RESUMO
A great deal of literature has drawn attention to the "complex Chiari," wherein the presence of instability or ventral brainstem compression prompts consideration for addressing both concerns at the time of surgery. This report addresses the clinical and radiological features and surgical outcomes in a consecutive series of subjects with hereditary connective tissue disorders (HCTD) and Chiari malformation. In 2011 and 2012, 22 consecutive patients with cervical medullary syndrome and geneticist-confirmed hereditary connective tissue disorder (HCTD), with Chiari malformation (type 1 or 0) and kyphotic clivo-axial angle (CXA) enrolled in the IRB-approved study (IRB# 10-036-06: GBMC). Two subjects were excluded on the basis of previous cranio-spinal fusion or unrelated medical issues. Symptoms, patient satisfaction, and work status were assessed by a third-party questionnaire, pain by visual analog scale (0-10/10), neurologic exams by neurosurgeon, function by Karnofsky performance scale (KPS). Pre- and post-operative radiological measurements of clivo-axial angle (CXA), the Grabb-Mapstone-Oakes measurement, and Harris measurements were made independently by neuroradiologist, with pre- and post-operative imaging (MRI and CT), 10/20 with weight-bearing, flexion, and extension MRI. All subjects underwent open reduction, stabilization occiput to C2, and fusion with rib autograft. There was 100% follow-up (20/20) at 2 and 5 years. Patients were satisfied with the surgery and would do it again given the same circumstances (100%). Statistically significant improvement was seen with headache (8.2/10 pre-op to 4.5/10 post-op, p < 0.001, vertigo (92%), imbalance (82%), dysarthria (80%), dizziness (70%), memory problems (69%), walking problems (69%), function (KPS) (p < 0.001). Neurological deficits improved in all subjects. The CXA average improved from 127° to 148° (p < 0.001). The Grabb-Oakes and Harris measurements returned to normal. Fusion occurred in 100%. There were no significant differences between the 2- and 5-year period. Two patients returned to surgery for a superficial wound infections, and two required transfusion. All patients who had rib harvests had pain related that procedure (3/10), which abated by 5 years. The results support the literature, that open reduction of the kyphotic CXA to lessen ventral brainstem deformity, and fusion/stabilization to restore stability in patients with HCTD is feasible, associated with a low surgical morbidity, and results in enduring improvement in pain and function. Rib harvest resulted in pain for several years in almost all subjects.
Assuntos
Malformação de Arnold-Chiari/complicações , Malformação de Arnold-Chiari/cirurgia , Doenças do Tecido Conjuntivo/complicações , Instabilidade Articular/complicações , Instabilidade Articular/cirurgia , Cifose/cirurgia , Adolescente , Adulto , Tronco Encefálico , Criança , Doenças do Tecido Conjuntivo/cirurgia , Feminino , Seguimentos , Humanos , Cifose/etiologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fusão Vertebral , Síndrome , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto JovemRESUMO
Pycnodysostosis (OMIM 265800) is an autosomal recessive skeletal disorder first described by Maroteaux and Lamy that is characterized by short stature, increased bone density, delayed closure of cranial sutures, loss of the mandibular angle, dysplastic clavicles, dissolution of the terminal phalanges of the hands and feet, dental abnormalities and increased bone fragility. Patients have a typical appearance secondary to prominence of the calvarium, smallness of the facial features, prominent nose and micrognathia. The French painter, Henri de Toulouse Lautrec (1864-1901), is believed to have had the disorder. Although more than 100 cases have been reported, we are aware of only two large consanguinous pedigrees in which the pycnodysostosis disorder segregates. We have studied the segregation of the pycnodysostosis phenotype in a large consanguinous Mexican pedigree, the clinical features of which are very similar to those described in the Arab pedigree studied by Edelson et al. Here, we report linkage for the pycnodysostosis phenotype in the 1cen-q21 region of human chromosome 1, and discuss candidate genes for this skeletal disorder.
