Research Request – Syndromic obesity & causative link to disability

DOCUMENT 2

Research Request – Syndromic obesity & causative link to disability

Contents

Issue: DRHS for NDIS participants with obesity ………………………………………………………………………….. 3 Gap in current guidance and legislation re: obesity ………………………………………………………………… 3 Syndromic obesity - overview ………………………………………………………………………………………………….. 4 Syndromic Forms of Human Obesity …………………………………………………………………………………….. 5 Obesity in Australia ………………………………………………………………………………………………………………… 6 Cost to Public Health System ……………………………………………………………………………………………….. 7 National Healthcare Agreement (2018) …………………………………………………………………………………. 7

1. Prader-Willi Syndrome (PWS) …………………………………………………………………………………………… 9 Causes of obesity in PWS ………………………………………………………………………………………………….. 9 Early Intervention ………………………………………………………………………………………………….. 10 Further research in PWS ………………………………………………………………………………………………….. 11
2. Bardet-Biedl syndrome (BBS) ………………………………………………………………………………………….. 11 Causes of obesity in Bardet-Biedl syndrome ………………………………………………………………………… 12 Early intervention ……………………………………………………………………………………………………………… 13
3. Alstrom syndrome …………………………………………………………………………………………………………. 13 Causes of obesity in Alstrom syndrome ……………………………………………………………………………….. 14 Early intervention ………………………………………………………………………………………………….. 14
4. WAGR syndrome …………………………………………………………………………………………………………… 15 Causes of obesity in WAGRO syndrome ………………………………………………………………………………. 15 Early intervention ……………………………………………………………………………………………………………… 16
5. Albright’s Hereditary Osteodystrophy ……………………………………………………………………… 16 Causes of obesity in Albright’s Hereditary Osteodystrophy …………………………………………. 17 Early intervention ……………………………………………………………………………………………………………… 17

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Further research ………………………………………………………………………………………………………………. 18 6) Down syndrome ……………………………………………………………………………………………………………. 18 Causes of Obesity in Down syndrome …………………………………………………………………………………. 18 Open source information …………………………………………………………………………………………………… 19 Academic Research sources ……………………………………………………………………………………………….. 19 Early Intervention ………………………………………………………………………………………………….. 21 Further Research Needed for Obesity and DS ……………………………………………………….. 22 7) Autism Spectrum Disorder (ASD) ……………………………………………………………………… 22 Causes of obesity in ASD ………………………………………………………………………………………………….. 22 Open Source Information ……………………………………………………………………………………. 23 Academic Research Sources ……………………………………………………………………………………. 23 16p11.2 deletion in ASD ……………………………………………………………………………………. 24 Further Research Needed for Obesity and ASD ……………………………………………………….. 26 8) Intellectual Disability (in general) ……………………………………………………………………… 26 Causes of obesity in Intellectual Disability ……………………………………………………………………… 27 Academic Research Resources ……………………………………………………………………………………. 27 Early Intervention ………………………………………………………………………………………………….. 28 Further Research Needed for Intellectual Disability ……………………………………………………….. 28 9) Psychosocial disability (medication side effects) ……………………………………………………….. 29 Weight loss interventions for psychosocial disability ……………………………………………………….. 31 Conclusion ………………………………………………………………………………………………………………… 32 Reference List ………………………………………………………………………………………………………………… 33

Please note: • The research and literature reviews collated by our TAT Research Team are not to be shared external to the Branch. These are for internal TAT use only and are intended to assist our advisors with their reasonable and necessary decision making. • Delegates have access to a wide variety of comprehensive guidance material. If Delegates require further information on access or planning matters they are to call the TAPS line for advice. • The Research Team are unable to ensure that the information listed below provides a holistic and contemporary snapshot of the aetiology of obesity in these disability groups.

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Scope of this document

This document examines the most common genetic disorders of obesity or syndromic forms of obesity for which the genetic basis of obesity has been partially or completely elucidated. These disorders include:

• Prada-Willi Syndrome, Bardet-Biedl syndrome, Alstrom syndrome, WAGR syndrome and other conditions with genetic deletions, particularly 16p11.2 deletions (commonly found in people with Autism Spectrum Disorder).

The document also examines:

• Down syndrome, Intellectual Disabilities (in general) and the impact that psychiatric medications have on weight gain / obesity have also been considered.

Issue: DRHS for NDIS participants with obesity

Gap in current guidance and legislation re: obesity

In the context of the NDIS and the funding of Disability Related Health Supports (DRHS), disabilities and chronic health conditions that may lead to obesity (directly and indirectly) require further consideration. This is because of:

• the stated ‘whole of person’ approach that must be taken during NDIS planning; and
• the associated functional impairment(s) that obesity commonly cause.

As outlined in the current guidance, the NDIS will fund a DRHS when it:

• directly relates to a person’s ongoing functional impairment, and
• is a regular part of daily life, and
• is most appropriately funded or provided by the NDIS, and
• is evidenced meaning supporting information can generally be obtained.

A DRHS support must still meet the NDIA’s legislative framework. As outlined in the DRHS PG:

• The NDIA takes a whole of person approach when funding supports in a participant’s NDIS plan. This means that funding for supports is based on the reasonable and necessary criteria in section 34 of NDIS Act and Rules and is not limited to the impairments which satisfy the criteria for accessing the NDIS.
• Specifically, in accordance with section 34(1)(f) of the NDIS Act, the NDIA needs to determine whether a disability-related health support for a participant is most appropriately funded or provided by the NDIS.
• The NDIS Supports for Participants Rules 2013, provide that the NDIS is responsible for supports related to a person’s ongoing functional impairment and that enable the person to undertake activities of daily living, including maintenance supports delivered or supervised by clinically trained or qualified health practitioners, where these are directly related to a functional impairment and integrally linked to the care and support a person requires to live in the community and participate in education and employment.

This legislation and guidance does not effectively consider how functional impairments associated with obesity factors into reasonable and necessary considerations.

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Syndromic obesity - overview

While overweight and obesity is most commonly due to excess caloric intake, it is well established that genetic mutations or chromosomal abnormalities can cause excess weight gain.

The term ‘syndromic obesity’ is used to describe obese children and adults with cognitive delay, dysmorphic features, organ-specific abnormalities, hyperphagia [abnormally increased appetite for consumption of food], and/or other signs of hypothalamic dysfunction”1

The Royal Australian College of General practitioners (RACGP) published a review in 2017 examining recent genetic discoveries about the basis of human obesity and familial or syndromic obesity. The review found that obesity is sometimes part of a rare but recognised syndrome2. The RACGP review lists the following syndromes:

• “Prader–Willi syndrome, an imprinting disorder, is the most common, occurring at a rate of one in 15,000. Babies with this syndrome are born ‘floppy’, have weak muscles and up-slanted eyes, and feed poorly. Over the first two years, the infant slowly develops a ravenous appetite, and has cognitive delay and behavioural issues. It is an imprinting defect, in the region of chromosome 15q11–13.
  • A variant of the Fragile X syndrome has also been described that has features of Prader–Willi syndrome, with severe obesity developing early.
• Bardet−Biedel syndrome is an autosomal recessive disorder of ciliary function characterised by obesity, cognitive delay, polydactyly and retinitis pigmentosa, renal dysfunction and hypogonadism, sometimes resulting in diabetes. It has so far been mapped to 19 different genes.
• Albright’s hereditary osteodystrophy (pseudohypoparathyroidism) is associated with hyperphagia, obesity, short stature, round face, skeletal anomalies and cognitive delay. The GNAS gene mutation results in resistance to hormones such as parathormone, thyroid hormone and gonadotrophins.
• WAGR syndrome (11p14 deletions leading to brain-derived neurotrophic factor haploinsufficiency) is characterised by aniridia, obesity, growth retardation, cognitive delay and genitourinary deformities.
• Copy-number variations (CNVs) in the genome have also been described in association with obesity. CNVs are segments of the genome that differ in the number of diploid copies carried by healthy individuals. About 5% of healthy people have common varieties of CNV, and 1% have rare varieties. Common CNVs include chromosome 10q11.22, a region associated with the pancreatic polypeptide receptor, where low CNV was recently reported to be associated with high BMI, and also on chromosome 11q11 around the olfactory receptor genes with early onset extreme obesity”3.

Similarly, a publication from 2011 by W. Chung examining ‘Mongenic and Syndromic Obesities in Humans’ considers the above conditions, but also lists Alstrom syndrome and conditions with 16p11.2 deletions as syndromic obesity conditions.

