L1CAM mutation in a Japanese family with X-linked hydrocephalus: a study for genetic counseling

Mutations in the gene encoding neural cell adhesion molecule L1 (L1CAM) are involved in X-linked hydrocephalus (HSAS, hydrocephalus due to stenosis of the aqueduct of Sylvius), MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs), and spastic paraplegia type 1. We examined the L1CAM mutation in a Japanese family with HSAS for the purpose of DNA-based genetic counseling. The proband was a 9-year-old boy who had a 1-bp deletion in exon 22 of the L1CAM gene. This resulted in a shift of the reading frame, and introduction of a premature stop codon. Translation of this mRNA will create a truncated protein without the transmembrane domain, which cannot be expressed on the cell surface. Magnetic resonance images (MRI) revealed markedly enlarged lateral ventricles, hypoplastic white matter, thin cortical mantle, agenesis of the corpus callosum and septum pellucidum, and a fused thalamus. These findings represented impaired L1CAM function during development of the nervous system with resultant adhesion between neurons, neurites outgrowth and fasciculation, and neural cell migration. Screening by Apa I digestion of polymerase chain reaction (PCR) products identified the mother and the younger sister as heterozygous carriers. The carriers were asymptomatic. The father and the other sister did not have the mutation. The identification of L1CAM mutation in families with HSAS will give them the opportunity for DNA-based counseling and prenatal diagnosis.     

A novel missense mutation in the L1CAM gene in a boy with L1 disease

Abstract A novel missense mutation of the L1CAM gene (Xq28) is described in an adult patient affected with severe mental retardation, spastic paraparesis, adducted thumbs, agenesis of corpus callosum and microcephaly (L1 disease). We detected a transition c2308G→A in exon 18 that caused an amino acid change in codon 770. The patient’s mother and two sisters were heterozygous for the same mutation. This newly described mutation predicts the substitution of an aspartate by asparagine (D770N) in the second fibronectin (Fn2) domain of the extracellular portion of the mature L1 protein. Even if amino acid substitution does not significantly change the physico-chemical properties of the Fn2 domain, it seems clear that the integrity of this domain is required to maintain the biological functions of the protein. The feature peculiar to this patient is the decelerated head growth post-natally, leading to microcephaly. Mutations of L1CAM associated with prolonged survival may hamper post-natal brain and head growth.     

X-linked hydrocephalus: a novel missense mutation in the L1CAM gene

X-linked hydrocephalus is associated with mutations in the L1 neuronal cell adhesion molecule gene. L1 protein plays a key role in neurite outgrowth, axonal guidance, and pathfinding during the development of the nervous system. A male is described with X-linked hydrocephalus who had multiple small gyri, hypoplasia of the white matter, agenesis of the corpus callosum, and lack of cleavage of the thalami. Scanning the L1 neuronal cell adhesion molecule gene in Xq28 revealed a novel missense mutation: transition of a guanine to cytosine at position 1,243, which led to conversion of alanine to proline at position 415 in the Ig 4 domain of the L1 protein. It is likely that the X-linked hydrocephalus and cerebral dysgenesis are a result of the abnormal structure and function of the mutant L1 protein.     

A novel CCM1 gene mutation causes cerebral cavernous malformation in a Chinese family

Familial cerebral cavernous malformations (CCMs) are characterized by an autosomal dominant transmission with incomplete penetrance. We have previously reported a 1292delAT mutation in the CCM1 gene in a Chinese family with CCM. Here we report a novel deletion of CCM1 that correlates strongly with CCM formation in another family. Ten affected family members were observed among the 25 participants, and multiple CCM lesions were detected in seven individuals. Nucleotide sequencing analysis in the index patient and other affected members showed a CAAA deletion in exon 12 at nucleotide (NT) 1197. We predict this deletion produces a premature stop code (TGA) at NT 1228, resulting in a truncated protein of 409 amino acids.     

Rumpshaker: an X-linked mutation affecting CNS myelination. A study of the female heterozygote

This study examines the myelin deficits found in the spinal cord and optic nerves of female mice heterozygotes for rumpshaker (rsh), an X-linked mutation causing hypomyelination. No clinical abnormalities were detected but morphological changes were evident, particularly in the spinal cord, which showed no evidence of resolving with age. In the spinal cord, scattered hypomyelinated axons, occasionally grouped in twos or threes, were the major feature; oligodendrocyte numbers were slightly elevated at all ages compared to normal male littermates and the total amount of myelin was reduced. Myelin protein composition of the sheaths was examined by immunostaining for myelin basic protein (MBP) and two peptide regions of PLP/DM-20 molecule; one being proteolipid protein (PLP)-specific and the other recognizing the c-terminal common to PLP-DM-20. The majority of myelin sheaths immunostained for MBP and PLP. Occasional MBP-positive sheaths failed to stain with PLP/DM-20 or PLP-specific antiserum. Therefore, at least two types of immunocytochemically-defined myelin sheaths are present in the heterozygotes. Changes in the optic nerves were much less obvious; glial cell numbers were increased but thinly myelinated axons were not detected although the total amount of myelin was reduced compared to normal littermates. In no instance were mosaic, amyelinated/hypomyelinated patches detected. Heterozygotes for rsh, therefore, are considerably different from those for other X-linked myelin mutations like the jimpy mouse and the myelin-deficient rat, both in regard to the severity of the lesions and their failure to recover with age.     

