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Lyonization Effects of the T(X;16) Translocation on the Phenotypic Expression in a Rare Female with Menkes Disease

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Lyonization Effects of the T(X;16) Translocation on the Phenotypic Expression in a Rare Female with Menkes Disease 0031-3998/09/6503-0347 Vol. 65, No. 3, 2009 PEDIATRIC RESEARCH Printed in U.S.A. Copyright © 2009 International Pediatric Research Foundation, Inc. Lyonization Effects of the t(X;16) Translocation on the Phenotypic Expression in a Rare Female With Menkes Disease PIETRO SIRLETO, CECILIA SURACE, HELENA SANTOS, ENRICO BERTINI, ANNA C. TOMAIUOLO, ANTONIETTA LOMBARDO, SARA BOENZI, ELSA BEVIVINO, CARLO DIONISI-VICI, AND ADRIANO ANGIONI Cytogenetics and Molecular Genetics [P.S., C.S., A.C.T., A.L., A.A.], Division of Metabolism [H.S., S.B., E.B., C.D.-V.], Molecular Medicine [E.B.], Bambino Gesu` Children’s Hospital, Roma 00165, Italy; Servic¸o de Pediatria [H.S.], Centro Hospitalar Gaia Espinho, EPE, Vila Nova de Gaia, 4400-129, Portugal ABSTRACT: Menkes disease (MD) is a rare and severe X-linked Because MD is X-linked recessive, affected females are very recessive disorder of copper metabolism. The MD gene, ATP7A rare. So far, only eight cases have been described in literature and ϩϩ (ATPase Cu transporting alpha polypeptide), encodes an ATP- cytogenetic studies have been reported only in five cases (Table dependent copper-binding membrane protein. In this report, we describe 1): one displayed a mosaicism 45,X/46,XX and the remaining a girl with typical clinical features of MD, carrying a balanced translo- cation between the chromosomes X and 16 producing the disruption of four showed a de novo balanced translocation between the chro- one copy of ATP7A gene and the silencing of the other copy because of mosome X and an autosome. The breakpoint on the X chromo- the chromosome X inactivation. Fluorescence in situ hybridization some is Xq13 where the gene ATP7A has been mapped. experiments with bacterial derived artificial chromosome probes re- In this article, we describe a female with MD carrying a vealed that the breakpoints were located within Xq13.3 and 16p11.2. balanced translocation between the chromosomes X and 16 Replication pattern analysis demonstrated that the normal X chromo- producing the disruption of one copy of ATP7A gene and some was late replicating and consequently inactivated, whereas the silencing of the other copy. Moreover, the late-replicating der(X)t(X;16), bearing the disrupted ATP7A gene, was active. An inno- chromosome X has been investigated and an easy and reliable vative approach, based on FMR1 (fragile X mental retardation 1) gene polymorphism, has been used to disclose the paternal origin of the innovative approach has been used to disclose the parental rearrangement providing a new diagnostic tool for determining the origin of the rearrangement. parental origin of defects involving the X chromosome and clar- Clinical report. A 6.5-mo-old girl presenting failure to ifying the mechanism leading to the cytogenetic rearrangement thrive, facial dysmorphisms, and psychomotor delay was ad- that occurred in our patient. (Pediatr Res 65: 347–351, 2009) mitted for evaluation. She was the only daughter of a remotely consanguineous couple (cousins in fourth degree); the father enkes disease (MD) is a recessive X-linked syndrome had two other twin daughters who died in the newborn period M described by Menkes (1) more than 40 y ago. It is with neonatal hepatitis. Family history was negative for neu- characterized by progressive cerebral and cerebellar degener- rologic diseases. Her gestation was the result of in vitro ation, growth retardation, and peculiar scalp hair (2). The fertilization, and she was born at 37 wk of gestation by incidence is 1/250,000 (ORPHA565, http://www.orpha.net) emergency caesarean section because of meconium staining of and, in most of the cases, it is responsible for death before 3 y of age. Patients with MD have been found to have a defect in amniotic fluid. Apgar score was 5 and 9 at first and fifth copper metabolism and low levels of serum copper and cer- minute after birth, needing resuscitation with cardiac massage uloplasmin (3). MD phenotype is due to mutations occurring and positive pressure ventilation. Birth weight was 2270 g in the ATP7A (ATPase Cuϩϩ transporting alpha polypeptide) (below the 10th percentile). gene, which encodes an ATP-dependent membrane protein (4) At 5 mo, during hospitalization for respiratory syncytial virus that regulates the release of Cu ions at the outer cell mem- (RSV), bronchiolitis, psychomotor delay, failure to thrive, and brane, affecting the amount of copper-loaded enzymes, as dysmorphic features facies (i.e. frontal bossing, epicanthus, ceruloplasmin and metallothionein (5). broad-based nose, low set ears) were noticed. Laboratory inves- Diagnosis can be established by detecting low levels of tigations showed reduced circulating levels of ceruloplasmin. copper and ceruloplasmin in the serum, and high levels in At 6.5 mo, she was referred to our hospital for a metabolic cutaneous fibroblasts. The diagnosis