Autosomal dominant optic atrophy with asymptomatic peripheral neuropathy

The association between hereditary motor and sensory neuropathy (HMSN) and optic atrophy has been termed HMSN type VI. The autosomal dominant inheritance of this syndrome is reported. Three generations were affected with optic atrophy, which differed in some respects from classic dominant optic atrophy, and an asymptomatic, mainly sensory, neuropathy.     

Colour discrimination ellipses in patients with dominant optic atrophy

Many colour tests require a visual acuity of at least 0.1, making them unsuitable for low vision patients. To assess colour vision in patients with sub-normal acuity, we re-designed a previously described test so that its spatial details would be coarse enough to be resolvable by subjects with severe visual impairment. The test measures chromatic discrimination along 20 axes evenly spaced in CIE 1976 L*u*v* colour space. We detail the results for this test in a group of patients with dominant optic atrophy. Despite the lack of evidence for genetic heterogeneity in dominant optic atrophy, we observed phenotypic variation both between and within families.     

Linkage studies in dominant optic atrophy, Kjer type: possible evidence for heterogeneity

Dominant optic atrophy, Kjer type, is an autosomal dominant disorder causing progressive loss of visual acuity and colour vision from early childhood. The gene (OPA1) has variable expressivity, a penetrance of 0.98, and the locus has been localised to 3q28-29. We have genotyped nine British families with the disease using 12 polymorphic microsatellite markers from this region. Linkage and haplotype analysis shows the OPA1 gene to be located in a 2.3 cM interval between markers D3S1601 and D3S2748. One family showed no evidence of linkage with the chromosome 3 markers, suggesting for the first time that locus heterogeneity for this disease may exist, although exclusion for linkage is based on unaffected subjects. In addition, analysis of recombinants has enabled us to order the 12 markers along chromosome 3.     

儿童侵袭性成熟B细胞淋巴瘤的临床病理学及分子遗传学特点

目的 分析总结中国儿童各类型侵袭性成熟B细胞淋巴瘤的临床病理学及分子遗传学特点,为其诊断的标准化提供依据.方法 收集97例儿童侵袭性成熟B细胞淋巴瘤石蜡包埋组织标本,包括伯基特淋巴瘤(BL)81例、弥漫大B细胞淋巴瘤(DLBCL)8例、介于BL和DLBCL间的不能分类的B细胞淋巴瘤(BL/DLBCL)8例,利用免疫组织化学技术和间期荧光原位杂交(FISH)技术检测其免疫表型和分子遗传学特征.结果 BL的bcl-2和MUM1的阳性率分别为3%(2/66)和17%(12/71),DLBCL分别为50%(4/8)和63%(5/8),BL/DLBCL分别为50%(4/8)和63%(5/8).BL、DLBCL和BL/DLBCL的Ki-67平均值分别为(93±4.4)%、(83±14.3)%和(80±11.5)%.BL、DLBCL和BL/DLBCL的c-myc基因易位的比例分别为98%(79/81)、38%(3/8)和50%(4/8).38%(3/8)的DLBCL和25%(2/8)的BL/DLBCL存在bcl-6基因的多拷贝,BL与DLBCL之间、BL与BL/DLBCL之间bcl-2、MUM1和Ki-67平均值的差异及c-myc基因易位和bcl-6基因多拷贝的差异均有统计学意义(均P＜0.05).结论 儿童侵袭性成熟B细胞淋巴瘤的诊断和分型需要综合分析形态学、免疫表型和分子遗传学特征.儿童BL/DLBCL可能是DLBCL的一个亚型.CD10+、bcl-6+、bcl-2-、Ki-67＞90%、伴有IGH/c-myc重排、不伴有bcl-2和bcl-6重排时,支持BL的诊断;bcl-2+、Ki-67为50%～90%,同时伴有bcl-6基因的多拷贝时,支持DLBCL或BL/DLBCL的诊断.     