Early-onset Alzheimer's disease with a de novo mutation in the presenilin 1 gene

A 32-year-old woman diagnosed with very rapidly progressing early-onset Alzheimer's disease (EOAD), age of onset 29 years, and S170F mutation in presenilin 1 gene (PSEN1) is presented. Neuroimaging conducted 2 years after the first symptoms was typical for the advanced stage of Alzheimer's disease (AD), showing cortical brain atrophy, particularly within hippocampus, frontal and temporal cortex. The unaffected parents of the proband are not carriers of the mutation. The paternity was confirmed by microsatellite typing, strongly suggesting de novo origin of S170F mutation. In silico modeling of S170F mutation impact on presenilin 1 (PS1) transmembrane structure indicates that the mutation considerably alters putative interactions of PS1 with other proteins within gamma-secretase complex.     

A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease

We studied a Cuban family with presenile dementia (autosomal dominant) consisting of 281 members within six generations, the proband descended from a Spanish founder. Mean age at onset was 59 years of age. Memory impairment was the main symptom in all patients, additionally, ischemic episodes were described in 4 (n=18) patients. Neuropathological examination of brain material (1 patient) revealed neuronal loss, amyloid plaques, and neurofibrillary tangles. Thirty DNA samples were genotyped (regions on chromosome 1, 3, 10, 12, 14, 17, 19, 20, and 21). A maximum Lod score of 3.79 at θ=0 was obtained for marker D14S43, located in a 9-cM interval in which all patients shared the same haplotype. Sequencing of the PSEN1 gene revealed a heterozygous base substitution, C520A (exon 6), which is predicted to cause an amino acid change from leucine to methionine in the TMIII of the presenilin 1 protein. The mutation was found to co-segregate with the disease phenotype and the associated disease haplotype. The C→A change was not observed in 80 control chromosomes from the Cuban population. Leucine at position 174 is highly conserved among species and is identical in presenilin 1 and presenilin 2 proteins. We propose the L174 M mutation might lead to an abnormal N-terminal and probably C-terminal fragments and malfunction of the protein complex. In conclusion, we found a novel PSEN1 mutation in a large family with clinical and pathological diagnosis of early onset familial Alzheimer disease, which may be relevant for other Hispanic populations. Electronic Publication     

A novel mutation in the MFSD8 gene in late infantile neuronal ceroid lipofuscinosis

Neuronal ceroid lipofuscinoses (NCL) are lysosomal storage disorders and constitute the most common group of progressive neurodegenerative diseases in childhood. Most NCLs are inherited in a recessive manner and are clinically characterised by a variable age at onset, epileptic seizures, psychomotor decline, visual impairment and premature death. To date, eight causative genes have been identified to underlie various clinical forms of NCL. We performed a genome-wide linkage analysis followed by sequencing the recently described NCL gene MFSD8 in three affected and three unaffected members of a consanguineous Egyptian family with an autosomal recessively inherited progressive neurodegenerative disorder. The clinical picture of the patients was compatible with a late infantile NCL (LINCL); however, impairment of the visual system was not a cardinal symptom in the respective family. By linkage analysis, we identified two putative loci on chromosome 1p36.11-p35.1 and 4q28.1-q28.2. The latter locus (4q28.1-q28.2) contained the MFSD8 gene, comprising a novel homozygous missense mutation in exon 5 (c.362a>g /p.Tyr121Cys), which segregated with the disease in the three affected sibs. We describe a novel mutation in the previously identified MFSD8 gene in a family with a common phenotype of LINCL, but no clinical report of vision loss. Our results enlarge the mutational and perhaps the nosological spectrum of one of the recently identified subtypes of NCL, called CLN7. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Pathomechanistic characterization of two exonic L1CAM variants located in trans in an obligate carrier of X-linked hydrocephalus