1 Irizarry, KA & Haqq, AM, ‘Syndromic Obesity’, Pediatric Obesity, Contemporary Endocrinology, 12 October 2017, pp. 153-182, https://link.springer.com/chapter/10.1007/978-3-319-68192-4_9, accessed 18 November 2019. 2 Campbell, LV, ‘Genetics of obesity’, Australian Family Physician, Royal Australian College of General Practitioners, vol. 46, No. 7, 2017, pp-456-459, https://www.racgp.org.au/afp/2017/july/genetics-of-obesity/, accessed 18 November 2019. 3 Ibid.

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• “Alstrom syndrome is a rare autosomal recessive, genetically homogeneous disorder characterized by mild truncal obesity that usually begins within the first year of life and continues throughout life unless caloric restriction is imposed. The gene for Alstrom syndrome, ALMS1, encodes a gene of unknown function expressed ubiquitously at low levels. The mechanism by which loss-of -function mutations in this gene produce obesity or any of the other associated phenotypes is still unknown”4.

This publication concludes that:

“Most syndromic forms of obesity are associated with mild to severe cognitive deficits and unusual behaviors. While many other syndromes affecting cognition such as Down syndrome are also associated with a higher incidence of obesity5, the syndromic forms of obesity described above appear to have specific effects on food intake. These data suggest that there may be specific neuroanatomic or functional deficits, particularly in the hypothalamus, that lead to increased energy intake. The development of new techniques including functional imaging of the brain should permit noninvasive determination of which parts of the brain function aberrantly in the context of food intake in each of the syndromic forms of obesity”.

Syndromic Forms of Human Obesity

According to Chung, these are the genetic causes and common phenotypes for the disorders that were considered.

4 Chung, WK, ‘An Overview of Mongenic and Syndromic Obesities in Human’, Paediatric Blood and Cancer, vol. 58, no. 1, 12 October 2011, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215910/, accessed 12 November 2019. 5 Bell AJ, Bhate MS. Prevalence of overweight and obesity in Down’s syndrome and other mentally handicapped adults living in the community. J Intellect Disabil Res. 1992;36 ( Pt 4):359–364, https://www.ncbi.nlm.nih.gov/pubmed/1388077, accessed 29 November 2019.

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| 16p11.2 deletion | 16p11.2 | Autosomal dominant | Progressive obesity, autism/mental retardation |

Table 1: Syndromic Forms of Human Obesity6

Obesity in Australia

In 2017-18, the Australian Bureau of Statistics’ National Health Survey showed that two thirds (67.0%) of Australian adults were overweight or obese (12.5 million people), an increase from 63.4% in 2014-15. Slightly more than a third (35.6%) were overweight and slightly less than a third were obese (31.3%). Just under one third (31.7%) were within the healthy weight range and one percent (1.3%) were underweight7. The National Health Survey also indicated that almost one quarter (24.9%) of children aged 5-17 years were overweight or obese in 2017-18 (17% overweight and 8.1% obese)8.

According to the Australian Government Department of Health:

Body mass index (BMI) is an index of weight-for-height that is commonly used to classify underweight, overweight and obesity in adults. It is calculated by dividing weight by the square of height: weight (kg)/height (m)92.

• Source: (WHO 2000).

The Australian Institute of Health and Welfare (AIHW) published a snapshot from 2014-2015 of prevalence of chronic health conditions in adults by weight status. It found that approximately 24%

6 Chung, K, loc cit. 7 Australian Bureau of Statistics, National Health Survey: First Results, 2017-18, Overweight and Obesity, 4364.0.55.001, https://www.abs.gov.au/ausstats/abs@.nsf/Lookup/by%20Subject/4364.0.55.001~2017-18~Main%20Features~Overweight%20and%20obesity~90, accessed 29 November 2019. 8 Department of Health, Australian Government, ‘Overweight and Obesity’, 19 June 2019, https://www1.health.gov.au/internet/main/publishing.nsf/Content/Overweight-and-Obesity, accessed 8 November 2019. 9 Australian Government, Department of Health, ‘Weight and body mass index’, 2019, https://www.health.gov.au/resources/pregnancy-care-guidelines/part-d-clinical-assessments/weight-and-body-mass-index, accessed 29 November 2019.

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of Australians with ‘mental and behavioural problems’ and approximately 28% of Australians with arthritis were obese10.

While not an Australian resource, the US Center for Disease Control generalise that “people with disabilities can find it more difficult to eat healthy, control their weight, and be physically active. This might be due to:

• A lack of healthy food choices.
• Difficulty with chewing or swallowing food, or its taste or texture.
• Medications that can contribute to weight gain, weight loss, and changes in appetite.
• Physical limitations that can reduce a person’s ability to exercise.
• Pain.
• A lack of energy.
• A lack of accessible environments (for example, sidewalks, parks, and exercise equipment) that can enable exercise.
• A lack of resources (for example, money, transportation, and social support from family, friends, neighbors, and community members)”11.

Cost to Public Health System

The AIHW found that:

• “The estimated cost of obesity on the Australian economy in 2011–12 was $8.6 billion, which included $3.8 billion in direct costs and $4.8 billion in indirect costs—including absences from work, forgone tax and government subsidies. It has been estimated that, if no preventative action is taken to slow the growth of obesity, up to $87.7 billion in additional direct and indirect costs due to obesity may be incurred by 2025”12.

Given that 2/3 adults and 1/4 children are overweight or obese (3/7 Australians), this poses a significant risk to Scheme sustainability if NDIS were to absorb the costs associated with obesity.

National Healthcare Agreement (2018)

The current National Healthcare Agreement (2018) firmly places obesity in the mainstream health care space:

The National Healthcare Agreement affirms the agreement of all governments that Australia’s health system should:

1. be shaped around the health needs of individual patients, their families and communities;
2. focus on the prevention of disease and injury and the maintenance of health, not simply the treatment of illness;

10 Australian Institute of Health and Welfare, ‘A picture of overweight and obesity’, 2017, p.28, https://www.aihw.gov.au/getmedia/45f6ecc6-0caf-4af4-9ffc-a44c885b33d2/aihw-phe-216.pdf.aspx?inline=true, accessed 11 The Centers for Disease Control and Prevention, Disability and Obesity, 16 September 2019, https://www.cdc.gov/ncbddd/disabilityandhealth/obesity.html, accessed 8 November 2019. 12 Ibid, p. 3.

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3. support an integrated approach to the promotion of healthy lifestyles, prevention of illness and injury, and diagnosis and treatment of illness across the continuum of care; and
4. provide all Australians with timely access to quality health services based on their needs, not ability to pay, regardless of where they live in the country.

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Specific genetic disorders and syndromes

The remainder of this paper provides a literature review on the common disorders and syndromes linked to obesity. These include:

1. Prada-Willi syndrome
2. Bardet-Biedl syndrome
3. Alstrom syndrome
4. WAGR syndrome
5. Albright’s Hereditary Osteodystrophy
6. Down syndrome
7. Autism Spectrum Disorder (16p11.2 deletion)
8. Intellectual disability (in general)
9. Psychosocial disability (medication side effects)

This list of conditions is not exhaustive. These are the most common disorders/syndromes that research identifies.

If there is information supporting early intervention or if there is an identified requirement for further research to be completed to substantiate the link to obesity this will be listed.

1) Prader-Willi Syndrome (PWS)

• Prader-Willi is the most common obesity syndrome.
• Prader-Willi Syndrome Australia describe PWS as “a rare and very complex, non-inherited genetic disorder. Several genes on chromosome 15 are deleted or unexpressed. The commonly observed characteristics include small hands and feet, abnormal growth and body composition (small stature, very low lean body mass and early onset childhood obesity), weak muscles, insatiable hunger, extreme obesity, intellectual disability and anxiety-driven behavioural outbursts. There is an underlying hormone deficiency”13.
• There is significant research on PWS indicating a causative genetic link to obesity.
• Most of the research suggests that obesity usually arises in later childhood, and that early intervention actions can assist in the management of obesity.

Causes of obesity in PWS

The research sourced suggests the following as the causes of obesity in PWS:

• Genetic disorder
• Insatiable appetite
• Imbalance between energy intake and expenditure due to hyperphagia
• Decreased physical activity

13 Prader-Willi Syndrome Australia, ‘About Prader-Willi Syndrome’, 2016, http://www.pws.org.au/prader-willi-syndrome/, accessed 12 November 2019.

