Novel SPG6 mutation p.A100T in a Japanese family with autosomal dominant form of hereditary spastic paraplegia.

We describe a Japanese family in which inheritance of a novel mutation p.A100T in SPG6 resulted in an autosomal dominant form of hereditary spastic paraplegia (ADHSP). Clinical investigation showed a pure form of HSP. Our study demonstrates further allelic heterogeneity of SPG6.     

Clinical and genetic study of a large SPG4 Italian family.

A novel SPG4 906delT frame-shift mutation in exon 6 was identified in a large Italian family with an autosomal dominant form of hereditary spastic paraplegia (ADHSP). Intrafamilial phenotypic variations observed in the pedigree included spasticity and additional clinical features, such as peripheral sensory-motor neuropathy, cognitive impairment, and urological dysfunction. Severe clinical features were found predominantly in the men who were affected, and there was no statistically significant correlation of disability and time since onset of symptoms, suggesting the existence of other genetic/nongenetic modifier(s), including gender.     

A large Japanese SPG4 family with a novel insertion mutation of the SPG4 gene: a clinical and genetic study

We studied a large Japanese family with autosomal dominant pure hereditary spastic paraplegia (ADPHSP) clinically and genetically. To date, seven loci causing ADPHSP have been mapped to chromosomes 14q, 2p, 15q, 8q, 12q, 2q, and 19q. Among these loci, the SPG4 locus on chromosome 2p21--p22 has been shown to account for approximately 40% of all autosomal dominant hereditary spastic paraplegia (ADHSP) families. Very recently, Hazan et al. identified the SPG4 gene encoding a new member of the AAA (ATPases associated with diverse cellular activities) protein family, named spastin. We found a novel insertion mutation (nt1272--1273insA) in exon 8 of the SPG4 gene in the present family. Our study is the first to confirm the causative mutation of the SPG4 gene in Japanese. Clinically, it is noteworthy that the disease progression in the patients of this family was slow in spite of the late onset, and more than half of the patients showed severe constipation in addition to pure spastic paraplegia.     

A novel insertion mutation in spastin gene is the cause of spastic paraplegia in a Chinese family

A total of eight loci for autosomal dominant hereditary spastic paraplegia (ADHSP) has been mapped to chromosome 14q, 2p, 15q, 8q, 10q, 12q, 19q, 2q, respectively, among which the SPG4 gene on chromosome 2p21–22 encoding spastin, an ATPase of the AAA family, accounts for 40–50% of all ADHSP families and is expressed in both adult and fetal tissues. In this work, we reveal a novel insertion mutation in exon 11 of the SPG4 gene found in a big Chinese family composed of 47 members, including 20 affected ones, using linkage analysis. The mutation was well demonstrated to be the cause of loss of production of the functional protein by pre-termination of translation in AAA cassette region. To our knowledge, this is the first report of spastin mutation in China.     

遗传性痉挛性截瘫一家系(SPG4)的临床与遗传学特点

目的 探讨遗传性痉挛性截瘫(HSP)4型患者的临床特点和基因突变. 方法观察HSP4型患者1个家系4例患者的临床特点,抽取家系5个成员的外周血,选择与已知HSP致病基因位点在物理距离上紧密连锁的微卫星分子STR进行标记.连锁分析并构建其单体型后进行突变筛选.结果 基因分型结果显示了D2S2351与D2S2255与致病基因不排除连锁.其他位点LOD值为负值排除连锁,因此初步定位于HSP致病基因(SPG)4,所对应的候选基因是spastin基因.突变筛查发现患者spastin基因第8外显子1168位置碱基A/G杂合突变.结论该HSP家系患者具有典型临床表现,为spastin基因第8外显子1168核苷酸的位置上A/G杂合突变所致.     

