Proximal myotonic myopathy: clinical and molecular investigation of a Norwegian family with PROMM

Proximal myotonic myopathy (PROMM) was first described in 1994 as a multisystem disorder with similarity to myotonic dystrophy (DM), but without the abnormal (CTG)n expansion in the DM protein kinase (DMPK) gene. The inheritance is autosomal dominant and the clinical features include myotonia, proximal muscle weakness and cataract. Linkage analysis in nine German PROMM families has indicated the possibility of linkage to DM2 locus on chromosome 3. We report a Norwegian PROMM family in which the proband was clinically diagnosed as DM but without the (CTG)n expansion. Using an intragenic marker we showed that the DMPK gene did not segregate with the disease in this family. All family members are heterozygous for the R894X mutation in CLCN1 gene. Linkage analysis could not be performed, but haplotyping probably excludes the DM2 locus as the disease locus in this family. The present family emphasises that myalgia is a prominent symptom in PROMM and the clinical differences may be explained by genetic heterogeneity. This family will be reinvestigated along with the identification of candidate genes or regions in larger PROMM families.     

线粒体脑肌病伴乳酸血症和卒中样发作综合征的临床特征及遗传学研究

目的探讨线粒体脑肌病伴乳酸血症和卒中样发作（MELAS）综合征临床与分子遗传学特征,寻找MELAS线粒体DNA（mtDNA）A3243G点突变比例与临床特征的关联性。方法对2001年1月至2008年1月在首都医科大学附属北京儿童医院神经内科住院和门诊临床疑似线粒体脑肌病的患儿,行外周血白细胞mtDNA A3243G点突变筛查、血乳酸检测和神经影像学等检查。A3243G点突变阳性病例中选取符合MELAS临床疑似诊断标准的患儿（突变阳性组）,对其家系进行调查,采集家族成员血进行mtDNA A3243G点突变筛查;A3243G点突变阴性病例中选取符合MELAS临床疑似诊断标准的患儿行肌肉病理活检和肌肉A3243G点突变筛查（突变阴性组）。分析比较两组的临床资料及MELAS遗传学特征。结果研究期间共有272例疑似线粒体脑肌病的患儿进行了外周血白细胞A3243G点突变的筛查。A3243G点突变的20例阳性标本中,突变均为异胞质性（heteroplasmy）,18例符合MELAS的临床疑似诊断标准。血细胞中突变型mtDNA的比例为9.0%-50.0%,其中4例同时在肌肉组织检测到相同突变,突变比例为42.4%-64.8%。临床症状以惊厥、乏力、智力进行性倒退、发热、呕吐、视力障碍和失语为主,身材矮小和体毛增多为主要体征,13例合并癫,血乳酸均升高,头颅CT/MRI显示双侧对称性苍白球钙化和脑梗死信号。A3243G点突变筛查阴性标本中有4例临床符合MELAS临床疑似诊断标准,肌肉病理可见破碎红边纤维,肌肉A3243G点突变筛查阴性。14个家庭中的37名家庭成员采集了外周血进行mtDNA A3243G点突变筛查,突变阳性组中患儿母亲5名检测到A3243G点突变,突变比例分别为3.0%,5.0%,11.8%,21.3%和26.9%,同胞兄弟4名检测到A3243G突变,突变比例分别为19.3%、33.3%,37.5%和41.5%,均无临床症状,其他成员未检测到突变。本研究A3243G点突变比例与发病年龄和就诊年龄呈负相关趋势,与病程未?     

Peripheral neuropathy in myotonic dystrophy: electrophysiological and clinical features.

Peripheral neuropathy was investigated in thirty-one patients with myotonic dystrophy (MyD) and sixteen relatives. Using standard electrophysiological criteria, a sensorimotor axonal peripheral neuropathy was found in 14 MyD cases (45%) and not in unaffected first-degree relatives. The whole group of the MyD patients showed significant impairment of mean motor and sensory conduction values, compared with controls. The presence of polyneuropathy was correlated with the patients' age and the severity and duration of the clinical manifestations of MyD.     

