A homozygous mutation in SLC1A4 in siblings with severe intellectual disability and microcephaly.

We performed exome analysis in two affected siblings with severe intellectual disability (ID), microcephaly and spasticity from an Ashkenazi Jewish consanguineous family. We identified only one rare variant, a missense in SLC1A4 (c. 766G>A [p. E256K]), that is homozygous in both siblings but not in any of their 11 unaffected siblings or their parents (Logarithm of odds, LOD score: 2.6). This variant is predicted damaging. We genotyped 450 controls of Ashkenazi Jewish ancestry and identified only 5 individuals who are heterozygous for this variant (minor allele frequency: 0.0056). SLC1A4 (ASCT1) encodes a transporter for neutral aminoacids such as alanine, serine, cysteine and threonine. L-Serine is essential for neuronal survival and differentiation. Indeed, L-serine biosynthesis disorders affect brain development and cause severe ID. In the brain, L-serine is synthesized in astrocytes but not in neurons. It has been proposed that ASCT1 mediates the uptake of L-serine into neurons and the release of glia-borne L-serine to neighboring cells. SLC1A4 disruption may thus impair brain development and function by decreasing the levels of L-serine in neurons. The identification of additional families with mutations in SLC1A4 would be necessary to confirm its involvement in ID.

Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease.

BACKGROUND: Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher's disease, among patients with Parkinson's disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson's disease. METHODS: Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson's disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. RESULTS: All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. CONCLUSIONS: Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson's disease.

LRRK2 and GBA mutations differentially affect the initial presentation of Parkinson disease.

GBA and LRRK2 mutations increase susceptibility to Parkinson disease (PD), which is characterized by various disabling symptoms. An extended cohort of 600 Ashkenazi PD patients was screened for the LRRK2 G2019S and for eight GBA mutations. Reported initial symptoms were compared between three genotypic groups of patients: carriers of GBA mutations, carriers of LRRK2 G2019S mutation, and non-carriers. More LRRK2 G2019S carriers reported muscle stiffness (rigidity, p = 0.007) and balance disturbances (p = 0.008), while more GBA mutation carriers reported slowness (bradykinesia, p = 0.021). These results suggest distinct effects of LRRK2 or GBA mutations on the initial symptoms of PD.

Candidate-gene approach in fibromyalgia syndrome: association analysis of the genes encoding substance P receptor, dopamine transporter and alpha1-antitrypsin.

BACKGROUND: Substance P receptor modulates stress, depression, anxiety and pain. Substance P is increased in CSF of fibromyalgia (FMS) patients. We examined the frequency of the substance P receptor (TACR1) 1354 G>C polymorphism in FMS.The dopamine transporter (DAT) SLC6A3 3' variable number tandem repeat (VNTR) polymorphism is associated with post traumatic stress disorder (PTSD), a condition with clinical and epidemiological overlap with FMS. We have evaluated the allele frequency of this polymorphism in FMS.Alpha1-antitrypsin (AAT) deficiency is an autosomal recessive metabolic disease. The PI ZZ phenotype, encoded by the E342K mutation, is associated with emphysema and liver disease, and has been linked with FMS. We have examined the frequency of this mutation in FMS. METHODS: Eighty-seven Jewish FMS patients participated; 45 of Ashkenazi origin, 32 of non-Ashkenazi origin and 10 of unknown or mixed Jewish origin. Controls consisted of 200 healthy Jewish individuals. Genotyping of the 1354G >C allele in the 3' UTR of TACR1 gene was performed by DdeI restriction analysis, genotyping the SCL6A3 DAT 3' VNTR polymorphism was performed by PCR combined with GeneScan analysis, and the AAT E342K mutation was identified by TaqI restriction analysis. RESULTS: No significant association was found between FMS and the three genetic markers studied here. CONCLUSIONS: The current candidate-gene approach study failed to identify significant associations between FMS and three genetic markers with hypothesis-driven clinical relevance. We suggest that a genome-wide association study would be a more fruitful approach for further investigation of the genetic basis of FMS.

Cellular prion protein co-localizes with nAChR beta4 subunit in brain and gastrointestinal tract.

