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Bachmann-Bupp syndrome (BABS) is a rare syndrome caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC coded by the ODC1 gene). BABS is characterized by developmental delay, macrocephaly, macrosomia, and an unusual pattern of non-congenital alopecia. Recent diagnosis of four more BABS patients provides further characterization of the phenotype of this syndrome including late-onset seizures in the oldest reported patient at 23 years of age, representing the first report for this phenotype in BABS. Neuroimaging abnormalities continue to be an inconsistent feature of the syndrome. This may be related to the yet unknown impact of ODC/polyamine dysregulation on the developing brain in this syndrome. Variants continue to cluster, providing support to a universal biochemical mechanism related to elevated ODC protein, enzyme activity, and abnormalities in polyamine levels. Recommendations for medical management can now be suggested as well as the potential for targeted molecular or metabolic testing when encountering this unique phenotype. The natural history of this syndrome will evolve with difluoromethylornithine (DFMO) therapy and raise new questions for further study and understanding.

International audience; Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping similar to 2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.

Background Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited and multi-disciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). Project To investigate the pathogenesis of 160 sporadic VMs in which known genetic causes had been excluded, sequencing of affected tissue DNA was undertaken using deep next generation sequencing with analysis optimised for detection of low mutant allele frequency. Results Mosaic activating variants in KRAS, NRAS, BRAF and MAP2K1 were identified, most commonly in AVM, both intracranial and extracranial. Transgenic zebrafish expressing BRAFV600E only in the vasculature recapitulated the human phenotype. Treatment of zebrafish with the BRAF inihibitor, vemurafinib, restored blood flow in AVM. Conclusions These findings reveal an important unifying cause of sporadic vascular malformations of different clinical types, and offer the potential of personalised medical treatment for affected individuals by repurposing of existing licensed cancer therapies.

Mitochondrial DNA (mtDNA) depletion syndrome encompasses a heterogeneous group of disorders characterized by a reduction in the mtDNA copy number. We identified two patients with clinical presentations consistent with mtDNA depletion syndrome (MDS), who were subsequently found to have apparently homozygous point mutations in TYMP and DGUOK, two of the nine nuclear genes commonly associated with these disorders. Further sequence analyses of parents indicated that in each case only one parent; the mother of the first and the father of the second, was a heterozygous carrier of the mutation identified in the affected child. The presence of underlying deletions was ruled out by use of a custom target array comparative genomic hybridization (CGH) platform. A high-density single-nucleotide polymorphism (SNP) array analysis revealed that the first patient had a region of copy-neutral absence of heterozygosity (AOH) consistent with segmental isodisomy for an 11.3 Mb region at the long-arm terminus of chromosome 22 (including the TYMP gene), and the second patient had results consistent with complete isodisomy of chromosome 2 (where the DGUOK gene is located). The combined sequencing, array CGH and SNP array approaches have demonstrated the first cases of MDS due to uniparental isodisomy. This diagnostic scenario also demonstrates the necessity of comprehensive examination of the underlying molecular defects of an apparently homozygous mutation in order to provide patients and their families with the most accurate molecular diagnosis and genetic counseling.

BACKGROUND: Microcephaly with or without chorioretinopathy, lymphedema, or mental retardation syndrome (MCLMR) is a rare autosomal dominant disorder with variable expressivity. It is characterized by mild-to-severe microcephaly, often associated with intellectual disability, ocular defects and lymphedema. It can be sporadic or inherited. Eighty-seven patients have been described to carry a mutation in KIF11, which encodes a homotetrameric motor kinesin, EG5. METHODS: We tested 23 unreported MCLMR index patients for KIF11. We also reviewed the clinical phenotypes of all our patients as well as of those described in previously published studies. RESULTS: We identified 14 mutations, 12 of which are novel. We detected mutations in 12 affected individuals, from 6 out of 6 familial cases, and in 8 out of 17 sporadic patients. Phenotypic evaluation of patients (our 26 + 61 earlier published = 87) revealed microcephaly in 91%, eye anomalies in 72%, intellectual disability in 67% and lymphedema in 47% of the patients. Unaffected carriers were rare (4 out of 87: 5%). Family history is not a requisite for diagnosis; 31% (16 out of 52) were de novo cases. CONCLUSIONS: All inherited cases, and 50% of sporadic cases of MCLMR are due to germline KIF11 mutations. It is possible that mosaic KIF11 mutations cause the remainder of sporadic cases, which the methods employed here were not designed to detect. On the other hand, some of them might have another mimicking disorder and genetic defect, as microcephaly is highly heterogeneous. In aggregate, KIF11 mutations likely cause the majority, if not all, of MCLMR.