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• Metabolic disorders (low metabolism)
• Inability to vomit

Prader-Willi syndrome is a rare genetic disorder that causes a range of physical, intellectual and behavioural issues. Although it has no cure, treatment, especially if received early on, can help with symptoms. As adolescents and adults, people with PWS tend to have breathing and sleeping issues, as well as a general lack of energy. Combined with an insatiable appetite, this can lead to life-threatening obesity14.

A substantial academic article by Professor Merlin G. Butler, MD, PhD of the Kansas University Medical Center, suggests that PWS often leads to childhood obesity [and that]:

“Obesity is a significant health problem, if uncontrolled. PWS is considered the most common known genetic cause of morbid obesity in children . . . that can be life-threatening . . . The clinical course of PWS has historically been divided into two distinct clinical stages (early failure-to-thrive and later childhood obesity). . . The obesity associated with PWS results from a chronic imbalance between energy intake and expenditure due to hyperphagia, decreased physical activity, reduced metabolic rate and an inability to vomit”15.

A systematic review of PWS and chromosomal abnormalities from 2014 reports that:

PWS is characterized by hypotonia during the neonatal stage and in childhood, accompanied by a delay in neuropsychomotor development. Overeating, obesity, and mental deficiency arise later on . . . It is worth mentioning that an early and precise diagnosis of PWS is essential for avoiding obesity and related co-morbidities. It also allows for the provision of adequate genetic counseling for the patients and their families. . . The onset of the second phase is marked by obesity, which usually occurs as a consequence of hyperphagia around 2 years of age“16.

Furthering the evidence of obesity arising later on in childhood, a cohort study of forty patients and literature review, supported that:

“The typical features [of PWS] begin in gestational life with poor fetal vigor and difficulties with birth and post-partum feeding. The classical features of hypotonia, small hands and feet, cryptorchidism can be identified at this time. The delayed milestones, mental retardation and obesity become more prominent later”17.

Early Intervention

Research indicates that early intervention actions are the most effective way to assist with the issue of obesity for people with PWS.

The Australian Brain Foundation charity, suggests that “Early diagnosis [of PWS] will allow parents to manage their child’s diet and avoid the problems resulting from obesity, and will facilitate access to early intervention services and identify areas of need or risk”18.

Australia’s Raising Children website suggests that “although there’s no cure for Prader-Willi syndrome, early intervention can make a difference. Through early intervention services, you can work with health professionals to choose therapy options to treat your child’s symptoms, support your child, improve outcomes for your child, and help your child reach his full potential”19.

A recent research paper suggests that “dietary restriction, physical activity, and behavior management are fundamental in the prevention and management of obesity in PWS . . . Subjects with PWS will become severely obese unless their food intake is strictly controlled. Constant and obsessive food seeking behavior can make life very difficult for both the family and caretakers. Prevention of obesity is mandatory in these patients from the first years of life, because once obesity develops it is difficult to maintain the control of food intake”20.

The 2017 RACGP publication concluded that “Early-onset hyperphagia and obesity in children should be regarded as a flag to consider specialist referral, especially for those with a positive family history or syndromic features, such as cognitive problems, growth disorders or developmental delay. Early treatment can prevent severe obesity and help with family counselling”21

Further research in PWS

There is significant research into PWS indicating a causative genetic link to obesity. It is likely that the available PWS genetic research will be used to inform obesity research into other genetic conditions.

In 2014 an international conference on hyperphagia was held at the Pennington Biomedical Research Center, Baton Rouge, Louisiana with 28 experts, including scientists and caregivers, providing presentations, panel discussions, and debates. This conference had a particular focus on PWS and highlighted that given the obesity epidemic “the interest in the study of PWS and other rare or uncommon single gene causes of obesity has the potential to gain specific knowledge to address obesity in the general population. . . The research community also believes that PWS presents a ‘Window of Opportunity’ to study appetite control in the extreme situation of PWS and uncover new science with application to the general population”22.

2) Bardet-Biedl syndrome (BBS)

The National Organization of Rare Disorders (NORD) defines Bardet-Biedl syndrome (BBS) as

• “A genetic condition that impacts multiple body systems. It is classically defined by six features. Patients with BBS can experience problems with obesity, specifically with fat deposition along the abdomen. They often also suffer from intellectual impairments.

14 Health Direct, “Prader-Willi syndrome”, [website], 2019, https://www.healthdirect.gov.au/prader-willi-syndrome, (accessed 14 September 2019) 15 M. Butler,

Commonly, the kidneys, eyes and function of the genitalia will be compromised. People with BBS may also be born with an extra digit on the hands. The severity of BBS varies greatly even among individuals within the same family. The symptoms discussed below are those generally seen with BBS. They may or may not be seen in any given person with the syndrome23.

• BSS is a rare genetic condition that affects approximately 1:150,000 newborns. The condition is more common in the Island of Newfoundland and in the Bedouin population of Kuwait24.

Causes of obesity in Bardet-Biedl syndrome

The research sourced suggests the following as the causes of obesity in BBS:

• Ciliopathy
• Inherited genetic disorder leading to truncal obesity / severe early-onset obesity
• Insatiable hunger
• Defective leptin hormone receptor signalling

According to NORD:

“The cardinal features of BBS are truncal obesity, intellectual impairment, renal anomalies, polydactyly, retinal degeneration and hypogenitalism… The term ‘truncal obesity’ refers to a condition where fat is disproportionately distributed onto the abdomen and chest rather than the arms and legs. Individuals can be described as having an apple-shape body type. Weight is usually normal at birth but weight gain is quickly evident through the first year of life in as many as 90% of people with BBS. Diabetes mellitus (specifically, type II diabetes, non-insulin dependent) has been estimated to affect up to 45% of patients with BBS. Weight management problems may further complicate problems with the heart and blood vessels seen in patients with BBS . . . BBS can be caused by changes (mutations) in more than 20 different genes. It is usually inherited as an autosomal recessive condition. Patients with mutations in the BBS10 gene generally have significantly increased tendency to obesity and insulin resistance”25.

Obesity is one of the more common symptoms of the syndrome. A publication by DF Guo & K Rahmouni from 2011 found that dysfunction in leptin hormone receptor signalling is a contributing factor to obesity in people with BSS. This article states that:

“Obesity is highly prevalent in BBS individuals and present in almost all patients carrying homozygous mutations. Of note, relative to non-BBS subjects with comparable body mass index (BMI), BBS subjects tends to have higher adiposity. Additionally, patients with BBS were found to have significantly more abdominal visceral fat compared to BMI-matched control subjects. Conversely, lean mass tends to be lower in BBS patients relative to non-BBS subjects. Predominance of morbid obesity (BMI over 40 kg/m2) is also elevated in BBS patients”26.

23 The National Organization of Rare Disorders, ‘Bardet Biedl Syndrome’, 2017, https://rarediseases.org/rare-diseases/bardet-biedl-syndrome/, accessed 12 November 2019. 24 U.S. National Library of Medicine, ‘Bardet-Biedl syndrome’, 29 October 2019, https://ghr.nlm.nih.gov/condition/bardet-biedl-syndrome#statistics, accessed 12 November 2019. 25 Ibid. 26 Guo, DF & Rahmouni, K, ‘Molecular basis of the obesity associated with Bardet-Biedl syndrome’, Trends in Endocrinology & Metabolism, vol.22, no., pp268-293, 21 April 2011, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130119/, accessed 12 November 2019.

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Heymsfield et al. also discussed how people with BBS often have selective leptin resistance and cilia dysfunction that results in secondary health implications such as obesity, hypertension and diabetes27.

Early intervention

As obesity is a common component of BSS, NORD acknowledges that it is

“a particularly important factor to address. This feature manifests typically by an age of two-three years. An active lifestyle incorporating athletic hobbies can make a significant impact. Both diet and exercise programs are also highly recommended. Good diet management can prevent the weight-related problems that manifest in later life. Consulting with a primary care physician and a dietician can help in planning for adequate nutrition and prevention of excess weight gain”28.

A publication from 2016 states that “Clinical management of BBS is largely limited to a symptomatic treatment”, that is managing the common features of the condition29.

Guo & Rahmouni conclude in their 2011 publication that “The progress in defining the biological basis for energy imbalance and obesity in BBS may help the patients with this disorder to dispel any perception of obesity as a lack of discipline and personal behavioral failure. Such progress will also be helpful for clinical management of BBS patients and for rationale mechanism-based therapies”30.

The Bardet Biedl Syndrome Foundation acknowledges that while there is currently no cure for BBS, this does not mean that there is nothing that can be done to help people with BBS. “Children with BBS benefit greatly from therapies like physical therapy, occupational therapy, speech therapy and vision services. Everyone with BBS benefits from exercise and careful attention to diet to limit weight gain”31. The BBS Foundation also notes that Obesity is primary characteristic and is typically apparent by age one.

