LETTERS TO THE EDITOR

 

Angelman syndrome and celiac disease

Síndrome de Angelman y enfermedades celiacas

 

 

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Key words: Angelman syndrome. Celiac disease.

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Dear Editor,

A 42-years old woman has been suffering from psychomotor retardation since early childhood. She needed permanent assistance from her family for all basic activities of daily life and never developed neither language skills, nor sphincter control. She has a peculiar face and walks with small steps, without motor deficit. She also presents traits of altered behavior, smiles continuously without apparent cause, and scratches when she is upset. She has severe constipation since childhood (1 deposition/week), and requires frequent intake of laxatives. The body mass index was normal (21 kg/m²).

At age of 11 she presented a picture of herpetiform dermatitis. She has suffered from epilepsy since adolescence. At first, she had frequent convulsive seizures, mixed with episodes of absence with a myoclonic component. She was also diagnosed of hypothyroidism at age 37, and has been treated since then with substitution therapy. The diagnosis of Angelman syndrome (AS) was established based on clinical features, and confirmed by fluorescence in situ hybridization (FISH) on the affected region, which showed the presence of a microdeletion in the q11-q13 region of one of the chromosomes 15.

The patient came to our clinic 2.5 years ago with the chief complaint of marked food intolerance with frequent nausea and repeated episodes of vomiting and acid reflux. She was unresponsive to antiemetics or PPIs. She had a significant ferropenic anemia (Hb = 10.4 g/dL), which was refractory to oral iron preparations.

A colonoscopy and an upper gastrointestinal (GI) endoscopy were normal. Duodenal biopsies showed an increase of intraepithelial lymphocytes (LIEs) (> 40%), without villous atrophy (Marsh I). A slightly increased tissue transglutaminase (3 U/ml) was detected, being DQ2-positive in one allele and DQ8-positive in both.

Based on the histological, serological, and genetic findings a celiac disease (CD) was diagnosed, and the family was advised to feed the patient with a gluten-free diet (GFD). We also administered parenteral iron, once/week during 3 months, with total resolution of anemia.

The follow-up examinations to date (five in two years and a half overall) show that the patient remains asymptomatic, without anemia and improved control of the hypothyroidism and epilepsy, after the first year of the GFD. Constipation has notably improved (1 deposition/2 days). Upper GI endoscopy was repeated after 2 years of the GFD, showing that the lymphocy-tic enteritis had resolved with normal appearance of the intestinal mucosa (Marsh 0). The follow-up laboratory tests performed during these 2 years are shown in table I.

 

The AS is different from the one caused by abnormal paternal contribution to the same locus, known as Prader-Willi syndrome. The genetic basis for AS was described for the first time in 1997, and consists of a disruption of the UBE3A/E6-AP gene. The corresponding protein plays a role in the ubiquitin-dependent degradation pathway, which is important for the regulation of protein homeostasis associated with the neuronal synaptic function (1-3).

We conclude that this patient presents CD associated with AS and epilepsy with an autoimmune disorder hypothyroidism, which is often associated with CD. She had also a herpetiform dermatitis, together with refractory chronic iron deficiency anemia, which was corrected permanently with parenteral iron and GFD. The seizures have also decreased and an improvement in behavior is apparent.

The patient presented duodenal lymphocytic enteritis (Oberhuber-Marsh modified classification) (4,5), with increased serological markers and compatible genetic susceptibility, as well as upper digestive intolerance and striking constipation as the predominant digestive symptoms.

We believe that to the same extent as in other chromosomopathies such as Turner's syndrome, Down's syndrome or Williams syndrome, in patients with AS and a compatible clinical picture, the presence of an associated CD should be considered and further investigated (6-10).

 

L. Rodrigo¹, N. Álvarez¹, J. Salas-Puig² and C. Hernández-Lahoz²
Departments of ¹Gastroenterology and ²Neurology. Hospital Universitario Central de Asturias (HUCA). Oviedo, Asturias. Spain.

 

References

1. Gurrieri F, Accadia M. Genetic imprinting: the paradigm of Prader-Willi and Angelman syndromes. Endocr Dev 2009; 14: 20-8.        [ Links ]

2. Williams C. Angelman syndrome scientific symposium on the structure and function of UBE3A/E6AP. J Child Neurol 2009; 24: 904-8.        [ Links ]

3. Tzagkaraki E, Christalena S, Helen F, Argyris D, Ariadni M, Emmanuel K. Novel human pathological mutations. Gene symbol: UBE3A. Disease: Angelman syndrome. Hum Genet 2009; 126: 331.        [ Links ]

4. Oberhuber G, Caspary WF, Kirchner T, Borchard F, Stolte M. Diagnosis of celiac disease and sprue. Recommendations of the German Society for the Pathology Task Force on Gastroenterology. Pathology 2001; 22: 72-81.        [ Links ]

5. Marsh MN. Gluten major histocompatibility complex and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (celiac sprue). Gastroenterology 1992; 102: 330-54.        [ Links ]

6. Rodrigo L. Celiac disease. World J Gastroenterol 2006; 12: 6585-93.        [ Links ]

7. Frost AR, Band MM, Conway GS. Serological screening for coeliac disease in adults with Turner's syndrome: prevalence and clinical significance of endomysium antibody positivity. Eur J Endocrinol 2009; 160: 675-9.        [ Links ]

8. Henderson A, Lynch SA, Wilkinson S, Hunter M. Adults with Down's syndrome: the prevalence of complications and health care in the community. Br J Gen Pract 2007; 57: 50-5.        [ Links ]

9. Giannotti A, Tiberio G, Castro M, Virgilii F, Colistro F, Ferretti F, et al. Celiac disease in Williams syndrome. J Med Genet 2001; 38: 767-8.        [ Links ]

10. Romanos J, van Diemen CC, Noite IM, Trynke G, Zhermakova A, Fu J, et al. Analysis of HLA and non-HLA alleles can identify individuals at high risk for celiac disease. Gastroenterology 2009; 137: 834-40.        [ Links ]