can be confirmed by evaluation. At admission weight, height, and head circumference identification of the gene mutations. Genetic analysis also were all below the third percentile; the skin was pale and dry, hair allows screening of carrier females, who may have patches was scarce, distorted and harsh, with alopecia in the occipital with cutaneous and hair anomalies, and prenatal diagnosis region. Physical examination showed axial hypotonia, motor through chorionic villus sampling. Abbreviations: ATP7A, ATPase Cuϩϩ transporting alpha polypeptide; Received September 2, 2008; accepted October 26, 2008. BAC, bacterial artificial chromosome; BrdU, 5-Bromo-2Ј-deoxyuridine; Correspondence: Cecilia Surace, Ph.D., Cytogenetics and Molecular Genetics, Bam- bino Gesu` Children’s Hospital, Piazza S. Onofrio 4, Roma 00165, Italy; e-mail: FMR1, fragile X mental retardation 1; MD, Menkes disease; WCP, whole [email protected] chromosome painting probe; XIST, X inactive-specific transcript 347 348 SIRLETO ET AL. Table 1. Summary of female patients affected by Menkes disease reported in literature Case Karyotype FISH Late replicating X Reference 1 46,X,t(X;2)(q13;q32.2) ϪϪ 14 2 45,X/46,XX ϪϪ 16 3 46,X,t(X;1)(q13;q12) ϩϪ 15 4 46,X,t(X;21)(q13.3;p11.1) ϩ 16/20 3 5 46,X,t(X;13)(q13.3;q14.3) ϩ 50/50 13 6 46,X,t(X;16)(q13.3;p11.2) ϩ 50/50 Present article Karyotype, FISH data, and replication pattern of normal chromosome X were listed. delay with no head control, with absence of abdominal organo- no evidence of urinary tract infections. Occasionally, she had megaly. Ophthalmogical examination was normal. brief seizures treatment consisted in carbamzepine, oral ba- As shown in Table 2, laboratory studies displayed marked clophen, cefixime as prophylaxis for urinary tract infections, reduction of serum copper and ceruloplasmin levels. Blood and rehabilitation physiotherapy. lactate was elevated (49 mg/dL; normal Ͻ20) and urine The study was approved by the Bambino Gesu` Children’s organic acid analysis showed increased excretion of lactate, Hospital Ethics Committee, and informed consent was ob- succinate, malate, and 2-ketoglutarate. tained from the patient’s parents. The 64Cu-uptake analysis in cultured fibroblasts showed a significant increase in copper uptake, confirming the clinical MATERIALS AND METHODS suspect of MD. Culturing, harvesting of peripheral blood cells, and chromosome banding Cerebral imaging by angio-MRI disclosed increased tortu- were performed according to standard methods. GTG-banded chromosomes osity of all intracranial arteries (Fig. 1). were studied and the karyotype was described consistent with the Interna- tional System for Human Cytogenetic Nomenclature (6). The karyotype analysis showed a balanced translocation Fluorescence in situ hybridization (FISH) was carried out as previously between the long arm of X chromosome and the short arm of described (7) using whole chromosome painting probes for the chromosomes X chromosome 16 described as 46,X,t(X;16)(q13.3;p11.2). and 16 (Appligene Oncor, Downers Grove, IL). To characterize the rearrange- ment, bacterial artificial chromosome (BAC) clones RP11-666O2 (AC020765; At 11 mo, she developed partial epileptic seizures that were 16p11.2), and RP11-101E7 (AC009019; 16p12.1) and P1 artificial chromosome controlled with carbamazepine. At 17 mo, right ureteral ecta- clone RP3-465G10 (AL645821; Xq21.1, containing ATP7A gene) were used as sia was detected. probes in FISH analysis. They were selected according to the NCBI database (www.ncbi.nlm.nih.gov, Build 35.1). The clones were obtained from the Roswell In the last evaluation, at the age of 26 mo, the child Park Cancer Institute library (http://www.chori.org/bacpac/). BAC and P1 artifi- maintained an inadequate growth (below third percentile), cial chromosome probes were directly labeled with Texas-Red-dUTP and fluo- with severe psychomotor delay, just being able to control the rescein-dUTP (PerkinElmer Lifesciences, Boston, MA). Further FISH experi- ments were carried out using X inactive-specific transcript (XIST) site probe head and visually following an object. She developed no (Appligene Oncor) Digital images were obtained using a Nikon Eclipse E1000 language, had bilateral convergent strabismus, severe axial epifluorescence microscope equipped with a cooled CCD camera Photometrics hypotonia with limb hypertonia, and right ureteral ectasia with CoolSNAP FX. Pseudo coloring and merging of images were performed with Genikon software v3.6.16. To evaluate the chromosome X late-replicating further experiments were Table 2. Levels of serum copper and ceruloplasmin at different performed using BrdU-Hoechst-Giemsa method. The thymidine analog, 2Јde- Ј ages of the patient oxycytidine hydrochloride and 5-Bromo-2 -deoxyuridine (BrdU), is incorpo- rated into chromosomes during the S phase (DNA synthesis) of the cell cycle. Months 6.5 11 26 If the BrdU have added when the S phase is ending and all DNA regions has Serum copper (␮g/dL) N: 51–133 8.4 22.6 — been synthesized except late replicating regions, only those that late replicate Ceruloplasmin (␮g/dL) N: 20–60 0 6 13 (e.g.
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