Clinical features and genetics of progressive myoclonus epilepsy of the Univerricht-Lundborg type

INTRODUCTION: We retrospectively reviewed the CT findings of the acute abdomen patients examined in the last two years to investigate the frequency of a new CT sign of intestinal infarction, the pneumoretroperitoneum, and its association with other CT findings highly suggestive of this condition. MATERIAL AND METHODS: The CT findings of 60 patients with diagnostic confirmation of intestinal infarction were retrospectively reviewed. CT was performed without (no. = 55) and with (no. = 5) oral administration of contrast material and without (no. = 3) and with (no. = 57) the i.v. injection of nonionic contrast agents in repeated 50 mL boluses. To assess the specificity of this sign, we selected a control group of 400 patients submitted to CT for acute abdomen, but not blunt trauma; 19 of these patients had pneumoretroperitoneum. RESULTS: Pneumoperitoneum was found in five patients with intestinal infarction; it was an isolated sign in two cases and it was associated with few small perihepatic air bubbles in one case. Finally, it was associated with highly suggestive findings of late intestinal infarction in the other two cases. All cases of pneumoretroperitoneum in the control group had been correctly referred to other diseases by previous plain film and/or CT findings and surgery and/or endoscopy confirmed this diagnosis. DISCUSSION AND CONCLUSIONS: Pneumoretroperitoneum has been described as a complication of different benign or severe disorders; prompt recognition of its origin is essential since surgical and/or septic conditions may be involved. However, if the patient's history is negative for abdominal trauma, gastroduodenal ulcer or sepsis, pneumoretroperitoneum is generally cured with conservative treatment. Intestinal infarction or severe ischemia, a usually surgical conditions, should be considered among the different causes of pneumoretroperitoneum alone or associated with pneumoperitoneum or with highly suggestive late findings of infarction such as portal venous gas or pneumatosis intestinalis. This sign had a non-negligible incidence in intestinal infarction in our review (8.5%), but it should be known of and sought with specific window setting to enhance gas depiction on CT images to avoid false negatives.     

Clinical and molecular features of spinocerebellar ataxia type 6

The mutation involved in spinocerebellar ataxia type 6 (SCA6) is a small CAG expansion in the alpha-1A subunit of the voltage-dependent calcium channel gene. We looked for this mutation in 91 families with autosomal-dominant cerebellar ataxias and found that SCA6 is a minor locus in our series (2%) and is rare in France (1%). Furthermore, we did not detect the SCA6 mutation on 146 sporadic cases with isolated cerebellar ataxia or olivopontocerebellar atrophy. The normal and expanded alleles ranged from 4 to 15 and 22 to 28 CAG repeats, respectively, and age at onset was correlated to CAG repeat length (r = -0.87). In contrast with other SCA, the expanded allele was stable during transmission. Clinically, SCA6 patients (n = 12) presented with moderate to severe cerebellar ataxia with a lower frequency of associated signs compared with other SCA and a mean age at onset of 45 +/- 14 years (range, 24 to 67). MRI showed extensive cerebellar atrophy but not of the brainstem or cerebral cortex.     

Motor neuropathy, putamen necrosis and optic nerve atrophy after acute methanol poisoning

Optic neuropathy and putaminal necrosis are the most common sequellae of methanol poisoning. We report a case in a patient with a chronic motor neuro(no)pathy in addition to these neurological complications. Peripheral nerve and spinal cord disorders, related to methanol poisoning, are uncommon and probably underestimated.     

Diabetes mellitus, diabetes insipidus, and optic atrophy. An autosomal recessive syndrome?

Twenty-one families were selected from the published reports in which the propositus had the triad of juvenile diabetes mellitus, diabetes insipidus, and optic atrophy. The data were consistent with the hypothesis of an autosomal gene which, in the homozygote, causes juvenile diabetes mellitus and one or more of diabetes insipidus, optic atrophy, and nerve deafness. Heterozygotes appear to have an increased probability of developing juvenile diabetes mellitus.     

The molecular and cellular pathophysiology of heart failure

In the United States, it is estimated that heart failure develops in 465,000 people each year. Heart failure occurs in both men and women and is associated with a high morbidity and mortality rate in both sexes and in all races. Our knowledge of the pathophysiology of heart failure has advanced beyond the cardiorenal-neurohumoral model and now includes changes in myocyte structure and function. Cellular changes in heart failure include myocyte hypertrophy, abnormalities in calcium homeostasis, excitation-contraction coupling, cross-bridge cycling, and changes in the cytoskeletal architecture. Data also indicate that some of these changes are found during the compensated stage of heart failure; whereas other changes are found during overt decompensation and are associated with changes in systolic and diastolic function. The transition from compensated to decompensated heart failure is more than likely related to the overexpression of neurohormones and peptides such as norepinephrine, angiotensin II, and proinflammatory cytokines. The purpose of this article is to review the epidemiology and cellular pathophysiology of heart failure.     

