Implication of a genetic variant at PICALM in Alzheimer’s disease patients and centenarians

A common polymorphism (rs3851179) in the PICALM (phosphatidylinositol-binding clathrin assembly protein) gene has been recently associated with reduced risk of developing late-onset Alzheimer’s disease (LOAD). We analyzed the genotype and allele distributions of the PICALM polymorphism in 813 Italian subjects, including LOAD patients and centenarians. The segregation of the PICALM rs3851179 showed no statistically significant difference between LOAD cases and controls. The implication of a genetic variant at PICALM is confirmed for the first time, in centenarians, thus suggesting a possible role in longevity.     

Graves’ disease and celiac disease in a patient with myotonic dystrophy type 2

We report a patient with progressive proximal muscle weakness in her legs, early-onset cataract and perceptive hearing loss, who was recently diagnosed with myotonic dystrophy type 2 (DM2). She also had two autoimmune disorders in her history, namely Graves’ disease and celiac disease. Previous studies have shown a high frequency of autoimmune diseases (21%) in patients with DM2. This is the first report of a patient with DM2 and two autoimmune diseases which both have not yet been described in DM2. The cause of this association might be explained at DNA, mRNA and protein levels, including genetic mutation in flanking genes and the toxic effect of the DM2 mutation on proteins involved in inflammation. This case report widens the spectrum of autoimmune diseases in DM2 and has implications both for clinical practice and for research.     

“Quadriceps myopathy”: a clinical variant form of becker muscular dystrophy

Summary A 26-year-old male with quadriceps myopathy is presented. He had a family history and only the bilateral quadriceps were wasted, without symptomatic weakness. The specimen of the muscle biopsy showed typical myopathic features without inflammatory reactions. The patchy defect of muscular dystrophin was proved by immunohistochemical study. Dystrophin analysis revealed abnormal 380 kDa dystrophin. Gene deletion was proved at exon 45–48 of Xp21 without frameshift. This case was considered to be a clinical variant form of Becker muscular dystrophy.     

Facial and skeletal malformations, mental retardation, aganglionosis, and neurogenic muscle weakness: a variant of Niikawa-Kuroki syndrome or a new syndrome?

We report a 10-year-old boy with multiple congenital anomalies/mental retardation syndrome, who also presented with aganglionosis and neurogenic muscle weakness. Some phenotypic manifestations of our patient overlap with those observed in the Niikawa-Kuroki syndrome; however, the hypothesis of a new distinct entity, with simultaneous involvement of the central and peripheral nervous system, is considered.     

The impact of genetic and environmental factors on the pathobiology of Alzheimer's disease: a multifactorial disorder?

Summary

Alzheimer's disease is the most common form of dementia, although its diagnosis can only be confirmed after autopsy. While 10% of cases show a family history of the disease, the remainder are sporadic. Disease-causing mutations in three genes (amyloid precursor protein and two presenilin genes) have been discovered which account for nearly all of the familial cases of Alzheimer's disease. The sporadic forms of the disease are associated with a number of genetic risk factors (apolipoprotein E, x₁antichymotrypsin, very low density lipoprotein receptor and mitochondrial DNA mutations) but none of these are either sufficient on their own or necessary for the disease. This leaves open the possibility that one or more extrinsic environmental factors may affect the progression of Alzheimer's disease. Although the evidence for specific extrinsic factors is lacking, the role of putative agents (aluminium, antioxidants, head trauma) and how they might interact with intrinsic genetic factors is discussed. Alzheimer's disease, therefore, demonstrates genetic heterogeneity and, in addition, may be considered as a multifactorial disorder.     

Hereditary sensory and autonomic neuropathy with autonomic crises: a Turkish variant of familial dysautonomia?

Hereditary sensory and autonomic neuropathies have different phenotypes. We report 2 cousins with differing clinical courses of a hereditary sensory and autonomic neuropathy. The progressive disease in case 1 is dominated by loss of sensation, autonomic crises, and pain. Case 2 shows loss of sensation, mental retardation, and deafness, clinically similar to patients with hereditary sensory and autonomic neuropathy type II. Detailed molecular studies in case 1 for all known genes that are associated with hereditary sensory and autonomic neuropathies were negative. However, the occurrence of the 2 cases within 1 kindred makes a common genetic background likely. We, therefore, propose a Turkish variant of familial dysautonomia in these 2 patients.     

Schizophrenia and beta-thalassemia: a genetic link?

This report of two cases in which schizophrenia and beta-thalassemia occurred simultaneously in several family members may suggest that a genetic link exists between these two disorders. A known genetic disease (beta-thalassemia) could help confirm the presence, on the short arm of chromosome 11, of a genetic susceptibility factor for schizophrenia.     

