Reversal of glycogen storage disease type IIIa-related cardiomyopathy with modification of diet.

Glycogen storage disease type III (GSD III) is caused by a deficiency in debranching enzyme, which leads to an accumulation of abnormal glycogen called limit dextrin in affected tissues. Muscle and liver involvement is present in GSD type IIIa, while the defect is limited to the liver only in GSD type IIIb. Besides skeletal muscle involvement, a cardiomyopathy resembling idiopathic hypertrophic cardiomyopathy is seen. Management consists of maintaining normoglycaemia by supplementation with cornstarch therapy and/or protein. While studies are lacking regarding the best treatment for skeletal muscle disease, a high-protein diet was previously reported to be beneficial. No cases of improvement in cardiomyopathy have been reported. Our patient presented in infancy with hypoglycaemia and hepatomegaly. His prescribed management consisted of cornstarch supplementation and a high-protein diet providing 20% of his total energy needs. At 16 years of age, he developed a severe cardiomyopathy with a left ventricular mass index of 209 g/m(2). The cardiomyopathy remained stable on a protein intake of 20-25% of total energy. At age 22 years, the diet was changed to increase his protein intake to 30% of total energy and minimize his cornstarch therapy to only what was required to maintain normoglycaemia. Dramatic improvement in the cardiomyopathy occurred. Over one year, his left ventricular mass index decreased from 159.7 g/m(2) to 78 g/m(2) (normal 50-86 g/m(2)) and the creatine kinase levels decreased from 455 U/L to 282 U/L. Avoidance of overtreatment with carbohydrate and a high-protein diet can reverse and may prevent cardiomyopathy.

Telegenetic medicine: improved access to services in an underserved area.

We used telemedicine to improve genetics services to patients in the rural northwestern region of Florida. Patients were first seen via videoconference by a genetic counsellor, who obtained family and medical history. A local paediatrician then performed the physical examination, and a plan for evaluation was established. The videoconferencing equipment was connected at a bandwidth of 384 kbit/s, using three ISDN lines. During the first three telemedicine clinics, seven patients were evaluated and then returned to the centre for a face-to-face consultation with the clinical geneticist. No new diagnoses were made face-to-face that had not been identified by telemedicine. No diagnoses made by telemedicine were judged to be wrong when the child was evaluated face-to-face. During a two-year study of patient satisfaction with 12 telegenetics clinics, the 50 families evaluated via videoconferencing were asked to complete surveys; 40 surveys were returned (a response rate of 80%). All individuals either strongly agreed or agreed that the evaluation of their child was appropriate, sufficient and sufficiently protective of their child's privacy. The waiting time for a new patient consultation with the clinical genetics team was 16.9 months (SD 1.9) at the start and 3.0 months (SD 1.0) at the end of the trial period. The difference was significant (t-test, P < 0.0001). Telegenetics allows more rapid assurance that a genetic syndrome has not been identified, or a quicker initial evaluation and diagnosis for children who do have an identifiable genetic syndrome.

Distinct phenotypes distinguish the molecular classes of Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a severe neurobehavioural disorder caused by defects in the maternally derived imprinted domain located on 15q11-q13. Most patients acquire AS by one of five mechanisms: (1) a large interstitial deletion of 15q11-q13; (2) paternal uniparental disomy (UPD) of chromosome 15; (3) an imprinting defect (ID); (4) a mutation in the E3 ubiquitin protein ligase gene (UBE3A); or (5) unidentified mechanism(s). All classical patients from these classes exhibit four cardinal features, including severe developmental delay and/or mental retardation, profound speech impairment, a movement and balance disorder, and AS specific behaviour typified by an easily excitable personality with an inappropriately happy affect. In addition, patients can display other characteristics, including microcephaly, hypopigmentation, and seizures. METHODS: We restricted the present study to 104 patients (93 families) with a classical AS phenotype. All of our patients were evaluated for 22 clinical variables including growth parameters, acquisition of motor skills, and history of seizures. In addition, molecular and cytogenetic analyses were used to assign a molecular class (I-V) to each patient for genotype-phenotype correlations. RESULTS: In our patient repository, 22% of our families had normal DNA methylation analyses along 15q11-q13. Of these, 44% of sporadic patients had mutations within UBE3A, the largest percentage found to date. Our data indicate that the five molecular classes can be divided into four phenotypic groups: deletions, UPD and ID patients, UBE3A mutation patients, and subjects with unknown aetiology. Deletion patients are the most severely affected, while UPD and ID patients are the least. Differences in body mass index, head circumference, and seizure activity are the most pronounced among the classes. CONCLUSIONS: Clinically, we were unable to distinguish between UPD and ID patients, suggesting that 15q11-q13 contains the only significant maternally expressed imprinted genes on chromosome 15.

