Journal of Genetic Disorders & Genetic Reports ISSN: 2327-5790

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Case Report, J Genet Disor Genet Rep Vol: 5 Issue: 4

Smith-Magenis Syndrome Treated with Ramelteon and Amphetamine-dextroamphetamine: Case Report and Review of the Literature

Baek WS1* and Elsea SH2
1Parkside Medical Group, 1310 San Bernardino Rd, Suite 102, Upland, CA 91786, USA
2Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB 2015, Houston, TX 77030, USA
Corresponding author : Dr. Baek WS
MD,Parkside Medical Group, 1310 San Bernardino Rd, Suite 102, Upland, CA 91786, USA
Tel: 909 608 2008
Fax:
909 608 7705
E-mail:
[email protected]
Received: October 18, 2016 Accepted: November 02, 2016 Published: November 09, 2016
Citation: Baek WS, Elsea SH (2016) Smith-Magenis Syndrome Treated with Ramelteon and Amphetamine-dextroamphetamine: Case Report and Review of the Literature. J Genet Disor Genet Rep 5:4. doi: 10.4172/2327-5790.1000145

Abstract

Objective: Smith-Magenis syndrome (SMS) is a monogenetic disorder caused by haploinsufficiency of the retinoic acid-induced 1 (RAI1) gene on 17p11.2. SMS patients are dysmorphic with developmental delay, autism, attention-deficit hyperactivity disorder (ADHD), and insomnia. Treating the insomnia, ADHD, and disruptive behavior are key in managing SMS; however, to date there are no treatment guidelines or FDA-approved medications.

Methods: We present a case of a 7-year-old girl with developmental delay, insomnia, and behavioral problems whom we had diagnosed with SMS, and treated her insomnia and ADHD.

Results: Ramelteon 4 mg at night decreased her CSHQ (Children Sleep Habits Questionnaire) score from 91 to 79, and amphetamine-dextroamphetamine salt 30 mg daily lowered her Vanderbilt ADHD parent rating scale from 70 to 54.

Conclusions: Ramelteon may be effective in treating insomnia in SMS; larger randomized studies would be beneficial in demonstrating the efficacy and safety of these medications in the future.

Keywords: SMS; RAI1; Ramelteon; ADHD; Amphetamine-dextroamphetamine; CSHQ; Vanderbilt ADHD parent rating scale

Keywords

SMS; RAI1; Ramelteon; ADHD, Amphetamine-dextroamphetamine; CSHQ; Vanderbilt ADHD parent rating scale

Abbreviations

SMS: Smith-Magenis syndrome; RAI1: Retinoic acid-induced 1; ADHD: Attention deficit hyperactivity disorder; CSHQ: Children Sleep Habits Questionnaire

Introduction

SMS is a monogenetic disorder caused by haploinsufficiency of the RAI1 gene on chromosome 17p11.2 [1,2]. It is a complex neurobehavioral disorder with features of brachycephaly, brachydactyly, intellectual and speech delay. Treating the insomnia, ADHD, obesity, and disruptive behavior is the main focus of clinically managing SMS [3,4].
We report a case of SMS where the combination of ramelteon and amphetamine-dextroamphetamine salts was safe and effective in treating this condition.