Proteus syndrome review: molecular,clinical, and pathologic features

Proteus syndrome is caused by an activating AKT1 mutation (c.49G>A, p.Glu17Lys). Many variable features are possible in this mosaic disorder, including: (i) disproportionate, asymmetric, and distorting overgrowth; (ii) bone abnormalities different from those observed in other disorders; (iii) a characteristic cerebriform connective tissue nevus made up of highly collagenized connective tissue; (iv) epidermal nevi in early life, consisting of acanthosis and hyperkeratosis; (v) vascular malformations of the capillary, venous, or lymphatic types; (vi) dysregulated adipose tissue including lipomas, lipohypoplasia, fatty overgrowth, and localized fat deposits; (vii) other unusual features, including bullous lung alterations; specific neoplasms; a facial phenotype associated with intellectual disability and/or seizures, and/or brain malformations; and (viii) deep vein thrombosis, resulting in premature death. Concluding remarks address diagnostic criteria, natural history, management, psychosocial issues, and differential diagnosis.     

Soft tissue sarcomas with non-EWS translocations: molecular genetic features and pathologic and clinical correlations

Many soft tissue sarcoma subtypes have consistent chromosomal translocations with novel fusion genes, which result in disordered cellular function. The microscopic appearances, immunophenotype and behaviour of such tumours relate to the genetic events to a variable extent. This paper reviews the molecular pathology and related morphological and clinical features of sarcomas with non-EWS translocations. These include synovial sarcoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, dermatofibrosarcoma protuberans, low-grade fibromyxoid sarcoma, infantile fibrosarcoma and inflammatory myofibroblastic tumour.     

Coffin-Lowry syndrome: clinical and molecular features

The Coffin-Lowry syndrome (CLS) is a rare X linked disorder in which affected males show severe mental retardation with characteristic dysmorphism, most notably affecting the face and hands. The typical facial features consist of a prominent forehead, hypertelorism, a flat nasal bridge, downward sloping palpebral fissures, and a wide mouth with full lips. Mild progression in facial coarsening occurs during childhood and adult life. The hands are broad with soft, stubby, tapering fingers. Other clinical findings include short stature (95%), a pectus deformity (80%), a kyphosis and/or scoliosis (80%), mitral valve dysfunction, and sensorineural hearing loss. The causal gene, RSK2, was identified in 1996 and contains 22 exons which encode a protein of 740 amino acids. Over 75 distinct pathogenic mutations have been identified in 250 unrelated CLS patients.     

Minimal expression of myotonic dystrophy: a clinical and molecular analysis.

A clinical and molecular study is reported of 83 patients considered to be minimally affected with myotonic dystrophy (DM). These had been identified in three ways: 60 subjects were identified on clinical grounds and were divided into those with and those without neuromuscular involvement (groups I and II); nine subjects were at high risk of carrying the DM gene but had a normal phenotype (group III); and 14 were parents of definitely affected patients where neither parent showed clinical abnormalities (group IV). PCR analysis of the CTG repeat in the DM gene showed a range of 70 to 230 repeats for the younger at risk patients in group III, while the asymptomatic gene carriers in group IV had 53 to 60 repeats. The sensitivity of diagnosis by EMG was found to be 39%. For ophthalmic signs this was 97.5%. This suggests that assignment on the basis of minimal clinical features carries a significant error. Molecular analysis, in conjunction with established clinical investigations, should prove valuable in the identification and exclusion of minimal myotonic dystrophy.     

Complex I deficiency: clinical features, biochemistry and molecular genetics

Complex I deficiency is the most frequent mitochondrial disorder presenting in childhood, accounting for up to 30% of cases. As with many mitochondrial disorders, complex I deficiency is characterised by marked clinical and genetic heterogeneity, leading to considerable diagnostic challenges for the clinician, not least because of the involvement of two genomes. The most prevalent clinical presentations include Leigh syndrome, leukoencephalopathy and other early-onset neurodegenerative disorders; fatal infantile lactic acidosis; hypertrophic cardiomyopathy; and exercise intolerance. Causative genetic defects may involve the seven mitochondrial-encoded or 38 nuclear-encoded subunits of the enzyme, or any of an increasing number of assembly factors implicated in the correct biosynthesis of complex I within the inner mitochondrial membrane. In this review, we discuss recent advances in knowledge of the structure, function and assembly of complex I and how these advances, together with new high-throughput genetic screening techniques, have translated into improved genetic diagnosis for affected patients and their families. Approximately 25% of cases have mitochondrial DNA mutations, while a further ～25% have mutations in a nuclear subunit or in one of nine known assembly factors. We also present a systematic review of all published cases of nuclear-encoded complex I deficiency, including 117 cases with nuclear subunit mutations and 55 with assembly factor mutations, and highlight clinical, radiological and biochemical clues that may expedite genetic diagnosis.     

