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Sarah H Elsea - One of the best experts on this subject based on the ideXlab platform.

  • Management of Sleep Disturbances Associated with Smith-Magenis Syndrome
    CNS Drugs, 2020
    Co-Authors: Kevin A. Kaplan, Sarah H Elsea, Lorraine Potocki
    Abstract:

    Smith-Magenis Syndrome is a genetic disorder caused by a microdeletion involving the retinoic acid-induced 1 ( RAI1 ) gene that maps on the short arm of chromosome 17p11.2 or a pathogenic mutation of RAI1 . Smith-Magenis Syndrome affects patients through numerous congenital anomalies, intellectual disabilities, behavioral challenges, and sleep disturbances. The sleep abnormalities associated with Smith-Magenis Syndrome can include frequent nocturnal arousals, early morning awakenings, and sleep attacks during the day. The sleep problems associated with Smith-Magenis Syndrome are attributed to haploinsufficiency of the RAI1 gene. One consequence of reduced function of RAI1 , and characteristic of Smith-Magenis Syndrome, is an inversion of melatonin secretion resulting in a diurnal rather than nocturnal pattern. Treatment of sleep problems in people with Smith-Magenis Syndrome generally involves a combination of sleep hygiene techniques, supplemental melatonin, and/or other medications, such as melatonin receptor agonists, β_1-adrenergic antagonists, and stimulant medications, to improve sleep outcomes. Improvement in sleep has been shown to improve behavioral outcomes, which in turn improves the quality of life for both patients and their caregivers.

  • Behavior and sleep disturbance in Smith-Magenis Syndrome.
    Current Opinion in Psychiatry, 2019
    Co-Authors: Brian J. Shayota, Sarah H Elsea
    Abstract:

    Purpose of reviewTo provide an update of the most recent studies on Smith–Magenis Syndrome (SMS) with a focus on the unique pattern of behavioral and sleep disturbances associated with the condition.Recent findingsThe recent literature on SMS has focused on the characteristic severe behavioral and s

  • Smith-Magenis Syndrome and its circadian influence on development, behavior, and obesity - own experience.
    Developmental period medicine, 2015
    Co-Authors: Li Chen, Sureni V. Mullegama, Joseph T. Alaimo, Sarah H Elsea
    Abstract:

    Smith-Magenis Syndrome (SMS) is a complex genetic disorder characterized by sleep disturbance, multiple developmental anomalies, psychiatric behavior, and obesity. It is caused by a heterozygous 17p11.2 microdeletion containing the retinoic acid-induced 1 (RAI1) gene or mutation within RAI1. Sleep disorder is one of the most penetrant features of SMS. Molecular genetic studies indicate that RAI1 regulates circadian rhythm genes and when haploinsucient, causes a distorted molecular circadian network that may be the cause of the sleep disturbance and the inverted rhythm of melatonin present in most individuals with SMS. RAI1 also regulates genes involved in development, neurobehavior, and lipid metabolism. Sleep debt, daytime melatonin secretion, and environmental stress often contribute to negative behavior in persons with SMS, and food entrained circadian rhythm also influences food intake behavior and humoral signals, which also affect development and neurobehavior. The cross-talk between circadian rhythm, development, metabolism and behaviors affect the multiple phenotypic outcomes in Smith-Magenis Syndrome. These findings shed light on possible effective and personalized drug treatments for SMS patients in the future.

  • Frameshift mutation hotspot identified in Smith-Magenis Syndrome: case report and review of literature
    BMC Medical Genetics, 2010
    Co-Authors: Hoa T. Truong, Tracy Dudding, Christopher Blanchard, Sarah H Elsea
    Abstract:

