Methylphenidate in children with monogenic obesity due to LEPR or MC4R deficiency improves feeling of satiety and reduces BMI‐SDS—A case series

The clinical phenotype of patients with monogenic obesity due to mutations in the leptin receptor (LEPR) or melanocortin 4 receptor (MC4R) gene is characterized by impaired satiety and hyperphagia, leading to extreme, sometimes life‐threatening weight gain.

The adipocyte hormone leptin regulates body fat mass and energy homeostasis by modulating energy intake and expenditure, autonomic nervous system tone, and neuroendocrine functions. 8 The hypothalamic leptin-melanocortin pathway plays a key-role in mediating these effects.
Leptin's interaction with its hypothalamic receptor activates POMC/ cocaine-and amphetamine-regulated transcript (CART) neurons and deactivates agouti-related protein (AgRP)/neuropeptide Y (NPY) neurons in the arcuate nucleus. It thereby inhibits the production of NPY and AgRP and induces the production of CART and POMC. POMC is a polypeptide that undergoes tissue-specific posttranslational processing.
The products of which include the melanocortin peptides α-, β-, and γ-melanocyte-stimulating hormone (MSH). 9 α-MSH activates, while AgPR deactivates MC4R in second-order neurons in the paraventricular nucleus. 10 However, β-MSH is also capable of activating MC4R. 11 MC4R activation in these neurons induces anorexigenic signals to affect food intake and energy expenditure through interaction with higher cortical centres, including dopaminergic neurons in the mesolimbic system.
Patients with disruptions of these pathways demonstrate impaired satiety, hyperphagia, and food-seeking behaviours leading to early onset severe obesity. [4][5][6]12,13 Lifestyle interventions are largely unsuccessful. 14 Children with pathogenic LEPR mutations show a tremendous increase in body mass index (BMI) during the first 2 years of life. 12 Compared with them, patients with MC4R mutations have later onset obesity with significantly lower BMI values. Unlike leptin deficiency where leptin replacement has been proven successful, 6,13,15 LEPR or MC4R deficiency have no causal treatment. Hence, other treatment options are needed to prevent the rapid progression of obesity and associated complications.
MPH is frequently used in the treatment of children with attention deficit hyperactivity disorder (ADHD) because it reduces hyperactivity and enhances attention. Reduced appetite and weight loss are among the most common side effects [16][17][18][19][20] and are likely mediated by increased sympathetic tone and dopamine reuptake inhibition in brain areas that regulate hedonic eating behaviour. These brain areas closely interact with the melanocortin pathway, as MC4R binding modulates activity of dopaminergic neurons in the mesolimbic system.
Recently, we have reported data of a boy with a heterozygous functionally relevant MC4R mutation and severe ADHD, in whom MPH use for 24 months led to a dramatic decrease in BMI standard deviation score (SDS) from 5.4 to 2.8. 21 The objective of this case series was to extend our observations on the effect of MPH on weight development in monogenic severe obesity. We described changes in eating behaviour, appetite, and BMI trajectories as well as adverse effects associated with off-label MPH use for 1 year in five patients with monogenic obesity due to mutations in the LEPR or in the MC4R gene.

| Study population
In a retrospective case series, we report data of n = 5 patients who presented to our outpatient clinic (2005-2013) with severe obesity early in childhood due to pathogenic mutations in the LEPR (n = 3) or MC4R (n = 2) gene. Clinical characteristics of three of the patients have been previously published. 2,5,6 After unsuccessful conventional treatment approaches including dietary and behavioural lifestyle interventions, the families of these patients agreed to off-label methylphenidate (MPH) use as an individual treatment using to control weight gain. An off-label individual treatment describes the application of an approved drug but in an indication for which it is not approved. Patients receive an off-label treatment with MPH in an individual case, which the physician decides on his own initiative and with the patient's consent within the framework of freedom of therapy (in accordance with item 32 of the Declaration of Helsinki; version 2000). Patients were treated and monitored according to a standardized clinical protocol as outlined below. Before starting MPH treatment, patients and parents were informed comprehensively about the off-label use and potential benefits and risks of MPH by trained paediatricians. Written informed consent was given by the parents. Baseline evaluation for contraindications for MPH (seizure disorders, depression, mood disorders, cardiovascular disease, hypertension, and arrhythmia) included a neurologic examination by a paediatric neurologist, a psychological evaluation by a clinical psychologist, and an in-depth cardiologic evaluation by a paediatric cardiologist including echocardiogram, electrocardiogram, and blood pressure measurements. MPH use was started as a single dose of 5 or 10 mg/ day and titrated to effect up to a maximum dose of 20 mg/day divided in two to three doses. Follow-up was recommended at 3-month intervals to assess eating behaviour, appetite, height and weight, and adverse events as outlined in the following sections. Baseline (T0) and 1-year follow-up (T1) data are presented.