一例貌似强直性肌营养不良的脊肌萎缩症的临床、病理及基因诊断

目的 明确1例表型复杂的神经肌病患者的诊断.方法 对该患者进行电生理、病理和致病基因突变分析,并结合国内外文献进行总结.结果 该患者临床病理表现貌似强直性肌营养不良( myotonic dystrophy,DM).基因诊断未发现假肥大型肌营养不良(Duchenne/Becker muscular dystrophy,DMD/BMD)致病基因Dystrophin 21个外显子的缺失突变以及DM1型致病基因DMPK的(CTG)n和DM2型致病基因ZNF9的(CCTG)n的重复扩增突变,但发现脊肌萎缩症(spinal muscular atrophy,SMA)致病基因SMN第7和8外显子的纯合缺失突变.结论 报告1例极为罕见的临床病理表现特殊而经基因诊断确诊的SMA.SMA有明显的临床异质性,临床电生理和病理诊断有其局限性,确诊必须结合基因诊断.     

Homozygous myotonic dystrophy: clinical and molecular studies of three unrelated cases.

We report the clinical and molecular study of three unrelated homozygous myotonic dystrophy patients. In the first family, the homozygous patient shows the classical form of the disease with two DM alleles of very different expansion sizes (1000 and 60 repeats). In the second family, the homozygous patient is mildly affected and carries a minimally expanded allele (64 repeats) and a "normal" allele (38 repeats) that increases in size when transmitted. Such an intergenerational expansion of an allele in this range of repeats has not been reported to date. The third homozygous case has late onset bilateral cataracts as the only symptom. She has two minimally expanded alleles (51 and 120 repeats) that showed different intergenerational enlargement during transmission to the next generation.     

强直性肌营养不良的临床、肌肉病理与肌电图、神经传导速度对比研究

目的；研究强直性肌营养不良（MD）的临床、病理与肌电图（EMG）、神经传导速度（NCV）变化的关系。方法：总结3例MD的临床特点、对肌活检标本进行病理学观察并对相关肌肉进行EMG、NCV检查。结果：3例MD患者年龄25－40岁，临床特点为缓慢进行性四肢无力，肌强直发作。腱反射对称迟钝，前额秃发，EMG示肌源性损害 ，可见肌强直电位发放，NCV减慢；肌活检光镜下可见肌纤维萎缩，肌核内移呈核链形成，电镜下可见肌纤维变性，溶解，X带破坏，线粒体肿胀、变性。结论：MD患者的肌肉病理学与临床表现、EMG、NCV改变相关，临床表现愈重，肌肉损害愈明显。     

Neurodevelopmental disorders as a cause of seizures: neuropathologic, genetic, and mechanistic considerations

This review will consider patterns of developmental neuropathologic abnormalities—malformations of cortical development (MCD)—encountered in infants (often with infantile spasms), children, and adults with intractable epilepsy. Treatment of epilepsy associated with some MCD, such as focal cortical dysplasia and tubers of tuberous sclerosis, may include cortical resection performed to remove the “dysplastic” region of cortex. In extreme situations (eg, hemimegalencephaly), hemispherectomy may be carried out on selected patients. Neuropathologic (including immunohistochemical) findings within these lesions will be considered. Other conditions that cause intractable epilepsy and often mental retardation, yet are not necessarily amenable to surgical treatment (eg, lissencephaly, periventricular nodular heterotopia, double cortex syndrome) will be discussed. Over the past 10 years there has been an explosion of information on the genetics of MCD. The genes responsible for many MCD (eg, TSC1, TSC2, LIS‐1, DCX, FLN1) have been cloned and permit important mechanistic studies to be carried out with the purpose of understanding how mutations within these genes result in abnormal cortical cytoarchitecture and anomalous neuroglial differentiation. Finally, novel techniques allowing for analysis of patterns of gene expression within single cells, including neurons, is likely to provide answers to the most vexing and important question about these lesions: Why are they epileptogenic?     

