Autosomal Dominant Late Onset Research Articles

Novel presenilin 1 mutation (Ile408Thr) in an Italian family with late-onset Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disease affecting over 20 million people worldwide, mainly adult subjects in advanced age.Over 240 different fully penetrant autosomal dominant mutations in 532 families around the world have been described in three genes [i.e., amyloid precursor protein (APP), and presenilins (PSEN1 and PSEN2)] causing 50% of all Familial AD.We report a new mutation (p.Ile408Thr, c. 1223T>C) in the PSEN1 gene in one autosomal dominant Late Onset AD patient. The genetic variation occurred in a conserved domain of the protein and was present in the proband and in the younger sister who is likely to be prodromal AD. Thus, we suggest that this variant will have probably a pathogenic effect, hypothesizing a possible key role of this new mutation in the pathogenesis of Alzheimer’s disease for this family.

RNAi or overexpression: Alternative therapies for Spinocerebellar Ataxia Type 1

Spinocerebellar Ataxia Type 1 (SCA1) is an autosomal dominant late onset neurodegenerative disease caused by an expanded polyglutamine tract in ataxin-1. Here, we compared the protective effects of overexpressing ataxin-1-like using recombinant AAVs, or reducing expression of mutant ataxin-1 using virally delivered RNA interference (RNAi), in a transgenic mouse model of SCA1. For the latter, we used an artificial microRNA (miR) design that optimizes potency, efficacy and safety to suppress ataxin-1 expression (miS1). Delivery of either ataxin-1-like or miS1 viral vectors to SCA1 mice cerebella resulted in widespread cerebellar Purkinje cell transduction and improved behavioral and histological phenotypes. Our data indicate the utility of either approach as a possible therapy for SCA1 patients.

Novel COCH mutation in a family with autosomal dominant late onset sensorineural hearing impairment and tinnitus

This report describes a three generation family with late onset bilateral sensorineural hearing impairment (BLSNHI) and tinnitus in which a novel mutation in the COCH gene was identified after a genome-wide linkage approach. The COCH gene is one of the few genes clinically examined when investigating the etiology of autosomal dominant late onset hearing impairment. Initially mutations in the COCH gene were only reported in exons 4 and 5, coding for the LCCL protein domain. More recently, additional mutations have been identified in exon 12, the only mutations identified outside of the LCCL domain. Currently clinical genetic testing for the COCH gene primarily focuses on identifying mutations in these three exons. In this study, we identify a novel mutation in the COCH gene in exon 11, which, like the exon 12 mutations, falls within the vWFA2 protein domain. This finding reinforces the need for clinical genetic screening of the COCH gene to be expanded beyond the current limited exon screening, as there is now more evidence to support that mutations in other areas of this gene are also causative of a similar form of late onset BLSNHI.

Autosomal dominant late onset ataxia linked to a new locus: Last but not least

Autosomal dominant late onset ataxia linked to a new locus: Last but not least

Autosomal dominant Late-onset Quadriceps Myopathy: Three Patients of a Taiwanese Kindred

Primary quadriceps weakness/atrophy is a rare disorder with variable etiologies; therefore, this disorder has been regarded as a clinical syndrome rather than a distinct entity. However, three affected patients of a Taiwanese family demonstrate a uniform pattern of quadriceps weakness and atrophy, their clinical manifestations and pattern of inheritance may suggest a new disease entity. Three patients in a Taiwanese kindred with selective quadriceps weakness and atrophy, which began after age 40 years, were examined. To disclose the confines of this disorder, muscle CT scans, electromyography, nerve conduction studies and muscle biopsies were performed; and to unravel and better understand the nature of this disorder, histopathological, ultrastructural, immunocytochemical and genetic studies were carried out. In two patients with long-standing disease, muscle imaging showed marked atrophy and fat replacement of the anterior thigh muscles and electromyography showed a mixture of myopathic and neuropathic changes. Muscle histopathology on the mildly affected tibialis anterior showed myopathic changes with myofibrillar degeneration and secondary neurogenic alterations. Immunocytochemical staining was not diagnostic but excluded the dystrophinopathies and other well-known muscular dystrophies. All previously identified diseases resulting in quadriceps weakness and atrophy have been ruled out and the present disorder appears to be a new disease entity of autosomal dominant late onset quadriceps myopathy.

Activation of FoxO by LRRK2 induces expression of proapoptotic proteins and alters survival of postmitotic dopaminergic neuron in Drosophila

Missense mutations in leucine-rich repeat kinase 2 (LRRK2)/Dardarin gene, the product of which encodes a kinase with multiple domains, are known to cause autosomal dominant late onset Parkinson's disease (PD). In the current study, we report that the gene product LRRK2 directly phosphorylates the forkhead box transcription factor FoxO1 and enhances its transcriptional activity. This pathway was found to be conserved in Drosophila, as the Drosophila LRRK2 homolog (dLRRK) enhanced the neuronal toxicity of FoxO. Importantly, FoxO mutants that were resistant to LRRK2/dLRRK-induced phosphorylation suppressed this neurotoxicity. Moreover, we have determined that FoxO targets hid and bim in Drosophila and human, respectively, are responsible for the LRRK2/dLRRK-mediated cell death. These data suggest that the cell death molecules regulated by FoxO are key factors during the neurodegeneration in LRRK2-linked PD.