| Child Eating Behaviour Questionnaires
A German translation of the Child Eating Behaviour Questionnaires (CEBQ) was completed by the parents 22 at initiation of MPH use (T0) and at the 1-year follow-up (T1). This questionnaire is routinely used in our outpatient clinic to assess eating behaviour in patients with severe obesity. The CEBQ consists of 35 questions that are categorized in eight subscales: food responsiveness, enjoyment of food, slowness in eating, food fussiness, satiety responsiveness, emotional overeating, emotional undereating, and desire to drink. Answers are recorded on a 5-point Likert scale where specific eating behaviours are quantified as never, rarely, sometimes, often, and always. Questions were scored as per Wardle et al. 22 Scores for each subscale were calculated as the average score of the individual questions. Subscales were then grouped into two categories: (a) food approach, which summarizes the categories food responsiveness, enjoyment of food, emotional overeating, and desire to drink questions and (b) food avoidance, which comprises slowness in eating, food fussiness, satiety responsiveness, and emotional undereating.

| Appetite and adverse effects
Visual analogue scales (VAS) with anchors 0 = never and 10 = always are routinely used in our outpatient clinic to get information about appetite in patients with severe obesity and were also used to assess the presence of disordered sleep, nervousness, hyperactivity, impulsivity, tics, aggression, and headaches. In addition, treating physician-

| Anthropometric data
All children in Germany have 10 well-child examinations between birth and the age of 5 years to assess psycho-motor development and provide health surveillance. Results (including measured weight and height) are recorded in health booklets. Additional height and weight measurements were available from medical records.
At all visits to our outpatient clinic, body weight was measured to the nearest 0.1 kg on a calibrated balance beam scale (Seca, Hamburg, Germany), and body height was measured to the nearest 0.1 cm (Stadiometer, Busse Design, Ulm, Germany). BMI was calculated by dividing weight (in kilograms) by the square of height (in meters). BMI was classified for children using the 90th/ 97th age-and sex-specific percentiles of the German reference data as cut-off point for overweight/obesity. BMI-SDS was calculated using the least mean squares method based on German references. 23 In addition, the degree of obesity was expressed as percentage of the 95th percentile (%BMIP95) of the Center of Disease Control and Prevention (CDC) BMI percentiles (2-20 years), as recommended recently in the Endocrine Society Clinical Practice Guideline for paediatric obesity. 24,25 Because of the observational nature of this case series, follow-up intervals were not consistent. Hence, not all patients had follow-up information at exactly 12 months (intervals between 9 and 15 months).
To adjust for different follow-up intervals, we calculated the extrapolated annualized BMI-SDS velocity by dividing the change in BMI-SDS by the observation interval in months and then multiplying by 12 months. This is analogous to the routinely performed calculation of height or weight velocity. 26 A retrospective chart review was conducted to establish BMI-SDS velocity prior to initiation on MPH use.
To assess the effect of MPH on longitudinal growth, the annualized growth velocity defined as change in body height per year (cm per year) as well as change in height SDS between T0 and T1 was calculated.

| Continuation of off-label individual MPH treatment after T1
Duration of off-label individual treatment with MPH varies between the five patients from 1.2 up to 4 years. Since all patients received MPH for 1 year, the time point "12 months after the start of off-label MPH treatment (T1)" was determined as the primary endpoint to investigate the effects of an off-label MPH treatment on eating behaviour, appetite, and BMI trajectories in children with severe obesity due to mutations in the LEPR or MC4R gene. In patient A, the offlabel MPH treatment was stopped after 2 years as the patient was included in a clinical study. In patient B, the parents stopped the offlabel treatment with MPH after 1.

| Statistics
Descriptive data analyses and BMI trajectories were computed using the Graph Pad Prism 7 (Graph Pad Software Inc, San Diego, CA). Data are presented as single data per patient and/or as mean and standard deviation (SD) for the group. Student t test was used for statistical comparisons. A P value (two-sided) of less than 0.05 was considered significant.

| Patient characteristics
Four of five patients (three females and two males) were born fullterm, and all patients were born appropriate for gestational age (data not shown). All patients had BMI-SDS values greater than 1 at 1 year of age (range BMI-SDS 1 year : 1.2-6.19) and BMI-SDS values greater than 3 at 2 years of age (range BMI-SDS 2 years : 3.32-6.02). Age at initiation of off-label MPH treatment ranged between 2.8 and 14.9 years (Table 1a).

| Eating behaviour (CEBQ)
At initiation of off-label MPH treatment, children had the highest scores in the pro-intake subscales "enjoyment of food," "desire to drink," and "food responsiveness" of the CEBQ. The subscale "FOOD RESPONSIVENESS" includes statements like "my child is always asking for food" or "given the choice, my child would eat most of the time." The subscale "enjoyment of food" includes the statements "my child loves food" or "my child looks forward for meal times" or "my child is interested in food." After 1 year of off-label MPH treatment, scores in the subscales "food responsiveness" and "enjoyment of food" decreased significantly (Figure 1).