Cannabis use and age at onset of symptoms in subjects at clinical high risk for psychosis

Dragt S, Nieman DH, Schultze‐Lutter F, van der Meer F, Becker H, de Haan L, Dingemans PM, Birchwood M, Patterson P, Salokangas RKR, Heinimaa M, Heinz A, Juckel G, Graf von Reventlow H, French P, Stevens H, Ruhrmann S, Klosterkötter J, Linszen DH, on behalf of the EPOS group. Cannabis use and age at onset of symptoms in subjects at clinical high risk for psychosis. Objective: Numerous studies have found a robust association between cannabis use and the onset of psychosis. Nevertheless, the relationship between cannabis use and the onset of early (or, in retrospect, prodromal) symptoms of psychosis remains unclear. The study focused on investigating the relationship between cannabis use and early and high‐risk symptoms in subjects at clinical high risk for psychosis. Method: Prospective multicenter, naturalistic field study with an 18‐month follow‐up period in 245 help‐seeking individuals clinically at high risk. The Composite International Diagnostic Interview was used to assess their cannabis use. Age at onset of high risk or certain early symptoms was assessed retrospectively with the Interview for the Retrospective Assessment of the Onset of Schizophrenia. Results: Younger age at onset of cannabis use or a cannabis use disorder was significantly related to younger age at onset of six symptoms (0.33 < r_s < 0.83, 0.004 < P < 0.001). Onset of cannabis use preceded symptoms in most participants. Conclusion: Our results provide support that cannabis use plays an important role in the development of psychosis in vulnerable individuals. Cannabis use in early adolescence should be discouraged.     

Platelet membrane fluidity,family history,severity and age of onset in Alzheimer's disease

Platelet membrane fluidity values were assessed in three groups of subjects: (1) 15 Alzheimer's disease patients with a first-degree family history of the disorder; (2) 16 Alzheimer's disease patients with no family history of the disorder; (3) 22 healthy control subjects. The distributions of platelet membrane fluidity changes were found to be the same in both Alzheimer disease groups, but none of the controls had raised platelet membrane fluidity Severity of Alzheimer's disease as measured by Mini-Mental State and Cambridge Cognitive Index scores correlated with platelet membrane fluidity values significantly for the non-family history group but not for the family history group. There was no apparent association between raised platelet membrane fluidity and age of onset of Alzheimer's disease. There was no evidence to indicate that raised platelet membrane fluidity is a peripheral marker for familial Alzheimer's disease.     

Differences in age at onset and familial aggregation between clinical types of idiopathic Parkinson's disease.

Idiopathic Parkinson's disease (PD) can be subdivided by its patterns of motor symptoms into tremor-dominant (TDT), akinetic-rigid (ART), and mixed type (MT). Our objective was to determine whether age at onset and family history are different in these three types. In total, 366 patients with PD were assigned in a standardized approach to one of the three subtypes. Age at onset and family history were obtained in all patients and all presumably affected family members were examined. Mean ages at disease onset were similar in all three groups, but distribution of age at onset was markedly different: monophasic in TDT with a peak around 60 years, biphasic in ART with two peaks, one in the middle of the sixth decade (earlier onset, ART-EO), another during the first half of the seventh decade (later onset, ART-LO), and increasing with age only in MT patients A positive family history was significantly associated only with TDT (odds ratio = 5.7) and ART-EO (odds ratio = 7.8), but not with MT or ART-LO patients. Segregation analysis suggested an autosomal recessive mode of transmission in ART-EO and an autosomal dominant mode of transmission in TDT.     

Striking intrafamilial phenotypic variability and spastic paraplegia in the presence of similar homozygous expansions of the FRDA1 gene.

We report on a Friedreich's ataxia (FA) family with 3 affected siblings with markedly different phenotypic presentations, including one with spastic paraplegia. Molecular analysis showed midsize GAA repeat expansion sizes in all 3 individuals. Gait spasticity in FA, although rare, has been described in a few patients who are compound heterozygotes for a point mutation, or who had GAA expansions of less than 200 repeats. The occurrence of spastic paraplegia in our family, in the presence of homozygous midsize GAA repeat expansions, is an unusual finding. Spasticity can be the main feature in both sporadic and familial patients with FA, either as an isolated finding, or in addition to other neurological abnormalities, and should be included as a rare feature in the clinical spectrum of FA. This family also demonstrates that in FA, marked intrafamilial phenotypic variability can arise in the presence of similar GAA expansion sizes. Therefore, in familial FA, the disease course in relatives therefore cannot be predicted solely from repeat length. Factors such as somatic mosaicism, repeat interruptions, modifying mutations and environmental factors must also be considered.     

