Aditi I Dagli

Clinical and genetic aspects of Angelman syndrome

Abstract: Angelman syndrome is characterized by severe developmental delay, speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavioral phenotype that includes happy demeanor and excessive laughter. Microcephaly and seizures are common. Developmental delays are first noted at 3 to 6 months age, but the unique clinical features of the syndrome do not become manifest until after age 1 year. Management includes treatment of gastrointestinal symptoms, use of antiepileptic drugs for seizures, and provision of physical, occupational, and speech therapy with an emphasis on nonverbal methods of communication. The diagnosis rests on a combination of clinical criteria and molecular and/or cytogenetic testing. Analysis of parent-specific DNA methylation imprints in the 15q11.2-q13 chromosome region detects ∼78% of individuals with lack of maternal contribution. Less than 1% of individuals have a visible chromosome rearrangement. UBE3A sequence analysis detects mutations in an additional 11% of individuals. The remaining 10% of individuals with classic phenotypic features of Angelman syndrome have a presently unidentified genetic mechanism and thus are not amenable to diagnostic testing. The risk to sibs of a proband depends on the genetic mechanism of the loss of the maternally contributed Angelman syndrome/Prader-Willi syndrome region: typically <1% for probands with a deletion or uniparental disomy; as high as 50% for probands with an imprinting defect or a mutation of UBE3A. Members of the mothers extended family are also at increased risk when an imprinting defect or a UBE3A mutation is present. Chromosome rearrangements may be inherited or de novo. Prenatal testing is possible for certain genetic mechanisms.

Chromosome 8p23.1 deletions as a cause of complex congenital heart defects and diaphragmatic hernia.

Recurrent interstitial deletion of a region of 8p23.1 flanked by the low copy repeats 8p‐OR‐REPD and 8p‐OR‐REPP is associated with a spectrum of anomalies that can include congenital heart malformations and congenital diaphragmatic hernia (CDH). Haploinsufficiency of GATA4 is thought to play a critical role in the development of these birth defects. We describe two individuals and a monozygotic twin pair discordant for anterior CDH all of whom have complex congenital heart defects caused by this recurrent interstitial deletion as demonstrated by array comparative genomic hybridization. To better define the genotype/phenotype relationships associated with alterations of genes on 8p23.1, we review the spectrum of congenital heart and diaphragmatic defects that have been reported in individuals with isolated GATA4 mutations and interstitial, terminal, and complex chromosomal rearrangements involving the 8p23.1 region. Our findings allow us to clearly define the CDH minimal deleted region on chromosome 8p23.1 and suggest that haploinsufficiency of other genes, in addition to GATA4, may play a role in the severe cardiac and diaphragmatic defects associated with 8p23.1 deletions. These findings also underscore the importance of conducting a careful cytogenetic/molecular analysis of the 8p23.1 region in all prenatal and postnatal cases involving congenital defects of the heart and/or diaphragm.

Genetic disorders associated with macrocephaly.

Macrocephaly is associated with many genetic disorders and is a frequent cause of referral to the clinical geneticist. In this review we classify the commonly encountered macrocephaly disorders into useful categories and summarize recent genetic advances. Conditions where macrocephaly is a predominant aspect of the clinical presentation are discussed and a diagnostic approach to the common macrocephaly disorders is provided. Some emphasis is placed on familial macrocephaly (sometimes referred to as benign external hydrocephalus) and on the macrocephaly associated with autism spectrum disorders. The more recent conditions associated with the leukodystrophies and the organic acidurias are reviewed, but the well known conditions involving storage disorders and bone dysplasias are mentioned but not discussed. The genetic macrocephaly conditions cover a broad spectrum of gene disorders and their related proteins have diverse biological functions. As of yet it is not clear what precise biological pathways lead to generalized brain overgrowth.

Molecular and Clinical Aspects of Angelman Syndrome.

The Angelman syndrome is caused by disruption of the UBE3A gene and is clinically delineated by the combination of severe mental disability, seizures, absent speech, hypermotoric and ataxic movements, and certain remarkable behaviors. Those with the syndrome have a predisposition toward apparent happiness and paroxysms of laughter, and this finding helps distinguish Angelman syndrome from other conditions involving severe developmental handicap. Accurate diagnosis rests on a combination of clinical criteria and molecular and/or cytogenetic testing. Analysis of parent-specific DNA methylation imprints in the critical 15q11.2–q13 genomic region identifies 75–80% of all individuals with the syndrome, including those with cytogenetic deletions, imprinting center defects and paternal uniparental disomy. In the remaining group, UBE3A sequence analysis identifies an additional percentage of patients, but 5–10% will remain who appear to have the major clinical phenotypic features but do not have any identifiable genetic abnormalities. Genetic counseling for recurrence risk is complicated because multiple genetic mechanisms can disrupt the UBE3A gene, and there is also a unique inheritance pattern associated with UBE3A imprinting. Angelman syndrome is a prototypical developmental syndrome due to its remarkable behavioral phenotype and because UBE3A is so crucial to normal synaptic function and neural plasticity.