Mortalin: a protein associated with progression of Parkinson disease?

Parkinson disease (PD) is a progressive neurodegenerative disorder that is considered to affect the brainstem at its early stages and other brain regions, including the limbic system and isocortex, in advanced stages. It has been suggested that PD progression is characterized pathologically by the spreading of Lewy body deposition. To identify novel proteins involved in PD progression, we prepared subcellular fractions from the frontal cortex of pathologically verified PD patients at different stages of disease and Lewy body deposition and from age-matched controls. Protein expression profiles were compared using a robust quantitative proteomic technique called isobaric tagging for relative and absolute quantification in conjunction with mass spectrometry. Approximately 200 proteins were found to display significant differences in their relative abundance between PD patients at various stages and controls. Gene ontology analysis indicated that these altered proteins belonged to many categories (e.g. mitochondrial function and neurotransmission) that were likely critically involved in the pathogenesis of PD. Of those, mortalin, a mitochondrial protein, was decreased in the advanced PD cases and was further validated to be decreased using independent techniques. These results suggest a role for mortalin in PD progression.     

Synaptic dysfunction in genetic models of Parkinson's disease: a role for autophagy?

The past decade in Parkinson's disease (PD) research has been punctuated by numerous advances in understanding genetic factors that contribute to the disease. Common to most of the genetic models of Parkinsonian neurodegeneration are pathologic mechanisms of mitochondrial dysfunction, secretory vesicle dysfunction and oxidative stress that likely trigger common cell death mechanisms. Whereas presynaptic function is implicated in the function/dysfunction of α-synuclein, the first gene shown to contribute to PD, synaptic function has not comprised a major focus in most other genetic models. However, recent advances in understanding the impact of mutations in parkin and LRRK2 have also yielded insights into synaptic dysfunction as a possible early pathogenic mechanism. Autophagy is a common neuronal response in each of these genetic models of PD, participating in the clearance of protein aggregates and injured mitochondria. However, the potential consequences of autophagy upregulation on synaptic structure and function remain unknown. In this review, we discuss the evidence that supports a role for synaptic dysfunction in the neurodegenerative cascade in PD, and highlight unresolved questions concerning a potential role for autophagy in either pathological or compensatory synaptic remodeling. This article is part of a Special Issue entitled "Autophagy and protein degradation in neurological diseases."     

Presenilin-1 mutation Alzheimer's disease: a genetic epilepsy syndrome?

Mutations in the presenilin-1 gene (PSEN1) on chromosome 14 are the most common cause of autosomal dominant Alzheimer's disease (AD), with around 180 mutations described to date. PSEN1 AD has a broad clinical phenotype, encompassing not only dementia but a variety of other neurological features which may include epileptic seizures. Around 20% of recorded PSEN1 mutations have been reported to be associated with epileptic seizures, sometimes occurring as an early feature of disease, sometimes late. The epilepsy-associated PSEN1 mutations are spread throughout the PSEN1 gene. This frequency of seizure-associated PSEN1 mutations may be an underestimate, as epileptic seizures may not be recognized as such in the context of a dementing disorder, perhaps being labeled as "confusion" or delirious episodes. A high index of clinical suspicion for epileptic seizures in PSEN1 AD is therefore appropriate. The neuropathological substrates of PSEN1 AD-related seizures remain to be determined, as few such cases have undergone detailed neuropathological examination. Nevertheless, PSEN1 AD should now be recognized, using the new International League Against Epilepsy nomenclature, as a genetic epilepsy syndrome.     

Chronic encephalitis and temporal lobe epilepsy: a variant of Rasmussen's syndrome?

The authors report two adult patients with chronic temporal lobe epilepsy and pathologic features consistent with Rasmussen's encephalitis. Although seizures persisted after temporal lobe surgery no progressive cognitive or neurologic deficit has emerged. Prominent auditory auras in each suggested a persisting epileptogenic focus in the superior temporal gyrus. The current findings expand the clinical spectrum of Rasmussen's encephalitis and suggest that chronic nonprogressive encephalitis may serve as the pathologic substrate of medically intractable temporal lobe epilepsy.     

