Alpha-Thalassemia/mental Retardation syndrome, X-Linked (ATRX)

What is Alpha-Thalassemia/mental Retardation syndrome, X-Linked (ATRX)?

This rare disease is a genetic condition that affects mainly males. There are more than 200 reported cases to date.

The main features of the syndrome include severe intellectual disability, developmental delay, and unique facial features.

This syndrome is also known as:
Alpha-thalassemia/mental Retardation Syndrome; Nondeletion Type Atr-x Syndrome Atr; Nondeletion Type ATR2

What gene changes cause Alpha-Thalassemia/mental Retardation syndrome, X-Linked (ATRX)?

Mutations to the ATRX gene are responsible for the syndromes. Mutations to this gene are then believed to affect the HBA1 and HBA2 genes, defects in which are responsible for alpha thalassemia.

As an X-linked recessive pattern inherited condition, males can not pass the mutation onto their sons.

Syndromes inherited in an X-linked recessive pattern generally only affect males. Males only have one X chromosome, and so one copy of a gene mutation on it causes the syndrome. Females, with two X chromosomes, only one of which will be mutated, are not likely to be affected.

What are the main symptoms of Alpha-Thalassemia/mental Retardation syndrome, X-Linked (ATRX)?

Intellectual disability and delayed development are serious symptoms of the syndrome. Most individuals will have very limited to zero speech and delayed motor skills.

Common facial features include widely spaced eyes, small nose, unturned nostrils, and low-set ears. Facial features become coarser over time, leading to a flatter face and shortened nose. A very small head, short stature and skeletal abnormalities are also common presenting features.

Health conditions related to the condition include mild alpha thalassemia, pale skin, weakness and fatigue. Reflux and severe constipation are also common.

Possible clinical traits/features:
Infantile muscular hypotonia, Abnormality of metabolism/homeostasis, Short nose, Nausea and vomiting, Neurological speech impairment, Anteverted nares, Myopia, Intellectual disability, Kyphoscoliosis, Muscular hypotonia, Macroglossia, Male pseudohermaphroditism, Tapered finger, Low-set ears, Micropenis, Microtia, Hypospadias, Visual impairment, Global developmental delay, Postnatal growth retardation, Cognitive impairment, Hypoplasia of penis, Hypertelorism, Hemivertebrae, Hemiplegia/hemiparesis, Short stature, Hydronephrosis, Gastroesophageal reflux, Depressed nasal bridge, Recurrent urinary tract infections, Shawl scrotum, Renal agenesis, Posteriorly rotated ears, Seizure, Optic atrophy, Sensorineural hearing impairment, Absent frontal sinuses, Aganglionic megacolon, Ambiguous genitalia, Abnormality of the dentition, Abnormality of the tongue, Aplasia/Hypoplasia of the corpus callosum, Self-injurious behavior, Autism, Abnormality of the fontanelles or cranial sutures, Abnormality of movement

How does someone get tested for Alpha-Thalassemia/mental Retardation syndrome, X-Linked (ATRX)?

The initial testing for Alpha-Thalassemia/mental Retardation Syndrome, X-Linked can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow. 

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.   

Medical information on Alpha-Thalassemia/mental Retardation Syndrome, X-Linked

Weatherall et al., (1981) first described a group of mentally retarded patients with haematological evidence of haemoglobin H disease. Wilkie et al., (1990) have carried out detailed molecular studies and demonstrated that some patients have extensive deletions involving the alpha-globin gene, whereas in others no deletion is apparent.
This entry refers to cases in the latter group which are caused by an X-linked gene. All cases have been male, apart from a phenotypic female in the original report who had a 46,XY karyotype. The X-linked family described by Porteous and Burn (1990) have been shown to have this condition. Clinically there is short stature, microcephaly, hypertelorism, a flat face with a depressed nasal bridge, epicanthic folds, macrostomia, small teeth, and a V-shaped upper lip or short philtrum with an everted lower lip. Cryptorchidism or hypogonadism is common and seizures are a feature. Reardon et al., (1995) and McPherson et al., (1995) and Jezela-Stanek (2009), reported further cases with male pseudohermaphroditism. Ogle et al., (1994) reported two sibs where the only genital abnormality was a deficiency of the foreskin. One reported case had hemivertebrae. Two cases have been reported with asplenia (Villard et al., 2000, Leahy et al., 2005).
Martucciello et al., (2006) reported on the gastointestinal symptoms in a group of 128 patients, and stressed the frequency of vomiting, regurgitation, abdominal pain and constipation. Pseudo-volvulus and ultra-short Hirschsprung does occur.
The diagnosis is confirmed by demonstrating haematological features of alpha thalassaemia. Red blood cells are usually hypochromic and microcytic and contain HbH bodies, which must be demonstrated by staining with 1% brilliant cresyl blue. HbH bodies are present in 1-40% of red cells. In some cases great difficulty might be encountered in demonstrating these, and tests might need to be repeated (see Logie et al., 1994 and Gibbons et al., 1995).
The X-linked pedigree described by Chudley et al., (1988) has similarities, but has been found to be negative for HbH bodies (but has a mutation - see Abidi et al., 2005). In general, about 85% of cases have HbH bodies (Reardon, 2005 - personal communication).