Adult onset hydrocephalus and situs inversus: new autosomal dominant syndrome?

Familial adult onset hydrocephalus is unusual and its genetic basis is unknown. We report a two-generation family with three members having hydrocephalus, two of them with complete situs inversus. Laterality syndromes were considered in the differential diagnosis and are unlikely. We suggest that this family represents a previously unrecognised form of autosomal dominant late onset hydrocephalus with situs inversus.

Expanded CAG repeats in spinocerebellar ataxia (SCA1) segregate with distinct haplotypes in South african families.

The autosomal dominant late onset spinocerebellar ataxias (SCAs) are genetically heterogeneous. Three genes, SCA1 on 6p, SCA2 on 12q and MJD1 on 14q, have been isolated for SCA1, SCA2 and Machado-Joseph disease (MJD), respectively. In these three autosomal dominant disorders the mutation is an expanded CAG repeat. Evidence for heterogeneity in families not linked to the SCA1, SCA2 and MJD loci is provided by the mapping of SCA loci to chromosomes 16q, 11cen and 3p. A total of 14 South African kindreds and 22 sporadic individuals with SCA were investigated for the expanded SCA1 and MJD repeats. None of the families nor the sporadic individuals showed expansion of the MJD repeat. Expanded SCA1 and CAG repeats were found to cosegregate with the disorder in six of the families tested and were also observed in one sporadic individual with a negative family history of SCA. The use of the microsatellite markers D6S260, D6S89 and D6S274 provided evidence that the expanded SCA1 repeats segregated with three distinct haplotypes in the six families. Use of the highly polymorphic tightly linked microsatellite markers is still important as this stage, particularly where this coincides with the possibility of a homozygous genotype with the trinucleotide repeat marker. Importantly, our molecular findings indicate: (1) an absence of MJD expanded repeats underlying SCA; (2) the major disease in this group is due to mutations in the SCA1 gene; and (3) the familial disorder in the majority population group (i.e. mixed ancestry) in the Western Cape region of South Africa is most likely to be the result of two distinct founder events.

The sword of Damocles: The psychosocial impact of familial spinocerebellar ataxia in South Africa

A survey was conducted on 30 unaffected individuals from a family with autosomal dominant late onset spinocerebellar ataxia in South Africa. The psychological impact of the disorder on individual lives, risk awareness, attitudes towards affected kin and reproduction were evaluated. Respondents employed various psychological strategies to deal with the threat of developing the disorder. In a comparison of "assigned" risk with "perceived" risk, 80% of unaffected persons reported incorrect perceptions of personal risk status. The disorder had little impact on attitudes concerning reproduction; the majority of individuals at risk wanted more children. These issues need to be addressed in the genetic and predictive testing service for familial ataxia in South Africa.

The sword of Damocles: the psychosocial impact of familial spinocerebellar ataxia in South Africa.

A survey was conducted on 30 unaffected individuals from a family with autosomal dominant late onset spinocerebellar ataxia in South Africa. The psychological impact of the disorder on individual lives, risk awareness, attitudes towards affected kin and reproduction were evaluated. Respondents employed various psychological strategies to deal with the threat of developing the disorder. In a comparison of "assigned" risk with "perceived" risk, 80% of unaffected persons reported incorrect perceptions of personal risk status. The disorder had little impact on attitudes concerning reproduction; the majority of individuals at risk wanted more children. These issues need to be addressed in the genetic and predictive testing service for familial ataxia in South Africa.

Mitochondrial disorders in degenerative ataxias

Current theory implicates mitochondrial defects in the mechanism of neuronal degeneration in several movement disorders. We performed analyses of mitochondrial function in 61 patients with different forms of degenerative ataxias. Mitochondrial enzyme defects were proven in five of 16 (31V.) patients with Friedreich's ataxia, in 14 of 30 (47%) patients with autosomal dominant late onset cerebellar ataxia, and in three of six (50%) patients with sporadic cerebellar atrophy. No abnormalities were found in secondary forms of cerebellar degenerations (due to paraneoplastic disorder, alcohol or sprue) or in spastic paraplegia. Mitochondrial defects affected most frequently the respiratory chain (19 patients) and especially its complex I (11 patients). Carnitine deficiency was found in three patients and severe loss of myoadenylate deaminase in one patient Genetic abnormalities could be proved neither in mitochondrial DNA nor in recently defined ataxia genes. Our results indicate that mitochondrial dysfunction occurs frequently in cerebellar atrophies. Therefore, disturbance of oxidative energy metabolism may be involved in the pathogenesis of degenerative ataxias, but it remains to be elucidated whether mitochondrial defects are primary or secondary effects.

Profiles of neuromuscular diseases. Limb-girdle syndromes.