PrP(C), the cellular isoform of prion protein, is widely expressed in most tissues, including brain, muscle and gastrointestinal tract. Despite its involvement in several bioprocesses, PrP has still no apparent physiological role. During propagation of transmissible spongiform encephalopathies (TSE), prion protein is converted to the pathological isoform, PrP(Sc), in a process believed to be mediated by unknown host factors. The identification of proteins associated with PrP may provide information about both the biology of prions and the pathogenesis of TSE. Thus far, PrP(C) has been shown to interact with synaptic proteins, components of the cytoskeleton and intracellular proteins involved in signalling pathways. Here, we describe the association of PrP with the beta4 subunit of nicotinic acetylcholine receptor (nAChR), as indicated by co-immunoprecipitation assays and double-label immunofluorescence. The interaction between prion protein and native beta4 subunit was further studied by affinity chromatography, using immobilized and refolded recombinant PrP as a bait and brain homogenates from normal individuals. Additionally, the participation of beta4 subunit in the pathogenesis of TSE was studied by in vivo assays. beta4(-/-) and wild-type mice were challenged with the RML (Rocky Mountain Laboratories) infectious agent. Transgenic animals displayed altered incubation times but the deletion of beta4 subunit did not result in a significant change of the incubation period of the disease. Our results suggest that PrP(C) is a member of a multiprotein membrane complex participating in the formation and function of alpha3beta4 nAChR.

Nicotinic acetylcholine receptor-subunit mRNAs in the mouse superior cervical ganglion are regulated by development but not by deletion of distinct subunit genes.

Mice with deletions of nicotinic ACh receptor (nAChR) subunit genes are valuable models for studying nAChR functions. We could previously show in the mouse superior cervical ganglion (SCG) that the absence of distinct subunits affects the functional properties of receptors. Here, we have addressed the question of whether deletions of the subunits alpha5, alpha7, or beta2 are compensated at the mRNA level, monitored by reverse transcription and quantitative real-time polymerase chain reaction. Relative to our reference gene, alpha3, which is expressed in all SCG nAChRs, mRNA levels of beta4 showed little change from birth until adult ages in intact ganglia of wild-type mice. In contrast, alpha4 declined sharply after birth and was barely detectable in adult animals. alpha5, alpha7, and beta2 subunit message levels also declined, though more slowly and less completely than alpha4. The subunits alpha6 and beta3 were detected by conventional polymerase chain reaction at very low levels, if at all, whereas alpha2 was never seen in any of our samples. The developmental profile of nAChR mRNA levels in the three knockout strains did not differ markedly from that of wild-type mice. Likewise, message levels of nAChR subunits were similar in cultures prepared from either wild-type or knockout animals. Our observations indicate a developmental regulation of nAChR subunit mRNAs in the SCG of mice after birth that was not affected by the three knockouts under investigation.

Catecholamine outflow from mouse and rat brain slice preparations evoked by nicotinic acetylcholine receptor activation and electrical field stimulation.

BACKGROUND AND PURPOSE: Mice with targeted deletions of neuronal nicotinic acetylcholine receptor (nAChR) subunit genes are valuable models to study nAChR function such as catecholamine outflow by presynaptic receptor activation. Contrary to the rat, our present knowledge on presynaptic nAChRs in mice primarily relies on observations made with synaptosomes. We have now used brain slices to investigate nicotine-induced catecholamine outflow in wild type (WT) and nAChR (beta2 and alpha5) knockout mice for a comparison with rat brain slice preparations. EXPERIMENTAL APPROACH: Brain slices from rat and mouse hippocampus, parieto-occipital neocortex, and corpus striatum were loaded with either [3H]-noradrenaline or [3H]-dopamine. We provoked catecholamine outflow by electrical field stimulation and nicotinic agonists. KEY RESULTS: When set in relation to electrical field stimulation, nicotine-evoked catecholamine release was sizeable in the striatum but low in the neocortex of both rats and mice. [3H]-noradrenaline outflow was, on the other hand, substantial in the rat but low in the mouse hippocampus. About 10% (or less) of nicotine-induced catecholamine release persisted in the presence of tetrodotoxin in all our preparations. CONCLUSIONS AND IMPLICATIONS: Targeted deletion of the beta2 subunit gene essentially abolished the effect of nicotine, indicating that this subunit is an essential constituent of nAChRs that indirectly (via action potentials) induce catecholamine release from hippocampal and striatal slices in mice. The impact of nAChRs in catecholaminergic projection areas differs between species and has thus to be considered when extrapolating results from animal models to human conditions.