3) Alstrom syndrome

The U.S. National Library of Medicine describes Alstrom Syndrome as follows:

• “Alström syndrome is a rare condition that affects many body systems. Many of the signs and symptoms of this condition begin in infancy or early childhood, although some appear later in life.
• Alström syndrome is characterized by a progressive loss of vision and hearing, a form of heart disease that enlarges and weakens the heart muscle (dilated cardiomyopathy), obesity, type 2 diabetes (the most common form of diabetes), and short stature. This disorder can also cause serious or life-threatening medical problems involving the liver, kidneys, bladder, and lungs. Some individuals with Alström syndrome have a skin condition called acanthosis nigricans, which causes the skin in body folds and creases to become thick,

27 Heymsfield et al. loc cit. 28 The National Organization of Rare Disorders, loc cit. 29 Suspitsin EN & Imyanitov EN, ‘Bardet-Biedl Syndrome’, Molecular Syndromology, vol. 7 no. 2 May 2016, https://www.ncbi.nlm.nih.gov/pubmed/27385962, accessed 22 November 2019. 30 Guo & Rahmouni, loc cit. 31 Bardet Biedl Syndrome Foundation, ‘What is BBS’, 2019, https://www.bardetbiedl.org/what-is-bbs/#ten, accessed 22 November 2019.

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dark, and velvety. The signs and symptoms of Alström syndrome vary in severity, and not all affected individuals have all of the characteristic features of the disorder”32.

Causes of obesity in Alstrom syndrome

The research sourced suggests the following as the causes of obesity in Alstrom syndrome:

• Mutations in the ALMS1 gene cause Alström syndrome
• Ciliopathy
• Genetic disorder resulting in disruption to neural pathways that regulate hunger
• Higher level of blood lipids

The National Organization for Rare Disorders explains that obesity is a common symptom of Alstrom syndrome:

• “Birth weight is normal in infants with Alström syndrome, but excessive eating beyond the normal need to satisfy hunger (hyperphagia) and rapid weight gain may occur during the first year of life. Some affected children develop childhood truncal obesity, a condition in which fat is disproportionately distributed on the abdomen and chest rather than the arms and legs. As affected individuals age, some may see their body weight fall, often regaining normal or slightly above-average weight for their size”33.

The U.S. National Library of Medicine explains the impact that the mutation in the ALMS1 gene has on people with Alstrom syndrome:

• “More than 80 mutations in the ALMS1 gene have been identified in people with Alström syndrome. Most of these mutations lead to the production of an abnormally small version of the ALMS1 protein that does not function properly. Researchers propose that a lack of normally functioning ALMS1 protein in the brain could lead to overeating. A loss of this protein in the pancreas may cause insulin resistance, a condition in which the body cannot use insulin properly. The combined effects of overeating and insulin resistance impair the body’s ability to handle excess sugar, leading to diabetes and obesity (two common features of Alström syndrome). It is unclear how ALMS1 mutations cause the other signs and symptoms of Alström syndrome. Researchers suspect that this condition is associated with malfunctioning cilia in many of the body’s tissues and organs”34.

Early intervention

Strict dietary measures and exercise programs may help to control obesity, as well as aid in the management of diabetes mellitus and/or glucose intolerance associated with Alström syndrome. In most of the diagnosed patients of Alström syndrome, diabetes is controlled by diet and exercise alone35. While the early onset obesity is common in Alstrom syndrome the permanency of obesity is not established. One UK based study from 2006 found that in AS cases, “severe childhood obesity, waist circumference, and body fat decrease with age, whereas insulin resistance increases”36.

32 U.S. National Library of Medicine, ‘Alstrom syndrome’, 12 November 2019, https://ghr.nlm.nih.gov/condition/alstrom-syndrome, accessed 22 November 2019. 33 National Organization for Rare Disorders, ‘Alstrom Syndrome’, 2016, https://rarediseases.org/rare-diseases/alstrom-syndrome/, accessed 22 November 2019. 34 U.S. National Library of Medicine, ‘ALMS1 gene’, 12 November 2019, https://ghr.nlm.nih.gov/gene/ALMS1#conditions, accessed 22 November 2019. 35 Ibid. 36 Minton, JA et al., ‘Syndromic obesity and diabetes: changes in body composition with age and mutation analysis of ALMS1 in 12 United Kingdom kindreds with Alstrom syndrome’, The Journal of Clinical

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4) WAGR syndrome

• WAGR syndrome is a chromosomal disorder caused by chromosome 11 deletion.
• WAGR syndrome affects many body systems and is named for its main features: Wilms tumor, anirida, genitourinary anomalies, and intellectual disability… When WAGR syndrome includes childhood-onset obesity, it is often referred to as WAGRO syndrome37.
• Synonyms for WAGR syndrome include: WAGR Complex, WAGRO syndrome, Chromosome 11p deletion syndrome, 11p deletion syndrome, Aniridia-Wilms Tumor Association/ATWA, Aniridia-Ambiguous Genitalia-Mental Retardation, AGR Triad38

Causes of obesity in WAGRO syndrome

The U.S. National Library of Medicine states that the cause of WAGR Syndrome is the deletion of genetic material on the short (p) arm of chromosome 11.

“In people with WAGRO syndrome, the chromosome 11 deletion includes an additional gene, BDNF [brain derived neurotrophic factor]. This gene is active (expressed) in the brain and plays a role in the survival of nerve cells (neurons). The protein produced from the BDNF gene is thought to be involved in the management of eating, drinking, and body weight. Loss of the BDNF gene is likely responsible for childhood-onset obesity in people with WAGRO syndrome. People with WAGRO syndrome may be at greater risk of neurological problems such as intellectual disability and autism than those with WAGR syndrome. It is unclear whether this increased risk is due to the loss of the BDNF gene or other nearby genes”39.

A case study from 2019 examined the symptoms of WAGR Syndrome displayed in an eight year old boy. :

The presence of obesity (“O” for obesity) differentiates WAGRO syndrome from WAGR by the extent of the deletion of the short arm of chromosome 11, which is larger and involves the BDNF gene. This gene is associated with symptoms of polyphagia/hyperphagia, which typically begin in the second year of life. All children with WAGRO are considered obese at age 10 years. High cholesterol levels are also common in such children. It is notable that BDNF codifies an important factor in energy homeostasis in regulating leptin metabolism, which is associated with the development of obesity. These findings are not observed in WAGR patients40.

A cohort study from 2008 examined the relationship between genotype, hyperphagia and body-mass index (BMI) in 33 patients with the WAGR syndrome who were recruited through the International WAGR Syndrome Association. The result confirmed the link between BDNF deletions and childhood obesity. The results concluded:

Endocrinology and Metabolism, vol. 91, no. 8, August 2006, pp3110-6, https://www.ncbi.nlm.nih.gov/pubmed/16720663, accessed 22 November 2019. 37 U.S. National Library of Medicine, WAGR Syndrome, 2019, https://ghr.nlm.nih.gov/condition/wagr-syndrome, accessed 25 November 2019. 38 International WAGR Syndrome Association, ‘WAGR Syndrome: A guide for Physicians’, 2007, https://wagr.org/wp-content/uploads/2017/11/IWSA-Physicians-Guide-pdf-Nov-2017.pdf, accessed 25 November 2019. 39 Ibid. 40 Tosi Ferreira, MA et al., ‘WAGRO syndrome: a rare genetic condition associated with aniridia and additional ophthalmologic abnormalities’, Arquivos Brasileiros de Oftalmologia, vol. 82, no. 4. July/August 2019, http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0004-27492019000400336, accessed 25 November 2019.

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“Deletions of chromosome 11p in the patients studied ranged from 1.0 to 26.5 Mb; 58% of the patients had heterozygous BDNF deletions. These patients had significantly higher BMI z scores throughout childhood than did patients with intact BDNF (mean [±SD] z score at 8 to 10 years of age, 2.08±0.45 in patients with heterozygous BDNF deletions vs. 0.88±1.28 in patients without BDNF deletions; P=0.03). By 10 years of age, 100% of the patients with heterozygous BDNF deletions (95% confidence interval [CI], 77 to 100) were obese (BMI ≥95th percentile for age and sex) as compared with 20% of persons without BDNF deletions (95% CI, 3 to 56; P<0.001). The critical region for childhood-onset obesity in the WAGR syndrome was located within 80 kb of exon 1 of BDNF. Serum BDNF concentrations were approximately 50% lower among the patients with heterozygous BDNF deletions (P=0.001)”41.