| Appetite
Patients reported high frequency of appetite at T0, with a significantly decreased frequency at T1. Mean value for appetite at the VAS was 8.3 ± 1.6 out of 10 at T0 and 3.5 ± 2.4 at T1 (P < .05) (Figure 2).

| Change in BMI-SDS velocity
Mean BMI-SDS velocity in the year before off-label MPH use was +0.18 ± 0.30. As shown in Figure 4, BMI-SDS velocity decreased sig-  Figure S1). The systolic blood pressure remained stable in four patients ( Figure S1). One patient showed a lower systolic blood pressure at T1 than at T0. The

| Continuation of off-label individual MPH treatment after T1
As shown in Figure S2, in two patients, off-label MPH treatment was stopped after 1.2 and 2 years ( Figure S2A,B). In those, off-label MPH treatment showed stabilization or further reduction in the BMI after

| DISCUSSION
In an observational case series, we analysed the effect of an off-label individual treatment with MPH for 1 year in five children with monogenic obesity due to mutations in LEPR or MC4R gene. We reported changes in weight trajectories as quantified by BMI, BMI-SDS, and BMI-SDS velocity, eating behaviour and appetite, as well as MPH adverse effects.
"Enjoyment of food" and "food responsiveness" (assessed by CEBQ), self-reported appetite (assessed by VAS), and mean BMI, BMI-SDS, and BMI-SDS velocity decreased in a clinically meaningful way. Self-reported frequency of disordered sleep, nervousness, hyperactivity, and tics increased in most patients but did not reach significance across the group and did not lead to discontinuation of MPH.
No additional adverse events were reported by physicians. If given the chance, my child would always have food in his/her mouth; C, score "emotional overeating"-questions: My child eats more when worried; My child eats more when annoyed; My child eats more when anxious; My child eats more when s/he has nothing else to do; D, score "enjoyment of food"-questions: My child loves food, My child is interested in food; My child looks forward to mealtimes, My child enjoys eating; E, score "food Fussiness"-questions: My child refuses new foods at first; My child enjoys tasting new foods, My child enjoys a wide variety of foods, My child is difficult to please with meals, My child is interested in tasting food s/he hasn't tasted before, My child decides that s/he doesn't like a food, even without tasting it; F, score "emotional undereating"-questions: My child eats less when angry, My child eats less when s/he is tired, My child eats more when she is happy, My child eats less when upset; G, score "satiety responsiveness"-questions: My child has a big appetite, My child leaves food on his/her plate at the end of a meal, My child gets full before his/her meal is finished, My child gets full up easily, My child cannot eat a meal if s/he has had a snack just before; H, score "slowness in eating"-questions: My child finishes his/her meal quickly, My child eats slowly, My child takes more than 30 minutes to finish a meal, My child eats more and more slowly during the course of a meal (score: 0 = never, 1 = rarely, 2 = sometimes, 3 = often, 4 = always) within clinical studies and only for patients older than 6 years of age.
Outside of clinical studies, there is no effective treatment available for patients with LEPR or MC4R mutation.
All children in this case series were affected by hyperphagia, excessive weight gain, and severe early onset obesity refractory to lifestyle intervention. Because hyperphagia is a cardinal feature of monogenic obesity, a plausible candidate approach might be the use of substances that impact appetite and satiety regulation. MPH has been the first choice in the pharmacological treatment of ADHD for many years, and extensive safety data are available in school-aged and younger children. 28 Poor appetite and weight loss are among the most common side effects. 20,29,30 We have chosen an off-label individual treatment option with off-label use of MPH to influence appetite and satiety and slow down the exaggerated weight gain in our group of patients.
We used the CEBQ to assess eating behaviour before and 1 year after starting MPH use. Two subscales of the CEBQ were significantly affected by MPH: "enjoyment of food" and "food responsiveness." We observed a strong decrease in the scores of these two subscales.
The baseline score of 2.4 in the subscale "food responsiveness" was consistent with published values of 2.2 for overweight boys and 2.4 for overweight girls (n = 1.058 children; 7-10 years). 31 With MPH, "food responsiveness" decreased to a score of 1.3, consistent with reported values in normal-weight children. 31 In addition, patients had a significant reduction in self-reported appetite.