Multiorgan autonomic dysfunction in mice lacking the beta2 and the beta4 subunits of neuronal nicotinic acetylcholine receptors.

Transcripts for the beta2 and the beta4 nicotinic acetylcholine receptor (nAChR) subunits are found throughout the CNS and the peripheral nervous system. These two beta subunits can form heteromultimeric channels with any of the alpha2, alpha3, alpha4, or alpha5 subunits in heterologous expression systems. Nonetheless, the subunit composition of native nAChRs and the role of different nAChR subtypes in vivo remain unclear. We prepared null mutations for the beta2 and the beta4 genes and bred beta2-/-beta4-/- mice by mating mice of identical beta2-/-beta4+/- or beta2+/-beta4-/- genotype. The beta2-/- and the beta4-/- single-mutant mice grow to adulthood with no visible phenotypic abnormalities. The beta2-/-beta4-/- double mutants survive to birth but have impaired growth and increased perinatal mortality. They also present enlarged bladders with dribbling urination and develop urinary infection and bladder stones. The ocular pupils are widely dilated and do not constrict in response to light. Histological studies revealed no significant abnormalities of brain or peripheral tissues except for hyperplasia in the bladder mucosa of beta4-/- and beta2-/-beta4-/- mutants. Bladder strips from beta2-/-beta4-/- mice did not respond to nicotine but contracted when stimulated with a muscarinic agonist or electric field stimulation. Bladder strips from beta4 mutants did not respond to nicotine despite the absence of major bladder dysfunction in vivo. Acetylcholine-activated whole-cell currents were absent in superior cervical ganglion neurons from beta2-/-beta4-/- mice and reduced in neurons from beta4-/- mice. Although there is apparent redundancy and a superficially normal phenotype in beta2-/- and beta4-/- mice, physiological studies indicate major deficits in the beta4-/- mice. Our previous description of a similar phenotype in alpha3-/- mice and the current data suggest that the alpha3 and the beta4 subunits are major components in autonomic nAChRs. The phenotype of the beta2-/-beta4-/- and alpha3-/- mice resembles the autosomal recessive megacystis-microcolon-hypoperistalsis syndrome in humans.

The Alzheimer disease BIN1 locus as a modifier of GBA-associated Parkinson disease.

GBA mutations are among the most common genetic risk factors for Parkinson disease (PD) worldwide. We aimed to identify genetic modifiers of the age at onset (AAO) in GBA-associated PD. The study included a genome-wide discovery phase, including a cohort of 79 patients with the GBA p.N370S mutation, and candidate validation and replication analyses of 8 SNPs in patients with mild (n = 113) and severe (n = 41) GBA mutations. Genotyping was performed using the Affymetrix human SNP 6.0 array and TaqMan assays. In the genome-wide phase, none of the SNPs passed the genome-wide significance threshold. Eight SNPs were selected for further analysis from the top hits. In all GBA-associated PD patients (n = 153), the BIN1 rs13403026 minor allele was associated with an older AAO (12.4 ± 5.9 years later, p = 0.0001), compared to patients homozygous for the major allele. Furthermore, the AAO was 10.7 ± 6.8 years later in patients with mild GBA mutations, (p = 0.005, validation group), and 17.1 ± 2.5 years later in patients with severe GBA mutations (p = 0.01, replication). Our results suggest that alterations in the BIN1 locus, previously associated with Alzheimer disease, may modify the AAO of GBA-associated PD. More studies in other populations are required to examine the role of BIN1-related variants in GBA-associated PD.

Novel mutations in the emerin gene in Israeli families.

Emery-Dreifuss Muscular Dystrophy (EMD or EDMD) is a rare X-linked recessive disorder, characterized by progressive muscle wasting and weakness, contractures, and cardiomyopathy, manifesting as heart block. Mutation analysis at the EMD gene locus was performed in 4 unrelated Israeli families with X-linked EMD and in one sporadic case. In the 4 families 4 different mutations were found, 3 of which were novel. These included two frame shift mutations in exon 2 (333delT and 412insA) and one base pair substitution at the consensus +1 donor splice in intron 5 (1429G-->A). The fourth mutation in exon 6 (1675-1678delTCCG) has been previously described. No mutations were identified in the one sporadic case. Two of the three novel mutations were found in exon 2. A summary of the previously published mutations described in the EMD Mutation Database (http://www.path.cam.ac.uk/emd/) as well as the mutations described in our study suggest that the distribution of mutations in EMD gene is not entirely random and that exon 2 is prone to mutations. Hum Mutat 17:522, 2001.