Case Presentation

A 7-year-old girl presented with developmental delay, insomnia, and behavioral problems.
She was born at 35 weeks and weighed 5 lbs. at birth. She had respiratory distress of the newborn. She had syndactyly on both hands but received surgery only for the right third and fourth digits.
Her first words were at 18 months, and she started walking at 5 years of age. At age 7, she was in special education and at times, would hit other children. She had severe insomnia with daytime sleepiness. She was impulsive, hyperactive, and inattentive. She demonstrated severe temper tantrums, self-injurious behavior such as head banging or finger biting, polyembolokoilamania (insertion of objects into body orifices), but not self-hugging.
She had normal brain MRIs at 3 months and 2 years of age. EEG could not be performed due to lack of cooperation. Family history was unremarkable.
On her initial visit at age 7, she was 49 inches tall, weighed 66 lbs. with a body mass index of 19. Exam revealed a broad, squareshaped facial appearance, brachycephaly, a prominent forehead, hypertelorism, small upslanting palpebral fissures, a broad bridged nose, and mild truncal obesity (Figure 1, top). She did not talk at all and was scribbling with her left hand. She had synbrachydactyly of the left third and fourth digits (Figure 1, bottom).
Figure 1: Characteristic facies of Smith-Magenis syndrome. Note the broad, square-shaped facial appearance, brachycephaly, a prominent forehead, small eyes with upslanting palpebral fissures, hypertelorism, a broad nasal bridge, and mild truncal obesity (top). Synbrachydactyly of the right third and fourth digits; her left hand was surgically corrected (bottom).
Her working diagnosis was developmental delay, autism, and ADHD. Risperidone 1 mg twice daily helped her behavior at school but increased her appetite even further. Risperidone was switched to lamotrigine, which only initially improved her behavior. Melatonin initially improved her insomnia but then became ineffective.
We increased lamotrigine to 50 mg twice daily and added guanfacine 1 mg at night to alleviate her insomnia, but she was lethargic on this dose of lamotrigine; hence, this was decreased to 25 mg in the morning and 50 mg in the evening.
Her baseline CSHQ score was 91. On the Vanderbilt ADHD parent rating scale, her baseline total score was 70 (and a total score of 30 for the last 8 questions), supporting her diagnosis of ADHD, combined type.
Karyotyping revealed an interstitial deletion of 17p11.2 encompassing the RAI1 gene, which was consistent with SMS (Figure 2). Chromosomal microarray was denied by her insurance. Her echocardiogram was normal.
Figure 2: Karyotyping showing 46, XX, del (17) (p11.2p11.2). An ideogram of a normal 17 is shown below (deletion site marked with an arrow).
Lamotrigine and guanfacine were discontinued and ramelteon (Rozerem®) 4 mg at night was initiated. She was able to sleep 3 more hours (from 3.5 hours to 6.5 hours) during the night with ramelteon (Rozerem®) 4 mg at night, and her CSHQ score decreased to 79, which was a significant improvement, over the course of 3 months and stabilized (Figure 3).
Figure 3: Combined treatment with ramelteon and amphetaminedextroamphetamine decreased the CSHQ score and the ADHD Vanderbilt Parent Rating score.
After treating her insomnia, we first treated her ADHD with methylphenidate ER 18 mg daily. She was unable to swallow the pills, therefore this was switched to amphetamine-dextroamphetamine sprinkles 10 mg daily with mild improvement, so her dose was gradually increased to 30 mg daily. At this dose, her Vanderbilt ADHD parent rating score decreased from 70 to 54 over the course of 3 months and stabilized (Figure 3). She was able to shake hands, play with videogames, and answer questions in short sentences. She remains stable 6 months after starting both medications.