    Smith-Magenis Syndrome (SMS) is a complex Syndrome involving intellectual disabilities, sleep disturbance, behavioural problems, and a variety of craniofacial, skeletal, and visceral anomalies. While the majority of SMS cases harbor an ~3.5 Mb common deletion on 17p11.2 that encompasses the retinoic acid induced-1 (RAI1) gene, some patients carry small intragenic deletions or point mutations in RAI1. We present data on two cases of Smith-Magenis Syndrome with mutation of RAI1. Both cases are phenotypically consistent with SMS and RAI1 mutation but also have other anomalies not previously reported in SMS, including spontaneous pneumothoraces. These cases also illustrate variability in the SMS phenotype not previously shown for RAI1 mutation cases, including hearing loss, absence of self-abusive behaviours, and mild global delays. Sequencing of RAI1 revealed mutation of the same heptameric C-tract (CCCCCCC) in exon 3 in both cases (c.3103delC one case and and c.3103insC in the other), resulting in frameshift mutations. Of the seven reported frameshift mutations occurring in poly C-tracts in RAI1, four cases (~57%) occur at this heptameric C-tract. Collectively, these results indicate that this heptameric C-tract is a preferential hotspot for single nucleotide insertion/deletions (SNindels) and therefore, should be considered a primary target for analysis in patients suspected for mutations in RAI1. We expect that as more patients are sequenced for mutations in RAI1, the incidence of frameshift mutations in this hotspot will become more evident.

  • a functional network module for Smith Magenis Syndrome
    Clinical Genetics, 2009
    Co-Authors: Santhosh Girirajan, Christopher Blanchard, H T Truong, Sarah H Elsea
    Abstract:

    Disorders with overlapping diagnostic features are grouped into a network module. Based on phenotypic similarities or differential diagnoses, it is possible to identify functional pathways leading to individual features. We generated a Smith–Magenis Syndrome (SMS)-specific network module utilizing patient clinical data, text mining from the Online Mendelian Inheritance in Man database, and in vitro functional analysis. We tested our module by functional studies based on a hypothesis that RAI1 acts through phenotype-specific pathways involving several downstream genes, which are altered due to RAI1 haploinsufficiency. A preliminary genome-wide gene expression study was performed using microarrays on RAI1 haploinsufficient cells created by RNAi-based ∼50% knockdown of RAI1 in HEK293T cells. The top dysregulated genes were involved in growth signaling and insulin sensitivity, neuronal differentiation, lipid biosynthesis and fat mobilization, circadian activity, behavior, renal, cardiovascular and skeletal development, gene expression, and cell-cycle regulation and recombination, reflecting the spectrum of clinical features observed in SMS. Validation using real-time quantitative reverse transcriptase polymerase chain reaction confirmed the gene expression profile of 75% of the selected genes analyzed in both HEK293T RAI1 knockdown cells and SMS lymphoblastoid cell lines. Overall, these data support a method for identifying genes and pathways responsible for individual clinical features in a complex disorder such as SMS.

A C M Smith - One of the best experts on this subject based on the ideXlab platform.

  • Auditory Phenotype of Smith–Magenis Syndrome
    Journal of Speech Language and Hearing Research, 2017
    Co-Authors: Megan A. Brendal, Kelly A. King, Christopher K. Zalewski, Brenda Finucane, Wendy J. Introne, Carmen C. Brewer, A C M Smith
    Abstract:

    Purpose The purpose of this study was to describe the auditory phenotype of a large cohort with Smith–Magenis Syndrome (SMS), a rare disorder including physical anomalies, cognitive deficits, sleep...

  • auditory phenotype of Smith Magenis Syndrome
    Journal of Speech Language and Hearing Research, 2017
    Co-Authors: Megan A. Brendal, Kelly A. King, Christopher K. Zalewski, Brenda Finucane, Wendy J. Introne, Carmen C. Brewer, A C M Smith
    Abstract:

    Purpose The purpose of this study was to describe the auditory phenotype of a large cohort with Smith–Magenis Syndrome (SMS), a rare disorder including physical anomalies, cognitive deficits, sleep...

  • Immune complex-mediated autoimmunity in a patient With Smith-Magenis Syndrome (del 17p11.2).
    Jcr-journal of Clinical Rheumatology, 2014
    Co-Authors: Jianying Yang, A C M Smith, Settara C. Chandrasekharappa, Thierry Vilboux, Erik J. Peterson
    Abstract:

    Smith-Magenis Syndrome (SMS) is a sporadic congenital disorder involving multiple organ systems caused by chromosome 17p11.2 deletions. Smith-Magenis Syndrome features craniofacial and skeletal anomalies, cognitive impairment, and neurobehavioral abnormalities. In addition, some SMS patients may exhibit hypogammaglobulinemia. We report the first case of SMS-associated autoimmunity in a woman who presented with adult onset of multiple autoimmune disorders, including systemic lupus erythematosus, antiphospholipid antibody Syndrome, and autoimmune hepatitis. Molecular analysis using single-nucleotide polymorphism array confirmed a de novo 3.8-Mb deletion (breakpoints, chr17: 16,660,721–20,417,975), resulting in haploinsufficiency for TACI (transmembrane activator and CAML interactor). Our data are consistent with potential loss of function for the BAFF (B cell–activating factor) receptor TACI as a contributing factor to human autoimmune phenomena.