The gene maps to Xq12-Xq21 (Gibbons et al., 1992). Houdayer et al., (1993) confirmed this linkage in a large French family. Gibbons et al., (1995) isolated a gene for the condition. It is a global transcriptional regulator, XNP (XH2), a member of a subgroup of the helicase superfamily (Hendrich and Bickmore (2001). Picketts et al., (1996) characterised the full length cDNA and described further mutations. Mutations in seven Japanese families were reported by Wada et al., (2000). Villard et al., (1996) reported a large family where one affected individual had clinical features of the condition but no HbH bodies, whereas affected cousins had classical features of the condition. Ion et al., (1996) demonstrated a four base pair deletion at an intron/exon boundary in a large family segregating for the condition associated with sex reversal. Some cases had features of partial optic atrophy and partial ocular albinism. Further mutations were reported by Gibbons et al., (1997) and Villard et al., (1999). Bachoo and Gibbons (1999) reported two females where there was evidence of gonadal mosaicism. McDowell et al., (1999) showed that the ATRX protein localises to pericentromeric heterochromatin and the short arms of acrocentric chromosomes.
Saugier-Veber et al., (1995) suggested that Juberg-Marsidi syndrome (qv) might be allelic. Mutations have now been found in cases with features of Juberg-Marsidi syndrome (Villard et al., 1996), and in cases with the full ATR-X phenotype without evidence of alpha thalassemia.
Ades et al., (1991) reported two brothers who were suggested to have Smith-Fineman-Myers syndrome (qv) (one with asplenia). There were similarities to alpha thalassaemia-mental retardation syndrome (non-deletional type). A splice site mutation in the ATRX gene was subsequently detected in this family (Villard et al., 2000).
The family reported by Carpenter et al., (1999) most likely manifested this condition, although mental retardation was only moderate and genitalia and testicular volumes were normal. Carrier females had skewed X-inactivation in this family. Lossi et al., (1999) report evidence that the mutation causes skewed X-inactivation in heterozygous females. A manifesting female (no pictures shown) with totally skewed X-inactivation was reported by Badens et al., (2006).
It is possible that the two male sibs reported by Achermann et al., (1999) had this condition. No mention of ATR-X was made in the article. Note that cases within a family vary considerably. Some might only have mild retardation, epilepsy and 'subtle dysmorphic features' - pictures shown (Guerrini et al., 2000). Gibbons and Higgs (2000) provide a good review of the molecular-clinical spectrum of the condition.
Yntema et al., (2002) reported a large pedigree where affected males had borderline to moderate mental retardation. Skewed X-inactivation was found in all carrier females. HbH inclusion bodies were found in three out of four affected males tested. The characteristic facial features were not present in adulthood from the photographs published. All showed behaviour problems with chaotic behaviour and aggressive outbursts. One patient appears to have had seizures. The genitalia are not mentioned.
A female reported by Akahoshi et al., (2005) with a 16p13 duplication, clinically looked like ATR-X. The authors suggested that some target genes of the ATRX protein might reside in the duplicated segment. This is the same patient that was reported by Kurosawa et al., (1996). Further evidence that duplications of the ATRX gene can cause the phenotype is reported by Thienpont et al., (2007). The duplication was identified by array-CGH. One of the sibs had an absent gall bladder. Another duplication was reported by Friez et al., (2009).
Badens et al., (2006) performed a genotype-phenotype analysis in 16 families and reported that mutations in the helicase domain are associated with a milder phenotype than those in the PHD domain.

* This information is courtesy of the L M D.

If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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