A novel mutation in the GTP cyclohydrolase I gene associated with a broad range of clinical presentations in a family with autosomal dominant dopa-responsive dystonia

We examined a large family of Ashkenazi Jewish origin with autosomal dominant dopa-responsive dystonia (DRD). Mutation analysis of the GTP cyclohydrolase I gene revealed in affected members a novel point mutation (a C/A change in exon 1) resulting in a threonine-to-lysine substitution at residue 94. The mutation was characterized by variable expressivity and was associated with either a 'classical' DRD phenotype or various atypical phenotypes, such as subtle transitory equinovarus postures of the feet or isolated hand tremor. This observation demonstrates the significance of the molecular testing in establishing the clinical diagnosis of DRD. Copyright Lippincott Williams & Wilkins     

The APOE4 effect: structural brain differences in Alzheimer's disease according to the age at symptom onset

Background and purpose

How the APOE genotype can differentially affect cortical and subcortical memory structures in biomarker-confirmed early-onset (EOAD) and late-onset (LOAD) Alzheimer's disease (AD) was assessed.

Method

Eighty-seven cerebrospinal fluid (CSF) biomarker-confirmed AD patients were classified according to their APOE genotype and age at onset. 28 were EOAD APOE4 carriers (+EOAD), 21 EOAD APOE4 non-carriers (–EOAD), 23 LOAD APOE4 carriers (+LOAD) and 15 LOAD APOE4 non-carriers (–LOAD). Grey matter (GM) volume differences were analyzed using voxel-based morphometry in Papez circuit regions. Multiple regression analyses were performed to determine the relation between GM volume loss and cognition.

Results

Significantly more mammillary body atrophy in +EOAD compared to –EOAD is reported. The medial temporal and posterior cingulate cortex showed less GM in +LOAD compared to –LOAD. Medial temporal GM volume loss was also found in +EOAD compared to –LOAD. With an exception for +EOAD, medial temporal GM was strongly associated with episodic memory in the three groups, whilst posterior cingulate cortex GM volume was more related with visuospatial abilities. Visuospatial abilities and episodic memory were also associated with the anterior thalamic nucleus in –LOAD.

Conclusions

Our results show that the APOE genotype has a significant effect on GM integrity as a function of age of disease onset. Specifically, whilst LOAD APOE4 genotype is mostly associated with increased medial temporal and parietal atrophy compared to –LOAD, for EOAD APOE4 might have a more specific effect on subcortical (mammillary body) structures. The findings suggest that APOE genotype needs to be taken into account when classifying patients by age at onset.     

Marked variation in clinical presentation and age of onset in a family with a heterozygous parkin mutation.

Parkin gene mutations have been detected in families with early-onset autosomal recessive parkinsonism. We report a novel heterozygous 40 base pair deletion in exon 3 of the parkin gene that increases the susceptibility of carriers to develop parkinsonism/dystonia and manifests remarkable variability in regard to age of onset and phenotype in a single family. After identifying the new mutation in the proband of this kindred, family members were contacted and evaluated by a movement disorders specialist using standardized protocols and prospectively set diagnostic criteria. Importantly, examining physicians and family members were blinded to the genetic testing. Five affected members in two generations carried the parkin mutation. The proband and one of his brothers had disease onset at 24 years of age while another brother had disease at age 44. One exhibited multi-focal dystonia and parkinsonism of 17 years duration, another suffered a unilateral slowly progressive parkinsonism over 13 years while the third suffered dystonia-parkinsonism of recent onset. A sibling pair in the preceding generation had mild previously undiagnosed parkinsonism. Clinicians should be aware that patients carrying a parkin gene mutation may present with dystonia-parkinsonism or very subtle parkinsonism with a markedly varied age of onset.     

A novel splice site mutation in the SPG7 gene causing widespread fiber damage in homozygous and heterozygous subjects