Assuntos
Cromossomos Humanos Par 1 , Mucopolissacaridose VI/genética , Sequência de Bases , Consanguinidade , Feminino , Genes Recessivos , Marcadores Genéticos , Humanos , Escore Lod , Masculino , Dados de Sequência Molecular , Linhagem , Polimorfismo GenéticoRESUMO
The expression of type X collagen is restricted to hypertrophic chondrocytes in regions undergoing endochondral ossification, such as growth plates. The precise function of type X collagen is unknown but the tissue-specific expression prompted us to examine the gene in hereditary disorders of cartilage and bone growth (osteochondrodysplasias). We have identified a 13 base pair deletion in one type X collagen allele segregating with autosomal dominant Schmid metaphyseal chondrodysplasia in a large Mormon kindred (lod score = 18.2 at theta = 0). The mutation produces a frameshift which alters the highly conserved C-terminal domain of the alpha 1(X) chain and reduces the length of the polypeptide by nine residues. This mutation may prevent association of the mutant polypeptide during trimer formation, resulting in a decreased amount of normal protein.
Assuntos
Colágeno/genética , Genes , Osteocondrodisplasias/genética , Alelos , Sequência de Aminoácidos , Animais , Sequência de Bases , Bovinos , Galinhas , Análise Mutacional de DNA , Genes Dominantes , Humanos , Camundongos , Dados de Sequência Molecular , Linhagem , Alinhamento de Sequência , Deleção de Sequência , Homologia de Sequência de Aminoácidos , Especificidade da EspécieRESUMO
Pfeiffer syndrome (PS; McKusick MIM 101,600) is an autosomal dominant craniosynostosis syndrome with characteristic craniofacial anomalies and broad thumbs and big toes. We have previously demonstrated genetic heterogeneity in PS and mapped a gene to chromosome 8 (ref. 3) and a second to chromosome 10 (ref. 4). The gene on chromosome 8 is the fibroblast growth factor receptor 1 (FGFR1) with a common mutation (C755G) predicting a Pro252Arg substitution. The gene on chromosome 10 is FGFR2 with several different mutations causing sporadic and familial PS (Table 1). We report a recurrent single point mutation in the FGFR3 gene, located on chromosome 4p, in ten unrelated families with craniosynostosis syndromes. This mutation (C749G) predicts a Pro250Arg amino acid substitution in the extracellular domain of the FGFR3 protein. Interestingly, this common mutation occurs precisely at the analogous position within the FGFR3 protein as the mutations in FGFR1 (Pro252Arg) and FGFR2 (Pro253Arg) previously reported in Pfeiffer and Apert syndromes, respectively.
Assuntos
Acrocefalossindactilia/genética , Craniossinostoses/genética , Mutação Puntual/genética , Receptores Proteína Tirosina Quinases/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Sequência de Aminoácidos , Disostose Craniofacial/genética , Análise Mutacional de DNA , Feminino , Genes Dominantes/genética , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , SíndromeRESUMO
Pseudoachondroplasia (PSACH) is a well characterized dwarfing condition mapping to chromosome 19p12-13.1. Cartilage oligomeric matrix protein (COMP), a cartilage specific protein, maps to the same location within a contig that spans the PSACH locus. Using single strand conformation polymorphism (SSCP) analysis and nucleotide sequencing we have identified COMP mutations in eight familial and isolated PSACH cases. All mutations involve either a single base-pair change or a three base-pair deletion in exon 17B. Six mutations delete or change a well conserved aspartic acid residue within the calcium-binding type 3 repeats. These results demonstrate that mutations in the COMP gene cause pseudochondroplasia.