Variable expression of rib, pectus, and scapular anomalies with Robin-type cleft palate in a 5-generation family: a new syndrome?

We report on a 5-generation family with multiple musculoskeletal anomalies, including: Robin-type cleft palate, rib "dysplasia," scapular hypoplasia, and pectus excavatum. Robin-type clefts are known to be associated with various skeletal malformations; however, most of these include limb anomalies which are not present in this family. To our knowledge, there are no reports of similar conditions in the literature. The transmission through 5 generations and the presence of male-to-male transmission are consistent with autosomal-dominant transmission of a trait with variable expressivity.

Smith-Lemli-Opitz syndrome in a female with a de novo, balanced translocation involving 7q32: probable disruption of an SLOS gene.

A 3-month-old infant girl had manifestations of the Smith-Lemli-Opitz syndrome (SLOS) including typical positional anomalies of the limbs, apparent Hirschsprung disease, cataracts, ptosis, anteverted nares, cleft of the posterior palate, small tongue, broad maxillary alveolar ridges, and abnormally low serum cholesterol levels. Chromosomal analysis showed a de novo balanced translocation interpreted as 46,XX,t(7;20)(q32.1;q13.2). We hypothesize that the translocation breakpoint in this case interrupts one SLOS allele and that the other allele at the same locus has a more subtle mutation that was inherited from the other parent. This case, as well as cytogenetic observations in other SLOS cases, suggests that SLOS could be due to autosomal recessive mutation at a gene in 7q32.

Germline PTEN mutation in a family with Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome.

Clinical overlap between Cowden disease and Bannayan-Riley-Ruvalcaba syndrome has rarely been described and identical germline mutations in the PTEN gene have been demonstrated in a few families with Cowden disease and some cases of Bannayan-Riley-Ruvalcaba syndrome. We report on a mother with Cowden disease and a son with Bannayan-Riley-Ruvalcaba syndrome. Mutation analysis of the PTEN gene demonstrated a heterozygous nonsense mutation R130X in both individuals. This might suggest that Cowden disease and Bannayan-Riley-Ruvalcaba syndrome are one causal entity.

Methylenetetrahydrofolate reductase deficiency in a patient with phenotypic findings of Angelman syndrome.

Deficiency of methylenetetrahydrofolate reductase (MTHFR) is associated with a variable phenotype that includes mental retardation, gait abnormalities, and seizures. Many of the same clinical findings are also seen in patients with Angelman syndrome. We report on a patient with MTHFR deficiency who was initially diagnosed as having Angelman syndrome. This case illustrates that MTHFR deficiency can mimic the phenotype of Angelman syndrome and that MTHFR deficiency should be excluded in patients with manifestations of Angelman syndrome whose molecular studies of chromosome 15 are normal.

Clinical, cytogenetic, and molecular evidence for an infant with Smith-Magenis syndrome born from a mother having a mosaic 17p11.2p12 deletion.

We describe an infant with del(17) (p11.2p12) whose deleted chromosome was inherited from a mosaic mother. The child had manifestations consistent with Smith-Magenis syndrome. The mother appeared to be of normal intelligence and she had minimal findings of Smith-Magenis syndrome. Separation of chromosome 17 homologues in somatic cell hybrids and molecular studies confirmed the cytogenetic diagnoses and the fact that the mother was mosaic. Furthermore, molecular analysis demonstrated novel breakpoints in this family, with the deletion extending into and completely encompassing the markers duplicated in Charcot-Marie-Tooth (CMT) disease. Although this Smith-Magenis syndrome patient is completely deleted for the CMT region, her electrophysiological findings are different from those found in CMT. This is the only reported case of Smith-Magenis syndrome with transmission from a partially affected mosaic mother. Transmission of interstitial deletions from mosaic parents may be more common than thought; therefore, parental chromosomes should be examined when interstitial deletions are identified.

