Early-onset Form Of Disease Research Articles

A Matter of Timing: Rudy Tanzi on Alzheimer's Disease

A Matter of Timing: Rudy Tanzi on Alzheimer's Disease

Pompe disease gene therapy: neural manifestations require consideration of CNS directed therapy.

Pompe disease is a neuromuscular disease caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase leading to lysosomal and cytoplasmic glycogen accumulation in neurons and striated muscle. In the decade since availability of first-generation enzyme replacement therapy (ERT) a better understanding of the clinical spectrum of disease has emerged. The most severe form of early onset disease is typically identified with symptoms in the first year of life, known as infantile-onset Pompe disease (IOPD). Infants are described at floppy babies with cardiac hypertrophy in the first few months of life. A milder form with late onset (LOPD) of symptoms is mostly free of cardiac involvement with slower rate of progression. Glycogen accumulation in the CNS and skeletal muscle is observed in both IOPD and LOPD. In both circumstances, multi-system disease (principally motoneuron and myopathy) leads to progressive weakness with associated respiratory and feeding difficulty. In IOPD the untreated natural history leads to cardiorespiratory failure and death in the first year of life. In the current era of ERT clinical outcomes are improved, yet, many patients have an incomplete response and a substantial unmet need remains. Since the neurological manifestations of the disease are not amenable to peripheral enzyme replacement, we set out to better understand the pathophysiology and potential for treatment of disease manifestations using adeno-associated virus (AAV)-mediated gene transfer, with the first clinical gene therapy studies initiated by our group in 2006. This review focuses on the preclinical studies and clinical study findings which are pertinent to the development of a comprehensive gene therapy strategy for both IOPD and LOPD. Given the advent of newborn screening, a significant focus of our recent work has been to establish the basis for repeat administration of AAV vectors to enhance neuromuscular therapeutic efficacy over the life span.

Therapeutic Potential of Regulatory T Cells in Preeclampsia-Opportunities and Challenges.

Inflammation is a central feature and is implicated as a causal factor in preeclampsia and other hypertensive disorders of pregnancy. Inflammatory mediators and leukocytes, which are elevated in peripheral blood and gestational tissues, contribute to the uterine vascular anomalies and compromised placental function that characterize particularly the severe, early onset form of disease. Regulatory T (Treg) cells are central mediators of pregnancy tolerance and direct other immune cells to counteract inflammation and promote robust placentation. Treg cells are commonly perturbed in preeclampsia, and there is evidence Treg cell insufficiency predates onset of symptoms. A causal role is implied by mouse studies showing sufficient numbers of functionally competent Treg cells must be present in the uterus from conception, to support maternal vascular adaptation and prevent later placental inflammatory pathology. Treg cells may therefore provide a tractable target for both preventative strategies and treatment interventions in preeclampsia. Steps to boost Treg cell activity require investigation and could be incorporated into pregnancy planning and preconception care. Pharmacological interventions developed to target Treg cells in autoimmune conditions warrant consideration for evaluation, utilizing rigorous clinical trial methodology, and ensuring safety is paramount. Emerging cell therapy tools involving in vitro Treg cell generation and/or expansion may in time become relevant. The success of preventative and therapeutic approaches will depend on resolving several challenges including developing informative diagnostic tests for Treg cell activity applicable before conception or during early pregnancy, selection of relevant patient subgroups, and identification of appropriate windows of gestation for intervention.

The mitochondrial metallochaperone SCO1 maintains CTR1 at the plasma membrane to preserve copper homeostasis in the murine heart.

SCO1 is a ubiquitously expressed, mitochondrial protein with essential roles in cytochrome c oxidase (COX) assembly and the regulation of copper homeostasis. SCO1 patients present with severe forms of early onset disease, and ultimately succumb from liver, heart or brain failure. However, the inherent susceptibility of these tissues to SCO1 mutations and the clinical heterogeneity observed across SCO1 pedigrees remain poorly understood phenomena. To further address this issue, we generated Sco1hrt/hrt and Sco1stm/stm mice in which Sco1 was specifically deleted in heart and striated muscle, respectively. Lethality was observed in both models due to a combined COX and copper deficiency that resulted in a dilated cardiomyopathy. Left ventricular dilation and loss of heart function was preceded by a temporal decrease in COX activity and copper levels in the longer-lived Sco1stm/stm mice. Interestingly, the reduction in copper content of Sco1stm/stm cardiomyocytes was due to the mislocalisation of CTR1, the high affinity transporter that imports copper into the cell. CTR1 was similarly mislocalized to the cytosol in the heart of knockin mice carrying a homozygous G115S substitution in Sco1, which in humans causes a hypertrophic cardiomyopathy. Our current findings in the heart are in marked contrast to our prior observations in the liver, where Sco1 deletion results in a near complete absence of CTR1 protein. These data collectively argue that mutations perturbing SCO1 function have tissue-specific consequences for the machinery that ultimately governs copper homeostasis, and further establish the importance of aberrant mitochondrial signaling to the etiology of copper handling disorders.

A POSSIBLE PATHOGENIC PSEN2 MUTATION, H169N IN A KOREAN EOAD PATIENT

Alzheimer’s disease is the most prevalent type of senile dementia, occurs mostly in the elderlies. Early onset form of disease is highly associated with genetics, since 3 genes can play role in disease onset: APP, PSEN1, and PSEN2. PSEN2 is a quite rare causative factor, but several emerging studies are available on it. 100 EOAD patients for complex genetic profiling with a gene panel of 50 genes, established as several causative and risk factor genes, and mutations were validated by standard sequencing and SSCP studies. We found a known PSEN2 mutation, H169N in an EOAD patient. Family studies and in silico modeling will be performed on it. PSEN2 H169N was found in a Chinese family, and phenotype was diverse, since AD and FTD symptoms were also appeared in the carriers. However, segregation in the disease was not established yet. This study might confirm that PSEN2 H169N could be associated with AD/dementia phenotype.