Assuntos
Acondroplasia/genética , Proteínas da Matriz Extracelular , Glicoproteínas/genética , Mutação , Sequência de Bases , Cartilagem/metabolismo , Proteína de Matriz Oligomérica de Cartilagem , Mapeamento Cromossômico , Cromossomos Humanos Par 19 , Primers do DNA/genética , Éxons , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Proteínas Matrilinas , Dados de Sequência Molecular , Linhagem , Mutação Puntual , Polimorfismo Conformacional de Fita Simples , Deleção de SequênciaRESUMO
Hypochondroplasia (MIM 146000) is an autosomal dominant skeletal dysplasia with skeletal features similar to but milder than those seen in achondroplasia. Within the past year, the achondroplasia locus has been mapped to 4p 16.3 (refs 5-7) and mutations in the fibroblast growth factor receptor 3 (FGFR3) gene have been identified in patients with the disorder. More than 95% of 242 cases reported so far are accounted for by a single Gly380Arg mutation. McKusick et al. proposed that achondroplasia and hypochondroplasia are allelic based on the similarities in phenotype between the two disorders and the identification of a severely dwarfed individual whose father had achondroplasia and whose mother had hypochondroplasia. There is also genetic linkage evidence that hypochondroplasia and achondroplasia map to the same locus. We therefore began a systematic screening of FGFR3 to detect mutations in patients with hypochondroplasia. We now report a single FGFR3 mutation found in 8 out of 14 unrelated patients with hypochondroplasia. This mutation causes a C to A transversion at nucleotide 1620, resulting in an Asn540Lys substitution in the proximal tyrosine kinase domain.
Assuntos
Acondroplasia/genética , Osteocondrodisplasias/genética , Mutação Puntual , Proteínas Tirosina Quinases/genética , Receptores de Fatores de Crescimento de Fibroblastos/genética , Acondroplasia/metabolismo , Sequência de Aminoácidos , Sequência de Bases , DNA/genética , Primers do DNA/genética , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Masculino , Dados de Sequência Molecular , Osteocondrodisplasias/metabolismo , Linhagem , Reação em Cadeia da Polimerase , Receptor Tipo 3 de Fator de Crescimento de FibroblastosRESUMO
The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor beta superfamily of signalling proteins (TGFbeta-FMs), such as BMP4 (ref. 1). By diffusing through extracellular matrices more efficiently than TGFbeta-FMs, noggin may have a principal role in creating morphogenic gradients. During mouse embryogenesis, Nog is expressed at multiple sites, including developing bones. Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton. We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents. We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. All seven NOG mutations alter evolutionarily conserved amino acid residues. The findings reported here confirm that NOG is essential for joint formation and suggest that NOG requirements during skeletogenesis differ between species and between specific skeletal elements within species.
Assuntos
Anormalidades Múltiplas/genética , Articulações/anormalidades , Mutação , Proteínas/genética , Sinostose/genética , Adolescente , Animais , Proteínas de Transporte , Gatos , Galinhas , Mapeamento Cromossômico , Feminino , Articulações dos Dedos/anormalidades , Regulação da Expressão Gênica no Desenvolvimento , Marcadores Genéticos , Gorilla gorilla , Heterozigoto , Humanos , Articulações/fisiologia , Masculino , Camundongos , Dados de Sequência Molecular , Morfogênese , Análise de Sequência , Homologia de Sequência de Aminoácidos , Homologia de Sequência do Ácido Nucleico , Suínos , Xenopus laevis , Peixe-ZebraRESUMO
Nonsense mutations create a premature signal for the termination of translation of messenger RNA. Such mutations have been observed to cause a severe reduction in the amount of mutant allele transcript or to generate a peptide truncated at the carboxyl end. Analysis of fibrillin transcript from a patient with Marfan syndrome revealed the skipping of a constitutive exon containing a nonsense mutation. Similar results were observed for two nonsense mutations in the gene encoding ornithine delta-aminotransferase from patients with gyrate atrophy. All genomic DNA sequences flanking these exons that are known to influence RNA splicing were unaltered, which suggests that nonsense mutations can alter splice site selection in vivo.
