular layers of the intestinal wall. These changes varied from cytoplasmic vacuolation to definite atrophy and disappearance of the muscular fibers. An extensive interstitial fibrosis underlined these atrophic changes in the late stages of the disease. A familial history was identified in three cases, one consistent with an autosomal dominant transmission.     

Acute metabolic decompensation and sudden death in Barth syndrome: report of a family and a literature review

Barth syndrome presents in infancy with hypotonia, dilated cardiomyopathy, and neutropenia. We report a patient whose family history included two males who had died suddenly at the age of 15 days and 2 years, respectively. The index case presented with acute metabolic decompensation at 13 days of age. Within 8 h of presenting with metabolic acidosis (pH 7.13), lactic acidemia (18.5 mmol/l), hyperammonemia (375 mug/dl), hypoglycemia (25 mg/dl), and coagulopathy, the patient developed respiratory failure and required intubation. The diagnosis was established by the presence of left ventricular noncompaction and molecular analysis (c.C153G or Y51X mutation of the TAZ gene). The gene product, taffazin, is a homologue of the glycerolipid transferases involved in the phospholipid metabolism as tetralinoleoyl-cardiolipin, a component of the mitochondrial inner membrane. In conclusion, mutations in taffazin impair mitochondrial respiratory chain complexes, which may results in the acute metabolic decompensation and sudden death; cardiac transplantation is the only possibility at the present time.     

Successful use of the new immune-suppressor sirolimus in IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome)

IPEX (immune-dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome is an autoimmune disorder with an often lethal outcome in spite of immunosuppressive therapy. We report the successful use of sirolimus in 3 patients with IPEX. The efficacy of sirolimus is probably due to its different mode of action compared to calcineurin-dependent agents.