Hereditary spastic paraplegias (HSP) are genetically and clinically heterogeneous neurodegenerative disorders. The purpose of this study was to assess the genotype and phenotype in a family with a complicated form of autosomal recessive hereditary spastic paraplegia (ARHSP). Neurological and neuropsychological evaluation, neurophysiologic studies, fiberoptic endoscopic evaluation of swallowing (FEES), neuroimaging analysis including diffusion tensor imaging (DTI), and mutation analysis of SPG4 and SPG7 gene were performed. The index case (mother) was affected by an adult‐onset form of complicated ARHSP due to the homozygous splice site mutation c.1552+1 G>T in the SPG7 gene. This mutation leads to an abnormally spliced mRNA lacking exon 11. Additional clinical features were bilateral ptosis and subtle deficits in executive function. All three asymptomatic daughters carried the sequence variation c.1552+1 G>T in heterozygous state. DTI of the mother revealed disturbance of white matter (WM) integrity in the left frontal lobe, the left corticospinal tract and both sides of the brainstem. DTI of the daughters showed subtle WM alteration in the frontal corpus callosum. The novel mutation is the first splice site mutation found in the SPG7 gene. It removes part of the AAA domain of paraplegin protein, probably leading to a loss‐of‐function of the paraplegin‐AFG3L2 complex in the mitochondrial inner membrane. The pattern of WM damage in the homozygote index case may be specific for SPG7‐HSP. The detection of cerebral WM alterations in the corpus callosum of asymptomatic heterozygote carriers confirms this brain region as the most prominent and early location of fiber damage in ARHSP. © 2010 Movement Disorder Society     

A novel mutation Asp90Val in the SOD1 gene associated with Japanese familial ALS

We have identified a novel mutation in exon 4 of the Cu/Zn superoxide dismutase (superoxide dismutase 1: SOD1) gene (GAC to GTC), which resulted in an Asp⁹⁰ to Val substitution in a Japanese family with amyotrophic lateral sclerosis (ALS) inherited as an autosomal dominant trait. The patients in this family usually died in 2–3 years without sensory or urinary impairment. The SOD1 activity was lower in the proband as compared to the normal controls. The clinical characteristics of this family resemble those of some patients heterozygous for the Asp90Ala mutation, but both the clinical features and SOD1 activity of this family differ from those of patients homozygous for the ASP90Ala mutation.     

Unusual features of central nervous system involvement in CMTX associated with a novel mutation of GJB1 gene

In this study, we report a novel connexin 32 (CX32) mutation associated with cognitive impairment and a differential degree of peripheral nerve involvement. We present clinical, electrophysiological, and neuroimaging data on a family with X‐linked Charcot‐Marie‐Tooth disease caused by a 41A>G mutation of the gap junction protein beta 1 (GJB1) gene. The proband and her sister presented with a severe neuropathy with subclinical cognitive impairment; the proband's brother showed severe cognitive impairment and a mild neuropathy. This family report confirms that Charcot‐Marie‐Tooth type X is a clinically heterogeneous group, with great variability of phenotypes, possible severe involvement in females and clinical signs of cognitive impairment. Thus, this novel mutation should be added to the group of CX32 mutations with a central nervous system phenotype.     

A novel PSEN1 mutation (K239N) associated with Alzheimer’s disease with wide range age of onset and slow progression

Objective: To describe a novel mutation (K239N) in the PSEN1 associated with familial Alzheimer’s disease (AD). Methods and results: The proband was a man who developed cognitive decline with marked behavioural abnormalities at age 57. At age 70, he was admitted into a psychiatric facility because of aggressiveness and a suicide attempt. Family history was consistent with autosomal dominant AD. One of the two other family members studied presented also with prominent behavioural symptoms at age 42 and has also been forced into a psychiatric facility because of aggressiveness at age 56. The remainder patient has presented a prototypical AD, but starting at age 71. Direct sequencing of PSEN1 in the three living affected members disclosed a heterozygous G to C transition in exon 7 of PSEN1 leading to the K239N mutation. Conclusion: The K239N mutation is associated with autosomal dominant AD with a wide range of age of onset and incomplete penetrance at the age of 65, prominent behavioural features and slow progression.     

Late-onset CMT2 associated with a novel missense mutation in the cytoplasmic domain of the MPZ gene

Phenotypic variations have been reported in Charcot-Marie-Tooth disease type 2 (CMT2) including age-at-onset, disease progression and severity. Sporadic cases with CMT2 have also been demonstrated by genetic test. We here report a patient with late-onset CMT2 without family history, who developed gait disturbance at the age of 68. Sequence analysis revealed a novel heterozygous Arg198Gly mutation in the cytoplasmic domain of the major peripheral myelin protein zero (MPZ). The mutation is located in the protein kinase C (PKC) alpha substrate motif (RSTK) of MPZ, presumably leading to the loss of PKC-mediated phosphorylation in adhesion. Routine genetic test for CMT is not recommended for every patient with late-onset peripheral neuropathy without known causes, however, the genetic test may be taken into consideration if the patient shows a clinical phenotype similar to that of CMT, and the possibility of a de novo mutation cannot be excluded.