Early intervention

In 2007 the International WAGR Syndrome Association published a ‘Guide for Physicians’. The booklet was designed to assist both primary and specialty care physicians caring for individuals with WAGR syndrome. Information about diagnosis, associated conditions, treatment, and follow-up care throughout life are given, along with resources for additional information and assistance’. One of the primary treatment considerations was for a dietary consultation. The booklet states that:

“Some individuals with WAGR syndrome may have a genetic predisposition to Early Onset Overweight and/or obesity. Consultation with a dietician and assistance with appropriate levels of physical activity may be necessary [and to] Encourage family to establish optimal dietary and physical exercise patterns to help prevent/manage obesity”42.

5) Albright’s Hereditary Osteodystrophy

The US Genetic and Rare Disease Information Center (GARD) describes Albright’s hereditary osetodystrophy as:

• “A rare disorder with a wide range of signs and symptoms, including short stature, obesity, round face, subcutaneous ossifications (formation of bone under the skin), and short fingers and toes (brachydactyly). When the disorder is inherited from the mother, the features of AHO can be associated with resistance to certain hormones, in particular the parathyroid hormone (PTH). This is called pseudohypoparathyroidism type 1a (PHP1a). When inherited from the father, an individual will have AHO without any hormone issues, which is called pseudopseudohypoparathyroidism (PPHP). This condition is inherited in an autosomal dominant manner due to a mutation in the GNAS gene”43.
• The condition is sometimes just referred to as Pseudohypothyroidism.
• The obesity generally occurs very early (within the first year) and tends to be severe in early childhood44.

41 Han, JC et al., ‘Brain-Derived Neurotrophic Factor and Obesity in the WAGR Syndrome’, The New England Journal of Medicine, vol. 359, pp. 918-927, 2008, https://www.nejm.org/doi/full/10.1056/NEJMoa0801119, accessed 25 November 2019. 42 International WAGR Syndrome Association, loc cit. 43 Genetic and Rare Disease Information Center, ‘Albright’s hereditary osetodystrophy’, March 2018, https://rarediseases.info.nih.gov/diseases/5770/albrights-hereditary-osteodystrophy, accessed 25 November 2018. 44 Weinstein, LS et al., ‘The Role of GNAS and Other Imprinted Genes in the Development of Obesity’, International Journal of Obesity, vol.34, no.1 pp.6-17, 2010, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931809/, accessed 25 November 2019.

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• There is very little research into Albright’s examining obesity specifically.

Causes of obesity in Albright’s Hereditary Osteodystrophy

The causes of obesity in Albright’s are complex. Put simply, the mutation in the GNAS gene disrupts gene expression and function causing irregular energy regulation.

There have been several studies, regarding the role of GNAS in weight regulation in humans, however a literature review from 2010 highlights that while the link between Albright’s and obesity is acknowledged, the genetic causation is not fully understood45. This literature review lists some on the conclusions that research has found to date:

“Few studies have been performed in humans examining the underlying mechanism for the obesity in PHPIA. Although one study showed evidence that adipocytes from PHP1A patients have reduced lipolytic responsiveness to epinephrine due to reduced levels of Gsα/cAMP signaling, the adipose tissue is unlikely to be involved in this parent-of-origin effect on energy balance as studies have shown no evidence for Gsα imprinting in adipose tissue. This same study did show PHP1A patients to have extremely low circulating norepinephrines, even when compared to similarly obese children without PHP1A, suggesting that the defect may lie in central nervous system (CNS) regulation leading to low sympathetic nervous system activity and metabolic rates. Although food intake has not been systematically examined in these patients, one recent case was reported in which severe obesity developed in the first year of life in the absence of hyperphagia, suggesting that low energy expenditure rates may be the major contributor to obesity in this disorder. There is some evidence that growth hormone deficiency due to growth hormone releasing hormone resistance in the pituitary may contribute to obesity in some cases. Although the incidence of comorbid metabolic abnormalities such as insulin resistance and diabetes in PHP1A has not been systematically examined, recently a case of severe insulin resistance in a young PHP1A patient has been reported. In addition to the monogenic obesity resulting from clear loss-of-function mutations, two single nucleotide polymorphisms have been identified within the GNAS locus that have been associated with altered body weight or response to weight loss regimens”46.

Early intervention

Ain 2018 an expert consensus statement on the ‘Diagnosis and management of pseudohypoparathyroidism and related disorders’ was published. The expert consensus provides 67 diagnostic and management recommendations.

The expert consensus states that:

“To date, no prospective clinical trials have been conducted in patients with PHP and related disorders that focus on the management and outcomes of treatment in these disorders. Large cohorts of molecularly diagnosed patients are needed for recruitment into clinical studies, which should also include long-term follow-up. As a result of the rarity of the disease, cohorts and research forces are scattered; there is a need to coordinate and implement multicentre international clinical trials. A multidisciplinary follow-up and early,

45 Ibid. 46 Ibid.

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specific interventions are necessary for efficient therapeutic management of these patients”47.

The consensus also recommends that:

• Medical evaluations for weight gain and BMI should be conducted from infancy into adulthood, however obesity I adulthood is less severe and less common than in childhood48.
• Lipid and blood glucose metabolism should be monitored regularly
• Educational programmes, as well as psychological support, should be provided to patients and families when obesity and/or eating disorders are present and even in the presence of a normal BMI as a preventive strategy, as these patients are at high risk. Dietary counselling should take into account that these patients have decreased resting energy expenditure49

Further research

The expert consensus concludes that:

Given the lack of strong evidence-based data, particularly for management of these patients, international collaboration and long-term clinical trials looking at the natural history, the diseases’ classification and the outcome of treatments are urgently needed50.

6) Down syndrome

Down syndrome is a common genetic disorder caused by an extra chromosome 21. People with DS will have:

• some characteristic physical features
• some health and development challenges
• some level of intellectual disability51.

There is significant research on DS indicating a link to obesity. Whilst there is research indicating such, the open source type information provided by advocacy group or public health websites does not bring this issue to prominence. This lack of published discourse may indicate a general desire from advocates not to create a common stigma around Down syndrome (DS) and overweight/obesity.

Causes of Obesity in Down syndrome

The research sourced suggests the following as the causes of obesity in DS:

• Metabolic disorders (low metabolism)
• Prevalence of dyslipidaemia (abnormal amounts of lipids in the blood)
• Pre-diabetes

47 Mantovani, G et al., Diagnosis and management of pseudohypoparathyroidism and related disorders’, Nature Revies Endocrinology, 29 June 2018, https://www.nature.com/articles/s41574-018-0042-0, accessed 25 November 2019. 48 Ibid, Table 4. 49 Ibid. 50 Ibid. 51 Down Syndrome Australia, ‘What is Down syndrome?’, 2019, https://www.downsyndrome.org.au/what_is_down_syndrome.html, (accessed 7 November 2019).

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• Sleep Apnoea (obstructive)
• Hyperinsulinemia (excess levels of insulin)
• Gait disorder

Open source information

Open source information websites were researched including Australian associations and support groups, and no reference to obesity as a direct feature of Down syndrome could be found. Sites sourced were: Down Syndrome Australia, Down Syndrome Western Australia, Down Syndrome Victoria, Better Health Channel (Victoria), Down Syndrome NSW, WebMD, Healthline, National Down Syndrome Society.

Neither the Raising Children website, nor the HealthDirect website suggest that obesity is a feature of DS. Health Direct suggests the risk of those with DS being overweight, whilst Raising Children has no mention of the weight factor.

Down Syndrome Australia, a peak body providing a voice for people living with DS, asserts only that “there can be a tendency for both children and adults with Down syndrome to become overweight. An active lifestyle with plenty of physical activity helps to counterbalance this tendency and encourages general health and fitness”52.

Similarly, the UK’s Down Syndrome Association suggests that

For many years there has been a myth circulating around the inevitably of people with Down’s syndrome gaining weight. Maybe this persists from the bad old days of institutions and hospitals. There are certainly many people with Down’s syndrome who defy this stereotype by leading very active and healthy lives. Obesity is not inevitable for people with Down’s syndrome such as hypothyroidism

53

Academic Research sources

Whilst the open source literature on Down syndrome does not appear to accept or draw attention to any link between obesity and Down syndrome, academic research provides a different narrative.