Assuntos
DNA/genética , Éxons , Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Mutação , Sequência de Aminoácidos , Sequência de Bases , Células Cultivadas , DNA/isolamento & purificação , Feminino , Fibrilinas , Fibroblastos/fisiologia , Humanos , Masculino , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Reação em Cadeia da Polimerase/métodos , Valores de ReferênciaRESUMO
Achondroplasia, the most common form of short-limbed dwarfism in humans, occurs between 1 in 15,000 and 40,000 live births. More than 90% of cases are sporadic and there is, on average, an increased paternal age at the time of conception of affected individuals. More then 97% of persons with achondroplasia have a Gly380Arg mutation in the transmembrane domain of the fibroblast growth factor receptor (FGFR) 3 gene. Mutations in the FGFR3 gene also result in hypochondroplasia, the lethal thanatophoric dysplasias, the recently described SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) dysplasia, and two craniosynostosis disorders: Muenke coronal craniosynostosis and Crouzon syndrome with acanthosis nigricans. Recent evidence suggests that the phenotypic differences may be due to specific alleles with varying degrees of ligand-independent activation, allowing the receptor to be constitutively active. Since the Gly380Arg achondroplasia mutation was recognized, similar observations regarding the conserved nature of FGFR mutations and resulting phenotype have been made regarding other skeletal phenotypes, including hypochondroplasia, thanatophoric dysplasia, and Muenke coronal craniosynostosis. These specific genotype-phenotype correlations in the FGFR disorders seem to be unprecedented in the study of human disease. The explanation for this high degree of mutability at specific bases remains an intriguing question.
Assuntos
Acantose Nigricans/genética , Acondroplasia/genética , Disostose Craniofacial/genética , Craniossinostoses/genética , Proteínas Tirosina Quinases , Receptores de Fatores de Crescimento de Fibroblastos/genética , Sequência de Aminoácidos/genética , Sequência de Bases/genética , Humanos , Receptor Tipo 3 de Fator de Crescimento de FibroblastosRESUMO
The recent explosion in the number of identified genes involved in the human skeletal dysplasias has dramatically advanced this particular field. While linkage efforts are mapping hereditary disorders of the skeleton at an ever accelerating pace, progress in the Human Genome Project is providing tools for rapid gene discovery after the map location is known. Emerging themes in the molecular analysis of the skeletal dysplasias include the identification of allelic series of disorders and the existence of mutational and genetic heterogeneity in many of these conditions. Allelic series include those conditions caused by mutations in the genes encoding type II collagen (COL2A1), cartilage oligomeric matrix protein (COMP), fibroblast growth factor receptor 3 (FGFR3) and the diastrophic dysplasia sulfate transporter (DTDST). The recognition of these phenomena has initiated the analysis of the relationship between disease phenotype and gene.
Assuntos
Doenças do Desenvolvimento Ósseo/genética , Proteínas de Transporte/genética , Colágeno/genética , Proteínas da Matriz Extracelular/genética , Glicoproteínas/genética , Proteínas de Transporte de Ânions , Transporte Biológico , Doenças do Desenvolvimento Ósseo/metabolismo , Proteína de Matriz Oligomérica de Cartilagem , Humanos , Proteínas Matrilinas , Proteínas de Membrana Transportadoras , Osteocondrodisplasias/genética , Osteocondrodisplasias/metabolismo , Transportadores de Sulfato , SulfatosRESUMO
To examine the associations among fibrillin gene mutations, protein function, and Marfan syndrome phenotype, we screened for alterations in the fibrillin coding sequence in patients with a range of manifestations and clinical severity. A cysteine to serine substitution at codon 1409 (C1409S) was identified in an epidermal growth factor (EGF)-like motif from one fibrillin allele which segregates with the disease phenotype through three generations of a family affected with the Marfan syndrome. This alteration was not observed in 60 probands from other families or in 88 unrelated normal individuals. The altered cysteine is completely conserved in all EGF-like motifs identified in fibrillin, and in all proteins that contain this motif. These observations strongly indicate that C1409S is the disease-producing mutation in this family. The phenotype of individuals carrying C1409S varied widely with respect to onset of disease, organ-system involvement, and clinical severity; certain affected adults were unaware of their status before being diagnosed through this investigation. We conclude that fibrillin gene defects cause familial Marfan syndrome, that mutations in the EGF-like motif of the fibrillin gene are not uniformly associated with severe disease, and that fibrillin genotype is not the sole determinant of Marfan phenotype.
