We report a family with autosomal dominant centronuclear (myotubular) myopathy caused by a novel mutation, p.A618D, in dynamin 2 (DNM2). The 64-year-old mother and 26-year-old daughter had neonatal onset with hypotonia and weak suckling, followed by improvement, then slowly progressive muscle weakness and respiratory restriction. Muscle biopsy showed radial sarcoplasmic strands around the frequent central nuclei. Electrophysiology revealed predominantly myopathic patterns without peripheral nerve involvement. Centronuclear myopathy with neonatal onset caused by a DNM2 mutation in the C-terminal part of the pleckstrin homology domain may have a favorable prognosis and follow a course similar to adult-onset centronuclear myopathy. We advise respiratory follow-up in these patients.
In most subjects with Parkinson's disease and dementia with Lewy bodies, alpha-synuclein (alphaS) immunoreactive pathology is found not only in the brain but also in the autonomic nuclei of the spinal cord. However, neither has the temporal course of alphaS pathology in the spinal cord in relation to the brain progression been established, nor has the extent of alphaS pathology in the spinal cord been analyzed in population-based studies. Using immunohistochemistry, the frequency and distribution of alphaS pathology were assessed semiquantitatively in the brains and spinal cord nuclei of 304 subjects who were aged at least 85 in the population-based Vantaa 85+ study. alphaS pathology was common in the spinal cord; 102 (34%) subjects had classic alphaS pathology in the thoracic and/or sacral autonomic nuclei. Moreover, 134 (44%) subjects showed grain- or dot-like immunoreactivity in neuropil (mini-aggregates) without classic Lewy neurites or Lewy bodies (LBs). The latter type of alphaS accumulation is associated with age, but also the classic alphaS pathology was found more often in the oldest compared to the youngest age group. The severity of alphaS pathology in the spinal cord autonomic nuclei is significantly associated with the extent and severity of alphaS pathology in the brain. Of the subjects, 60% with moderate to severe thoracic alphaS pathology and up to 89% with moderate to severe sacral alphaS pathology had diffuse neocortical type of LB pathology in the brain. alphaS pathology exclusively in the spinal cord was rare. Our study indicates that in general alphaS pathology in the spinal cord autonomic nuclei is associated with similar pathology in the brain.
Cortical and cerebrovascular amyloid-? (A?) deposition is a hallmark of Alzheimer's disease (AD), but also occurs in elderly people not affected by dementia. The apolipoprotein E (APOE) e4 is a major genetic modulator of A? deposition and AD risk. Variants of the amyloid-? protein precursor (A?PP) gene have been reported to contribute to AD and cerebral amyloid angiopathy (CAA). We analyzed the role of APOE and A?PP variants in cortical and cerebrovascular A? deposition, and neuropathologically verified AD (based on modified NIA-RI criteria) in a population-based autopsy sample of Finns aged = 85 years (Vantaa85 + Study; n = 282). Our updated analysis of APOE showed strong associations of the e4 allele with cortical (p = 4.91 ? 10-17) and cerebrovascular (p = 9.87 ? 10-11) A? deposition as well as with NIA-RI AD (p = 1.62 ? 10-8). We also analyzed 60 single nucleotide polymorphisms (SNPs) at the A?PP locus. In single SNP or haplotype analyses there were no statistically significant A?PP locus associations with cortical or cerebrovascular A? deposition or with NIA-RI AD. We sequenced the promoter of the A?PP gene in 40 subjects with very high A? deposition, but none of these subjects had any of the previously reported or novel AD-associated mutations. These results suggest that cortical and cerebrovascular A? depositions are useful quantitative traits for genetic studies, as highlighted by the strong associations with the APOE e4 variant. Promoter mutations or common allelic variation in the A?PP gene do not have a major contribution to cortical or cerebrovascular A? deposition, or very late-onset AD in this Finnish population based study.
Cites: Nat Genet. 2009 Oct;41(10):1088-9319734902
Cites: CNS Neurol Disord Drug Targets. 2009 Mar;8(1):16-3019275634
The Arctic mutation (APP E693G) is unique, since it is located within the amyloid-beta (Abeta) sequence and leads to Alzheimer's disease (AD). Arctic Abeta peptides more easily form Abeta protofibrils in vitro, but little is known about the pathogenic mechanism of the Arctic mutation in vivo. Here, we analyzed APP transgenic mice with both the Swedish and Arctic mutations (tg-APPArcSwe) and transgenic mice with the Swedish mutation alone (tg-APPSwe). Intense intraneuronal Abeta-immunoreactive staining was present in young tg-APPArcSwe mice, but not in tg-APPSwe mice. Intracellular Abeta aggregates in tg-APPArcSwe were strongly stained by antibodies recognizing the N-terminus of Abeta, while those recognizing the C-terminus of Abeta stained weakly. The Abeta aggregates inside neurons increased with age and predated extracellular Abeta deposition in both tg-APPArcSwe and tg-APPSwe mice. Senile plaque deposition was markedly accelerated in tg-APPArcSwe mice, as compared to tg-APPSwe mice. We conclude that the Arctic mutation causes AD by facilitating amyloidosis through early accumulation of intracellular Abeta aggregates in association with a rapid onset of senile plaque deposition.
