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.     

The role of white matter damage in late onset bipolar disorder

Bipolar disorder in elderly is probably heterogenous and the age of onset has been considered to be a potential clinical marker of heterogeneity for this disease. Early- and late-onset bipolar disorders share symptoms, but it is not clear whether they have different aetiologies and vulnerabilities. In bipolar disorder one of the most frequent neuroimaging finding is the white matter hyperintensities (WMHs). The disruption caused by WMHs in the connectivity between structures related to mood regulation and cognition in elderly may be responsible for the affective symptomatology seen in these patients. White matter hyperintensities are found both in late onset patients and in early age onset bipolar patients. It is likely that the aetiology of the white matter hyperintensities in late-onset bipolar disorder be multifactorial, although cardiovascular changes in particular seem to contribute to their physiopathology. In early life onset the aetiology of these lesions is less clear, although probably genetic factors are more important than cardiovascular factors. Understanding the aetiopathogenesis is of key importance when dealing with this disease.     

Novel POLG mutations in progressive external ophthalmoplegia mimicking mitochondrial neurogastrointestinal encephalomyopathy

Autosomal recessive progressive external ophthalmoplegia (PEO) is one clinical disorder associated with multiple mitochondrial DNA deletions and can be caused by missense mutations in POLG, the gene encoding the mitochondrial DNA polymerase gamma. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is another autosomal recessive disorder associated with PEO and multiple deletions of mitochondrial DNA in skeletal muscle. In several patients this disorder is caused by loss of function mutations in the gene encoding thymidine phosphorylase (TP). We report a recessive family with features of MNGIE but no leukoencephalopathy in which two patients carry three missense mutations in POLG, of which two are novel mutations (N846S and P587L). The third mutation was previously reported as a recessive POLG mutation (T251I). This finding indicates the need for POLG sequencing in patients with features of MNGIE without TP mutations.     

Cardiac involvement in mitochondrial disease: a clinical study of 38 patients

Several reports showed that abnormality of mitochondrial DNA (mt DNA) can be an etiology of cardiomyopathy in recent years. Cardiac involvement in mitochondrial disease other than Kearns-Sayre syndrome (KSS), however, has not been documented clearly. Therefore, cardiac involvement, abnormality of mt DNA and defects of the respiratory chain in mitochondrial disease were studied. Thirty-eight patients with mitochondrial disease were studied. The patients were consisted of 2 patients with KSS, 1 patient with probable KSS, 15 patients with ocular myopathy, 1 patient with myoclonus epilepsy with ragged-red fibers (MERRF), 6 patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), 5 patients with undefined mitochondrial encephalomyopathy and 8 patients with mitochondrial myopathy. Cardiac involvement was evaluated by electrocardiogram (ECG), chest roentgenogram and echocardiogram. Abnormality of mt DNA was examined using Southern blotting and polymerase chain reaction method in 25 patients. Defects of the respiratory chain were examined in 27 patients. All of the KSS and probable KSS showed heart block, and 2 of the 3 patients showed abnormalities on echocardiogram. Five of the 15 patients with ocular myopathy showed abnormalities on EGG. Four of the 6 patients with MELAS showed abnormalities on ECG, 1 showed cardiomegaly, and 3 showed left ventricular hypertrophy on echocardiogram. Three of the 5 patients with undefined mitochondrial encephalomyopathy showed abnormalities on ECG, 2 showed cardiomegaly and 2 showed asymmetric septal hypertrophy and wall motion abnormalities on echocardiogram. Large-scale deletions of mt DNA were detected in all of the KSS and probable KSS, and 7 patients with ocular myopathy. Deletions of mt DNA in the skeletal and cardiac muscles were proved to be identical in a case of KSS. A point mutation in mt DNA was detected in 5 patients with MELAS. Defects of the respiratory chain were detected in 22 patients. In conclusion, cardiac involvement is frequently seen in mitochondrial disease. Abnormality of ECG, especially heart block, is characteristic of KSS. Left ventricular hypertrophy is characteristic of mitochondrial encephalomyopathy.     

Microvascular Pathology and Morphometrics of Sporadic and Hereditary Small Vessel Diseases of the Brain

Small vessel diseases (SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology.     