We report the first frame-shift truncation mutation in a mitochondrial DNA (mtDNA)-encoded subunit II of cytochrome c oxidase (COXII). The mutation was identified by temporal temperature gradient gel electrophoresis (TTGE) followed by direct DNA sequencing in an infant who died at 12 days of age following a course of apnea, bradycardia, and severe lactic acidosis. The patient had a twin brother who died at two days of age of similar course. The mutation, 8042delAT, produced a truncated protein that was 72 amino acids shorter than the wild type protein. The mutant protein, missing one third of the amino acid residues at the C-terminal essential for hydrophilic interaction with cytochrome c, ligand binding to CuA and Mg, and the formation of proton and water channels, apparently has devastating effects on mitochondrial respiratory function. © 2001 Wiley-Liss, Inc.

The oral-facial-digital syndromes (OFDS) have in common minor facial and oral anomalies (including tongue lobulation and/ or hamartomas, accessory frenula, and alveolar anomalies) and variable digital defects such as polydactyly. The classification based on the presence of additional findings [Toriello, 1988, 1993] is not perfect, as many reported examples of a particular OFDS have some other condition. Here we describe six children, all diagnosed as having OFDS IV (OFDS with tibial defects), whose manifestations illustrate the apparent genetic heterogeneity.

Introduction: 3-Methyl CoA carboxylase (3-MCC) deficiency is an inborn error of metabolism in the catabolism of the amino acid leucine. Original reports suggested this disorder was associated with significant neurological and biochemical effects. However newborn screening has identified a higher than expected incidence of this disorder with apparent normal outcome in most cases. Method: A retrospective analysis of thirty-five cases of 3-MCC deficiency identified by newborn screening and diagnosed by enzyme or molecular analysis. Results: There was a strong inverse correlation between initial C5OH level and residual enzyme activity. A few reports of hypoglycemia, ketosis, poor feeding/failure to thrive or fasting intolerance were reported, but there was no clear relationship between symptoms and residual enzyme activity. Developmental outcome included several children with mental retardation (including one with Down syndrome and one with schizencephaly) and two with Autism Spectrum disorders but there was no apparent relationship to residual enzyme activity. Free carnitine deficiency was relatively common. Discussion: Although residual enzyme activity was clearly related to metabolite elevation, there was no apparent relationship with other measures of outcome. The number of reports of neurologic abnormalities or metabolic symptoms (poor feeding, hypoglycemia, fasting intolerance, etc.) is concerning, but the significance is unclear in this retrospective sample. (C) 2012 Elsevier Inc. All rights reserved