Assuntos
Síndrome de Marfan/genética , Proteínas dos Microfilamentos/genética , Sequência de Aminoácidos , Sequência de Bases , Sequência Consenso , DNA/genética , Fator de Crescimento Epidérmico/química , Fibrilinas , Humanos , Dados de Sequência Molecular , Mutação , Oligodesoxirribonucleotídeos/química , Linhagem , Alinhamento de SequênciaRESUMO
Systematic organization of documented data coupled with ready accessibility is of great value to research. Catalogs and databases are created specifically to meet this purpose. The Skeletal Gene Database evolves as part of the Skeletal Genome Anatomy Project (SGAP), an ongoing multi-institute collaborative effort, to study the functional genome of bone and other skeletal tissues. The primary objective of the Skeletal Gene Database is to create a contemporary list of skeletal-related genes, offering the following information for each gene: gene name, protein name, cellular function, disease(s) caused by mutation of the corresponding gene, chromosomal location, LocusLink number, gene size, exon/intron numbers, messenger RNA (mRNA) coding region size, protein size/molecular weight, Online Mendelian Inheritance in Man (OMIM) number of the gene, UniGene assignment, and PubMed reference. The database includes genes already known and published in the literature as well as novel genes not yet characterized but known to be expressed in skeletal tissue. It will be posted on the web for easy access and swift referencing. The data will be updated in tempo with current and future research, thereby providing an invaluable service to the scientific community interested in obtaining information on bone-related genes.
Assuntos
Osso e Ossos/fisiologia , Bases de Dados Factuais , Genes , Músculo Esquelético/fisiologia , HumanosRESUMO
Ecm1, the mouse gene encoding extracellular matrix protein 1, is highly expressed in bone and cartilage as well as in osteogenic, preosteoblastic and chondroblastic cell lines. Ecm1 was recently localized to a chromosomal region in mouse syntenic to human chromosome 1q21, establishing this gene as a prime candidate gene for pycnodysostosis, a rare, autosomal recessive sclerosing skeletal dysplasia. Shortly thereafter, it was determined that cathepsin K is the pycnodysostosis gene. We now report the radiation hybrid mapping of human ECM1 to 1q21, and the gene structure and coding sequence of human ECM1.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 1/genética , Proteínas da Matriz Extracelular/genética , Sequência de Aminoácidos , Animais , Mapeamento Cromossômico/métodos , Proteínas da Matriz Extracelular/química , Humanos , Células Híbridas/efeitos da radiação , Camundongos , Dados de Sequência Molecular , Análise de Sequência de DNARESUMO
PURPOSE: To compare the Berlin and Ghent diagnostic criteria for Marfan syndrome and evaluate the utility of screening for dural ectasia in the diagnosis of Marfan syndrome. METHODS: Review of clinical and radiographic data on 73 patients evaluated for Marfan syndrome at the National Institutes of Health. RESULTS: Nineteen percent of patients diagnosed under the Berlin criteria failed to meet the Ghent standard. Dural ectasia was the second most common major diagnostic manifestation, and screening for dural ectasia established the diagnosis of Marfan syndrome in 23% of patients under the Ghent criteria. CONCLUSIONS: Some patients are appropriately excluded from the diagnosis of Marfan syndrome by the Ghent criteria. Determination of dural ectasia is valuable in the diagnosis of Marfan syndrome.
Assuntos
Síndrome de Marfan/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Síndrome de Marfan/diagnóstico por imagem , National Institutes of Health (U.S.) , Radiografia , Estudos Retrospectivos , Estados UnidosRESUMO
Achondroplasia is the most common human skeletal dysplasia. It is inherited as an autosomal dominant trait but the underlying biochemical cause is unknown. Genomic DNA from 49 affected individuals and two multiplex families with achondroplasia was studied using probes spanning COL2A1, the structural gene for type II collagen. Two lines of evidence speak against mutation in COL2A1 as the cause of achondroplasia: (1) no gross rearrangements are seen on Southern blot analysis of DNA from probands, and (2) linkage studies in multiplex families demonstrate discordant inheritance of achondroplasia and COL2A1 alleles.
