Onofre Combarros

APOE and Alzheimer disease: a major gene with semi-dominant inheritance

Apolipoprotein E (APOE) dependent lifetime risks (LTRs) for Alzheimer Disease (AD) are currently not accurately known and odds ratios alone are insufficient to assess these risks. We calculated AD LTR in 7351 cases and 10 132 controls from Caucasian ancestry using Rochester (USA) incidence data. At the age of 85 the LTR of AD without reference to APOE genotype was 11% in males and 14% in females. At the same age, this risk ranged from 51% for APOE44 male carriers to 60% for APOE44 female carriers, and from 23% for APOE34 male carriers to 30% for APOE34 female carriers, consistent with semi-dominant inheritance of a moderately penetrant gene. Using PAQUID (France) incidence data, estimates were globally similar except that at age 85 the LTRs reached 68 and 35% for APOE 44 and APOE 34 female carriers, respectively. These risks are more similar to those of major genes in Mendelian diseases, such as BRCA1 in breast cancer, than those of low-risk common alleles identified by recent GWAS in complex diseases. In addition, stratification of our data by age groups clearly demonstrates that APOE4 is a risk factor not only for late-onset but for early-onset AD as well. Together, these results urge a reappraisal of the impact of APOE in Alzheimer disease.

Charcot-Marie-Tooth disease type 1A with 17p duplication in infancy and early childhood: a longitudinal clinical and electrophysiologic study.

Objective: We describe longitudinal clinical and electrophysiologic evaluation of Charcot-Marie-Tooth disease type 1A (CMT-1A) in infancy and early childhood. Background: The clinical picture and electrophysiologic evaluation of CMT-1A during the age of nerve conduction maturation have not been documented. Design/Methods: Twenty at-risk children from six unrelated CMT-1A families were examined in the first 5 years of life. Initial ages were 1 month to 4 years (mean, 1.5 years) and final ages 4 to 19 years (mean, 9 years). All subjects had two or more motor and sensory conduction velocities (MCV and SCV), corrected distal motor latencies (DML), and F-waves. Results: Twelve children were affected. Initially, two of these (17%) had symptoms, whereas five (42%) were symptomatic at the end. Numbers of abnormal examinations at the beginning was six (50%) and at conclusion was 10 (83%). None of the patients were disabled. From 2 years of age, all affected children had abnormal MCV, SVC, F-waves, and DML. Prolonged DML was already present in the first months of life and preceded slowing of MCV in three cases. Conclusion: The electrophysiologic studies were concordant with the presence or absence of the CMT-1A DNA duplication. In most CMT-1A patients, symptoms appear in early childhood, although the florid clinical picture does not occur until the second decade of life. Serial electrophysiologic studies can detect the CMT-1A gene carrier in infancy.

Spinocerebellar ataxias in Spanish patients: genetic analysis of familial and sporadic cases

Abstract Autosomal dominant cerebellar ataxias (ADCA) are a clinically heterogeneous group of neurodegenerative disorders caused by unstable CAG repeat expansions encoding polyglutamine tracts. Five spinocerebellar ataxia genes (SCA1, SCA2, SCA3, SCA6 and SCA7) and another related dominant ataxia gene (DRPLA) have been cloned, allowing the genetic classification of these disorders. We present here the molecular analysis of 87 unrelated familial and 60 sporadic Spanish cases of spinocerebellar ataxia. For ADCA cases 15% were SCA2, 15% SCA3, 6% SCA1, 3% SCA7, 1% SCA6 and 1% DRPLA, an extremely rare mutation in Caucasoid populations. About 58% of ADCA cases remained genetically unclassified. All the SCA1 cases belong to the same geographical area and share a common haplotype for the SCA1 mutation. The expanded alleles ranged from 41 to 59 repeats for SCA1, 17 to 29 for SCA2, 67 to 77 for SCA3, and 38 to 113 for SCA7. One SCA6 case had 25 repeats and one DRPLA case had 63 repeats. The highest CAG repeat variation in meiotic transmission of expanded alleles was detected in SCA7, this being of +67 units in one paternal transmission and giving rise to a 113 CAG repeat allele in a patient who died at 3 years of age. Meiotic transmissions have also shown a tendency to more frequent paternal transmission of expanded alleles in SCA1 and maternal in SCA7. All SCA1 and SCA2 expanded alleles analyzed consisted of pure CAG repeats, whereas normal alleles were interrupted by 1–2 CAT trinucleotides in SCA1, except for three alleles of 6, 14 and 21 CAG repeats, and by 1–3 CAA trinucleotides in SCA2. No SCA or DRPLA mutations were detected in the 60 sporadic cases of spinocerebellar ataxia, but one late onset patient was identified as a recessive form due to GAA-repeat expansions in the Friedreich’s ataxia gene.