Constitutional mosaicism for a chromosome 9 inversion resulting in recombinant aneusomy in an offspring.

We report on a case of constitutional mosaicism for a large pericentric inversion of chromosome 9 in a man whose daughter had recombinant aneusomy resulting in partial 9q duplication and partial 9p deletion. At age 6 months, the girl was evaluated because of congenital anomalies [corrected] and developmental delay. Chromosomal analysis on this infant showed a derivative chromosome 9 which was later determined to be a recombinant chromosome with trisomy of 9q34.1-->qter and monosomy of pter-->9p24. Chromosomal analysis in her father showed the presence of two cell lines; 75% of lymphocytes had a 46,XY pattern, and 25% had a 46,XY,inv(9)(p24q34.1) karyotype. The infant's physical findings represent a composite of the reported cases of both trisomy 9q34.1-->qter and monosomy pter-->9p24. The infant's father was phenotypically and cognitively normal. This case broadens the spectrum of reported cases of mosaicism for an autosomal structural rearrangement generating unbalanced gametes, and further supports the tenet that constitutional mosaicism has clinical relevance for genetic counseling.

Segregation of a paternal insertional translocation results in partial 4q monosomy or 4q trisomy in two siblings.

A genetics evaluation was requested for a 6-week-old infant with multiple congenital malformations including mild craniofacial anomalies, truncal hypotonia, hypospadias, and a ventriculoseptal defect. Blood obtained for chromosome analysis revealed an abnormal chromosome 4. Paternal chromosome analysis showed a 46,XY, inv ins (3;4)(p21.32;q25q21.2), inv(4)(p15.3q21.2) karyotype. Therefore, the proband's chromosome 4 was the unbalanced product of this insertional translocation from the father resulting in partial monosomy 4q. Additionally, the derivative 4 had a pericentric inversion which was also seen in the father's chromosome 4. During genetic counseling, the proband's 2-year-old brother was evaluated. He was not felt to be abnormal in appearance, but was described as having impulsive behavior. Chromosome analysis on this child revealed 46,XY,der(3)inv ins(3;4)(p21.32;q25q21.2)pat. This karyotype results in partial trisomy 4q. FISH using two-color "painting" probes for chromosomes 3 and 4 confirmed the G-banded interpretation in this family. The segregation seen in this family resulted in both reciprocal products being observed in the two children, with partial 4q monosomy showing multiple congenital anomalies, and partial 4q trisomy showing very few phenotypic abnormalities.

Familial adenomatous polyposis at the Tel Aviv Medical Center: demographic and clinical features.

UNLABELLED: Familial adenomatous polyposis (FAP) is an uncommon, but widespread genetic disorder that develops multiple colonic adenomatous polyps and, if untreated, can lead to large bowel cancer. Little is known about its occurrence and characteristics in the Israeli population. AIMS: To evaluate FAP prevalence, phenotypic manifestations and compliance for diagnosis and follow-up in our registry. METHODS: Since 1993 approximately one-half of FAP patients in Israel have been seen and followed-up by us before and/or after colectomy. They and their families were encouraged to have mutation analysis, genetic and/or endoscopic screening. RESULTS: 37 pedigrees were identified, including 2 non-Jewish. The Jewish ethnic distribution was similar to that of the general population and the point prevalence rate estimated as 28.4/one million Jewish inhabitants. There were 461 first-degree relatives at-risk for FAP. Genetic screening was completed and successful in 28 pedigrees (87.5%), and 73 FAP patients entered the registry. Marked intra- familial phenotypic variations with minimal disease manifestation were noted in 11 patients belonging to 4 pedigrees. Cancer occurred in 15.1% (11 patients), in 10 before FAP diagnosis or during follow- up elsewhere, but one non-compliant patient developed duodenal cancer. One other patient died from a massive, neglected, intra- abdominal desmoid. Compliance for evaluation and follow-up of pedigree members and individual FAP patients was inadequate in 29% and 27%, respectively. CONCLUSIONS: FAP occurs in the Israeli Jewish population at the expected rate, but is inadequately recognized in non-Jews. The inadequate compliance for screening and post-surgical follow-up needs to be addressed by educating the public, health care workers and Health Insurers.