Short lexicon of molecular genetics

The cytologic examination of fine-needle aspirates and fluid specimens is plagued by a persistent false negative rate. The rate of false negative results will be decreased if sensitive molecular assays can be developed to detect cytologically malignant cells. The current study investigated telomerase expression as a potential marker of malignancy, using the telomeric repeat amplification protocol (TRAP) in fine-needle aspirates and fluid specimens. TRAP was performed on 24 fine-needle aspirate and 24 fluid specimens from different body sites and of different histological diagnoses. We found that 6 of 12 fine-needle aspirate specimens that were cytologically positive for malignant cells expressed telomerase activity, while no specimens that were cytologically suspicious for malignancy, atypical, or negative tested positive for telomerase activity. Of the fluid specimens, 4 of 6 cytologically positive cases and 1 of 18 cytologically negative cases expressed telomerase. Seven of eight telomerase negative, cytologically positive specimens contained only rare malignant cells in a very bloody background. Peripheral blood contamination is a possible pitfall in the TRAP assay, as applied in the current study, because the assay is standardized to protein concentration that may be derived from lysed red blood cells. We conclude that with further technical refinement, the TRAP assay could become a useful adjunct in the cytologic examination of fine-needle aspirates and fluid samples.     

Autosomal dominant progressive external ophthalmoplegia with multiple deletions of mtDNA: clinical, biochemical, and molecular genetic features of the 10q-linked disease

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disease characterized by accumulation of multiple large deletions of mtDNA in patients' tissues. We previously showed that the disease is genetically heterogeneous by assigning two nuclear loci predisposing to mtDNA deletions: one on chromosome 10q 23.3-24.3 in a Finnish family and one on 3p 14.1-21.2 in three Italian families. To reveal any locus-specific disease features, we report here the clinical, biochemical, and molecular genetic characteristics of the 10q-linked disease in the single family reported to date. All seven patients and four asymptomatic subjects had ragged-red fibers and multiple deletions of mtDNA in their muscle. Ptosis and external ophthalmoplegia were the major clinical findings, and depression or avoidant personality traits were frequently, but not consistently, present in the subjects carrying mutant mtDNA. In six of the subjects with mutant mtDNA, the activities of the respiratory chain complexes I or IV, or both, were below or within the low normal range. Two autopsy studies revealed the characteristic distribution of mutant mtDNA in these patients: highest proportion of mutant mtDNA is found in different parts of the brain, followed by the skeletal and ocular muscle, and the heart.     

Dominant optic atrophy: exclusion and fine genetic mapping of the candidate gene, HRY

The treatment of infants and children with short bowel syndrome aims at restoring the intestinal continuity and at improving the physiological process of gut adaptation. Mucosal hyperplasia allows the remaining gut to ensure an adequate digestion and an absorption process leading to intestinal autonomy. During the period of adaptation, appropriate parenteral and/or enteral feeding must be directed at maintaining an optimal nutritional status. Delay of intestinal autonomy depends on the characteristics of the residual intestine: length, presence of the ileocecal valve and colon, and motor function. Bacterial overgrowth compromises intestinal adaptation and increases the risk of liver disorders. Few patients will remain long-term dependent on parenteral nutrition. All approaches aimed at achieving intestinal autonomy should be tried: use of trophic factors, intestinal tapering, and lengthening. In a few residual patients, permanent intestinal failure or extreme short bowel syndrome require intestinal transplantation.     