Motor neuron disease in Cantabria

ABSTRACT— Sixty‐two patients with motor neuron disease (MND), encompassing amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP) and progressive muscular atrophy (PMA), were selected from within a defined area (Cantabria) in northern Spain, from 1974 to 1985. The annual incidence of MND was 1.01 per 100,000 inhabitants and the prevalence rate was 3.52 per 100,000. The male to female ratio was 1.78:1. Age‐specific incidence rates increased with advanced age, with a maximum between 60 and 69 years for males and over 70 years for females. The median age at onset was 60.5 years. The average interval between the onset symptoms and diagnosis was 11 months. Fifty‐three per cent of the patients had conventional or pseudopolyneuritic ALS, 36% had PBP and 11% had PMA. There were three familial cases. Two PMA patients had had acute poliomyelitis. The mean duration of the disease was 26.6 months and was significantly longer in males aged under 60 years. The survival rates in 50 patients with adequate follow‐up were 18% after 5 years from onset and 6% after 10 years.

Epistasis in sporadic Alzheimer's disease.

The traditional approach in case-control association studies, to evaluate candidate genes individually, either single markers or haplotypes, has had limited success. The multifactorial nature of complex diseases suggests the alternative of examining gene-gene interactions (epistasis) within biological networks. We have used synergy factor analysis to assess over 100 claims of epistasis in sporadic Alzheimers disease (AD), in networks involving, e.g. cholesterol, beta-amyloid, inflammation and oxidative stress. We found 27 gene-gene interactions that were significantly associated with AD. In most of these the main effect of one of the genes was so small that it would probably have been missed by the traditional locus-by-locus approach. There are questions, however, about the quality of replication studies: about sample sizes, about homogeneity, characterization and matching of sample sets, and about the statistical methods commonly used to assess interactions. Meta-analyses could now be conducted of the four interactions that have been sufficiently replicated, all involving APOE4: ACT -17AA; BACE1 exon5 GG; IL6 -174C; BCHE K. Only that between BACE1 exon5 GG and APOE4 has so far been consistently replicated. We conclude that epistasis is a crucial feature of complex diseases, that its study is a promising approach to the genetics of AD and that larger and more rigorous studies are needed to establish interactions.

Dementia risk in Parkinson disease: disentangling the role of MAPT haplotypes.

BACKGROUND Dementia in Parkinson disease (PD) causes nursing home placement, caregiver distress, higher health care burden, and increased mortality. OBJECTIVE To determine whether the microtubule-associated protein tau (MAPT) H1 haplotype and MAPT subhaplotypes play a role in the risk of PD and Parkinson disease-dementia (PDD) complex. DESIGN Case-control genetic analysis. SETTING Movement Disorders and Memory Units, Hospital de Sant Pau, Barcelona, Spain. PARTICIPANTS Two hundred two patients with PD (48 of whom developed dementia>2 years after disease onset), 41 patients with Lewy body dementia (LBD, pathologically confirmed in 17), 164 patients with Alzheimer disease (AD), and 374 controls. METHODS The MAPT haplotype was determined by testing for a 238-base pair deletion between exons 9 and 10, which is characteristic of the H2 haplotype. Haploview was used to visualize linkage disequilibrium relationships between all genetic variants (5 single-nucleotide polymorphisms and the del-In9 variant) within and surrounding the MAPT region. RESULTS The H1 haplotype was significantly overrepresented in PD patients compared with controls (P=.001). Stratifying the PD sample by the presence of dementia revealed a stronger association in PDD patients (sex- and age-adjusted odds ratio, 3.73; P=.002) than in PD patients without dementia (sex- and age-adjusted odds ratio, 1.89; P=.04). Examination of specific subhaplotypes showed that a rare version of the H1 haplotype (named H1p) was overrepresented in PDD patients compared with controls (2.3% vs 0.1%; P=.003). No positive signals for any of the MAPT variants or H1 subhaplotypes were found in AD or LBD. CONCLUSIONS Our data confirm that MAPT H1 is associated with PD and has a strong influence on the risk of dementia in PD patients. Our results also suggest that none of the MAPT subhaplotypes play a significant role in other neurodegenerative diseases, such as LBD or AD.