Background Phenylketonuria (PKU) results from impaired breakdown of phenylalanine (Phe) due to deficient phenylalanine hydroxylase (PAH) activity. Sapropterin dihydrochloride (sapropterin, Kuvan®) is the only US- and EU-approved pharmaceutical version of naturally occurring 6R-BH 4 , the cofactor required for PAH activity. Sapropterin enhances residual PAH activity in sapropterin-responsive PKU patients and, in conjunction with dietary management, helps reduce blood Phe concentrations for optimal control. Approval was based on the positive safety and efficacy results of four international clinical studies, the longest of which was 22 weeks in duration. Objective To evaluate the safety of long-term treatment with sapropterin in PKU subjects who participated in previous Phase 3 sapropterin trials. Methods PKU-008 was designed as a Phase 3b, multicenter, multinational, open-label, 3-year extension trial to evaluate the long-term safety of sapropterin in patients with PKU who were classified as sapropterin responders and participated in prior Phase 3 sapropterin studies: 111 subjects aged 4–50 years completed prior studies and were subsequently enrolled in study PKU-008. Routine safety monitoring was performed at 3-month intervals and included adverse event reporting, blood Phe monitoring, clinical laboratory evaluations, physical examinations and vital sign measurements. Results Average exposure during PKU-008 was 658.7 ± 221.3 days (range, 56–953; median, 595). The average total duration of participation in multiple studies (PKU-001, PKU-003, PKU-004, and PKU-008; or PKU-006 and PKU-008) was 799.0 ± 237.5 days (range, 135-1151). The mean sapropterin dose was 16.2 ± 4.7 mg/kg/day. Most adverse events were considered unrelated to treatment, were mild or moderate in severity, and were consistent with prior studies of sapropterin. No age-specific differences were observed in adverse event reporting. Three subjects discontinued treatment due to adverse events that were considered possibly or probably related to study treatment (one each of difficulty concentrating, decreased platelet count, and intermittent diarrhea). No deaths were reported. Of seven reported serious adverse events, one was considered possibly related to study treatment (gastroesophageal reflux). There were no laboratory or physical examination abnormalities requiring medical interventions. For most subjects, blood Phe concentrations were consistently within target range, confirming the durability of response in subjects undergoing extended treatment with sapropterin. Conclusion Sapropterin treatment was found to be safe and well tolerated at doses of 5 to 20 mg/kg/day for an average exposure of 659 days. This study supports the safety and tolerability of sapropterin as long-term treatment for patients with PKU.

Newborn screening (NBS) by tandem mass spectrometry (MS/MS) has allowed for early detection and initiation of treatment in many patients with maple syrup urine disease (MSUD) (OMIM 248600), however, a recent report suggests that variants forms may be missed. Information on these patients is limited. We present clinical, biochemical and molecular information on patients with variant forms of MSUD not detected by the California Newborn Screening Program. Between July 2005 and July 2009, 2200,000 newborns were screened in California by MS/MS. Seventeen cases of MSUD were detected and three (two siblings) were missed. Additionally, the NBS cards of two siblings with late onset MSUD, who were born pre-expanded NBS, were retrospectively analyzed. None of the five patients met criteria to be considered presumptive positive for MSUD (leucine>200micromol/L and a ratio of leucine/alanine>or=1.5). Alloisoleucine (allo-ile) was subsequently analyzed in the NBS cards of all five patients, two of whom were found to have elevated levels. The proband in each family was diagnosed following symptoms triggered by an intercurrent illness or increased protein intake. At diagnosis, leucine levels ranged between 561 and >4528micromol/L, and allo-ile ranged from 137 to 239micromol/L. Two affected siblings had normal plasma amino acids when asymptomatic; however, their biochemical profiles were diagnostic of MSUD during intercurrent illnesses. The median age at diagnosis of all patients was one year (range 0.8-6.7). Heterozygous BCKDHB (E1beta) mutations (c.832G>A/c.970C>T) were identified in one family and a homozygous DBT (E2) sequence variant (c.1430 T>G) in another. The third family had one identifiable DBT mutation (c.827T>G), however, a second mutation was not detected. This report provides further evidence that NBS by MS/MS is unable to detect all cases of MSUD. Second-tier testing with allo-ile may improve sensitivity; however, some children with variant forms will invariably be missed.

Current practices in prenatal diagnosis of rhizomelic chondrodysplasia punctata (RCDP) are reviewed. A case is presented with a family having one daughter affected with RCDP due to alkyldihydroacetonephosphate acyltransferase synthase (DHAPAT synthase) deficiency, and three subsequent pregnancies. Biochemical test values are presented for the pregnancies and daughter. Post-mortem tests of one fetus of a terminated pregnancy showed that radiologic examination could not make the diagnosis of RCDP. We conclude that biochemical or molecular testing is necessary to accurately diagnose this type of RCDP prenatally.

We report on a case of thanatophoric dysplasia type 1 (TD1) due to a Tyr373Cys mutation in the fibroblast growth factor receptor 3 (FGFR3) gene with soft tissue syndactyly of the fingers and toes. Syndactyly has not been previously described in TD or other conditions with FGFR3 mutations, but occurs in several craniosynostosis syndromes due to mutations in FGFR2. We conclude that mutations in FGFR3 may also be associated with developmental abnormalities due to interference with programmed cell death.