The Arctic (p. E693G) mutation in the amyloid-ß precursor protein (AßPP) facilitates amyloid-ß (Aß) protofibril formation and generates clinical symptoms of Alzheimer's disease (AD). Here, molecular details of Aß in post mortem brain were investigated with biochemical and morphological techniques. The basic structure of Arctic plaques resembled cotton wool plaques. However, they appeared ring-formed with Aß42-specific antibodies, but were actually targetoid, since the periphery and center of many parenchymal Aß deposits stained differently with mid-domain, N- and C-terminal Aß antibodies. Aß fibrils were similar in shape, albeit shorter than in sporadic AD brain, when examined by electron microscopy. Aßwild-type and Aßarctic codeposited and parenchymal deposits were highly enriched in both N- and C-terminally truncated Aß. In contrast, cerebral amyloid angiopathy (CAA) contained a substantial amount of Aß1-40. The absence of plaques with cores of fibrillary Aß might be due to the scarcity of full-length Aß, although other mechanisms could be involved. Our findings are discussed in relation to mechanisms and relevance of amyloid formation and to the clinical features of AD.
Thirty-nine members, ages 1 to 67 years, of a Swedish family with rippling muscle disease (RMD) were investigated to assess genotype-phenotype correlations. Clinical, neurophysiological, and muscle morphological examinations were performed. Genetic analysis was performed in 38 individuals. Twenty-three patients had percussion-induced muscle mounding (PIMM) and percussion-induced rapid contractions (PIRC). Rippling and hyperCKemia were not found in all patients. Weakness was minor or absent. The electromyogram showed absence of electrical activity in ripples and PIMM, and muscle biopsy specimens confirmed caveolin-3 deficiency and absence of caveolae. Genetic analysis revealed a CAV3 c.G136A transition resulting in a p.A46T missense mutation in affected family members. The phenotype in these 23 cases of RMD with this mutation appears to be homogenous, benign, and nonprogressive. The presence of PIMM and PIRC seems to be diagnostic at all ages, whereas the absence of hyperCKemia and rippling does not exclude the diagnosis.
The objective is to refine the clinical and morphological phenotype and the chromosomal region of interest, in the recently reported 7q36 linked autosomal dominant limb-girdle muscular dystrophy (LGMD1 D/E), by describing four new informative Finnish families. Examinations of the patients included serum CK, neurophysiological studies, cardiac and respiratory function examinations, muscle biopsies and muscle imaging. DNA samples were analyzed by genotyping. Patients in all families had very similar phenotypes with onset of muscle weakness in the pelvic girdle muscles between the fourth and sixth decade, later involvement of the shoulder girdle, and marked walking difficulties in the eighth decade. Muscle biopsies showed myopathic and/or dystrophic features. Genotyping confirmed linkage to the same locus at chromosome 7q36 in all families by one identically segregating haplotype. The linked region was narrowed down from
The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases. We have previously shown that a founder haplotype, covering the MOBKL2b, IFNK, and C9ORF72 genes, is present in the majority of cases linked to this region. Here we show that there is a large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72 on the affected haplotype. This repeat expansion segregates perfectly with disease in the Finnish population, underlying 46.0% of familial ALS and 21.1% of sporadic ALS in that population. Taken together with the D90A SOD1 mutation, 87% of familial ALS in Finland is now explained by a simple monogenic cause. The repeat expansion is also present in one-third of familial ALS cases of outbred European descent, making it the most common genetic cause of these fatal neurodegenerative diseases identified to date.
Amyloid-beta (Abeta) is a major drug target in Alzheimer's disease. Here, we demonstrate that deposited Abeta is SDS insoluble in tgAPP-ArcSwe, a transgenic mouse model harboring the Arctic (E693G) and Swedish (KM670/671NL) APP mutations. Formic acid was needed to extract the majority of deposited Abeta in both tgAPP-ArcSwe and Alzheimer's disease brain, but not in a commonly used type of mouse model with the Swedish mutation alone. Interestingly, the insoluble state of Arctic Abeta was determined early on and did not gradually evolve with time. In tgAPP-ArcSwe, Abeta plaques displayed a patchy morphology with bundles of Abeta fibrils, whereas amyloid cores in tgAPP-Swe were circular with radiating fibrils. Amyloid was more densely stacked in tgAPP-ArcSwe, as demonstrated with a conformation sensitive probe. A reduced increase in plasma Abeta was observed following acute administration of an Abeta antibody in tgAPP-ArcSwe, results that might imply reduced brain to plasma Abeta efflux. TgAPP-ArcSwe, with its insoluble state of deposited Abeta, could serve as a complementary model to better predict the outcome of clinical trials.
Mutations in the NOTCH3 gene cause cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), which is clinically characterised by recurrent ischemic strokes, migraine with aura, psychiatric symptoms, cognitive decline and dementia. We have previously described a patient with CADASIL caused by a R133C mutation in the NOTCH3 gene and with a concomitant myopathy caused by a 5650G>A mutation in the MTTA gene in mitochondrial DNA (mtDNA). We assume that the co-occurrence of the two mutations is not coincidental and that mutations in the NOTCH3 gene may predispose the mtDNA to mutations. We therefore examined the nucleotide variation in the mtDNA coding region sequences in 20 CADASIL pedigrees with 77 affected patients by conformation-sensitive gel electrophoresis and sequencing. The sequence variation in mtDNA was then compared with that among 192 healthy Finns. A total of 180 mtDNA coding region sequence differences were found relative to the revised Cambridge reference sequence, including five novel synonymous substitutions, two novel nonsynonymous substitutions and one novel tRNA substitution. We found that maternal relatives in two pedigrees differed from each other in their mtDNA. Furthermore, the average number of pairwise differences in sequences from the 41 unrelated maternal lineages with CADASIL was higher than that expected among haplogroup-matched controls. The numbers of polymorphic sites and polymorphisms that were present in only one sequence were also higher among the CADASIL sequences than among the control sequences. Our results show that mtDNA sequence variation is increased within CADASIL pedigrees. These findings suggest a relationship between NOTCH3 and mtDNA.