A prospective study of stroke in young adults in Cantabria, Spain.

Background and Purpose The aim of this study was to determine the incidence, type, and prognosis of stroke in young adults in Cantabria, Spain. Methods We investigated prospectively all patients aged 50 years or below who were admitted with the diagnosis of a stroke to the University Hospital “Marqués de Valdecilla” from April 1,1986, to March 31, 1988. This is the main hospital of the region to which all patients with neurological problems are referred. These patients underwent a complete clinical and laboratory assessment for stroke and had 1-year mean follow-up. Results The total series included 81 patients. The annual age-specific crude incidence rates of stroke were 17.3 and 10.4 per 100,000 for males and females, respectively. Twenty-four patients (30%) were diagnosed as having nonembolic cerebral infarction, 14 (17%) embolic cerebral infarction, 20 (25%) subarachnoid hemorrhage, 22 (27%) spontaneous cerebral hemorrhage, and one case (1%) cerebral venous thrombosis. Eighteen patients (22%) died within 30 days of the cerebrovascular event, and two others died during the follow-up period. Seventy-nine percent of the survivors recovered and were completely self-sufficient. Conclusions The incidence of stroke in the young found in Cantabria is comparable with that in previous studies. The initial hospital mortality was not negligible, but the prognosis among the survivors was favorable.

Prevalence of hereditary motor and sensory neuropathy in Cantabria.

ABSTRACT— One hundred and forty‐four patients with hereditary motor and sensory neuropathy (HMSN) were selected from within a defined area (Cantabria) in Northern Spain, from 1974 to 1984. The series comprises 49 index cases and 95 affected relatives. The prevalence ratio was 28.2 cases per 100.000. The results of the study indicate that the majority of cases were hereditary as a dominant trait. The prevalence for the Type I HMSN cases did not differ from that of Type II cases. Previous population‐surveys of these disorders.

Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations.

Recent genome-wide association studies have identified 5 loci (BIN1, CLU, CR1, EXOC3L2, and PICALM) as genetic determinants of Alzheimers disease (AD). We attempted to confirm the association between these genes and the AD risk in 3 contrasting European populations (from Finland, Italy, and Spain). Because CLU and CR1 had already been analyzed in these populations, we restricted our investigation to BIN1, EXO2CL3, and PICALM. In a total of 2816 AD cases and 2706 controls, we unambiguously replicated the association of rs744373 (for BIN1) and rs541458 (for PICALM) polymorphisms with the AD risk (odds ratio [OR] = 1.26, 95% confidence interval [CI] [1.15-1.38], p = 2.9 × 10(-7), and OR = 0.80, 95% CI [0.74-0.88], p = 4.6 × 10(-7), respectively). In a meta-analysis, rs597668 (EXOC3L2) was also associated with the AD risk, albeit to a lesser extent (OR = 1.19, 95% CI [1.06-1.32], p = 2.0 × 10(-3)). However, this signal did not appear to be independent of APOE. In conclusion, we confirmed that BIN1 and PICALM are genetic determinants of AD, whereas the potential involvement of EXOC3L2 requires further investigation.

Clinico-electrophysiological correlation of extensor digitorum brevis muscle atrophy in children with Charcot–Marie–Tooth disease 1A duplication ☆

The purpose of the study is to describe the electrophysiologic abnormalities accounting for the appearance and progression of extensor digitorum brevis (EDB) muscle atrophy in Charcot-Marie-Tooth-disease type 1A (CMT-1A) children. Twelve children with CMT-1A duplication were serially evaluated. Initial ages of clinico-electrophysiological exams ranged from 1 month to 4 years (mean: 2 years) and final ages from 6 to 23 years (mean: 13). All subjects had two or more electrophysiological studies of the peroneal nerve. EDB atrophy was observed in two out of 12 (17%) patients by the age of 5, in eight out of ten (80%) examined between 5 and 9 years, and in all eight (100%) patients who had reached the second decade at the end. Nerve conduction maturation was systematically abnormal, but by age of 5 the mean values of nerve conduction parameters of peroneal nerve did not significantly differ from those in older patients. Compound muscle action potential (CMAP) amplitudes of EDB were reduced in 42% of cases initially and 100% upon last exam. Furthermore, a constant finding throughout the study was progressive attenuation of CMAPs, these becoming unobtainable in four cases. EDB muscle atrophy in CMT-1A children is an age-dependent sign which is accounted for by gradual reduction of the distal peroneal nerve CMAP amplitudes.