Regional features of autosomal-dominant cerebellar ataxia in Nagano: clinical and molecular genetic analysis of 86 families

The frequency of autosomal-dominant cerebellar ataxia (ADCA) subtypes was examined in 86 unrelated families originating from Nagano prefecture. In Nagano, the prevalence of spinocerebellar degeneration (SCD) was approximately 22 per 100,000 population. Among ADCA families, SCA6 was the most prevalent subtype (16 families, 19%), followed by DRPLA (nine families, 10%), SCA3/MJD (three families, 3%), SCA1 (two families, 2%), and SCA2 (one family, 1%). No families with SCA7, SCA12, or SCA17 were detected. Compared with other districts in Japan, the prevalence of SCA3/MJD was very low in Nagano. More interestingly, the ratio of genetically undetermined ADCA families was much higher in Nagano (55 families, 65%) than in other districts in Japan. These families tended to accumulate in geographically restricted areas such as Kiso, Saku, and Ina, indicating that the founder effect might be responsible for the high frequency of ADCA in these areas. Most patients clinically showed slowly progressive pure cerebellar ataxia of late-onset (ADCA III). In the case of 36 patients from 36 genetically undetermined ADCA III families, however, no one was completely consistent with the founder allele proposed for 16q-ADCA. These results indicate that there might be genetically distinct ADCA subtypes in Nagano.     

Problems arising in correlating clinical and molecular data in myotonic dystrophy

The number of copies of CTG trinucleotide repeats in the myotonic dystrophy gene correlates to a certain degree with the clinical symptoms in the patient. Routine molecular analysis of myotonic dystrophy is performed on peripheral blood cells, detecting the size of the expansion in leukocytes. However, in some cases somatic mosaicism is responsible for the presence of differently sized myotonic dystrophy alleles in different tissues of the same affected individual, complicating diagnosis and prognosis. Here we report two cases in which the correlation between molecular and clinical analysis performed with standard procedures posed some interpretative problems. The first individual was affected by an atypical clinical picture of myotonic dystrophy, the severity of which was not correlated with the low number of triplet repeats detected in his leukocyte DNA. The second case illustrates a prognostic problem in the presence of a low degree expansion in leukocytes. These examples outline the limits of standard molecular and clinical analysis in myotonic dystrophy.     

Fatal familial insomnia: clinical features and molecular genetics

Fatal familial insomnia (FFI) is an autosomal dominant prion disease clinically characterized by inattention, sleep loss, dysautonomia, and motor signs and pathologically characterized by a preferential thalamic degeneration. FFI is linked to a missense mutation at codon 178 of the prion protein gene, PRNP, coupled with the presence of the codon methionine at position 129, the locus of a methionine-valine polymorphism. Homozygotes at codon 129, expressing methionine also in the nonmutated allele, have a shorter disease course (often less than 1 year), prominent sleep and autonomic disturbances at disease onset, and pathology restricted to the thalamus. Heterozygotes at codon 129, expressing valine in the nonmutated allele, have a longer disease course (often longer than 1 year), ataxia and dysarthria at disease onset, and lesions widespread to cerebral cortex. Both in the thalamus and in the cortex, the limbic structures are those most consistently and severely involved: the anterior ventral and mediodorsal thalamic nuclei, the cingulate gyrus, and the orbitofrontal cortex. FFI is thus a prion disease selectively damaging the thalamocortical limbic structures. Loss of sleep, sympathetic hyperactivity, and flattening of vegetative and hormonal circadian oscillations characterize FFI and result from a homeostatic imbalance caused by the interruption of the thalamocortical limbic circuits, the phylogenetically most advanced structures involved in the control of the sleep–wake cycle and the body's homeostasis. The selective atrophy of the limbic thalamus that characterizes FFI might be due to the binding of FFI toxic PrP or PrP^res to specific receptors on thalamolimbic neurons.     