We documented a significant decrease in BMI, BMI-SDS, and BMI-SDS velocity after 1 year of MPH use in five children with monogenic obesity due to mutations in LEPR or MC4R gene. Several reports quantify the effect of MPH on anthropometric parameters in children with ADHD. [16][17][18][19][32][33][34] Two studies reported long-term reductions in body weight of −1.2 kg after 21 months 34 and of −1.6 kg after 48 months on MPH. 18 One trial describing MPH for 3 years and 3 months showed that half of the children with a BMI-SDS greater than 1.5 maintained, while the other half reduced their BMI-SDS. 19 MPH effects on weight and appetite are likely mediated by a combination of direct and indirect sympathomimetic effects, as well as brain reuptake inhibition of norepinephrine and dopamine.
MPH binds to and inhibits pre-synaptic norepinephrine (NET) and dopamine transporters (DAT), leading to decreased reuptake and thus increased synaptic norepinephrine 35 and dopamine concentrations, 36 both targets for many weight-loss drugs. 37 Dopamine is a key transmitter in the meso-limbic system signalling food reward and craving. 38 Evidence from animal and human studies demonstrate altered dopamine signalling in individuals with obesity compared individuals with normal weight possibly due to rapid dopamine transport and/or reduced numbers of postsynaptic dopamine receptors [39][40][41][42] . Together, this is thought to promote reward attenuation with compensatory overeating. 43,44 Increasing brain dopamine activity with dopamine agonists or reuptake inhibitors leads to weight loss and reduced food intake. 17 Notably, decreased mesolimbic dopamine levels may specifically contribute to the hyperphagia observed in individuals with impaired leptin-melanocortin signalling. Neurons signalling to mesolimbic brain areas express MC4R. Receptor stimulation leads to increased dopamine release and turn over in mesolimbic brain areas 45 and decreased food-seeking behaviours and preference for high-fat foods in animals. 46,47 In the absence of MC4R signalling, low dopamine levels and associated hyperphagia would be expected. 41 Indeed, hyperphagia in MC4R deficient rats/mice improves with selective restoration of MC4R signalling in the mesolimbic system, 47 and imaging studies in leptin deficient humans show changes in brain activity in response to leptin substitution predominantly in the dopaminergic brain areas. 48,49 Restoration of mesolimbic dopamine levels by MPH would conceptually lead to improved control of hedonic feeding and food-seeking behaviours and decreased hyperphagia. In addition to mesolimbic signalling, dopamine inhibits hypothalamic NPY expression and activity and stimulates POMC expression 40 and may therefore affect hypothalamic intake regulation downstream of LEPR but upstream of MC4R. It is also assumed that MPH has direct (via norepinephrine stimulation of energy expenditure) and indirect (via anorexigenic effects of norepinephrine) sympathomimetic effects. Figure 5  T A B L E 1 B Absolute values and differences for BMI, BMI-SDS, and %BMIP95 between T0 and T1 and BMI-SDS velocity before and under off-label methylphenidate treatment for 1 y in n = 5 patients with severe obesity due to mutations in the LEPR or MC4R gene Mean ± SD 38.5 ± 5.9 37.7 ± 6.4 −0.7 ± 0.9 4.3 ± 0.7 3.9 ± 0.6 0.18 ± 0.30 −0.32 ± 0.20* 182 ± 16 175 ± 17 −6.6 ± 7.8 Abbreviations: BMI, body mass index; LEPR, leptin receptor; MC4R, melanocortin 4 receptor; MPH, methylphenidate; SD, standard deviation; SDS, standard deviation score; T0, initiation of MPH; T1, 1-y follow-up. *P < .05.
F I G U R E 4 Boxplots of body mass index standard deviation score (BMI-SDS) velocity before (unfilled squares) and during the year of off-label methylphenidate treatment (filled squares) in n = 5 patients with severe obesity due to mutations in the leptin receptor (LEPR) or melanocortin 4 receptor (MC4R) gene (*P < .05) F I G U R E 5 Differences in the regulation of dopamine levels in the pre-synaptic cell as well as in the synaptic cleft in individuals with normal weight, in individuals affected by overweight/obesity and in individuals treated with methylphenidate (DAT, dopamine transporter protein; MPH, methylphenidate) The search for a pharmacological treatment option for patients with monogenic obesity is of immediate interest. Very recently, it has been reported that patients with LEPR mutations can be treated successfully with a specific melanocortin receptor agonist, setmelanotide. 27 To date, setmelanotide is available only within clinical studies and only for patients older than 6 years of age. Long-term data that show the effect of setmelanotide on BMI in patients with LEPR mutations are not available. These and the corresponding approval must be awaited.
In conclusion, our results show that an off-label individual treatment with MPH for 1 year may improve weight trajectory, decrease appetite, and favourably effect eating behaviour in children with LEPR/MC4R deficiency. These results correlate well with the reported anorexic effect of MPH in children and adolescents with ADHD and are plausibly explained by the mechanism of action of MPH. A decrease or even a stabilization of BMI-SDS is highly meaningful in this group of patients, since the natural trajectory would be associated with rapid weight gain leading to obesity complications in short time.
However long-term effects, especially on cardiometabolic risk profiles, are unknown.