Neuropsychiatric applications of DTI - a review

Psychiatric disorders are common throughout the world and are a leading cause of disability. There is a growing appreciation of the importance of connectivity to brain function. Disruption of this connectivity can result in brain dysfunction manifested in impaired cognitive functioning and the development of clinical symptoms. White matter forms the basis of anatomical connectivity. Diffusion tensor imaging (DTI) is a useful tool for examining and quantifying white matter microstructure. Clinical research studies in alcoholism, HIV-1 infection, geriatric depression and schizophrenia using DTI have revealed abnormalities in white matter microstructure. The use of complementary imaging methods may be helpful in further characterizing these abnormalities. Other psychiatric disorders may also have white matter involvement amenable to study with DTI. Advances in acquisition and analysis methods will be necessary to further advance work in this field. The study of animal models and postmortem tissue may be helpful in elucidating the neurobiological underpinnings of abnormalities observed with DTI.     

常染色体显性遗传病伴皮质下梗死和白质脑病的临床研究进展

常染色体显性遗传病伴皮质下梗死和白质脑病(cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy,CADASIL)是一种临床上罕见的以中年人发病的遗传性微小动脉疾病,由19号染色体上Notch3基因突变所致的遗传性卒中疾病.该病患者初期多有偏头痛发作史,中年时反复发作短暂性脑缺血发作(transient ischemic attack, TIA)或缺血脑卒中,病程晚期患者可出现进行性加重的痴呆及精神症状.头颅磁共振成像(magnetic resonance imaging,MRI)检查显示双侧大脑半球多发的白质病变,为本病特征性的影像学表现.本文总结了该病临床研究进展,包括临床表现、神经影像学表现、CADASIL量表、病理学及分子遗传学,以加深对该病的认识,从而有助于早期诊断,减少误诊和漏诊.     

Pick's Disease: A Modern Approach

Pick's disease is a rare dementing disorder that is sometimes familial. The cardinal features are circumscribed cortical atrophy most often affecting the frontal and temporal poles and argyrophilic, round intraneuronal inclusions (Pick bodies). Clinical manifestations reflect the distribution of cortical degeneration, and personality deterioration and memory deficits are often more severe than visuospatial and apraxic disorders that are common in Alzheimer's disease, but clinical overlap with other non-Alzheimer degenerative disorders is increasingly recognized. Neuronal loss and degeneration are usually maximal in the limbic system, including hippocampus, entorhinal cortex and amygdala. Numerous Pick bodies are often present in the dentate fascia of the hippocampus. Less specific features include leukoencephalopathy and ballooned cortical neurons (Pick cells). Glial reaction is often pronounced in affected cerebral gray and white matter. Tau-immunoreactive glial inclusions are a recently recognized finding in Pick's disease, and neuritic changes have also recently been described. Variable involvement of the deep gray matter and the brainstem is typical, with a predilection for the monoaminergic nuclei and nuclei of the pontine base. Neurochemical studies demonstrate deficits in intrinsic cortical neurotransmitter systems (e.g., somatostatin), but inconsistent loss of transmitters in systems projecting to the cortex (e.g., cholinergic neurons of the basal nucleus). Biochemical and immunocytochemical studies have demonstrated that abnormal tau proteins are the major structural components of Pick bodies. A specific tau protein immunoblotting pattern different from that seen in Alzheimer's disease and certain other disorders has been suggested in some studies. A specific molecular marker and a genetic locus for familial cases are not known.     

Lymphomatosis cerebri as a cause of white matter dementia

Primary central nervous system lymphoma most often presents as a solitary, isolated lesion in immunocompetent patients. Rarely, the disease presents as a diffuse, infiltrating condition without formation of a cohesive mass, a pattern called lymphomatosis cerebri. We present 3 immunocompetent individuals who developed rapidly progressive dementia. Magnetic resonance imaging features mimicked other disorders of white matter and prompted preoperative diagnoses of Binswanger's disease (subcortical ischemic vascular dementia), unknown leukoencephalopathy, viral infection, or infiltrating glioma. Neuropathologic examination at biopsy (Poon T, Matoso I, Tchertkoff V, Weitzner I Jr, Gade M. CT features of primary cerebral lymphoma in AIDS and non-AIDS patients. J Comput Assist Tomogr . 1989;13:6-9) and autopsy (Schwaighofer BW, Hesselink JR, Press GA, Wolf RL, Healy ME, Berthoty DP. Primary intracranial CNS lymphoma: MR manifestations. Am J Neuroradiol . 1993;10:725-9) demonstrated nonnecrotic, diffusely infiltrating, large-cell B-cell lymphoma of white matter, with relative sparing of gray matter, and without significant leptomeningeal involvement or bulky periventricular disease at autopsy. Microglial and astrocytic reactions, but only subtle myelin pallor, were evident as individual tumor cells permeated the entire brain and spinal cord, albeit with considerable variation in cell density. Individual tumor cells could be identified from the optic nerve to spinal cord, documenting the "whole-brain" nature of the disease. CD20 immunostaining was necessary to fully appreciate the extent of individual lymphoma cell percolation through the white matter. The neurobehavioral deficits manifested by these patients demonstrate that lymphomatosis cerebri is an additional neoplastic cause of white matter dementia and can be added to the growing list of disorders responsible for this syndrome.     