Abstract 1101 BACKGROUND: Type 1 Gaucher disease (GD) is an inherited storage disease characterized by acid-β-glucosidase deficiency and the accumulation of glucosylceramide in the mononuclear phagocyte system. Hematologists are commonly the specialists to whom affected individuals present; findings may include anemia, thrombocytopenia, splenomegaly, hepatomegaly, and skeletal and bone marrow pathology. HGT-GCB-058 was a multicenter treatment protocol initiated at the request of the US Food and Drug Administration (FDA) in 2009 (ClinicalTrials.gov identifier NCT00954460). It provided velaglucerase alfa, then an investigational drug, to patients with type 1 GD who would otherwise have experienced a disruption or delay in receiving enzyme replacement therapy (ERT) due to a global supply shortage of imiglucerase at that time. OBJECTIVE: We report safety results in patients who received up to 12 months of velaglucerase alfa in protocol HGT-GCB-058, and the transition from administration at the clinical site to home infusions. METHODS: To enroll, patients had to be aged >2 years, with a documented diagnosis of type 1 GD and no history of an anaphylactic or anaphylactoid reaction to ERT. Patients who were treatment-naïve received 60 U/kg (body weight) of velaglucerase alfa as an intravenous infusion every other week (EOW). Patients who were previously treated with imiglucerase (switch patients) received the same EOW dose of velaglucerase alfa as their prior imiglucerase treatment. Each patient could continue in the protocol until commercial therapy was available to him or her. Adverse events (AEs) were monitored throughout the patient's participation in the protocol. Switch patients were eligible for home therapy if they received their first 3 infusions, at the clinical site, in the absence of an infusion-related AE or treatment-related, serious AE (SAE). RESULTS: Across 23 centers, 211 patients were enrolled. The median age was 54 years (range 6–89 years); 8 patients were aged CONCLUSIONS: Velaglucerase alfa was generally well-tolerated in a large, clinically heterogeneous group of patients with type 1 GD. Of 205 patients in treatment protocol HGT-GCB-058 who switched from imiglucerase, 91% met the safety criteria for early transition to home infusions and 26% received ≥1 home infusion, which supports home therapy as a treatment option depending on the patient's response and the recommendation of the treating physician. Disclosures: Pastores: Actelion: Research Funding; Amicus: Research Funding; Biomarin: Research Funding; Genzyme Corp: Research Funding; Protalix: Research Funding; Shire HGT: Research Funding. Rosenbloom:Genzyme Corporation: Educational Grant; Shire Pharmaceuticals: Research Funding, Speakers Bureau; Genzyme Corp: Research Funding, Speakers Bureau. Weinreb:Shire HGT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amicus: Research Funding; Actelion: Speakers Bureau. Goker-Alpan:Shire HGT: Consultancy, Research Funding; Genzyme Corp: Research Funding, Speakers Bureau; Amicus: Research Funding; Pfizer-Protalix Biotherapeutics: Consultancy, Research Funding. Lipson:Kaiser-Permanente: Employment. Ibrahim:Shire HGT: Research Funding. Cohn:Shire HGT: Employment. Zahrieh:Shire HGT: Employment. Mistry:Shire: Research Funding.

Trisomy 14 mosaicism produces a distinct phenotype. Among the 13 reported and 2 additional patients, the following findings were present in more than 90%: growth retardation (15/15), psychomotor retardation (10/10), broad nose (13/14), "dysplastic" and/or apparently low-set ears (15/15), micrognathia (15/15), short neck (11/12), congenital heart disease (14/15), and micropenis and cryptorchidism (6/6). Other frequent findings were prominent forehead (12/14), hypertelorism (8/13), narrow palpebral fissure (7/9), large mouth (10/14), cleft or highly arched palate (10/14), body asymmetry (8/12), and abnormal skin pigmentation (6/10). Sex ratio was 6M:9F. Four patients died before age 4 months, while at least 2 patients survived through teens. One boy died at age 3 years following cardiac surgery. One girl with tetralogy of Fallot showed a remarkable improvement in health after Blalock-Taussig procedure. Although the surviving patients showed moderate growth and mental retardation, the oldest surviving woman at 29 years demonstrates functional language and appropriate self help skills.