Analysis of the Hoxd-3 gene: structure and localization of its sense and natural antisense transcripts.

This study set out to investigate the structure and localized expression of the mouse homeobox-containing gene Hoxd-3. In addition to identifying a transcript of the type known from other Antennapedia (Antp)-like mammalian homeobox cDNAs, an antisense transcript was also detected. The antisense form of Hoxd-3 overlaps with 603 bp of the sense transcript including the homeobox. Active antisense transcription has been confirmed by RNA blot analysis with single-stranded probes and by the direction of splicing of an intron in the antisense transcript. The localized expression of sense and antisense transcripts was compared by in situ hybridization. Hoxd-3 expression was observed from 8.5 days p.c., in the neural tube with a sharp border in the hind brain at the level of rhombomeres 4-5. In contrast, the earliest antisense expression was detected at 10.5 days p.c. in cDNA libraries. At 12.5 days p.c., sense and antisense transcripts colocalized in the liver. The possible role of antisense homeobox transcripts during liver and the hematopoietic development is discussed.

Normal apoptosis levels in mice expressing one alpha7 nicotinic receptor null and one L250T mutant allele.

The alpha7 nicotinic receptor (nAChR) is a ligand-gated ion channel mediating cholinergic transmission throughout the nervous system. To further characterize the function of this receptor, we generated mice expressing the alpha7 L250T nAChR mutation and demonstrated that homozygous (T/T) L250T mice die within 24 h of birth and display extensive apoptosis and abnormal layering within their cortex. We now demonstrate that mice with one alpha7 null and one L250T allele (-/T) show little apoptosis and normal development of their cortex yet exhibit the same lethal phenotype as T/T mice. Furthermore, L250T mice show normal levels of apoptosis in other nervous system regions expressing alpha7 nAChRs. These results suggest that apoptosis is not the cause of death for L250T neonatal mice.

Altered baroreflex responses in alpha7 deficient mice.

The autonomic nervous system controls and coordinates several cardiovascular functions, including heart rate, arterial pressure, blood flow and vasomotor tone. Neuronal nicotinic acetylcholine receptors (nAChRs) are the interface between the nervous system and the cardiovascular system, but it is not known which nAChR subtypes regulate autonomic function in vivo. Nicotinic AChRs containing the alpha7 subunit are a candidate subtype in autonomic ganglia. Stimulation of these nAChRs can increase neurotransmitter release via presynaptic mechanisms, as well as mediate fast synaptic transmission via postsynaptic mechanisms. To investigate the role of the alpha7 nAChR subunit in cardiac autonomic function, we measured baroreflex-mediated responses in alpha7 null mice. Here we show that the alpha7 null mice have impaired sympathetic responses to vasodilatation, as sodium nitroprusside infusion triggered a 48% heart rate increase in wild type mice but only a 21% increase in the alpha7 nulls (P < 0.001). The mutant mice developed supersensitivity to adrenergic agonists, although norepinephrine release from sympathetic nerve terminals could be elicited through mechanisms alternative to nAChR stimulation. Baroreflex-mediated parasympathetic responses were normal in alpha7 null mice. The decreased baroreflex-mediated tachycardia in alpha7 mutant mice indicates that alpha7-containing nAChRs participate in the autonomic reflex that maintains blood pressure homeostasis. The alpha7 mutant mice may serve as a model of baroreflex impairment arising from autonomic dysfunction.

High frequency of a common Bloom syndrome Ashkenazi mutation among Jews of Polish origin.