A Paediatric Nursing journal from 2010 published a literature review on Obesity in Children with DS and concluded that children with DS have a higher risk of developing obesity due to physiological and behavioural factors. Regarding the percentage of children with DS who are obese, the research states that:

“A more recent concern for children born with Down syndrome is their tendency to become overweight and obese. Approximately 17.1% of children in the U.S. are obese (Ogden, Carroll et al., 2006). Some research suggests the number of children with Down syndrome who are obese approximates national trends (Cohen, 1999). However, the rate of obesity may be much higher than the general population; another study stated that up to 30% to 50% of children with Down syndrome are obese (Harris, Rosenberg, Jangda, O’Brien, & Gallagher, 2003). Fonesca, Amaral, Ribeiro, Beserra, and Guimaraes (2005) found children with Down syndrome had an increased risk for developing Type 2 diabetes mellitus due to their propensity for obesity and large amounts of abdominal fat stores”54.

Setting out to assess whether children with DS in the US are at an increased risk for obesity, the evaluation of 303 individuals in a 2015 cohort study, found that children with DS are at a substantial risk for obesity55.

The issue of low metabolism as having an effect on obesity in Down syndrome is commonly featured in the research sourced.

A journal publication from 2015 highlights the common link to secondary health and developmental challenges that people with DS commonly experience, noting that:

“Down syndrome (DS) is one of the more commonly occurring genetic disorders, where mental retardation is combined with nutritional diseases… Symptoms include intellectual disability/mental retardation, early onset of Alzheimer’s disease and the appearance of various phenotypic features… In addition, there are other health problems throughout the body, consisting in part of cardiac defects and thyroid function abnormalities along with nutritional disorders (i.e. overweight, obesity, hypercholesterolemia and deficiencies of vitamins and minerals)… Many studies indicate excessive or deficient nutrient uptakes associated with making inappropriate foodstuff choices, food intolerance, (e.g. celiac disease) or malabsorption. DS persons with overweight or obesity are linked with a slow metabolic rate, abnormal blood leptin concentrations and exhibit low levels of physical activity. Vitamin B group deficiencies and abnormal blood homocysteine levels decrease the rate of intellectual development in DS cases. Zinc deficiencies result in short stature, thyroid function disorders and an increased appetite caused by excessive supplementation”56.

While this article focusses on lifestyle factors including excessive food intake and lack of exercise, there is an acknowledgement that people with DS typically have a slower metabolic rate and high lipid levels.

Several other studies have considered this metabolic connection to obesity:

• A control study from 1994 investigated the relationship between energy expenditure and obesity in DS children, using 10 control subjects matched for age, weight, and percentage of fat, using indirect calorimetry and the doubly labelled water method. The results of the study indicated that prepubescent children with DS have decreased resting metabolic rate compared with control children57.
• Another observational, cross-sectional study from 1995 set out to compare the resting metabolic rates (RMRs) of adults with and without DS while controlling for potential confounds. The study demonstrated that persons with DS have lower RMRs than do persons without DS58.

52 Down Syndrome Australia, “Down syndrome”, [website}, 2019, https://www.downsyndrome.org.au/health_wellbeing.html, (accessed 21 September 2019) 53 Down’s Syndrome Australia, “Common Sense Tips for Weight Management”, [website}, 2019, https://www.downs-syndrome.org.uk/for-families-and-carers/health-and-well-being/weight-management, (accessed 21 September 2019) 54 J. Murray and P. Ryan-Krause, “Obesity in Children with Down Syndrome: Background and Recommendations for Management”, Pediatric Nursing, Vol. 36, No. 6, pp. 314-9, 2010.

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https://search.proquest.com/openview/17e743f38ff81c67a9d3f8ecf85aaaf3/1?pq-origsite=gscholar&cbl=47659, accessed 7 November 2019 [secondary referenced research in quote could not be accessed]. 55 J. Basil et al., “Retrospective Study of Obesity in Children with Down Syndrome”, J Pediatr., vol. 173, pp. 143-148, 2016. https://www.ncbi.nlm.nih.gov/pubmed/26987801 56 D. Mazurek and J. Wyka, “Down syndrome–genetic and nutritional aspects of accompanying disorders”, Rocz Panstw Zakl Hig., vol. 66, no. 3, pp. 189-94, 2015. https://pdfs.semanticscholar.org/3115/eb99ebdc101f3f995c8a2f530066d739a49f.pdf?_ga=2.36055072.1886279669.1571626672-558858406.1571626672 57 A. Luke, et al., “Energy expenditure in children with Down syndrome: Correcting metabolic rate for movement”, The Journal of Pediatrics, Vol. 125, No. 5, pp.829-838, 1994. https://www.sciencedirect.com/science/article/abs/pii/S0022347606801939 58 D. Allison, “Decreased resting metabolic rate among persons with Down Syndrome”, International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity, vol. 19, no. 12, pp. 858-861, 1995. https://europepmc.org/abstract/med/8963352

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• A more recent control study from 2014 “aimed to describe anthropometric differences in weight-related disorders between adults with Down syndrome (DS and healthy controls, as well as their disparate impact on glucose and lipid metabolism disorders . . . Adults with DS were significantly younger and more often male, with a higher prevalence of overweight and obesity than controls. Adults with DS also had a higher WHR [waist-hip ratio], and more frequently presented abdominal obesity”. The study concluded that the prevalence of obesity was higher in adults with DS than in the controls, and that adults with DS showed higher insulin resistance than the controls“59.
• A 2019 study which describes DS as a condition associated with obesity, looked at whether BMI (body mass index) captures adiposity and cardiometabolic risk in DS by comparing cardiometabolic risk measures in youth with DS and typically developing matched controls. It concluded that despite similar insulin resistance, youth with DS had greater prevalence of dyslipidemia (an abnormal amount of lipids e.g. triglycerides, cholesterol and/or fat phospholipids, in the blood) and prediabetes than typically developing youth60.

Noting that there has been no large scale comprehensive studies published regarding the prevalence of obesity in people with DS, a recent 2019 study used a database of children from a single U.S. medical centre (DS specialty clinic) to “calculate rates of obesity and overweight by age group and examined possible associations with common comorbidities including cardiac disease, thyroid disease, sleep apnea, autism, and visual and hearing impairment”61. This study concluded that children with DS have higher rates of obesity than the general population, with especially high risk for girls. Much of the increase in obesity occurs between ages 2 and 6 years62.

Note: the research team have completed a separate research document examining the strong link between Down syndrome and sleep apnoea.

Early Intervention

There is a theme in the research of early intervention having a positive effect on obesity and weight issues within those with DS. The majority of studies sourced recommend early interventions during childhood to assist with the issue.

A significant cohort study of children with DS suggested “that children with Down syndrome are at a substantial risk for obesity and OSAS (obstructive sleep apnoea syndrome). These findings support the need for more aggressive weight management in early childhood and throughout the lifespan”63.

A comprehensive article from Paediatric Nursing asserts that children with Down syndrome

“Have a higher risk for developing obesity. The primary care provider can assist the family in preventing or managing obesity by recognizing the physiological and behavioural factors that place children and adolescents with Down syndrome at increased risk to become obese, and establishing a screening and management plan early to prevent or treat excess weight gain. By using adapted strategies, the negative physiological and psychological outcomes associated with obesity may be lessened or avoided in this specific population”64.

59 D. de Asua et al., “Evaluation of the impact of abdominal obesity on glucose and lipid metabolism disorders in adults with Down syndrome”, Research in Developmental Disabilities, Vol 35, No 11, pp.2942-2949, 2014, https://www.sciencedirect.com/science/article/abs/pii/S089142221400314X 60 S. Magge et al., “Cardiometabolic Risk and Body Composition in Youth With Down Syndrome”, Pediatrics, vol. 144, no. 2, 2019. https://www.ncbi.nlm.nih.gov/pubmed/31315916 61 M. Pierce et al., “Trends in Obesity and Overweight in Oregon Children With Down Syndrome”, Glob Pediatr Health, vol. 2, no. 6, 2019. https://www.ncbi.nlm.nih.gov/pubmed/31044152 62 Ibid. 63 Basil et al. 64 Murray & Ryan-Krause, loc cit.

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A 2015 peer reviewed journal article [previously cited] concludes that:

Scientific advances in the research and diagnosis of DS, as well as preventing any associated conditions, have significantly increased life expectancies of those with this genetic disorder. Early dietary interventions by parents or guardians of DS children afford an opportunity for decreasing the risk or delaying some of the DS associated conditions from appearing, thus beneficially impacting on their quality of life“65.