The molecular genetics of pancreatic cancer

Exaggerated blood pressure (BP) response to exercise in normotensive subjects is considered as a predictor of future hypertension. The aim of the study was to find out whether elevated BP response to exercise is associated with any other haemodynamic, metabolic or hormonal abnormalities. Abnormal BP response to exercise, i.e. systolic BP (SBP) > 200 mmHg at 150 W or lower workload, was found in 37 out of 180 normotensive, male students, aged 20-24 years. Fifteen students with elevated exercise BP (group E) volunteered for further examinations. Their resting and ambulatory BP showed high normal values. Eight of them had a family history of hypertension. Four subjects met the criteria of cardiac hypertrophy. Significant correlations were found between exercise SBP and left ventricular mass index, average 24 h and daytime SBP recordings. In comparison with normal subjects of the same age (group N, n = 13), those from group E did not differ in body mass index, plasma lipid profile, fasting glucose, insulin and catecholamine (CA) concentrations, but had increased erythrocyte sodium content, slightly elevated plasma renin activity and cortisol level. During exercise, E subjects showed greater cardiac output (CO) increases with normal heart rate, total peripheral resistance (TPR) and plasma CA. There were no significant differences between groups in haemodynamic and plasma CA responses to posture change from supine to standing. Glucose ingestion (75 g) caused smaller increases in CO and smaller decreases in TPR in E than in N subjects without differences in BP, blood glucose plasma insulin and CA. It is concluded that young normotensive men with exaggerated BP response to exercise show some other characteristics that may be considered as markers of predisposition to hypertension or factors promoting the development of hypertension.     

The Wolfram syndrome: diabetes mellitus, hypacusis, optic atrophy and short stature in STH deficiency

HISTORY AND CLINICAL FINDINGS: A 43-year-old man was known for 3 years to have diabetes mellitus. For 2 months before admission he had symptoms of hyperglycaemia with polyuria, polydipsia, weight loss, as well as impairment of vision and declining fitness. In addition to bilateral deafness he was clearly of normally proportioned short stature (150 cm). INVESTIGATIONS: The levels of blood sugar (221 mg/dl), HbA1c(10.2%), triglycerides (496 mg/dl) and cholesterol (323 mg/dl) were raised, while the concentration of somatotropic hormone was diminished, both before and after arginine administration. Fundoscopy revealed concentric diminution of the visual fields with left amblyopia. Visual evoked potentials and colour sense testing revealed bilateral optical atrophy, and the audiogram demonstrated deafness. These findings provided the diagnosis of Wolfram syndrome, namely insulin-dependent diabetes mellitus, deafness, optical atrophy and small stature with somatotropic hormone deficiency. TREATMENT AND COURSE: On insulin treatment the metabolic state became normal (HbA1c 7.5%, normal lipid profile). It was decided that the deficiency in somatotropic hormone regulation did not require treatment. CONCLUSION: Cardinal symptoms of the autosomally recessive Wolfram syndrome are insulin-dependent diabetes and optic nerve atrophy. Several types of hormonal abnormalities are associated with it, including a deficiency in the somatotropic axis. To obtain early and adequate hormonal substitution requires extensive endocrinological diagnosis of a disease which frequently becomes manifest in childhood or adolescence.     

The molecular genetics of endocrine tumours

The molecular genetics of endocrine tumours is an area of great interest, due to the heterogeneity of endocrine tumour types, the association of hormone over-production in some cases, and the wide variation in tumour behaviour. Genes implicated fall into functional categories such as oncogenes, in which mutations tend to cause activation, and tumour suppressor genes, in which mutations lead to loss of function. Oncogenes include the receptor tyrosine kinases such as RET, signal transduction proteins and other molecules such as cell cycle regulators and nuclear proteins. Tumour suppressor genes include cell cycle regulators such as p53 and other molecules such as the MEN 1 gene. Loss of heterozygosity studies help in the initial localisation of the latter. Endocrine tumours, as with other tumours, develop as a result of a combination of genetic events, and in the paediatric age group they often occur in the setting of familial cancer syndromes. In this review we analyse the main genetic lesions which have been described in endocrine tumours. There has been an explosion of knowledge in the last 5 years including the identification of the causative genes for MEN 2 and most recently for MEN 1. Characterisation of such genes also aids in the study of somatic mutations in sporadic versions of the same tumour types as occur in the familial syndromes. Identification of a genetic predisposition to a certain tumour has management implications that are still to be clarified in most cases, although in the case of MEN 2 the guidelines for prophylactic thyroidectomy are generally well accepted.