Ultrastructural study of florid plaques in variant Creutzfeldt-Jakob disease: a comparison with amyloid plaques in kuru, sporadic Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker disease

Background: Although the histological features of the amyloid plaques in variant Creutzfeldt–Jakob disease (vCJD) are distinct from those in other forms of prion disease [kuru, sporadic Creutzfeldt–Jakob disease (sCJD) and Gerstmann–Sträussler–Scheinker disease (GSS)], their ultrastructural features have only been described in a single case report. Aims: To study vCJD plaques systematically and compare them with plaques in kuru, sCJD, GSS and Alzheimer disease (AD). Methods: Amyloid plaques were studied by transmission electron microscopy and image analysis in five cases of vCJD, three cases of GSS, two cases of sCJD, one case of kuru and five cases of AD. Immunohistochemistry was performed on paraffin sections from one case of vCJD, two cases of GSS, one case of kuru and two cases of sCJD. Results: The florid plaques in vCJD were either compact or more diffuse; in both forms, the radiating fibrils were organized into thick 'tongues', in contrast to kuru plaques. Dystrophic neurites (DNs) containing lysosomal electron-dense bodies or vesicles surrounded florid plaques. Microglial cells were found within florid plaques; occasional amyloid fibrils were identified in membrane-bound pockets of microglial cells. In vCJD, there was significant tau immunoreactivity in DNs around florid plaques while, in sCJD, GSS and kuru, minimal tau immunoreactivity was observed around plaques. Conclusions: The ultrastructure of the florid plaques and DNs in vCJD is more reminiscent of neuritic plaques in AD than kuru or multicentric plaques. These findings may reflect differences both in the strains of the transmissible agents responsible for these disorders and in host factors.     

Posterior cortical atrophy: variant of Alzheimer’s disease?

Abstract Nine patients with posterior cortical atrophy (PCA), a rare degenerative brain disease of unclear etiology and nosology, were followed over a mean time of 7.4 years. The mean age at onset was low (56.2 years). At onset, eight patients had visuo-spatial and eight had memory impairment. A minority showed early signs of occipital lobe involvement with visual agnosia or hemianopia. Eight patients developed dementia after a mean course of five years. 18F-FDG-PET data of six patients were analysed with statistical parametric mapping. They showed hypometabolism centred on the lateral and medial parietal associative cortex, with variable involvement of the adjacent temporal and occipital associative cortex. A minority showed involvement of the frontal lobes, possibly related to deafferenting of areas related to the control of eye movements. Atrophy and hypometabolism were markedly asymmetric in a subset of cases. Autopsy was performed in one patient. Presenile onset, location, and asymmetry of atrophy suggest that PCA represents a biologically separable variant of Alzheimers disease.     

Clinical, pathologic, and neurochemical studies of an unusual case of neuronal storage disease with lamellar cytoplasmic inclusions: a new genetic disorder?

A child of first-cousin Puerto Rican parents had global developmental delay, failure to thrive, and hypotonia since early infancy. At 1 1/2 years of age, she developed clinical and electrophysiologic evidence of progressive motor and sensory neuropathy. At 2 1/2 years, she developed visual impairment and optic atrophy followed by gradual involvement of the 7th, 9th, 10th, and 12th cranial nerves. Uncontrollable myoclonic seizures began at 4 years and she died at 6 years of age. Motor nerve conduction velocities were initially normal and later became markedly slowed. Sensory distal latency responses were absent. Lysosomal enzyme activities in leukocytes and fibroblasts were normal. Sural nerve and two muscle biopsies showed only nondiagnostic abnormalities. Electron microscopy of lymphocytes, skin, and fibroblasts showed cytoplasmic inclusions. Light microscopy of frontal cortex biopsy showed neuronal storage material staining positively with Luxol fast blue, and electron microscopy showed cytoplasmic membranous bodies in neurons, suggesting an accumulation of a ganglioside. At autopsy, all organs were small but otherwise normal and without abnormal storage cells in the liver, spleen, or bone marrow. Anterior spinal nerve roots showed loss of large myelinated axons. The brain was small and atrophic; cortical neurons showed widespread accumulation of storage material, most marked in the pyramidal cell layer of the hippocampus. Subcortical white matter was gliotic with loss of axons and myelin sheaths. In cortical gray matter there was a 35% elevation of total gangliosides, with a 16-fold increase in GM3, a three- to four-fold increase in GM2 gangliosides, and a 15-fold elevation of lactosyl ceramide. GM3 sialidase activity was normal in gray matter at 3.1 nmols/mg protein per hour and lactosyl ceraminidase I and II activities were 70% to 80% of normal. In white matter, total myelin was reduced by 50% but its composition was normal. Phospholipid distribution and sphingomyelin content were normal in gray matter, white matter, and in the liver. These biochemical findings were interpreted as nonspecific abnormalities. The nature of the neuronal storage substance remains to be determined.