Wednesday, October 25, 2017

Alpha-thalassemia X-linked intellectual disability syndrome

Inspired by a patient

Schenkel LC, Kernohan KD, McBride A, Reina D, Hodge A, Ainsworth PJ, Rodenhiser DI, Pare G, Bérubé NG, Skinner C, Boycott KM, Schwartz C, Sadikovic B. Identification of epigenetic signature associated with alpha thalassemia/mental retardation X-linked syndrome. Epigenetics Chromatin. 2017 Mar 10;10:10.

Alpha thalassemia/mental retardation X-linked syndrome (ATR-X) is caused by a mutation at the chromatin regulator gene ATRX. The mechanisms involved in the ATR-X pathology are not completely understood, but may involve epigenetic modifications. ATRX has been linked to the regulation of histone H3 and DNA methylation, while mutations in the ATRX gene may lead to the downstream epigenetic and transcriptional effects. Elucidating the underlying epigenetic mechanisms altered in ATR-X will provide a better understanding about the pathobiology of this disease, as well as provide novel diagnostic biomarkers.
We performed genome-wide DNA methylation assessment of the peripheral blood samples from 18 patients with ATR-X and compared it to 210 controls. We demonstrated the evidence of a unique and highly specific DNA methylation "epi-signature" in the peripheral blood of ATRX patients, which was corroborated by targeted bisulfite sequencing experiments. Although genomically represented, differentially methylated regions showed evidence of preferential clustering in pericentromeric and telometric chromosomal regions, areas where ATRX has multiple functions related to maintenance of heterochromatin and genomic integrity.
Most significant methylation changes in the 14 genomic loci provide a unique epigenetic signature for this syndrome that may be used as a highly sensitive and specific diagnostic biomarker to support the diagnosis of ATR-X, particularly in patients with phenotypic complexity and in patients with ATRX gene sequence variants of unknown significance.

Stevenson RE. Alpha-Thalassemia X-Linked Intellectual Disability Syndrome. 2000 Jun 19 [updated 2014 Nov 6]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, Stephens K, Amemiya A, Ledbetter N, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017. Available from
PubMed PMID: 20301622.

Alpha-thalassemia X-linked intellectual disability (ATRX) syndrome is characterized by distinctive craniofacial features, genital anomalies, severe developmental delays, hypotonia, intellectual disability, and mild-to-moderate anemia secondary to alpha-thalassemia. Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short nose, tented vermilion of the upper lip, and thick or everted vermilion of the lower lip with coarsening of the facial features over time. Although all affected individuals have a normal 46,XY karyotype, genital anomalies range from hypospadias and undescended testicles to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Global developmental delays are evident in infancy and some affected individuals never walk independently or develop significant speech.
The diagnosis of ATRX syndrome is established in individuals with somatic abnormalities, intellectual disability, hypotonia, abnormal hemoglobin H production, and a family history consistent with X-linked inheritance. ATRX is the only gene in which mutation causes ATRX syndrome.
Treatment of manifestations: Calorie-dense formula and/or gavage feeding as needed for adequate nutrition; anticholinergics, botulinum toxin type A injection of the salivary glands, and/or surgical redirection of the submandibular ducts for excessive drooling; early intervention programs and special education. Prevention of secondary complications: Antibiotic prophylaxis and vaccination to prevent pneumococcal and meningococcal infection in those with asplenia. Surveillance: Regular assessment of growth in infancy and childhood; regular monitoring of developmental progress. Other: Anemia rarely requires treatment.
ATRX syndrome is inherited in an X-linked manner. The mother of a proband may be a carrier or the affected individual may have a de novo pathogenic variant. Female carriers have a 50% chance in each pregnancy of transmitting the ATRX pathogenic variant; offspring with a 46,XY karyotype who inherit the ATRX pathogenic variant will be affected; offspring with a 46,XX karyotype who inherit the pathogenic variant are unaffected female carriers. Affected individuals do not reproduce. Carrier testing for at-risk females and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known.

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