Assuntos
Colágeno/genética , Mutação , Osteocondrodisplasias/genética , Alelos , Feminino , Genes Dominantes , Ligação Genética , Humanos , Masculino , Linhagem , Polimorfismo de Fragmento de RestriçãoRESUMO
Jeune syndrome (JS) and short-rib polydactyly syndrome type III (SRP type III) are autosomal recessive disorders characterized by short ribs and polydactyly. They are distinguished from each other by the more severe radiological and histological bone findings as well as the occurrence of facial anomalies, ambiguous genitalia, and occasionally, cloacal abnormalities in SRP type III. We present a family in which two children have mild JS and one has SRP type III as evidence that JS and SRP type III are variants of the same disorder. The intrafamilial variability may reflect the effects of modifying loci on gene expression.
Assuntos
Anormalidades Múltiplas/patologia , Asfixia Neonatal/patologia , Osteocondrodisplasias/patologia , Polidactilia/patologia , Anormalidades Múltiplas/diagnóstico por imagem , Asfixia Neonatal/diagnóstico por imagem , Criança , Feminino , Humanos , Recém-Nascido , Masculino , Osteocondrodisplasias/diagnóstico por imagem , Linhagem , Polidactilia/diagnóstico por imagem , Radiografia , Costelas/anormalidades , UltrassonografiaRESUMO
The Marfan syndrome is an autosomal dominant connective tissue disorder with pleiotropic manifestations affecting skeletal, ocular and cardiovascular systems. Because the fibrillar collagens are major structural components of connective tissue, the hypothesis has long been set forth that the Marfan syndrome is a disorder of fibrillar collagen. We have investigated this hypothesis by performing linkage studies in 12 multiplex families with the Marfan syndrome, using restriction fragment length polymorphisms (RFLP's) associated with 3 genes encoding chains of fibrillar collagens. The data exclude linkage to all 3 candidate genes in 2 families and at least 1 of the candidates is excluded in 6 additional families. Each candidate was excluded in at least 3 families. In no case was strong evidence in favor of linkage of the Marfan syndrome to any of the 3 genes observed. These data speak against the hypothesis that mutations in one or more of these 3 fibrillar collagens cause the classic Marfan syndrome.
Assuntos
Colágeno/genética , Síndrome de Marfan/genética , Ligação Genética , HumanosRESUMO
The Skeletal Gene Database (SGD) is an integrated resource that provides comprehensive information about bone-related genes, mRNA, and proteins expressed in human and mouse, with rich links to numerous other electronic tools. SGD contains expressed sequence tag (EST) data from all the skeletal-related cDNA libraries that are available to the public. It supplies the query/data access analytic tools for users to search and compare each gene expressed in skeletal tissue(s). The results derived from EST tissue expression profiling will allow users to get the data on the mRNA copy numbers of each gene expressed in each tissue and its normalized value. From the SGD, researchers can obtain information regarding the name, symbol, size, exon/intron number, chromosomal location, LocusLink, and related disease (if any is known) of each gene. This electronic compendium also furnishes information on the protein of the corresponding gene including the protein size (amino acid number and molecular weight). It provides swift and ready access to other useful databases including OMIM, UniGene and PUBMED. The data will be updated regularly in step with current and future research, thereby providing what we hope will serve as a highly useful source of information and a powerful analytic tool to the scientific community.
Assuntos
Desenvolvimento Ósseo/genética , Bases de Dados como Assunto , Biblioteca Gênica , Animais , Humanos , CamundongosRESUMO
Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (EDM1) are allelic disorders caused by mutations in the gene encoding cartilage oligomeric matrix protein (COMP). PSACH is a dominant condition characterized by disproportionate short stature, joint laxity, and early-onset osteoarthritis. EDM1 is a less severe skeletal dysplasia associated with average to mild short stature, joint pain, and early-onset osteoarthritis. COMP is an extracellular matrix protein present in cartilage, ligament, and tendon tissues. Here, we report on nine novel mutations in COMP causing PSACH and EDM1. Four of these mutations are in exons 13C and 14 where no previous mutations had been reported. One of those mutations was identified in two separate EDM1 families. In addition, we have identified the first case of PSACH resulting from an expansion of the five aspartates in exon 17B. We are also reporting a mutation in a third PSACH family with somatic/germline mosaicism. Therefore, this report increases the range of mutations that cause PSACH and EDM1 and provides additional regions to target for mutational analysis.