Hallermann-Streiff syndrome (HSS) is a rare disorder with an associated constellation of radiological findings that may aid in the diagnosis of affected individuals. We reviewed the skeletal surveys of 5 affected individuals and noted some characteristic and constant findings. Radiological findings can include a large, poorly ossified skull with decreased ossification in the sutural areas. There was an increase in the number of Wormian bones. Severe mid-facial hypoplasia was present along with a prominent nasal bone. The skull films also showed an abnormally obtuse or nearly straight gonial angle. The teeth appeared small. The long bones were thin and gracile in appearance and often showed poor demarcation of the cortex from the medullary portion. Abnormal bowing of the radius and ulna was seen neonatally in 2 cases. There was widening at the metaphyseal ends of the long bones. The ribs were thin, but normal in length. The vertebral bodies were noted to be small and 3 cases had platyspondyly. There was a decreased number of sternal ossification enters. The metacarpals were also thin and gracile in appearance with metaphyseal widening. We conclude that these characteristic radiological findings in the newborn with HSS can aid in the diagnosis, and a skeletal survey in suspected individuals may be valuable in confirming the diagnosis.

We observed an autosomal dominant disorder of abnormal upper lip, which resembles a poorly repaired cleft lip, malformed nose with broad bridge and flattened tip, lacrimal duct obstruction, malformed ears, and branchial cleft sinuses and/or linear skin lesions behind the ears in several persons in 3 families. In each of the 3 families, an affected parent had at least one affected child. Father-to-son transmission in one of these families ruled out X-linked inheritance. Other anomalies include coloboma, microphthalmia, auricular pits, lip pits, highly arched plate, dental anomalies, and subcutaneous cysts of the scalp. Premature graying of hair occurred in the affected adults. Growth retardation, developmental delay, and hand anomalies are variable components of the syndrome.

In 1980 a syndrome was first described in two adult males, consisting of macrocephaly, pigmented macules on the glans and shaft of the penis, and hamartomatous intestinal polyps. Since then, 10 additional cases have been identified. Herein, we present two new cases and review the cutaneous manifestations as well as additional features in patients with the Ruvalcaba-Myhre-Smith syndrome.

cat ion recognized to date in a pa t ient with hemophi l ia A who is "pro tec ted" by an inhibitor . Whe t he r Factor IX concentrate, the antifibrinolytic therapy, or the combination was responsible for this compl icat ion in our pat ient remains inconclusive. Fibr inolyt ic inhibi tors have been effectively used in combina t ion with an act ivated Factor IX concentrate,: ' bu t their use with a Fac tor IX preparation should be circumspect because of the risk of thrombosis.

Two patients with the Marshall-Smith syndrome are described. Both had significant and fatal respiratory distress attributable to this condition. Congenital, functional, and acquired abnormalities of the respiratory tract are described in nine of the 11 case reports in the literature and are characteristic of this syndrome as well as a primary cause of failure to thrive and death in these patients. Unusual immunologic findings in one of our two patients are the first to be reported in the Marshall-Smith syndrome. Quantitation of immune function in other patients with this condition will be helpful in determining the significance of these results. It is hoped that the etiology of the syndrome will be discovered as more cases are recognized and reported by pediatricians caring for infants with failure to thrive, advanced bone age, and chronic respiratory symptomatology.

Human skin fibroblasts were grown in culture medium containing virtually no pyridoxal. Cells cultured under these conditions grew to confluence for several passages without morphologic signs of degeneration and without changes in activity of two control enzymes, hexokinase and lactate dehydrogenase. The pyridoxal 5′-phosphate content of these fibroblasts fell to about 3% of values obtained during growth in pyridoxal-supplemented medium. The effect of such depletion on the activities of three pyridoxal 5′-phosphate-dependent enzymes was assessed during four consecutive passages. Total activity of cystathionine β-synthase and of aspartate aminotransferase in cell extracts fell to a mean of 50% of control values whereas total activity of alanine aminotransferase remained unchanged. Saturation of these enzymes with cofactor differed as well. The ratio of holoenzyme activity to total enzyme activity fell to less than 15% or predepletion values for cystathionine β-synthase and to 60% for aspartate aminotransferase. In contrast, alanine aminotransferase remained completely saturated with cofactor. Maximal saturation of aspartate amino-transferase with pyridoxal 5′-phosphate was achieved when pyridoxal 5′-phosphate-depleted fibroblasts were grown in medium containing as little as 1 ng/ml of pyridoxal, but addition of 10 ng/ml of pyridoxal was required for maximal saturation of cystathionine β-synthase. Maximal intracellular content of pyridoxal 5′-phosphate was achieved only when 100 ng/ml of pyridoxal was added to the growth medium. Interestingly, the activity of pyridoxine kinase remained constant during all depletion and repletion experiments. We conclude that the ability to grow human fibroblasts under these conditions provides a system for the study of apoenzyme-coenzyme interactions both in intact cultured cells and in cell extracts.