NOVEL, PSEN1 T119I MUTATION IN AN EARLY-ONSET ALZHEIMER'S DISEASE PATIENT

Alzheimer’s disease is the most common form of senile dementia, occurs mostly in the elder ages. Early onset form of disease could be associated with genetics, where 3 genes were established to play role in disease onset: APP, PSEN1, and PSEN2. PSEN1 is the most common causative gene for EOAD. Next generation sequencing approaches have been performed with a gene panel of 50 neurodegenerative disease-associated genes, published last year. 100 EOAD patients were screened, and the mutations were verified by standard sequencing and SSCP studies. A novel mutation T119I was found in one of the EOAD patient. This mutation was not reported any of the known EOAD mutation databases, neither in the HapMap or ExAC database. In silico modeling will be performed on its pathogenic nature. More studies are needed on PSEN1 T119I, however, since it is located on the conservative TM-I, it might be possible that this variant could result significant changes in PSEN1. A similar mutation PSEN1 T116I was already reported, which was established as pathogenic mutation. This could be evidence that PSEN1 T119I could be a pathogenic mutation.

Analysis of Leucine-rich repeat kinase 2 (LRRK2) and Parkinson protein 2 (parkin, PARK2) genes mutations in Slovak Parkinson disease patients.

Parkinson disease (PD) is a chronic neurodegenerative movement disorder characterized by selective loss of nigrostriatal dopaminergic neurons and formation of Lewy bodies. Clinical manifestations include motor impairments involving tremor, bradykinesia, postural instability and rigidity. Using dHPLC method we screened exons 31, 35, 41, 48 of the Leucine-rich repeat kinase 2 (LRRK2) gene and exons 2, 6 and 7 of Parkinson protein 2 (parkin, PARK2) genes in a cohort of 216 consecutive, unrelated Slovak patients with familial or sporadic PD, including early and late onset. By this means we aimed to detect the most common pathogenic mutations within LRRK2 (Arg1441Cys, Arg1441Gly, Arg1628Pro, Tyr1699Cys, Gly2019Ser, Ile2020Thr, Gly2385Arg) and parkin genes responsible for late and early onset forms of disease, respectively. However, none of these mutations was identified in our cohort. Heterozygous point mutation p.Arg275Trp in exon 7 of parkin gene was identified in one patient with age at onset 61 years. Furthermore, we observed the presence of one exonic (LRRK2 ex 48: 7155A>G) and eight intronic polymorphisms (in LRRK2: IVS35+23T>A, IVS47-91insGCCAT, IVS47-91insGCAT, IVS47-41A>G, IVS47-9delT, IVS47-20C>T, IVS47-90A>G, in parkin: IVS2+25T>C), three of which were novel.

The influence of the central region containing residues 19-25 on the aggregation properties and secondary structure of Alzheimer's beta-amyloid peptide.

Alzheimer's beta-amyloid peptide (Abeta) is a 39- to 43-amino-acid peptide that is the major component of neuritic plaques found in Alzheimer's disease (AD). The central region of Abeta plays a crucial role in many of its properties, including aggregation, neurotoxicity, proteolytic processing and interactions with other proteins, such as apolipoprotein E. Two mutations in this region, Ala21-->Gly and Glu22-->Gln, give rise to early onset forms of disease. We have studied several peptides based on the central region of Abeta in order to clarify the influence of specific amino acid residues on physicochemical behaviour. To avoid difficulties due to oxidation of Met35, the latter was replaced by the amino acid isostere, norleucine (Ahx), giving [Ahx35]Abeta-(25-35)-amide as a prototype structure. To this prototype, addition of pairs of amino acid residues from the sequence of Abeta, forming the corresponding 23-, 21- and 19-35 derivatives, resulted in peptides that aggregated to form fibrils of diameter 6-10 nm. The rate of aggregation was more rapid as peptide length increased. Circular dichroism spectra of aged solutions of peptides revealed that aggregation was accompanied by a transition from random structure to beta sheet for some, but not all, peptides. The mutation from Ala to Gly at position 21 increased the rate of aggregation and altered the tendency to adopt secondary structure in the direction away from alpha helix and towards beta sheet. In individuals with the Ala21-->Gly mutation, these results would suggest that truncated species with N-termini in the region containing residues 17-20 would be more amyloidogenic than the wild type homologues.

Genetic and heritable risk factors in periodontal disease.

The purpose of this paper is to review current knowledge of genetic risk factors for the periodontal diseases and to present updated and additional data from the Minnesota Twin Periodontal Study. Family studies suggest that susceptibility to the early onset forms of disease, particularly prepubertal and juvenile periodontitis, is, at least in part, influenced by host genotype. Inherited phagocytic cell deficiencies appear to confer risk for prepubertal periodontitis. The prevalence and distribution of juvenile periodontitis in affected families are most consistent with an autosomal recessive mode of inheritance. However, considerable etiologic as well as genetic heterogeneity within these clinically-defined diseases is evident. Whether or not genetic factors influence the more common adult chronic periodontitis is less clear. Although results from family studies suggest that environmental factors appear to be the major determinants of variance in adult periodontitis, data from our twin studies indicate that both genetic and environmental factors influence disease. Furthermore, comparisons between reared-together and reared-apart adult monozygous twins indicate that early family environment has no appreciable influence on probing depth and attachment loss measures in adults.