Further Research Needed for Obesity and DS

While the academic research verifies that there is a link between DS and obesity due to both physiological and behavioural factors, there is a theme in much of the literature calling for further research to understand and substantiate the link.

A 2016 literature review on the subject concluded that “population-based research is needed to identify risk factors and support multi-factorial strategies for reducing overweight and obesity in children and adolescents with DS”66. The review found that the “combined prevalence of overweight and obesity varied between studies from 23% to 70%. Youth with DS had higher rates of overweight and obesity than youths without DS. Likely determinants of obesity included increased leptin, decreased resting energy expenditure, comorbidities, unfavourable diet, and low physical activity levels. Obesity was positively associated with obstructive sleep apnea, dyslipidemia, hyperinsulinemia, and gait disorder. Interventions for obesity prevention and control were primarily based on exercise-based programs, and were insufficient to achieve weight or fat loss”67.

An earlier case control study suggested that “the impact on the health of people with Down syndrome of being overweight or obese is uncertain, this is an area that requires further study”68.

While people with Down syndrome may experience metabolic disorders making weight gain more likely, it appears from the research that this risk can easily be mitigated/effectively managed through early dietary intervention and encouraging a healthy active lifestyle choices. That is, just because someone has Down syndrome does not mean they will inevitably become overweight.

7) Autism Spectrum Disorder (ASD)

• There is significant research on ASD indicating a link to obesity.
• The prevalence of overweight and obesity in people with ASD is high and is attributed to a variety of factors: common comorbidities, medication side effects, social/environmental factors.

Causes of obesity in ASD

The research sourced suggests the following as the causes of obesity in ASD:

• Psychopharmacological effects
• Genetic Basis
• Gastrointestinal disorders

65 Mazurek and Wyka, loc cit. 66 F. Bertapelli et al., “Overweight and obesity in children and adolescents with Down syndrome-prevalence, determinants, consequences, and interventions: A literature review”, Res Dev Disabil., vol. 57, pp. 181-92, 2016. https://www.ncbi.nlm.nih.gov/pubmed/27448331 67 Ibid. 68 C. Melville et al., “Obesity in adults with Down syndrome: a case-control study”, J Intellect Disabil Res., Vol. 49, pp 125-33, 2005. https://www.ncbi.nlm.nih.gov/pubmed/15634321

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• Sensory processing disorders
• Physical activity and sedentary behaviours
• Sleep disorders
• Food as reward for learning and behaviour management

Open Source Information

The popular Australian websites HealthDirect and Raising Children, although providing comprehensive information and referral on ASD, make no reference to obesity or weight control being common issues. The following popular sites were also researched and provided no reference to obesity or weight issues: Amaze, Australian Institute of Health and Welfare, Autism SA, Brain Foundation, Australian Autism Alliance, Autism CRC, Australian Medical Association, Scope, Autism Western Australia.

Autism Spectrum Australia does make reference to diet, nutrition and obesity stating that: “When comparing autistic teens with their typically-developing peers, perhaps the most obvious difference when it comes to eating is the high prevalence of restricted diets in those on the spectrum, due to their inherent sensory defensiveness and/or rigidity [which can] lead to nutritional deficiencies”69.

Another common concern for adolescents with ASD is not participating in team sports.

Autism Spectrum Australia state that “The obvious corollary from lack of exercise is becoming overweight [and that] A recent American study found that nearly half of young autistic people aged 10 to 17 were overweight or obese, compared with less than one-third of their typically developing peers

70. However this indicates that the cause of weight concerns for people with ASD stem from sensory or behavioural issues.

Academic Research Sources

There is a significant amount of academic research examining the link between ASD and obesity.

In 2017 a comprehensive literature review or ‘meta-analysis’ of epidemiological studies examined the association among obesity, overweight and ASD. The research included 15 studies published on databases such as PubMed, Embase, and Cochrane Library. The 15 studies collectively included a total of 49,937,078 participants and 1,045,538 individuals with ASD. The results showed that obesity was clearly associated with ASD. However, no significant association were identified between overweight and ASD71.

Citing other studies, the meta-analysis identified four major causes of obesity in ASD patients:

“First, individuals with ASD often have eating problems, such as food selectivity and specialized dietary habits, which make healthy dietary interventions less effective. Second, individuals with ASD spend less time on physical activities and more time on sedentary activities. They also have difficulty in participating in standard obesity prevention initiatives due to behavioral problems. Third, individuals with ASD have more chances to be treated with various antipsychotic medications, which are known to be associated with weight gain. Fourth, individuals with ASD also have comorbidities associated with obesity, such as sleep problems, gastrointestinal disorders, ADHD. Finally, some individuals with ASD have been

69 Autism Awareness Australia,

reported to have 16p11.2 or 11p14.1 microdeletions, which encompass genes related to obesity susceptibility”72.

The meta-analysis suggested further prospective studies with more accurate measures of weight status and better control of confounding factors are warranted73.

16p11.2 deletion in ASD

Noting the above mentioned link between ASD and genetic microdeletions, 16p11.2 ‘deletion syndrome’ is listed on the U.S. National Library of Medicine website and acknowledges that “People with this disorder are also at increased risk of obesity compared with the general population. However, there is no particular pattern of physical abnormalities that characterizes 16p11.2 deletion syndrome. Signs and symptoms of the disorder vary even among affected members of the same family. Some people with the deletion have no identified physical, intellectual, or behavioral abnormalities”74. It cannot be concluded that all people with ASD have this predisposition.

A recent literature review from 2014 published in the Harvard Review of Psychiatry by Carol Curtin et al. examined Obesity in Children with Autism Spectrum Disorder75. This article examined prevalence of obesity in people with ASD when linked with: genetics, psychopharmacological effects (antipsychotics, mood stabilizers, and antidepressants), sleep problems, food selectivity, delayed/impaired motor development, family functioning and other factors. The ‘other factors’ considered is the use of applied behavioural analysis treatment as a cause because food is often used as a primary reinforcer and this may impact of ongoing food intake. The altered social dimensions of eating and drinking that people with ASD experience also need to be researched further.

Regarding genetic causes of obesity in people with ASD, the Curtin et al publication also noted the 16p11.2 genomic deletion, however “given the significant gene variability and penetrance emerging in both animal and human models of ASD, more work is needed to draw definitive genetic associations between ASD and obesity”76. A more recent publication from 2019 has found that approximately 15% of people with ASD have the duplication or deletion of genome 16p11.277.

This Curtin et al publication concluded that:

The prevalence of obesity is at least as high, if not higher, in children with ASD compared to other children. Research has documented that atypical antipsychotic medication is a clear risk for weight gain in this clinical population. Studies on diet, physical activity, and sleep in typically developing children have shown positive associations with obesity, but this work remains to be done in children with ASD, as do other investigations on the implications of gastrointestinal disorders and using food as a reward for learning and behaviour management. Obesity and its associated sequelae represent significant threats to

72 Ibid. 73 Zheng et al., loc cit. 74 U.S. National Library of Medicine, ‘16p11.2 deletion syndrome’, https://ghr.nlm.nih.gov/condition/16p112-deletion-syndrome, accessed 7 November 2019. 75 C. Curtin et al., “Obesity in Children with Autism Spectrum Disorder”, Harvard Review of Psychiatry, Vol. 22, No. 2, pp. 93–103, 2014, https://journals.lww.com/hrpjournal/Fulltext/2014/03000/Obesity_in_Children_with_Autism_Spectrum_Disorder.4.aspx 76 Ibid. 77 S. Trambacz-Oleszak, “Why are individuals with autism spectrum disorder at risk group for unhealthy weight?”, Anthropological Review, Vol. 82, No. 3, pp. 313–326, 2019, <https://content.sciendo.com/configurable/contentpage/journals$002fanre$002f82$002f3$002farticle-p313.xml, p.316

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independent living, self-care, quality of life, and long-term health outcomes for individuals with ASD“78.

In 2019, Sylwia Trambacz-Oleszak from the Adam Mickiewicz University, Poland, conducted a comprehensive literature search and review of the PubMed database for papers published between January 2000 and June 2019. The intention of the review was to summarize the current state of knowledge on the genetic basis of obesity in ASD and answer the question ‘Why are individuals with autism spectrum disorder at risk group for unhealthy weight?’79

Trambacz-Oleszak states that several studies have indicated that the prevalence of overweight and obesity is high in autistic children and adolescents. There are significantly higher odds of being overweight or obese for children and adolescents with ASD, in comparison to typically developing children and youths. Both, overweight and obesity are risk factors for the incidence of multiple comorbidities, such as type 2 diabetes, cardiovascular diseases, sleep apnoea, cancers, psychological and social disorders80.