A girl with multiple anomalies was found to have trisomy 14 mosaicism. The physical findings in reported cases indicate the condition is a recognizable syndrome.

A fetus at risk for asphyxiating thoracic dysplasia was studied with ultrasound examination at 16, 18, and 23 weeks of pregnancy. Definite shortness of fetal femora was observed. Radiographic and histologic examinations after pregnancy termination confirmed the diagnosis. Asphyxiating thoracic dysplasia appears to be one of an increasing number of skeletal dysplasias that can be diagnosed prenatally with ultrasound.

Previous attempts to correlate in vivo pyridoxine-responsiveness with in vitro assays of cystathionine beta-synthase activity in synthase-deficient homocystinuric patients have been only partially successful. All such studies, however, have been conducted with extracts of cultured skin fibroblasts grown in medium containing a high concentration (1,000 ng/ml) of pyridoxal. Having recently shown that such growth conditions may obscure important aspects of enzyme-coenzyme interactions by saturating most synthase molecules with their cofactor, pyridoxal 5'-phosphate, we have established conditions for growth of cells in pyridoxal-free medium. Under these conditions, intracellular pyridoxal 5'-phosphate fell by >95%, and saturation of cystathionine beta-synthase apoenzyme with pyridoxal 5'-phosphate decreased from a predepletion value of 70% to

We report clinical and biochemical studies in patients with multiple acyl-CoA dehydrogenation disorders (MAD) and their parents. A severely affected (MAD:S) patient presented with neonatal acidosis leading to death and excreted a wide range of straight- and branched-chain acyl CoA derivatives. Two patients with mild variants of the same disorder (MAD:M) presented with neurologic abnormalities, acidotic coma, and/or poor growth; they primarily excreted ethylmalonate and variable amounts of adipate. Fibroblasts from the MAD:S patient demonstrated severely defective radiolabeled substrate oxidation, while the MAD:M cells had milder oxidative defects. Fibroblasts from two other MAD:M and six other MAD:S patients demonstrated analogous defects in substrate oxidation. As a group, MAD:S cells deficient in electron transfer flavoprotein:ubiquinone oxidoreductase had significantly lower residual oxidative activities than did MAD:S cells deficient in electron transfer flavoprotein. Fibroblasts from the parents of four MAD:S patients oxidized radiolabeled substrates significantly less effectively than did normal infant controls but were indistinguishable from normal adult cells. We found relatively higher residual oxidative activities in maternal than in paternal cells. Amniocytes from a fetus at risk for MAD:S catabolized labeled substrates normally; the infant has been clinically and biochemically normal up to 30 months of age.

Summary Thirty-two unrelated patients with features of Saethre-Chotzen syndrome, a common autosomal dominant condition of craniosynostosis and limb anomalies, were screened for mutations in TWIST,FGFR2, and FGFR3. Nine novel and three recurrent TWIST mutations were found in 12 families. Seven families were found to have the FGFR3 P250R mutation, and one individual was found to have an FGFR2 VV269–270 deletion. To date, our detection rate for TWIST or FGFR mutations is 68% in our Saethre-Chotzen syndrome patients, including our five patients elsewhere reported with TWIST mutations. More than 35 different TWIST mutations are now known in the literature. The most common phenotypic features, present in more than a third of our patients with TWIST mutations, are coronal synostosis, brachycephaly, low frontal hairline, facial asymmetry, ptosis, hypertelorism, broad great toes, and clinodactyly. Significant intra- and interfamilial phenotypic variability is present for either TWIST mutations or FGFR mutations. The overlap in clinical features and the presence, in the same genes, of mutations for more than one craniosynostotic condition—such as Saethre-Chotzen, Crouzon, and Pfeiffer syndromes—support the hypothesis that TWIST and FGFR s are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans.

Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are autosomal dominant osteochondrodysplasias that result in mild to severe short-limb dwarfism and early-onset osteoarthrosis. PSACH and some forms of MED result from mutations in the gene for cartilage oligomeric matrix protein (COMP; OMIM 600310 [http://www3.ncbi.nlm. nih.gov:80/htbin-post/Omim/dispmim?600310]). We report the identification of COMP mutations in an additional 14 families with PSACH or MED phenotypes. Mutations predicted to result in single-amino acid deletions or substitutions, all in the region of the COMP gene encoding the calmodulin-like repeat elements, were identified in patients with moderate to severe PSACH. We also identified within this domain a missense mutation that produced MED Fairbank. In two families, one with mild PSACH and the second with a form of MED, we identified different substitutions for a residue in the carboxyl-terminal globular region of COMP. Both the clinical presentations of these two families and the identification of COMP-gene mutations provide evidence of phenotypic overlap between PSACH and MED. These data also reveal a role for the carboxyl-terminal domain in the structure and/or function of COMP.

Mark H. Lipson, M.D., James O'Donnell, M.D:, J. W. Callahan, Ph.D., David A. Wenger, Ph.D., and Seymour Packman, M.D. From the Department of Pediatrics, Kaiser Permanente Medical Center, Sacramento, California; the Departments of Pediatrics and Ophthalmology, University of California, San Francisco; Research Institute, Hospital for Sick Children, Toronto; and the Department of Pediatrics, University of Colorado Health Sciences Center, Denver

• Susceptibility to Epstein-Barr virus (EBV) infection in 1,729 pregnant women was evaluated by screening for EBV antibodies. Fifty-eight subjects (3.4%) had no detectable EBV antibody and were presumably susceptible. Of the 54 women who agreed to participate in this study, none acquired EBV antibody during pregnancy. Our results are in general agreement with some published reports that primary EBV infection during `pregnancy is rare. The role of EBV in congenital infections and perinatal morbidity remains to be defined. (Am J Dis Child1983;137:466-468)

Testing of all newborn infants for certain disorders is now mandatory in California. Blood tests for phenylketonuria (PKU), galactosemia, and hypothyroidism, performed around the second day of life, have been found to be accurate and cost-effective. The early identification of these disorders may lead to appropriate therapy, but without detection serious mental retardation or death may occur. In California, screening for galactosemia is done by fluorescent measurement of the enzyme galactose-1-phosphate uridyl transferase 1 (gal-1-PUT) and by semiquantitative measurement of blood galactose through Escherichia coli inhibition. 2,3 We studied the case of an infant with galactosemia who, at the initial screening, had normal levels of blood galactose. Report of a Case .—A 3,570-g, white female infant was the first child born to a nonconsanguinous 29-year-old woman and her 31-year-old husband. The pregnancy, labor, and delivery were normal. Routine newborn screening tests for PKU, galactosemia, and hypothyroidism were performed on the

We recently encountered three patients whose antibody status was initially reported as positive at the time of exposure but who went on to develop classical primary chickenpox. We hereby report these cases and briefly discuss the accuracy of various serologic tests for varicella immunity to alert physicians about the possibility and potential consequences of false positive tests

Niemann-Pick disease (NPD) is a heterogeneous group of disorders usually designated types A-E. Each type is characterized by the accumulation of excessive sphingomyelin. This classification scheme fails for an ever-growing number of NPD patients. We report a 7½ year old male with type B Niemann-Pick disease with normal neurological and intellectual function, but who does have cherry red spots. This patient represents the fourth case of a child with the clinical and biochemical findings of type B NPD, but with evidence of involvement of neural tissue. These patients may represent a distinct clinical variant of NPD, in whom the natural history has not yet been elucidated. The existence of this subset of type B NPD has implications for genetic and biochemical studies in NPD, as well as for genetic and prognostic counseling of families.