聚焦髓鞘和少突胶质细胞的变化：深刻认识阿尔茨海默病白质病变

文题释义： 髓鞘：是包裹在神经细胞轴突外面的一层膜,即髓鞘由许旺细胞和髓鞘细胞膜组成。其作用是绝缘,防止神经电冲动从神经元轴突传递至另一神经元轴突。髓鞘一般只出现在脊椎动物以及一些桡脚类动物的神经元轴突外围。目前研究注意髓鞘成分的抗原性,如：髓鞘碱性蛋白、髓鞘相关糖蛋白、髓鞘少突胶质细胞糖蛋白等。 少突胶质细胞：分布于中枢神经系统。在银浸染标本中,少突胶质细胞比星状胶质细胞小,其突起也较小而少,呈珠状,故被称为少突胶质细胞或寡突胶质细胞。但是用特异性免疫细胞化学染色显示的少突胶质细胞,其突起并不少,而且还有许多分支。少突胶质细胞的主要功能是在中枢神经系统中包绕轴突、形成绝缘的髓鞘结构、协助生物电信号的跳跃式高效传递并维持和保护神经元的正常功能,其异常不仅会导致中枢神经系统脱髓鞘病变,还会引起神经元损伤或精神类疾病,甚至可以引发脑肿瘤。 背景：既往研究认为阿尔茨海默病是脑灰质病变,灰质改变一直是阿尔茨海默病病理和影像研究的热点,近年来发现阿尔茨海默病进展过程中除了神经元缺失,白质的退变和脱髓鞘改变也是重要的特征,脑白质病变的研究越来越得到重视。 目的：阐述阿尔茨海默病脑内存在广泛的白质损害及其发生机制,并探讨脑白质损害与认知功能的关系。 方法：由第一作者检索PubMed数据库及CNKI数据库1998年1月至2019年4月的相关文献,并进行筛选、归纳和总结;英文检索词为“Alzheimer’s disease,white matter injury,neurodegeneration,oligodendrocyte”,中文检索词为“阿尔茨海默病,白质损害,神经退行性变,少突胶质细胞”,选择有关阿尔茨海默病、脑白质病变、少突胶质细胞死亡机制及白质改变与认知功能关系的相关研究,共检索41篇。 结果与结论：阿尔茨海默病患者脑内存在广泛的白质损害,且这种改变发生较早。脑白质病变在阿尔茨海默病病理及发病机制有着重要的意义,多种途径如β-淀粉样蛋白毒性和Tau蛋白、氧化应激、兴奋性毒性作用、铁过量等都可影响少突胶质细胞,导致髓鞘的破坏。脱髓鞘或轴索损伤可以改变轴索的传导速度,直接/间接影响认知功能。可见,阿尔茨海默病白质病理改变与认知功能损害密切相关。脑白质损害与阿尔茨海默病的相关性研究不仅为阿尔茨海默病的发病机制提供理论依据,而且为阿尔茨海默病的治疗提供了新的途径。 ORCID: 0000-0001-6888-3485(赵红) 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程     

DNA repair deficiency in neurodegeneration

Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby causing Huntington's disease. Single-strand breaks are common DNA lesions and are associated with the neurodegenerative diseases, ataxia-oculomotor apraxia-1 and spinocerebellar ataxia with axonal neuropathy-1. DNA double-strand breaks are toxic lesions and two main pathways exist for their repair: homologous recombination and non-homologous end-joining. Ataxia telangiectasia and related disorders with defects in these pathways illustrate that such defects can lead to early childhood neurodegeneration. Aging is a risk factor for neurodegeneration and accumulation of oxidative mitochondrial DNA damage may be linked with the age-associated neurodegenerative disorders Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Mutation in the WRN protein leads to the premature aging disease Werner syndrome, a disorder that features neurodegeneration. In this article we review the evidence linking deficiencies in the DNA repair pathways with neurodegeneration.     