  • Autism Spectrum Features in Smith-Magenis Syndrome
    American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2010
    Co-Authors: Gonzalo Laje, Rebecca Morse, William Richter, Jonathan Ball, Maryland Pao, A C M Smith
    Abstract:

    Smith–Magenis Syndrome (SMS; OMIM 182290) is a neurodevelopmental disorder characterized by a welldefined pattern of anomalies. The majority of cases are due to a common deletion in chromosome 17p11.2 that includes the RAI1 gene. In children with SMS, autistic-like behaviors and symptoms start to emerge around 18 months of age. This study included 26 individuals (15 females and 11 males), with a confirmed deletion (del 17p11.2). Parents/caregivers were asked to complete the Social Responsiveness Scale (SRS) and the Social Communication Questionnaire (SCQ) both current and lifetime versions. The results suggest that 90% of the sample had SRS scores consistent with autism spectrum disorders. Moreover, females showed more impairment in total T-scores (P ¼ 0.02), in the social cognition (P ¼ 0.01) and autistic mannerisms (P ¼ 0.002) subscales. The SCQ scores are consistent to show that a majority of individuals may meet criteria for autism spectrum disorders at some point in their lifetime. These results suggest that SMS needs to be considered in the differential diagnosis of autism spectrum disorders but also that therapeutic interventions for autism are likely to benefit individuals with SMS. The mechanisms by which the deletion of RAI1 and contiguous genes cause psychopathology remain unknown but they provide a solid starting point for further studies of gene–brain–behavior interactions in SMS and autism spectrum disorders. Published 2010 Wiley-Liss, Inc. {

  • Autism spectrum features in Smith-Magenis Syndrome.
    American journal of medical genetics. Part C Seminars in medical genetics, 2010
    Co-Authors: Gonzalo Laje, Rebecca Morse, William Richter, Jonathan Ball, Maryland Pao, A C M Smith
    Abstract:

    Smith-Magenis Syndrome (SMS; OMIM 182290) is a neurodevelopmental disorder characterized by a well-defined pattern of anomalies. The majority of cases are due to a common deletion in chromosome 17p11.2 that includes the RAI1 gene. In children with SMS, autistic-like behaviors and symptoms start to emerge around 18 months of age. This study included 26 individuals (15 females and 11 males), with a confirmed deletion (del 17p11.2). Parents/caregivers were asked to complete the Social Responsiveness Scale (SRS) and the Social Communication Questionnaire (SCQ) both current and lifetime versions. The results suggest that 90% of the sample had SRS scores consistent with autism spectrum disorders. Moreover, females showed more impairment in total T-scores (P = 0.02), in the social cognition (P = 0.01) and autistic mannerisms (P = 0.002) subscales. The SCQ scores are consistent to show that a majority of individuals may meet criteria for autism spectrum disorders at some point in their lifetime. These results suggest that SMS needs to be considered in the differential diagnosis of autism spectrum disorders but also that therapeutic interventions for autism are likely to benefit individuals with SMS. The mechanisms by which the deletion of RAI1 and contiguous genes cause psychopathology remain unknown but they provide a solid starting point for further studies of gene-brain-behavior interactions in SMS and autism spectrum disorders.

Lorraine Potocki - One of the best experts on this subject based on the ideXlab platform.

  • Management of Sleep Disturbances Associated with Smith-Magenis Syndrome
    CNS Drugs, 2020
    Co-Authors: Kevin A. Kaplan, Sarah H Elsea, Lorraine Potocki
    Abstract:

    Smith-Magenis Syndrome is a genetic disorder caused by a microdeletion involving the retinoic acid-induced 1 ( RAI1 ) gene that maps on the short arm of chromosome 17p11.2 or a pathogenic mutation of RAI1 . Smith-Magenis Syndrome affects patients through numerous congenital anomalies, intellectual disabilities, behavioral challenges, and sleep disturbances. The sleep abnormalities associated with Smith-Magenis Syndrome can include frequent nocturnal arousals, early morning awakenings, and sleep attacks during the day. The sleep problems associated with Smith-Magenis Syndrome are attributed to haploinsufficiency of the RAI1 gene. One consequence of reduced function of RAI1 , and characteristic of Smith-Magenis Syndrome, is an inversion of melatonin secretion resulting in a diurnal rather than nocturnal pattern. Treatment of sleep problems in people with Smith-Magenis Syndrome generally involves a combination of sleep hygiene techniques, supplemental melatonin, and/or other medications, such as melatonin receptor agonists, β_1-adrenergic antagonists, and stimulant medications, to improve sleep outcomes. Improvement in sleep has been shown to improve behavioral outcomes, which in turn improves the quality of life for both patients and their caregivers.

  • Circadian rhythm abnormalities of melatonin in Smith-Magenis Syndrome
    2016
    Co-Authors: Lorraine Potocki, Daniel Glaze, Dun-xian Tan, Sung-sup Park, Catherine D Kashork, Lisa G Shaver, Russel J Reiter, James R Lupski
    Abstract:

    Background—Smith-Magenis Syndrome (SMS) is a multiple congenital anomalies/ mental retardation Syndrome associated with a hemizygous deletion of chromosome 17, band p11.2. Characteristic features include neurobehavioural abnormalities such as aggressive and self-injurious be-haviour and significant sleep disturbances. The majority of patients have a common deletion characterised at the molecular level. Physical mapping studies indicate that all patients with the common deletion are haploinsuYcient for subunit 3 of the COP9 signalosome (COPS3), which is con

  • Cognitive and adaptive behavior profiles in Smith-Magenis Syndrome.
    Journal of Developmental and Behavioral Pediatrics, 2006
    Co-Authors: Niru Madduri, James R Lupski, Sarika U. Peters, Robert G. Voigt, Antolin M. Llorente, Lorraine Potocki
    Abstract:

    Smith-Magenis Syndrome (SMS) is a multiple congenital anomalies and mental retardation Syndrome associated with an interstitial deletion of chromosome 17 band p11.2. The incidence of this microdeletion Syndrome is estimated to be 1 in 25,000 individuals. Persons with SMS have a distinctive neurobehavioral phenotype that is characterized by aggressive and self-injurious behaviors and significant sleep disturbances. From December 1990 through September 1999, 58 persons with SMS were enrolled in a 5-day multidisciplinary clinical protocol. Developmental assessments consisting of cognitive level and adaptive behavior were completed in 57 persons. Most patients functioned in the mild-to-moderate range of mental retardation. In addition, we report that patients with SMS have low adaptive functioning with relative strengths in socialization and relative weakness in daily living skills. These data were analyzed in light of the molecular extent of the microdeletion within 17p11.2. We found that the level of cognitive and adaptive functioning does depend on deletion size, and that a small percentage of SMS patients have cognitive function in the borderline range.

  • Epilepsy and chromosomal rearrangements in Smith-Magenis Syndrome [del(17)(p11.2p11.2)]
    Journal of Child Neurology, 2006
    Co-Authors: Alicia M. Goldman, James R Lupski, Lorraine Potocki, Katherina Walz, Jennifer M. Lynch, Daniel G. Glaze, Jeffrey L. Noebels
    Abstract:

    Smith-Magenis Syndrome is a multiple congenital anomalies/mental retardation Syndrome associated with a heterozygous deletion of chromosome 17p11.2. Seizures have not been formally studied in this population. Our objectives were to estimate the prevalence of seizures and electroencephalographic (EEG) epileptiform abnormalities in patients with Smith-Magenis Syndrome with defined chromosomal rearrangements and to describe the spectrum of abnormal EEG patterns. Prolonged video-EEGs were obtained in 60 patients. Eighteen percent of patients reported a seizure history; however, abnormal EEGs were identified in 31 of the 60 subjects and 27 of 31 were epileptiform. Generalized epileptiform patterns were the most common (73%). Most patients with either small or large deletions had an abnormal EEG (83%; 75%) in contrast to those with a common deletion (49%). Our results indicate that epileptiform EEG abnormalities are frequent in patients with Smith-Magenis Syndrome. Considering that close to one third of individuals with Smith-Magenis Syndrome with epileptiform abnormalities also had a history of clinical seizures, cortical hyperexcitability and epilepsy should be considered an important component of the Smith-Magenis Syndrome clinical phenotype.

  • Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis Syndrome [del(17)(p11.2p11.2)].
    Genetics in Medicine, 2003
    Co-Authors: Lorraine Potocki, Christine J. Shaw, Pawel Stankiewicz, James R Lupski
    Abstract:

    Variability in clinical phenotype despite common chromosomal deletion in Smith-Magenis Syndrome [del(17)(p11.2p11.2)]

James E Metherall - One of the best experts on this subject based on the ideXlab platform.

  • hemizygosity for the cop9 signalosome subunit gene sgn3 in the Smith Magenis Syndrome
    American Journal of Medical Genetics, 1999
    Co-Authors: Sarah H Elsea, Kirk Mykytyn, Katherine Ferrell, Kathryn L Coulter, Wolfgang Dubiel, Pragna Patel, James E Metherall
    Abstract:

    Smith-Magenis Syndrome (SMS) is a multiple congenital anomaly/mental retardation Syndrome associated with an interstitial deletion of chromosome band 17p11.2. The critical region is extremely gene-rich and spans approximately 1.5-2.0 Mb of DNA. Here we report the localization and partial characterization of the gene for subunit 3 of the COP9 signalosome, SGN3. SGN3 maps to the distal portion of the SMS critical interval, between SREBF1 and cCI17-638. We assessed the potential effect of haploinsufficiency of SGN3 in SMS patient lymphoblastoid cell lines through transfection studies and western analysis. Our results indicate that the COP9 signalosome assembles properly in these cells and appears to have normal expression and a kinase function intact. However, because the role of the COP9 signalosome in embryogenesis or differentiation is still uncertain, we cannot rule out the involvement of this gene in the Smith-Magenis Syndrome. Am. J. Med. Genet. 87:342–348, 1999. © 1999 Wiley-Liss, Inc.

  • Hemizygosity for the COP9 signalosome subunit gene, SGN3, in the Smith-Magenis Syndrome
    American Journal of Medical Genetics, 1999
    Co-Authors: Sarah H Elsea, Kirk Mykytyn, Katherine Ferrell, Kathryn L Coulter, Wolfgang Dubiel, Pragna Patel, Parimal Das, James E Metherall
    Abstract:

    Smith-Magenis Syndrome (SMS) is a multiple congenital anomaly/mental retardation Syndrome associated with an interstitial deletion of chromosome band 17p11.2. The critical region is extremely gene-rich and spans approximately 1.5-2.0 Mb of DNA. Here we report the localization and partial characterization of the gene for subunit 3 of the COP9 signalosome, SGN3. SGN3 maps to the distal portion of the SMS critical interval, between SREBF1 and cCI17-638. We assessed the potential effect of haploinsufficiency of SGN3 in SMS patient lymphoblastoid cell lines through transfection studies and western analysis. Our results indicate that the COP9 signalosome assembles properly in these cells and appears to have normal expression and a kinase function intact. However, because the role of the COP9 signalosome in embryogenesis or differentiation is still uncertain, we cannot rule out the involvement of this gene in the Smith-Magenis Syndrome.

Pragna Patel - One of the best experts on this subject based on the ideXlab platform.

  • hemizygosity for the cop9 signalosome subunit gene sgn3 in the Smith Magenis Syndrome
    American Journal of Medical Genetics, 1999
    Co-Authors: Sarah H Elsea, Kirk Mykytyn, Katherine Ferrell, Kathryn L Coulter, Wolfgang Dubiel, Pragna Patel, James E Metherall
    Abstract:

    Smith-Magenis Syndrome (SMS) is a multiple congenital anomaly/mental retardation Syndrome associated with an interstitial deletion of chromosome band 17p11.2. The critical region is extremely gene-rich and spans approximately 1.5-2.0 Mb of DNA. Here we report the localization and partial characterization of the gene for subunit 3 of the COP9 signalosome, SGN3. SGN3 maps to the distal portion of the SMS critical interval, between SREBF1 and cCI17-638. We assessed the potential effect of haploinsufficiency of SGN3 in SMS patient lymphoblastoid cell lines through transfection studies and western analysis. Our results indicate that the COP9 signalosome assembles properly in these cells and appears to have normal expression and a kinase function intact. However, because the role of the COP9 signalosome in embryogenesis or differentiation is still uncertain, we cannot rule out the involvement of this gene in the Smith-Magenis Syndrome. Am. J. Med. Genet. 87:342–348, 1999. © 1999 Wiley-Liss, Inc.