Preaxial acrofacial dysostosis (Nager syndrome) associated with an inherited and apparently balanced X;9 translocation: prenatal and postnatal late replication studies.

We report on an infant with preaxial acrofacial dysostosis (Nager syndrome) who was diagnosed prenatally as having an apparently balanced X/autosome translocation [46,X,t(X;9)(p22.1;q32)mat] inherited from a previously diagnosed mosaic translocation carrier mother [46,XX/46,X,t(X;9)(p22.1;q32)]. Replication studies on amniocytes showed the normal X chromosome to be late replicating while the same studies repeated on the infant's lymphocytes showed the translocated X chromosome to be late replicating in most cells. Late replication studies of the mother's lymphocytes demonstrated that the normal X chromosome was late replicating in most cells. The presence of Nager syndrome in this infant may be the result of critical breakpoints and/or position effects on chromosome 9, inducing expression of a gene responsible for the syndrome.

Juvenile rheumatoid arthritis in velo-cardio-facial syndrome: coincidence or unusual complication?

We report on two patients with velo-cardio-facial syndrome (VCFS) and juvenile rheumatoid arthritis (JRA). The first, a 9-year-old girl, presented with microcephaly, characteristic face, congenital heart disease, and velopharyngeal insufficiency. Fluorescence in situ hybridization (FISH) study showed deletion of D22S75 (N25), confirming the diagnosis of VCFS. At age 7, she developed joint pain, and polyarticular JRA was diagnosed. Awareness of this case led to the subsequent diagnosis of VCFS (also confirmed by FISH) in another, unrelated 12-year-old girl with characteristic face, hypernasal speech, and obesity. JRA was first diagnosed in this case at age 5 years, and she subsequently developed severe polyarticular disease. Neither patient had clinical or laboratory evidence of immunodeficiency. This observation represents the first report of the association of JRA with VCFS and raises the question of whether this is a coincidental association or a rare complication of this condition.

Maternal origin of 15q11-13 deletions in Angelman syndrome suggests a role for genomic imprinting.

Six persons with the classical Angelman syndrome (AS) phenotype and de novo deletions of chromosome 15q11-q13 were studied to determine the parental origin of the chromosome deletion. Four of the 6 patients had informative cytogenetic studies and all demonstrated maternal inheritance of the deletion. These findings, together with other reported cases of the origin of the chromosome 15 deletion in AS, suggest that deletion of the maternally contributed chromosome leads to the AS phenotype. This contrasts with the Prader-Willi syndrome (PWS) in which a similar deletion of the paternally contributed chromosome 15 is observed. In deletion cases, a parental gamete effect such as genomic imprinting may be the best model to explain why apparently identical 15q11-q13 deletions may develop the different phenotypes of AS or PWS.

Cytogenetic and molecular analysis in Angelman syndrome.

We report on cytogenetic and molecular analyses of 29 Angelman syndrome (AS) individuals ascertained in 1990 through the first National Angelman Syndrome Conference. High resolution GTG- and GBG-banded chromosomes were studied. Standard molecular analysis with six 15q11q13 DNA sequences was used to analyze copy number and parental origin of 15q11q13. Concordance between molecular and cytogenetic data was excellent. The combined data showed that 23 of the 27 probands (85%) on whom we had definitive results have deletions of the chromosome 15q11q13 region. Two classes of deletion were detected molecularly: most patients were deleted for the 5 more proximal probes, but in 2 cases the deletion extended distally to include in sixth probe. In the 13 cases where the parental origin of the deleted chromosome 15 could be established, it was maternal. There were no cases of uniparental disomy. Cytological observations of the relative sizes of the heterochromatic regions of the short arm of chromosome 15 suggested that chromosomes with large heterochromatic blocks may be more prone to de novo deletion.

Newly described form of X-linked arthrogryposis maps to the long arm of the human X chromosome.

Arthrogryposis is a heterogeneous birth defect characterized by limitation of movement at multiple joints. One in 3,000 infants is born with arthrogryposis, and at least a third of these cases have a genetic cause. Four distinct types of X-linked arthrogryposis have been reported, and a severe lethal form recently was mapped to Xpll.3-qll.2. We now report an extended family affected with a novel variant of X-linked arthrogryposis that involves only the lower limbs. Linkage analysis with polymorphic DNA markers maps the disease locus in this unique family to the long arm of the human X chromosome between DXS1220 and DXS1205 in Xq23-27.