Haploinsufficiency of MBD5 associated with a syndrome involving microcephaly, intellectual disabilities, severe speech impairment, and seizures

Microdeletion of chromosome 2q23.1 results in a novel syndrome previously reported in five individuals. Many of the del(2)(q23.1) cases were thought to have other syndromes such as Angelman, Prader–Willi, or Smith–Magenis because of certain overlapping clinical features. We report two new cases of the 2q23.1 microdeletion syndrome, describe the syndrome phenotype, define the minimal critical region, and analyze the expression of critical region genes toward identification of the causative gene(s) for the disorder. Individuals with del(2)(q23.1) have severe developmental and cognitive delays, minimal speech, seizures, microcephaly, mild craniofacial dysmorphism, behavioral disorders, and short stature. The deletions encompassing 2q23.1 range from >4 Mb to <200 kb, as identified by oligonucleotide and BAC whole-genome array comparative hybridization. The minimal critical region includes a single gene, MBD5, deleted in all cases, whereas all but one case also include deletion of EPC2. Quantitative real-time PCR of patient lymphoblasts/lymphocytes showed an ∼50% reduced expression of MBD5 and EPC2 compared with controls. With similar phenotypes among the 2q23.1 deletion patients, the idea of one or more common genes causing the pathological defect seen in these patients becomes evident. As all five previous cases and the two cases in this report share one common gene, MBD5, we strongly suspect that haploinsufficiency of MBD5 causes most of the features observed in this syndrome.

Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics.

Disclaimer: This guideline is designed primarily as an educational resource for clinicians to help them provide quality medical services. Adherence to this guideline is completely voluntary and does not necessarily ensure a successful medical outcome. This guideline should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this guideline. Clinicians also are advised to take notice of the date this guideline was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Purpose:Glycogen storage disease type I (GSD I) is a rare disease of variable clinical severity that primarily affects the liver and kidney. It is caused by deficient activity of the glucose 6-phosphatase enzyme (GSD Ia) or a deficiency in the microsomal transport proteins for glucose 6-phosphate (GSD Ib), resulting in excessive accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa. Patients with GSD I have a wide spectrum of clinical manifestations, including hepatomegaly, hypoglycemia, lactic acidemia, hyperlipidemia, hyperuricemia, and growth retardation. Individuals with GSD type Ia typically have symptoms related to hypoglycemia in infancy when the interval between feedings is extended to 3–4 hours. Other manifestations of the disease vary in age of onset, rate of disease progression, and severity. In addition, patients with type Ib have neutropenia, impaired neutrophil function, and inflammatory bowel disease. This guideline for the management of GSD I was developed as an educational resource for health-care providers to facilitate prompt, accurate diagnosis and appropriate management of patients.Methods:A national group of experts in various aspects of GSD I met to review the evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management.Results:This management guideline specifically addresses evaluation and diagnosis across multiple organ systems (hepatic, kidney, gastrointestinal/nutrition, hematologic, cardiovascular, reproductive) involved in GSD I. Conditions to consider in the differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, hepatic and renal transplantation, and prenatal diagnosis, are also addressed.Conclusion:A guideline that facilitates accurate diagnosis and optimal management of patients with GSD I was developed. This guideline helps health-care providers recognize patients with all forms of GSD I, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It also helps to identify gaps in scientific knowledge that exist today and suggests future studies.Genet Med 16 11.

A patient with the syndrome of megalencephaly, mega corpus callosum and complete lack of motor development

The syndrome of megalencephaly, mega corpus callosum and complete lack of motor development (MCC; OMIM 603387) is an apparently rare condition since only three sporadic cases have been reported [Gohlich‐Ratmann et al. (1998); Am J Med Genet 79:161–167]. We describe an additional case that was not diagnosed until age 15 months. The MRI showed generalized, severe enlargement of the corpus callosum and thickening of the cortex. The cause for the MCC syndrome is unknown and both autosomal recessive and spontaneous dominant genetic mechanisms are possibilities.

Facial dysmorphism and digit anomalies in three siblings with severe developmental delay

R.C. Philips Unit, Division of Genetics and Metabolism, Department of Pediatrics, University of Florida, Gainesville, USA and Section of Cancer Genetics, Brookes Lawley Building, Institute of Cancer Research, Sutton, Surrey, UK Correspondence to Dr Charles A. Williams, MD, Division of Genetics and Metabolism, University of Florida, 1600 SW Archer Road, PO BOX 100296, Gainesville, FL 32610, USA Tel: + 1 352 294 5050; fax: + 1 352 392 3051; e-mail: willicx@peds.ufl.edu