Primary and secondary cutaneous angiosarcoma: Distinctive clinical,pathological and molecular features

Angiosarcomas are ubiquitous neoplasms involving both cutaneous and soft tissue and visceral locations. Accumulating biomolecular evidences suggest that cutaneous angiosarcomas are distinctive entities with molecular, clinical and pathological peculiarities. Despite several ongoing clinical trials with promising therapeutic agents, the prognosis of cutaneous angiosarcomas is dismal and survival still rely on early diagnosis and surgery. An accurate diagnosis and the knowledge of the underlying molecular landscape are therefore essential to improve the prognosis. We detail the molecular, clinical, dermoscopic, morphological and prognostic features of cutaneous angiosarcoma. Although the molecular landscape of cutaneous angiosarcoma is not completely understood, accumulating evidences suggest that there are characteristic molecular alterations including dysregulation of angiogenesis and several complex molecular pathways. Secondary cutaneous angiosarcomas, arising in correlation with chronic lymphedema and ionizing radiation, have different molecular hallmarks, which are also leading to the first diagnostic applications. The diagnosis of cutaneous angiosarcoma may be challenging, as well-differentiated forms can be hard to distinguish from benign and low-grade vascular neoplasms, while poorly differentiated forms can be easily confounded with other non-vascular high-grade neoplasms. An accurate and early diagnosis, which is mandatory to ensure the best survival for the patients, is mainly based on morphological hallmarks.     

Adult onset leukodystrophy with neuroaxonal spheroids: clinical, neuroimaging and neuropathologic observations

Pigmented orthochromatic leukodystrophy and hereditary diffuse leukoencephalopathy with spheroids are two adult onset leukodystrophies with neuroaxonal spheroids presenting with prominent neurobehavioral, cognitive and motor symptoms. These are familial or sporadic disorders characterized by cerebral white matter degeneration including myelin and axonal loss, gliosis, macrophages and axonal spheroids. We report clinical, neuroimaging and pathological correlations of four women ages 34–50 years with adult onset leukodystrophy. Their disease course ranged from 1.5–8 years. Three patients had progressive cognitive and behavioral changes; however, one had acute onset. Neuroimaging revealed white matter abnormalities characterized by symmetric, bilateral, T2 hyperintense and T1 hypointense Magnetic Resonance Imaging signal involving frontal lobe white matter in all patients. Extensive laboratory investigations were negative apart from abnormalities in some mitochondrial enzymes and immunologic parameters. Autopsies demonstrated severe leukodystrophy with myelin and axonal loss, axonal spheroids and macrophages with early and severe frontal white matter involvement. The extent and degree of changes outside the frontal lobe appeared to correlate with disease duration. The prominent neurobehavioral deficits and frontal white matter disease provide clinical-pathologic support for association pathways linking distributed neural circuits sub-serving cognition. These observations lend further support to the notion that white matter disease alone can account for dementia.     

HER2 status in molecular apocrine breast cancer: associations with clinical,pathological, and molecular features

Molecular apocrine breast cancer (MABC) is a distinct subtype of breast cancer. The purpose of this study was to investigate the relationship between HER2 status and clinicopathologic characteristics of MABCs from Chinese Han cohort. A cohort of 90 MABC patients were enrolled. Immunohistochemical method was performed to analyze the molecular expression, and the human epidermal growth factor receptor 2 (HER2) amplification was verified by fluorescence in situ hybridization (FISH). By studying these 90 MABC cases, the majority of studied patients were premenopausal young women (median age 48 yr) with high grade tumors. We also found that MABCs had high positive expression rates of HER2, CK8, CD44, CD166, p53 and BRCA1, the elevated Ki-67 labeling index, and favorable prognosis. There was a significantly higher incidence of lymph node metastasis and lower CD166 positive rate in HER2-negative patients compared to HER2-positive patients (54.5% vs. 37.0%, P = 0.044 and 72.7% vs. 91.3%, P = 0.021, respectively). The CK5/6 and EGFR expression rates were significant higher in HER2-negative cases than in HER2-positive cases, suggesting that there is overlap between MABC with HER2-negative phenotype and basal-like breast cancer. In addition, HER2 positive was found to be significantly associated a poor overall survival in MABCs. In conclusion, HER2 are highly expressed, and HER2 positivity could be considered as a significant biomarker of poor prognosis in MABC. The results also suggest that a subtype tumor with distinct patterns of molecule expression depending on HER2 status presented in MABC.