Mutations in the gene encoding the neural cell adhesion molecule L1CAM cause several neurological disorders collectively referred to as L1 syndrome. We report here a family case of X-linked hydrocephalus in which an obligate female carrier has two exonic L1CAM missense mutations in trans substituting amino acids in the first (p.W635C) or second (p.V768I) fibronectin-type III domains. We performed various biochemical and cell biological in vitro assays to evaluate the pathogenicity of these variants. Mutant L1-W635C protein accumulates in the endoplasmic reticulum (ER), is not transported into axons, and fails to promote L1CAM-mediated cell-cell adhesion as well as neurite growth. Immunoprecipitation experiments show that L1-W635C associates with the molecular ER chaperone calnexin and is modified by poly-ubiquitination. The mutant L1-V768I protein localizes at the cell surface, is not retained in the ER, and promotes neurite growth similar to wild-type L1CAM. However, the p.V768I mutation impairs L1CAM-mediated cell-cell adhesion albeit less severe than L1-W635C. These data indicate that p.W635C is a novel loss-of-function L1 syndrome mutation. The p.V768I mutation may represent a non-pathogenic variant or a variant associated with low penetrance. The poly-ubiquitination of L1-W635C and its association with the ER chaperone calnexin provide further insights into the molecular mechanisms underlying defective cell surface trafficking of L1CAM in L1 syndrome.     

一个肾上腺脑白质营养不良家系的ABCD1基因突变分析

目的 通过对1例疑似肾上腺脑白质营养不良(ALD)患者及该家系其他成员进行ALD基因分析来明确诊断. 方法 从患者和家庭成员的外周血白细胞提取总RNA和基因组DNA:应用RT-PCR技术,首先对先证者cDNA的ABCD1基因编码区进行序列分析,寻找突变位点,再通过PCR和直接测序等方法 进一步确证该突变位点;同时对该家系其他成员的相应基因组DNA进行ABCD1基因分析. 结果 先证者的ABCD1基因第656(G)、657(A)位碱基缺失,造成移码突变fs R89,可以确诊为ALD.该家系其他成员基因突变分析结果 为:先证者表弟存在与先证者相同的突变,为ALD半合子;先证者的母亲、小姨、表妹均为ALD携带者;先证者姐姐为ABCD1正常基因型. 结论 在中国人ALD患者中发现了1个新的ABCD1基因突变(fs R89),ABCD1基因突变分析是诊断X-ALD最可靠的方法 .     

A new mutation of GCH1 in triplets family with dopa‐responsive dystonia

Background: Dopa‐responsive dystonia (DRD) is associated with mutations of the GCH1. We first report four female siblings with DRD from one family, including three monozygotic triplets patients clinically and genetically. Methods: We performed GCH1 analysis by direct sequencing of PCR product amplified with primers designed to cover the entire exons of GCH1 in those four patients and their mother. Results: In all four patients with DRD, a new frameshift mutation (c.729delG; p.A190fsX191) was identified in the exon 5 of GCH1. Conclusions: The frameshift mutation results in truncated GCH1 protein which is suspected to result in loss of function of the catalytic GTP‐cyclohydrol domain.     

A novel deletion mutation in GJB1 causes X-linked Charcot-Marie-Tooth disease in a Han Chinese family

X-linked Charcot-Marie-Tooth disease CMT (CMTX) is predominantly caused by mutations in the GJB1 gene that encode connexin32. We describe the clinical findings and the identification of a novel mutation in GJB1 in a large Han Chinese family with CMTX. Linkage to GJB1 was determined by genotyping five polymorphic markers flanking GJB1. Sequence alterations were determined by directly sequencing the coding region of the GJB1 gene. The affected members have variable clinical manifestations. Linkage analysis confirmed the cosegregation of the disease with the GJB1 locus. Sequencing of the GJB1 gene revealed a 1-basepair deletion (c.110delT) in the coding region. The frameshift begins at amino acid 37 and generates a premature stop codon at position 83. The shortened peptide is unlikely to be functional, as it lacks most of the functional domains. The CMTX in this family is caused by a novel loss of function mutation.     

Variable neurologic phenotype in a GEFS+ family with a novel mutation in SCN1A

PurposeTo describe the spectrum of clinical disease in a mutliplex family with an autosomal dominant form of generalized epilepsy with febrile seizures plus (GEFS+) and determine its genetic etiology.MethodsMedical and family history was obtained on 11 clinically affected individuals and their relatives across three generations through medical chart review and home visits. A candidate gene approach including haplotype analysis and direct sequencing was used.ResultsAn epilepsy-associated haplotype was identified on 2q24. Direct sequencing of the entire SCN1A gene identified seven sequence variants. However, only one of these, c.1162 T > C, was not found in population controls. This transition in exon 8 of SCN1A predicts a substitution (Y388H) of a highly conserved tyrosine residue in the loop between transmembrane segments S5 and S6 of the sodium channel protein (Na_v1.1). Clinical features in mutation carriers of this novel missense mutation were highly variable, ranging from febrile seizures to severe refractory epilepsy.ConclusionA novel missense mutation in the pore-forming region of the sodium channel gene SCN1A causes GEFS+ with a variable phenotype that includes mood and anxiety disorders, as well as ataxia, expanding the GEFS+ spectrum to include neuropsychiatric disease.     