White Matter Changes in Dementia: Role of Impaired Drainage of Interstitial Fluid

White matter abnormalities on magnetic resonance imaging (MRI) are associated with dementia and include white matter hyperintensities (WMH; also termed leukoaraiosis) and visible perivascular spaces (PVS). We review the potential role of impaired drainage of interstitial fluid in the pathogenesis of WMH and PVS. Whereas the volume of extracellular space in the grey matter is tightly controlled, fluid accumulates and expands the extracellular spaces of the white matter in acute hydrocephalus, vasogenic edema and WMH. Although there are no conventional lymphatic vessels in the brain, there is very effective lymphatic drainage for fluid and solutes along restricted pathways in the basement membranes of cerebral capillaries and arteries in young individuals. Lymphatic drainage of the brain is impaired with age and in association with apolipoprotein E ε4, risk factors for Alzheimer's disease and cerebral amyloid angiopathy (CAA). Deposition of proteins in the lymphatic drainage pathways in the walls of cerebral arteries with age is recognized as protein elimination failure angiopathy (PEFA), as in CAA and cerebral autosomal dominant arteriopathy and leukoencephalopathy (CADASIL). Facilitating perivascular lymphatic drainage from the aging brain may play a significant role in the prevention of CAA, WMH and Alzheimer's disease and may enhance the efficacy of immunotherapy for Alzheimer's disease.     

Membranous lipodystrophy of the bone

Membranous lipodystrophy is a rare disease in which cyst-like lesions of fat occur in subcutaneous and other sites including bone marrow, together with sudanophilic leukoencephalopathy. The disease has been reported mostly in Finland and in Japan, with sporadic cases from USA, Belgium, Italy, and France. The cyst-like lesions of limb bones progress in early adult life, usually followed by neurological disorders including convulsions and presenile dementia. Histologically, the fat cells of the bone marrow, synovial membrane, and other sites, are replaced by a convoluted, hyaline, eosinophilic membrane that surrounds a large space. The histochemical and ultrastructural characteristics of the membranes are described. In the brain, atrophy of the subcortical white matter of the frontal and temporal lobes with marked astrocytosis and fibrillary gliosis, and a slight or moderate degeneration of myelin sheaths, are the most prominent changes. Genetic studies of the disease have been reported, revealing an autosomal recessive gene, explaining both its sporadic and familial occurrence, with mutations involving the gene encoding a transmembrane protein, key activating signal transduction element in NK cells (TYROBP). The pathogenesis of membranocystic changes is still unknown: result of a metabolic disorder or circulatory disturbances.     

Diseases caused by nuclear genes affecting mtDNA stability

Diseases caused by nuclear genes that affect mitochondrial DNA (mtDNA) stability are an interesting group of mitochondrial disorders, involving both cellular genomes. In these disorders, a primary nuclear gene defect causes secondary mtDNA loss or deletion formation, which leads to tissue dysfunction. Therefore, the diseases clinically resemble those caused by mtDNA mutations, but follow a Mendelian inheritance pattern. Several clinical entities associated with multiple mtDNA deletions have been characterized, the most frequently described being autosomal dominant progressive external ophthalmoplegia (adPEO). MtDNA depletion syndrome (MDS) is a severe disease of childhood, in which tissue-specific loss of mtDNA is seen. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) patients may have multiple mtDNA deletions and/or mtDNA depletion. Recent reports of thymidine phosphorylase mutations in MNGIE and adenine nucleotide translocator mutations in adPEO have given new insights into the mechanisms of mtDNA maintenance in mammals. The common mechanism underlying both of these gene defects could be disturbed mitochondrial nucleoside pools, the building blocks of mtDNA. Future studies on MNGIE and adPEO pathogenesis, and identification of additional gene defects in adPEO and MDS will provide further understanding about the mammalian mtDNA maintenance and the crosstalk between the nuclear and mitochondrial genomes.     

The definition of HIV-specific neuropathology

Evaluation of a neuropathological series of 160 HIV-infected patients, almost all in the terminal AIDS stage of the infection, allowed recognition of novel syndromes which can be regarded as HIV-specific neuropathology because: 1) they are not observed in non-HIV tissues; 2) HIV is, in our hands consistently by immunocytochemistry, demonstrable in large amounts within these lesions; 3) other pathogens are not detectable within these lesions; and 4) these lesions may occur in isolated fashion within CNS tissues (40% of HIV-specific neuropathology in this series), without any other CNS pathology. HIV-specific neuropathology was found in 34% in this series and comprised two prototypes within a spectrum of frequently overlapping changes: multifocal microgranulomatous lesions of HIV encephalitis, and diffuse white matter damage of HIV leukoencephalopathy. In almost all cases, multinucleated giant cells signal the local presence of HIV in routine stains. In contrast to HIV-specific neuropathology, various unspecific nervous tissue syndromes do not consistently exhibit the local presence of HIV and thus are designated HIV-associated or possibly HIV-induced lesions: lymphocytic meningitis, vacuolar myelopathy, multifocal vacuolar leukoencephalopathy, and diffuse poliodystrophy. Although these unspecific syndromes may also contribute to clinical manifestations, their pathogenetic relation with HIV remains to be established.     