Sixty-six individuals with Limb-Girdle Syndrome (LGS) were evaluated over a 10-yr period and classified into three types: 19 severe autosomal recessive muscular dystrophy of childhood (ARMDC), alternatively referred to by some as SCARMD, 18 autosomal dominant late onset (ADLO), and 29 pelvifemoral (PF) individuals. ARMDC subjects showed the greatest weakness, 2.5 +/- 1.0, mean Manual Muscle Test (MMT) grade for all muscles combined, and the only significant progression of loss of strength, -0.59 MMT unit decline per decade. Strength loss in ADLO and PF types was about the same, 3.7 +/- 0.7 and 4.0 +/- 0.7 grades, respectively. Quantitative strength measurements in ADLO and PF types were more sensitive than MMTs, showing losses of 30-40% strength in muscle groups with MMT grades of 4 or higher. All three types showed greater proximal and lower extremity weakness but usually no difference between flexor and extensor strength. There was a high percentage (44%) of mild very slowly progressive scoliosis in ARMDC, but spine deformity was unusual in ADLO and PF (11%) LGS. Contractures were few, slowly progressive, and usually mild in severity in all types, although more frequent in ARMDC. There also was a low frequency of severe restrictive lung disease in all types (10%) but a high percentage of electrocardiogram abnormalities (62-73%). The most common electrocardiogram abnormalities were increased R/S ratio in V1 and infranodal conduction defects. Intellectual and cognitive functions were within normal limits. Mobility and extremity function reflected the strength differences between the ARMDC and other types of LGS. Eight-five percent of ARMDC individuals relied on a wheelchair for all or part of their mobility, and all were unable to complete timed motor performance tests within the 99th percentile range for controls.

Detection of the Machado-Joseph disease/spinocerebellar ataxia three trinucleotide repeat expansion in families with autosomal dominant motor disorders, including the Drew family of Walworth

Affected members of 63 families with a variety of autosomal dominant late onset cerebellar ataxias (ADCA), and 29 patients with similar phenotypes but no affected relatives, were investigated for the trinucleotide (CAG) repeat expansion described in Japanese families with Machado-Joseph disease (MJD). This disorder had previously been shown to map to the region of chromosome 14 which also contains a locus causing ADCA in French families, spinocerebellar ataxia 3 (SCA3). The MJD/SCA3 mutation was identified in nine families with ADCA type I, and a further family in which affected members had parkinsonism, peripheral neuropathy, dystonia, and spasticity, but little evidence of cerebellar disease. Only one of the 10 families was British (the Drew family of Walworth); the others originated from India, Jamaica, Ghana, Brazil and France. There was no single clinical feature which distinguished patients with the MJD/SCA3 mutation from those with the CAG expansion on chromosome 6 (SCA1) or ADCA type I families with no known mutation. The CAG repeat length ranged from 13-41 copies on normal chromosomes and 62-80 copies on affected chromosomes. There was a significant inverse correlation between age of onset of symptoms and repeat length, but no significant effect of parental sex on repeat length or age of onset in offspring. DNA analysis for the MJD/SCA3 mutation is useful for diagnosis in patients with familial ataxic or extrapyramidal syndromes, and will aid genetic counselling in these disorders.

The trinucleotide repeat expansion on chromosome 6p (SCA1) in autosomal dominant cerebellar ataxias.

Affected members of 73 families with a variety of autosomal dominant late onset cerebellar ataxias (ADCAs) were investigated for the trinucleotide (CAG) repeat expansion which is found in pedigrees exhibiting linkage to the SCA1 locus on chromosome 6. Most of the families were too small for linkage analysis. The mutation was only found in ADCA type I, in 19 out of 38 such kindreds investigated (50%). It was slightly more common in Italian (59%) than British (50%) families, and was also found in Malaysian, Bangladeshi and Jamaican kindreds. Overall, ADCA type I patients with the expansion had a lower incidence of hyporeflexia and facial fasciculation than those without. The trinucleotide expansion was not found in eight families with ADCA and maculopathy or 24 kindreds with a pure type of ADCA, confirming that these syndromes are genetically distinct. It was also not detected in 12 patients with sporadic degenerative ataxias. DNA analysis for the SCA1 mutation is useful diagnostically in single patients or small families, and can be used for presymptomatic testing where appropriate.

Heredo-ataxia in a large Dutch pedigree: M.R.I. findings

One segment of a large Dutch pedigree with heredoataxia is presented. The clinical and genetic features of the disease, together with the M.R.I. findings, indicate the diagnosis of autosomal dominant late onset olivo-ponto-cerebellar atrophy. The clinical picture remained invariant through successive generations. Emphasis is put on the diagnostic usefulness of M.R.I. technique in the absence of neuropathological data.

Genetic aspects of autosomal dominant late onset cerebellar ataxia.

The genetic features of eight families with autosomal dominant late onset cerebellar ataxia with randomly distributed associated clinical features are described. The ratio of affected to unaffected offspring of affected subjects was not significantly different from 1:1. The mutant gene was fully penetrant when cases who died before the period of risk of developing the disease were excluded. The proportion of new mutants with this disorder appears to be low. Biological fitness was not impaired. Affected females tended to have large families than affected males. The ages of onset of females and males were not significantly different, but the offspring of affected males had earlier ages of onset and death than those of affected females. A cumulative age of onset curve is presented which should aid genetic counselling of subjects at risk and their children.