Some of the outcomes of the review are as follows:

• Genetic basis of ASD: It is currently well-known that autism has a genetic basis and the mapping of key genomes is becoming more understood. “Genomic imbalances and high rates of recurrent CNVs (misplaced or duplicated segments of chromosomes) are also emerging as risk factors for obesity. The genetic basis of different types of obesity, including monogenic and polygenic obesity, pleiotropic syndromes and chromosomal rearrangement are also well-documented now”81.
• Gastrointestinal disorders: Gastrointestinal disorders [vomiting, diarrhoea, constipation, abdominal pain, bloating, gaseousness, belching and reflux] are often observed among individuals with ASD and can affect up to 54% of patients. The review found that “On one hand, gastrointestinal problems may cause body mass loss. On the other hand, epidemiologic data indicated that obesity is associated with chronic gastrointestinal disorders. Therefore, gastrointestinal problems can contribute to an unhealthy body weight, either underweight or overweight, and obesity in children and adolescents with ASD”82.
• Sensory processing disorders: “Children with ASD very often suffer from sensory processing disorders, including irregularities in the reception and processing of sensory stimuli . . . Sensory processing disorders may be one of the causes of food selectivity and affect body weight”83.
• Depression: “A growing body of research has demonstrated the increased prevalence of comorbid depression among individuals with ASD . . . The association between depression and obesity is ambiguous. Although some studies have indicated a certain relation between obesity and depression, other studies have not confirmed it . . . However, psychological disorders comorbid with ASD, including depression and anxiety, are possible risk factors associated with unhealthy weight in this group”84.

78 Curtin, loc cit. 79 Trambacz-Oleszak, p.313. 80 Trambacz-Oleszak, p. 314. 81 Op cit, p.316. 82 Op cit, p.317. 83 Ibid. 84 Op cit, p.318.

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• Physical activity and sedentary behaviours: “The association between physical activity and sedentary behaviours with overweight and obesity is well documented in scientific literature”85.

Furthermore, a clinical control study from 2014 examined over 6000 identified children with ASD or Asperger’s syndrome and found that “Children with autism and Asperger syndrome had significantly higher odds of overweight and obesity than control subjects”86.

Another clinical trial in 2015 looked at the prevalence of overweight and obesity in a multisite clinical sample of children with ASDs and explored concurrent associations with variables identified as risk factors for unhealthy weight in the general population. The study found a

strong confirmatory evidence that young children with ASDs are at risk for unhealthy weight trajectories and that the presence of sleep or affective problems may confer increased risk

Further Research Needed for Obesity and ASD

There is a clearly a rising trend in the academic research examining the link between obesity and ASD, particularly in examining genetic anomalies. The majority of the academic resources discussed above advocate for further research to be conducted to draw definitive genetic association between ASD and obesity.

For example, a 2017 critical review that investigated potential contributing factors to the aetiology [cause; origin] and maintenance of obesity within the ASD child population concluded that “Research should continue to investigate excess weight gain in this population in order to adapt weight loss interventions for children with ASD

In conclusion, the majority of research examines the secondary impact of symptoms/behaviours associated with the disability: e.g. issues with sensory processing, gastrointestinal disorders, sleeping disorders, medication, and physical issues resulting from lack of exercise.

While research demonstrates that the prevalence of obesity in people with ASD is high, there is not a definitive understanding of the genetic causative factors. Also, the available information highlights that the symptoms and experiences of people with ASD are unique and that this genetic predisposition to weight gain would not be experienced by all people with ASD. There is also no evidence to suggest that this genetic predisposition could not be effectively managed/controlled by mainstream capacity building behavioural therapy and health education.

8) Intellectual Disability (in general)

• There is significant research on Intellectual Disabilities in general indicating an increased risk of obesity for this cohort.

85 Op cit. p.320. 86 S. Broder-Fingert et al., “Prevalence of Overweight and Obesity in a Large Clinical Sample of Children With Autism”, Academic Pediatrics Vol. 14, No. 4, pp. 408-414, 2014. https://www.sciencedirect.com/science/article/abs/pii/S1876285914001351 87 A. Presmanes et al., “Obesity and Autism”, PEDIATRICS, Vol.136, No. 6, 2015. https://pediatrics.aappublications.org/content/pediatrics/136/6/1051.full.pdf 88 B. Matheson and J. Douglas, “Overweight and Obesity in Children with Autism Spectrum Disorder (ASD): a Critical Review Investigating the Etiology, Development, and Maintenance of this Relationship”, Review Journal of Autism and Developmental Disorders, Vol. 4, No. 2, pp. 142-156, 2017. https://link.springer.com/article/10.1007/s40489-017-0103-7

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• Research sourced for this brief focuses on information and studies where ID is identified as the primary disability. However, much of the research sourced examines ID collectively with developmental disability, Prada-Willi syndrome and Down syndrome.
• As intellectual disabilities have been grouped together in much of the research, the genetic predisposition that these sources refer to is difficult to differentiate from these other genetic disorders. That is, you cannot make a blanket statement about obesity and intellectual disability.

Causes of obesity in Intellectual Disability

The research sourced suggests the following as the common causes of obesity in people with Intellectual Disability:

• Behavioural, environmental and biological factors
• Independent living without supervision
• Lack of exercise
• The disability hindering the persons understanding of managing nutrition and exercise.

Academic Research Resources

The majority of studies sourced identified lack of exercise and food choices in those with intellectual disability as the key contributing factors to obesity.

In 2016, an Australian cross sectional survey looked at the prevalence and associated characteristics of obesity in adolescents with ID. The study examined obesity in a community sample of adolescents with ID attending special education facilities in South-East Queensland across a four year period. Information on age, gender, weight, height, syndrome specific diagnoses, problematic behaviours, mobility, taking psychotropic or epileptic medication, and perceived household financial difficulties was collected. The study concluded that the prevalence of obesity and overweight were increased compared to general Australian adolescents. The study also found that adolescents with Down syndrome were more likely to be obese than other participants with ID89.

Another Australian cohort study from 2015 set out to describe the nutrition, food choice, physical activity and weight status in a group of adults with intellectual disability in Victoria. 51 disability workers and 68 adults with ID participated in the research. Disability workers provided information about the nutrition, food choice and physical activity levels of adults with ID through a questionnaire administered by a general practitioner or research nurse. The questionnaire also included the Australian Nutrition Screening Initiative checklist. The study found that “people with ID are at risk of developing diseases associated with obesity, inactivity, and poor nutrition [and that] Strategies to encourage people with ID to engage in physical activity and healthy eating are, therefore, a matter of priority and should involve their disability workers”90.

A 2016 literature review published by The University of Hertfordshire (UK) found that “The higher prevalence of obesity in people with intellectual disabilities is due to a complex mix of behavioural,

89 S. Krause et al., “Obesity in adolescents with intellectual disability: Prevalence and associated characteristics”, Obesity Research & Clinical Practice, Vol 10, No 5, pp. 520-530, 2016, https://www.sciencedirect.com/science/article/abs/pii/S1871403X15001659 90 S. Koritsas and T Iacono, “Weight, nutrition, food choice, and physical activity in adults with intellectual disability”, Journal of Intellectual Disability Research, Vol, 60, No. 4, pp. 355-364, 2016, https://onlinelibrary.wiley.com/doi/full/10.1111/jir.12254

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environmental and biological factors”91. For example, those living independently or with less supervision are at increased risk of developing obesity, and the use of psychotropic medication in adults with intellectual disabilities is considered to be a major cause of weight gain. Note: The ‘biological’ predisposition that this article refers to is only for Prada-Willi syndrome and Down syndrome.

Early Intervention

Research suggests that people with ID may benefit greatly from early interventions targeted at preventing and managing obesity. In fact, a great deal of the studies cited were initiated in order to identify early intervention efficacy. Much of the literature suggests physical exercise and nutrition choices as the key early interventions.

Further Research Needed for Intellectual Disability

Much of the research sourced calls for further studies regarding early intervention and other obesity management interventions. For example, the literature review published by The University of Hertfordshire concluded that “there is a need for methodologically robust studies to investigate further, both the aetiology and management of obesity in this population for prevention and early intervention”92.

A recent 2018 UK systematic review by A.J. Doherty et al. encapsulates this point clearly:

Responding to obesity and obesity‐related health risks in individuals with intellectual disabilities should be seen as an important health inequality issue by healthcare policymakers, service commissioners, providers and practitioners. . . . There is also an identified lack of evidence‐based research in this field