A novel proteolipid protein 1 gene mutation causing classical type Pelizaeus-Merzbacher disease

Pelizaeus-Merzbacher disease (PMD) is a rare dysmyelinating disorder caused by mutations in the proteolipid protein 1 (PLP1) gene. PMD is generally classified according to its clinical or pathological features into classical or connatal forms. We describe here a 19-year-old male with classical form PMD who presented with stridor and nystagmus in early infancy and whose psychomotor development has been severely delayed. Brain magnetic resonance imaging revealed white matter abnormalities typical of PMD. Direct sequencing of the PLP1 gene identified two nucleotide substitutions. One was a C-to-T transition at -31 in the 5’-flanking region of exon 1; the other was a novel point mutation, T-to-C transition in exon 4, which led to substitution of cysteine for arginine at residue 184. Because Cys184 forms a disulphide bridge with Cys228, the Cys184Arg mutation probably removes the bridge and changes the tertiary structure of PLP protein. A defective disulfide bond in PLP protein could be important in the pathogenesis of PMD.     

Electroencephalographic changes and seizures in familial hemiplegic migraine patients with the CACNA1A gene S218L mutation

The S218L CACNA1A mutation has been previously described in two families with familial hemiplegic migraine. We present three siblings with the mutation with the novel association of childhood seizures, and highlight the dynamic changes seen on electroencephalography during hemiplegic migraine attacks. Depressed activity contralateral to the hemiparesis was seen on electroencephalography during acute hemiplegic migraine attacks, which may be due to changes to calcium channels caused by the S218L mutation. Both parents were asymptomatic and did not carry the S218L mutation in their blood. This suggests the presence of mosaicism in the transmitting parent.     

A new model of congenital hydrocephalus in the rat

Summary Hydrocephalic neonates were observed in a small breeding colony of rats. Normal rats from this colony were obtained and brother-sister mated for seven generations. The overall prevalence of hydrocephalics was approximately 23%; however, in one subline, the prevalence approached 50%. Breeding data suggested the trait to be polygenic. Hydrocephalics could be detected at 1–2 days of age, and survived for 4–5 weeks. Dilatation of the ventricles was restricted to the lateral ventricles. No evidence of developmental anomalies was seen within the ventricles. Preliminary evidence suggested that the pathophysiology may be related to poorly developed veins in the periosteal-dural layers and to underdeveloped pia-arachnoid cells. The hydrocephalus was classified as being of the communicating type.     

Clinical characteristics of paroxysmal nonkinesigenic dyskinesia in serbian family with Myofibrillogenesis regulator 1 gene mutation

The aim of this study was to describe the clinical features of a large Serbian family with paroxysmal nonkinesigenic dyskinesia (PNKD) and one of the two previously described mutations in the Myofibrillogenesis regulator 1 gene (MR‐1), which causes an alanine‐to‐valine substitution at position 9. In 5 examined out of 12 affected family members, attacks of dyskinesias appeared in the first 6 months of life. Both frequency and severity of attacks showed an age‐dependent incremental–decremental pattern with a peak between 13 to 15 years of age. They were frequently precipitated by stress, caffeine, fever, hunger, tiredness, as well as abrupt changes in temperature. Three of our patients differentiated two types of attacks: mild (120–180 minutes), with a predominance of functionally insignificant choreoathetoid movements, and severe (～ 15–30 minutes), characterized by disabling dystonic and choreic movements of the extremities, trunk, and face. Sleep was the most reliable factor to discontinue an attack. This Serbian family further demonstrates that recurrent MR‐1 mutations are associated with PNKD worldwide, which will affect genetic testing. © 2006 Movement Disorder Society     

A clinicopathological study of ALS with L126S mutation in the SOD1 gene presenting with isolated inferior olivary hypertrophy

We report an autopsy case of amyotrophic lateral sclerosis with L126S mutation in the superoxide dismutase 1 (SOD1) gene (SOD1). The patient was a 69-year-old Japanese man without relevant family history, who initially presented with slow progressive muscle weakness of the lower extremities without upper motor neuron signs, and died of respiratory failure 6 years after the onset. Neuropathological examination revealed a loss of lower motor neurons and degeneration of Clarke's column commensurate with that of the posterior spinocerebellar tract and the middle root zone of the posterior column. The primary motor area was minimally affected. Characteristic SOD1-immunopositive neuronal intracytoplasmic inclusions, mixed with neurofilament accumulation, were present in the affected areas. Isolated inferior olivary hypertrophy was observed, but did not involve the contralateral dentate nucleus, or the ipsilateral red nucleus and central tegmental tract, where no neuronal inclusions were found. In combination with data from a previous autopsy case, this study suggests that the L126S mutation may cause focal neuronal degeneration in the brainstem.