  • Hemizygosity for the COP9 signalosome subunit gene, SGN3, in the Smith-Magenis Syndrome
    American Journal of Medical Genetics, 1999
    Co-Authors: Sarah H Elsea, Kirk Mykytyn, Katherine Ferrell, Kathryn L Coulter, Wolfgang Dubiel, Pragna Patel, Parimal Das, James E Metherall
    Abstract:

    Smith-Magenis Syndrome (SMS) is a multiple congenital anomaly/mental retardation Syndrome associated with an interstitial deletion of chromosome band 17p11.2. The critical region is extremely gene-rich and spans approximately 1.5-2.0 Mb of DNA. Here we report the localization and partial characterization of the gene for subunit 3 of the COP9 signalosome, SGN3. SGN3 maps to the distal portion of the SMS critical interval, between SREBF1 and cCI17-638. We assessed the potential effect of haploinsufficiency of SGN3 in SMS patient lymphoblastoid cell lines through transfection studies and western analysis. Our results indicate that the COP9 signalosome assembles properly in these cells and appears to have normal expression and a kinase function intact. However, because the role of the COP9 signalosome in embryogenesis or differentiation is still uncertain, we cannot rule out the involvement of this gene in the Smith-Magenis Syndrome.

  • Definition of the critical interval for Smith-Magenis Syndrome.
    Cytogenetic and Genome Research, 1997
    Co-Authors: Sarah H Elsea, Brenda Finucane, Smita M. Purandare, R.a. Adell, Ramesh C. Juyal, Jessica G. Davis, R.e. Magenis, Pragna Patel
    Abstract:

    Smith-Magenis Syndrome (SMS) comprises a complex physical and behavioral phenotype that is associated with an interstitial deletion of chromosome 17p11.2. The deletions observed in patients can range

  • Mosaicism for del(17) (p11.2p11.2) underlying the Smith-Magenis Syndrome
    American Journal of Medical Genetics, 1996
    Co-Authors: Ramesh C. Juyal, Akira Kuwano, Ikuko Kondo, Federico Zara, Antonio Baldini, Pragna Patel
    Abstract:

    Smith-Magenis Syndrome (SMS) is a multiple congenital anomalies/mental retardation Syndrome associated with deletion of band p11.2 of chromosome 17. The deletion is typically detected by high-resolution cytogenetic analysis of chromosomes from peripheral lymphocytes. Fluorescence in situ hybridization (FISH) has been previously used to rule out apparent mosaicism for del(17)(p11.2p11.2) indicated by routine cytogenetics. We now report mosaicism for del(17)(p11.2p11.2) in a child with SMS. The mosaicism had gone undetected during previous routine cytogenetic analysis. FISH analysis of peripheral lymphocytes as well as immortalized lymphoblasts using markers from 17p11.2 revealed that approximately 60% of cells carried the deletion. To our knowledge, this is the first case of SMS associated with mosaicism for del(17)(p11.2p11.2).

  • Haploinsufficiency of cytosolic serine hydroxymethyltransferase in the Smith-Magenis Syndrome.
    American Journal of Human Genetics, 1995
    Co-Authors: Sarah H Elsea, Brenda Finucane, Ramesh C. Juyal, Frank Greenberg, Antonio Baldini, Sarn Jiralerspong, Massimo Pandolfo, Patrick J. Stover, Pragna Patel
    Abstract:

    Folate-dependent one-carbon metabolism is critical for the synthesis of numerous cellular constituents required for cell growth, and serine hydroxymethyltransferase (SHMT) is central to this process. Our studies reveal that the gene for cytosolic SHMT (cSHMT) maps to the critical interval for Smith-Magenis Syndrome (SMS) on chromosome 17p11.2. The basic organization of the cSHMT locus on chromosome 17 was determined and was found to be deleted in all 26 SMS patients examined by PCR, FISH, and/or Southern analysis. Furthermore, with respect to haploinsufficiency, cSHMT enzyme activity in patient lymphoblasts was determined to be approximately 50% that of unaffected parent lymphoblasts. Serine, glycine, and folate levels were also assessed in three SMS patients and were found to be within normal ranges. The possible effects of cSHMT hemizygosity on the SMS phenotype are discussed.