Angelman syndrome: The blurred lines of interpretation in cognitive defects.

Angelman syndrome is a neuro-developmental disorder with a genetic basis in maternal genomic imprinting that presents with cognitive and behavioral impairment. The distinction between the presentations of disorders causing developmental delay may be vague in early life, resulting in the potential delay in diagnosis and intervention. We report a case of Angelman syndrome with initial diagnostic confusion with multiple associated pathologies. A holistic evaluation and management of such patients is necessary.

Introduction

Born out of the description of three seemingly dissimilar cases in 1965, Angelman syndrome is a neurological disorder with an estimated prevalence in children and young adults between 1 in 10,000 and 1 in 20,000.[12] It presents with consistent features of developmental delay, speech impairment, movement or balance disorders typified by gait ataxia and tremulous movements and the behavioral uniqueness in the form of a happy demeanor.[3] Microcephaly and seizures though common are not universal.[3] We report a 10-year-old girl with Angelman Syndrome with initial diagnostic confusion due to unusual findings.

Case Report

A 10-year-old girl presented with developmental delay as noticed by her mother, abnormal limb movements, recurrent fever and multiple episodes of seizures. Symptoms were first noticed after a bout of fever at 1-year of age associated with seizures involving jerky movements of all limbs and uprolling of eyes. There had been multiple episodes of seizures since then, the last one being 2 years back. There was a history of delay of all motor, social adaptive and language milestones. At the time of presentation, child had achieved sitting with support (7–8 months), sitting without support (1.5 years), standing with support (4–5 years) and walking with support (7–8 years). She was unable to hold on to objects, showed no ability in toilet training and was only able to coo and utter monosyllables. Parents also gave a history of recurrent episodes of passage of worms. There was a history of the child biting at her own fingers to the point where ulcers developed over them, and her parents often had to restrict her hands with a cloth to prevent injury. Antenatal, perinatal and postnatal history was uneventful. She had one elder brother who had been a normal child without any complaints.

On evaluation, she weighed 17.58 kg (<3 SD), was 110 cm (<3 SD) tall and had a head circumference of 47 cm (<2 SD). Vital parameters were normal. Marked pallor was present along with platynychia. Skin was dry with no neurocutaneous markers. There were bite marks and ulcers over fingers of both hands with the thumbs, especially affected badly having bleeding ulcers and abrasions present bilaterally. Microcephaly was present with hypertelorism and synophrys along with a tendency to keep her mouth open with a protruding tongue. On central nervous system examination, the child had stranger anxiety, bilateral upper and lower limbs were wasted, along with increased tone in all four limbs. Attitude was one of flexion at the elbow joint. Tremors were present bilaterally but more in the right hand than left. The child had a wide based gait. All deep tendon reflexes were brisk. On cranial nerve examination, bilateral optic disc atrophy was noted on fundoscopy. There was no appreciable sensory deficit or cerebellar dysfunction, autonomic deficit or neck rigidity. A soft systolic murmur was present over the apical area on auscultation, which was probably hemodynamic.

On investigations hemoglobin was 3 g%, red cell indices were reduced and peripheral smear was suggestive of microcytic hypochromic anemia. The erythrocyte sedimentation rate was 25 mm in the 1st h. Serum iron was 55 μg%, total iron binding capacity was 445 μg% and transferrin saturation was 15%. Renal function tests, liver profile, serum uric acid, vitamin B12 and folate levels were normal. Electroencephalography (EEG) showed abnormal interictal sleep with epileptiform activity in bifrontal region. Magnetic resonance imaging of the brain was normal. Considering her tendency towards self-mutilation in the form of biting, she was evaluated for Lesch Nyhan syndrome but high performance liquid chromatography for nucleic acids were found to be normal. After consulting a pediatric neurologist, the child was evaluated for Angelman syndrome by fluorescence in situ hybridization, which revealed 100% heterozygous deletion of small nuclear ribonucleoprotein N (SNRPN), which is diagnostic of Angelman syndrome.

There is no definitive cure for Angelman syndrome. The patient was managed for iron deficiency anemia with blood transfusions. Oral iron replacement therapy was started along with vitamin B12 and folate supplementation. Sodium valproate was started for control of seizures. The prognosis was explained to the parents, and she was discharged after her symptoms had receded.

Discussion

Angelman syndrome is a genetic disorder resulting from micro-deletion in the maternally derived chromosome 15q11.2–15q13. The UBE3A has been identified as the Angelman syndrome gene.[45] This is under further regulation of the SNRPN gene via a distant imprinting control area.[6] Our patient had a 100% deletion of SNRPN and hence conformed to the diagnosis of Angelman syndrome.

Initial diagnostic confusion in this case stemmed from the typical tendency towards self-mutilation, which in conjunction with cognitive defects in the child aroused clinical suspicion of Lesch Nyhan syndrome. In a recent report, the authors hypothesized that self-injurious behavior may present a diagnostic challenge in cases of mental retardation as the lines between separate disease entities with this presentation blurs.[7] The diagnosis of Angelman syndrome in this patient ultimately conformed to the established criteria for clinical diagnosis which divides presenting clinical features as consistent (100%), frequent (>80%) and associated (20–80%).[3] The consistent features include functionally severe developmental delay, speech impairment involving minimal or no use of words with relatively advanced receptive and nonverbal communication as compared to verbal, movement and balance disorders chiefly as gait ataxias and tremulous limb movements and the behavioral uniqueness seen as a happy demeanor. Frequent features include a delayed, disproportionate growth of head circumference, seizures characteristically presenting before 3 years of age and EEG findings of typically large amplitude slow spike waves (usually 2–3/s) facilitated by eye closure. Multiple associated features are also described including morphological and behavioral traits.

Our patient conformed to all the consistent features and the first two frequent features. EEG findings for our patient included epileptiform activity in bilateral frontal region suggestive of abnormal interictal sleep. In literature, the EEG is reported to be more abnormal than clinically expected, consisting of symmetrical high voltage slow wave activity (4–6 c/s) throughout, unrelated to drowsiness, very large amplitude slow activity at 2–3 c/s occurring in runs and more prominent anteriorly along with spikes or sharp waves, mixed with large amplitude 3–4 c/s components, seen posteriorly during eye closure.[8910]

Facial morphology of hypertelorism and synophrys seen in our patient are not recognized features of Angelman syndrome though the microcephaly present does conform to the literature. Atypical neurological finding in our patient involved optic atrophy present bilaterally with no seemingly explainable antecedent cause. The severe anemia present in this patient could be explained by the nutritional deficiency due to worm infestation.

The co-existent pathologies in the child were a cause of significant morbidity. With adequate counseling of the family, care may be taken to prevent the development of such eventualities.

Conclusion

The exact incidence and prevalence of Angelman syndrome has not been studied in India. The blurred lines of distinction between diseases presenting in childhood with cognitive disturbances, warrants holistic evaluation for such congenital neurodevelopmental disorders. The affection in such cases may be global albeit stemming from the cognitive defect. A properly counseled family in such cases may lead to a better quality of life.