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Progressive multifocal leukoencephalopathy developed in a 70-year-old man with hepatoma treated with oncostatica. The brain showed multiple demyelinated lesions in the upper half of the cerebral white matter. The lesions consisted of proliferation of hypertrophied astrocytes and glial cells with abnormally large nuclei. These nuclei were shown to be filled with DNA by DAPI staining and reacted specifically with anti-JC antibody by immunofluorescence. Papova-like virions were confirmed on both the sections and negatively-stained brain extract under electron microscopy. The sixteen cases so far reported in Japan were reviewed.     

Focal pontine leukoencephalopathy in immunosuppressed patients

In three patients who died of immunodeficiency syndromes, including two patients with acquired immunodeficiency syndrome (AIDS), foci of necrotizing leukoencephalopathy were found in the basis pontis. The lesions were identical in location and morphology to those previously described in patients who received chemotherapy and central nervous system radiotherapy for various malignancies, and (except for their restricted anatomic location) resembled the disseminated necrotizing leukoencephalopathy that complicates central nervous system leukemia and lymphoma. The lesions are to be distinguished from central pontine myelinolysis, are confined to pontocerebellar tracts, and are not specific for the immunodeficient state, but may reflect preterminal metabolic derangements, since they seem unrelated in this clinical setting to malignancy and/or its treatment. Alternatively, they may be a consequence of the immunosuppressed state. The presence of this morphologic abnormality in two AIDS patients is especially intriguing, in view of the frequency with which white matter lesions are seen in the AIDS population.     

NDUFAF3 variants that disrupt mitochondrial complex I assembly may associate with cavitating leukoencephalopathy

Genetic abnormalities in mitochondrial complex assembling factors are associated with leukoencephalopathy. We present a 1‐year‐old girl with consciousness disturbance after a respiratory infection. Brain MRI revealed leukoencephalopathy with bilaterally symmetrical hyperintensity in the substantia nigra, medial thalamic nuclei, and basal nuclei, as well as cavities in the cerebral white matter and corpus callosum. Lactate levels in the spinal fluid were high, while magnetic resonance spectroscopy of the cerebral white matter and basal nuclei showed high peak lactate levels, suggesting mitochondrial dysfunction. The respiratory enzyme activity of complex I was reduced to 17% to 21% in skeletal muscle. Whole exome sequencing identified compound heterozygous variations in NDUFAF3, involved in the assembly of mitochondrial complex I (c.342_343insGTG:p.117Valdup, c.505C > A:p.Pro169Thr). Two‐dimensional, blue‐native polyacrylamide gel electrophoresis (PAGE) and sodium dodecyl sulfate‐PAGE revealed reductions in Q‐module (NDUFS2, NDUFS3, and NDUFA9) and P‐module (NDUFB10 and NDUFB11) subunits, indicating disruption of mitochondrial complex I assembly. Our report expands the spectrum of clinical phenotypes associated with pathogenic variants of NDUFAF3.     

The Definition of HIV-specific Neuropathology

Evaluation of a neuropathological series of 160 HIV infected patients, almost all in the terminal AIDS stage of the infection, allowed recognition of novel syndromes which can be regarded as HIV specific neuropathology because: 1) they are not observed in non HIV tissues; 2) HIV is, in our hands consistently by immunocytochemistry, demonstrable in large amounts within these lesions; 3) other pathogens are not detectable within these lesions; and 4) these lesions may occur in isolated fashion within CNS tissues (40% of HIV-specific neuropathology in this series), without any other CNS pathology. HIV specific neuropathology was found in 34% in this series and comprised two prototypes within a spectrum of frequently overlapping changes: multifocal microgranulomatous lesions of HIV encephalitis, and diffuse white matter damage of HIV leukoencephalopathy. In almost all cases, multinucleated giant cells signal the local presence of HIV in routine stains. In contrast to HIV-specific neuropathology, various unspecific nervous tissue syndromes do not consistently exhibit the local presence of HIV and thus are designated HIV associated or possibly HIV induced lesions: lymphocytic meningitis, vacuolar myelopathy, multifocal vacuolar leukoencephalopathy, and diffuse poliodystrophy. Although these unspecific syndromes may also contribute to clinical manifestations, their pathogenetic relation with HIV remains to be established.