Bloom syndrome (BS) is an autosomal recessive disorder characterized by small stature, immunodeficiency, chromosomal instability, and a predisposition to different types of cancer. Although extremely rare in the general population, BS is seen in about 1 in 48,000 Ashkenazi Jews. Mutation analysis of seven Ashkenazi BS probands has shown that all were homozygous for the same mutation in the BLM gene: 2281delATCTGAinsTAGATTC, also known as blmAsh. This finding, along with the increased incidence of BS among Ashkenazi Jews, suggests a founder effect for BS in this population. The purpose of this study was to determine the frequency of blmAsh mutation carriers in a randomly sampled Ashkenazi Jewish population in Israel. The initial study group included 1,613 Ashkenazi Jews who were referred for routine DNA screening tests (cystic fibrosis, Gaucher, Canavan, fragile X). None had a family history of BS. A group of 552 non-Ashkenazi Jews served as controls. Mutation analysis was performed by PCR amplification followed by analysis of a specific BstN1 restriction site, created by the blmAsh mutation. All positive carriers were confirmed by direct sequencing. Sixteen blmAsh carriers were detected among 1,613 Ashkenazi Jews (1 in 101), compared to none among 552 non-Ashkenazi individuals. In this study, Ashkenazi Jews of biparental Polish descent had a significantly higher proportion of the blmAsh mutation (1 in 37) compared to Ashkenazi Jews of non-Polish descent. These results provide further evidence that a founder effect is responsible for the increased incidence of Bloom syndrome among Ashkenazi Jews, particularly those of Polish descent.

The risk of fragile X premutation expansion is lower in carriers detected by general prenatal screening than in carriers from known fragile X families.

The Fragile X syndrome is the most common cause of inherited mental retardation. For a female premutation carrier, the risk of having a child with a full mutation is positively correlated with the size of the premutation. The current study was performed to evaluate the risk of premutation expansion in the offspring of average-risk carriers detected by general prenatal screening. Over a 4-year period, 9,660 women underwent DNA screening for FMR1 mutation/premutation at the Tel Aviv Sourasky Medical Center. A premutation was defined as a CGG repeat number >50 in the 5' untranslated region (UTR) of exon 1 in the FMR1 gene. The study included only individuals with no family history of X-linked mental retardation or known FMR1 mutations. A premutation was found in 85 women (1 in 114), 68 of whom consented to have prenatal diagnoses in 74 pregnancies. The abnormal allele was transmitted to the offspring in 44 pregnancies. Of these, no change in allele size was noted in 35 pregnancies (79.6%), and expansion within premutation range was evident in 4 pregnancies (9%). In 5 pregnancies (11.4%), expansion to the full mutation was noted. This occurred only in carriers having more than 90 repeats. We conclude that the likelihood of Fragile X premutation expansion to full mutation is significantly lower in individuals ascertained by general prenatal carrier testing than in those from known Fragile X families.

[Neurosurgical aspects in achondroplasia: evaluation and treatment].

Achondroplasia is the most common genetic disorder associated with bone dysplasia. The mode of inheritance is autosomal dominance, while most cases appear to represent a new mutation. Achondroplastic patients suffer from dwarfism, and from typical features of the head and limbs (rhizomelia, macrocephaly, frontal bossing and kyphosis). Half of the patients show various neurological complications. The most serious complication of achondroplasia is respiratory impairment, apnea and sudden infant death, resulting from compression of the medulla oblongata. This study describes the neurosurgical sequels in 10 achondroplastic patients, who underwent 12 surgical procedures. The average age was 14 years (ages ranged from 3 months to 40 years). The patients suffered from back pain, muscle weakness, incontinence, hypotonia, psychomotor delay, apnea and respiratory arrest. Four patients were diagnosed as suffering from obstructive sleep apnea. Craniocervical MRI showed: narrowing of the foramen magnum, fusion of C1, spinal stenosis, and severe cervicomedullary or spinal cord compression. In 5 patients the MRI also showed ventriculomegaly of the lateral and third ventricles. Seven patients underwent foramen magnum decompression and C1 laminectomy. Three patients with severe spinal cord compression underwent laminectomy of the involved spines (T12-L5). Two of the patients required more then one operation due to the recurrence of their neurological symptoms. There was no need for duraplasty or shunt procedures. The average hospital stay was 6 days. Eight patients showed improvement or resolution of symptoms, with an average follow-up period of 13.5 months after the last operation (ranged 6-24 months). We conclude that early neurological and MRI evaluations are required in achondroplasia patients, in order to prevent the high morbidity and mortality during infancy and childhood. In adults, MRI evaluation is needed if the patient has neurological symptoms. Early identification and immediate cervicomedulary decompression procedure can prevent the serious complications occurring in achondroplasia, including respiratory failure, apnea and sudden death.