Prevalence of 22q11 region deletions in patients with velopharyngeal insufficiency.

Velo-cardio-facial syndrome, DiGeorge syndrome, conotruncal anomaly face syndrome, tetralogy of Fallot, and pulmonary atresia with ventricular septal defect are all associated with hemizygosity of 22q11. While the prevalence of the deletions in these phenotypes has been studied, the frequency of deletions in patients presenting with velopharyngeal insufficiency (VPI) is unknown. We performed fluorescence in situ hybridization for locus D22S75 within the 22q11 region on 23 patients with VPI (age range 5-42 years) followed in the Craniofacial Clinic at the University of Florida. The VPI occurred either as a condition of unknown cause (n=16) or as a condition remaining following primary cleft palate surgery (n=7). Six of sixteen patients with VPI of unknown cause and one of seven with VPI following surgery had a deletion in the region. This study documents a high frequency of 22q11 deletions in those presenting with VPI unrelated to overt cleft palate surgery and suggests that deletion testing should be considered in patients with VPI.

Fluorescence in situ hybridization assessment of the telomeric regions of jumping translocations in a case of aggressive B-cell non-Hodgkin lymphoma.

We report a jumping translocation involving a donor chromosome 1 long arm in a case of aggressive B-cell non-Hodgkin lymphoma (NHL). Conventional cytogenetic banding studies demonstrated a breakpoint distal to the heterochromatic region of the donor 1q chromosome. Characterization by fluorescence in situ hybridization (FISH) of the jumping translocation demonstrated an apparent telomeric sequence loss of the recipient chromosomes. Additional cytogenetic aberrations, including the t(18;22) translocation associated with non-Hodgkin lymphoma, were also observed in this case. Cytogenetically similar cases of jumping translocations reported in the literature have implicated a preferential involvement of the donor chromosomes' heterochromatic regions and the telomeric regions of the recipient chromosomes. Jumping translocations are still considered rare and their appearance is associated with a poor prognosis. The presence of these specific findings for this case are discussed and compared with those previously reported in other hematologic disorders.

Angelman syndrome: clinical profile.

To further delineate the clinical and developmental features of Angelman syndrome, we collected data through three sources of information: (1) physical examinations; (2) laboratory data and family questionnaire data of affected individuals; and (3) literature review. The questionnaire data describes a generally normal prenatal and birth history. Feeding difficulties, developmental delay, or seizures were the presenting problems in all infants. The diagnosis of Angelman syndrome, however, was not made in any infant prior to 1 year of age. Except for seizures, no medical or surgical complication was common, although a variety of visual complaints or findings were common. Sixty percent of Angelman syndrome children had a cytogenetically demonstrated deletion of chromosome 15q11-q13. The individuals with and without a deletion could not be differentiated clinically. Diagnosis in early childhood is therefore difficult, and a high index of suspicion is recommended.

Prolonged neuromuscular block in a patient undergoing renal transplantation.

Prolonged neuromuscular block is an anesthetic complication that every anesthesiologist should understand. This article presents a case of prolonged neuromuscular block in a renal transplant patient that was likely due to pseudocholinesterase deficiency. The different types of pseudocholinesterase deficiency and their clinical implications are reviewed. Also discussed are the workup and other causes for prolonged neuromuscular blockade.

High cognitive functioning and behavioral phenotype in Pallister-Killian syndrome.

Pallister-Killian syndrome (PKS) is a rare syndrome of multiple congenital anomalies attributable to the presence of a mosaic supernumerary isochromosome 12p. The syndrome presents with a recognizable pattern of findings including: pigmentary skin changes, characteristic facial features (sparse anterior scalp hair, flattened midface, macrostomia, and coarsening of the facial features), and developmental delay. The developmental phenotype of PKS is quite variable, but most are considered to fall into the profound range of developmental retardation. We report on an individual with classical features of PKS with development significantly better than that reported in the literature. Developmental and behavioral testing in this individual alters the range of developmental expectation in PKS, and highlights the need for consideration of chromosomal analysis in individuals with normal or near-normal intelligence if other physical phenotypic features of PKS are present.