Discussion

This was a case of SMS presenting with developmental delay, autism and ADHD, where refractory insomnia and ADHD were both successfully managed with off-label ramelteon and amphetaminedextroamphetamine.
SMS affects at least 1 out of 25,000 individuals worldwide and is typically not inherited.
SMS (OMIM 182290) was first described by Smith and Magenis in 1986 [3] and is caused by haploinsufficiency of RAI1on chromosome 17p11.2 [1,2]. SMS is a complex neurobehavioral disorder with features such as brachycephaly, brachydactyly, midface hypoplasia, prognathism, hoarse voice, intellectual and speech delay, insomnia, obesity, polyembolokoilamania (insertion of objects into body orifices), ‘self-hugging’, and disruptive behavior [3,4]. Most of the SMS features are due to RAI1 haploinsufficiency resulting in reduction of total RAI1 transcription factor activity [5], while the variability and severity of the disorder are modified by other genes in the 17p11.2 region [2].
Management of SMS requires a multidisciplinary approach and includes treatment of the sleep disturbance, speech and occupational therapy, minor medical interventions, and management of the behaviors [6].
SMS and inversion of the circadian rhythm
The disrupted circadian rhythm in SMS manifests as difficulty falling asleep, shortened sleep cycles, frequent and prolonged nocturnal awakenings, excessive daytime sleepiness, daytime napping, snoring, and bed-wetting [7]. The inverted melatonin rhythm (i.e., melatonin peaks during the day instead of at night) and associated sleep-phase disturbances in SMS, as well as a short-period circadian rhythm in mice with a chromosomal deletion of RAI1, support SMS as a circadian-rhythm-dysfunction disorder. RAI1 is a positive transcriptional regulator of circadian locomotor output cycles kaput (CLOCK), a key component of the mammalian circadian oscillator that transcriptionally regulates many critical circadian genes. Haploinsufficiency of RAI1 in SMS fibroblasts and Rai1 in the mouse hypothalamus results in transcriptional dysregulation of the circadian clock, causing altered expression and regulation of multiple circadian genes [8].
Therefore, based on the aforementioned underlying pathophysiology, the original therapeutic approach in SMS was blockade of endogenous melatonin production during the day combined with exogenous melatonin administration in the evening [9]. There have been case reports of administering beta (1)-adrenergic antagonists in the morning to suppress the diurnal melatonin secretion and melatonin in the evening to generate a nocturnal peak of melatonin [10]. However, in this present case, the patient did not respond to melatonin. We had considered enrolling the patient in the tasimelteon (Hetlioz) clinical trial [11], but the patient was less than 16 years of age and not part of the Vanda Pharmaceutical’s Hetlioz Solutions program; hence, we started the patient on ramelteon (Rozerem®) 4 mg at night as a last resort, although this is not indicated for use in children.
Ramelteon is the first in a new class of hypnotics that selectively binds to the MT1 and MT2 receptors in the suprachiasmatic nucleus. Ramelteon is approved by the U.S. Food and Drug Administration (FDA) for insomnia only in adults.
There are no standard outcome measures to assess insomnia in SMS; we had chosen the CSHQ. The CSHQ is a useful sleep screening instrument to identify both behaviorally based and medically-based sleep problems in school-aged children [12]. A cut-off total CSHQ score of 41 yields a sensitivity of 0.80 and specificity of 0.72; our patient’s baseline CSHQ score was very high at 91, which decreased to 79 with ramelteon (Rozerem®) 4 mg at night. We did not increase the dose further, as the optimal dose has yet to be established for children.
SMS and the behaviors, obesity, and ADHD
Our patient demonstrated severe temper tantrums, hyperactivity, aggressive and self-injurious behavior such as head banging or finger biting, all of which have been reported in SMS. She also had polyembolokoilamania but not self-hugging, both of which are more characteristic for SMS [7]. Risperidone has been reported to decrease aggression in SMS [13], which was also observed in our case but led to weight gain, which is common in SMS, as RAI1 regulates genes involved in lipid metabolism [14].
ADHD has been previously reported in SMS [6]. Our patient manifested symptoms of ADHD which we quantified using the Vanderbilt ADHD parent rating scale. Although stimulants have been reported to be ineffective in SMS [15], we were able to demonstrate that amphetamine- dextroamphetamine sprinkles 30 mg daily significantly decreased her Vanderbilt ADHD parent rating score from 70 to 54. We chose a stimulant instead of the anecdotallyused beta (1)-adrenergic antagonist for several reasons: A. To control her symptoms of ADHD, B. To help control her body weight (which unfortunately was unsuccessful; her BMI nonetheless increased from 19 at 7 years of age to 26 at 9 years of age), and C. To counteract her daytime sleepiness. We had switched to the sprinkle form of amphetamine-dextroamphetamine mixed salts as the patient could not swallow pills.

Conclusions

SMS is a rare genetic disorder that presents with 3 main points in clinical management: insomnia, ADHD, and autism-related behavior. Understanding the underlying pathophysiology of the condition is crucial for designing a pharmacological treatment plan. In this case, we were able to demonstrate the efficacy and tolerability of ramelteon and amphetamine-dextroamphetamine salts in treating SMS; large-scale, randomized, placebo-controlled trials are required to demonstrate the true benefits of these medications in the future.

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