Table 2 Qualitative and quantitative articles included in this review

Hoffmann et al. [58]

MPS I patients reported lower frequency of challenging behaviour & better perceived manageability than MPS II & -III

Aggression, hyperactivity, agitation, orality, & sleep disturbance highly frequent & stressful symptoms

Medication & non-medication approaches rated similarly effective

Parents grow into a state of acceptance, largely uninfluenced by child behavior or state of illness

Social exchange & private space are important to strengthen personal & interfamilial functioning

Support managing challenging & uncooperative behaviors

Family networking & sharing of management strategies

Yazdani et al. [47]

Perceived impact of the pandemic on healthcare services:

Delays & losses: cancelled appointments, prolonged waiting time for services, loss of home care support, loss of school-related services, parental decision to delay services for the safety of their family

Management of child’s needs independently associated with perceived amplification of child’s symptoms

Advantages: reduced emotional & physical burden of going to the hospital; reduced travel time; more quality time with loved ones; saved costs associated with gas & parking; reduced work absenteeism; reduced child & parent exhaustion; improved communication between parents & healthcare professionals

Concern: parents experience a higher level of stress owing to the shortage of services & the child’s vulnerability

Stress fear that physicians might miss important clinical features regarding child’s regression

Desire for telemedicine in their child’s long-term care

Telemedicine only employed when physical examination is not necessary, when the child is stable & well known to the physician

Preference of video consultations over phone appointments

Eichler et al. [50]

Diagnostic process: misdiagnoses, difficulty with length of time taken to obtain a final MLD after symptom onset

Most troublesome symptoms: immobility & respiratory difficulties

Frequent healthcare visits: 8/22 patients experienced 11 hospitalizations since diagnosis, & 14/22 parents reported these lasted 4 days

Visits to healthcare professionals had an emotional impact on parents: overwhelmed with decisions, grief & guilt watching their child in pain, struggling to communicate "slowly deteriorate & die"

Time & attention required to care for child limited time for social activities, confined to home, contributed to relationship breakdowns

Depression, feelings of fear, guilt, remorse, & hopelessness

Impacted decision to have further children & impacted siblings as they struggled to understand the disease

Comprehensive information about psychiatric/behavioral signs & symptoms

Increase awareness & knowledge of MLD to reduce misdiagnoses & diagnostic delays

Treatment priorities:

Preference for a treatment that stops the disease progression or slows progression of disease to improve quality of life

Therapy to improve speech or communication & reduce decline in mobility, pain, cognitive ability, communication, respiratory problems or food intake

Needham et al. [55]

Communication, daily living skills, socialization, & motor skills were significantly lower for patients with severe MPS II

Receptive, expressive & written communication; personal & community daily living skills; play & leisure time; coping skills; & fine motor skills were significantly lower for patients with severe MPS II

Within the severe MPS II group, there was a strong significant & negative correlation between all Vineland domains & age. Thus, for those with severe MPS II, the older the patients are, the lower their adaptive behavior functioning

A more severe presentation of MPS II was correlated with more impact (i.e. lower HRQOL, lower family functioning, lower social, physical functioning, daily living & family relationships) for the parents & families

Levels of support & ways to maintain psychological health varied widely for parents

Parents reported maintaining employment, staying active, going to church, attending therapy, positive thinking, support from friends & family, social networking, & going out with friends supported their psychological health

Fear of the child’s death &/or life expectancy, worry for their child’s pain, future level of functioning, how the patient will cope with having MPS II, & social isolation

Greatest worry is what would happen to their children if the parent died before the patient

Support systems to improve social life & methods to maintain psychological health

Krantz et al. [51]

Long processing times & lack of knowledge about the disease

Society not developed for progressive disease where worsening of symptoms can happen suddenly

Limited support & access to contacts in the health &/or social insurance system

Adult healthcare system was not seen as fit for purpose

Recurring losses & grief throughout the course of the disease which began with diagnosis & continued with progressive loss of child's function

Difficulties finding time to recharge, less time available outside of the family & a loss of relationships with people who used to be close

Negative impact on romantic relationships

Side-lined siblings

The end stage of the disease with the child completely dependent & with possible psychotic symptoms brings a sense of an additional loss, not only related to their death but also a loss of identity

Guilt, frustration, hopelessness

Shared resilience adapting to new circumstances using acceptance & adopting new shared beliefs about what is important & meaningful in life

Relief from care assistants, relatives & a short-term stay at a care centre where families of children with disabilities could meet

Time to recharge without guilt & spending time without affected child was important to maintain family functioning

Organizational processes: need for flexibility & workplace adjustments

Parental support groups to share knowledge & experiences was a way to create understand & learn from other parents

A result-oriented vision including collaborative problems solving within the families & seeing the disease as a common enemy could help with dealing with the grief of the diagnosis

Porter et al. [52]

Two overarching impact domains

cognitive/behavioral/psychological &

physical health

Cognitive/behavioral/psychological impact:

Child: frustration, anxiety/unhappiness in child

Child & family: communication, frustration, hyperactivity

Family: relationship & social deficits, impulse control/aggressive behaviors, unsafe behaviours, sleep disturbance/night-time waking

Physical health impact:

Child: Sleep problems, seizures, feeding & maintaining nutrition

Child & family: Pain/headaches (experienced & anticipated), mobility, illness/vulnerability to illness

Family: digestive issues & toileting

Pressing treatment needs related to communication & behavior

Parents highly valued incremental benefits targeting symptoms, to maintain current skills set & treatments that would slow or stop symptom progression or rate of decline

Broad as possible access to clinical trials (without age limitations) & later to approved therapies

Emphasis on improving quality of life for the child, parents, & family as their primary goal for new treatments

Clinical trials that assess outcomes other than, or in addition to, currently used global cognitive measures of evidence for global improvement in cognition

Grant et al. [56]

Older children with MPS III were more intellectual impaired

As children with MPS III got older the frequency of their challenging behaviour decreased, but there was no significant relationship with how difficult parents found these behaviours to manage

Children with MPS III had a significantly higher level of intellectual disability than the children with ID

Social resources as their highest protective factor & planned future as their lowest protective factor

Parents experienced similar levels of perceived social support & reported feeling significantly more supported by their significant other than by family or friends

Acceptance was most frequently used coping strategy & self-blame was least used coping strategy

Both groups of parents scored above the clinical cut off for anxiety & depression

Mean scores of both groups of parents were higher in all categories than those of mothers of children in oncology services indicating high levels of stress in both groups

Behaviour support packages, with appropriate adaptations to learn behaviour management techniques, coping strategies, how to build, resilience factors, & social support networks

Flexible strategies to respond to their child’s current needs & unpredictable behavior patterns rather than focusing on future planning

Professional psychological support for families during transition periods to discuss their mixed emotional challenges

Referral to appropriate psychological services, together with support from relevant parental support groups, who play an important role in providing social & emotional support to parents who are geographically diverse & do not have access to face-to-face support groups

Somanadhan et al. [49]

Frustration waiting long time for diagnosis & spending significant amount of time navigating bureaucracy for basic needs

Future is unknown from prognosis to outcome

Unsatisfactory collaboration & communication between healthcare professionals

Hospital Vs. Home: preferred to be in their home rather than a hospital, aided routine & structure in their regular life

Devastated by the enormity of the debilitating nature of their child’s rare genetic life-limiting condition & the impact on their child’s life expectancy

Process of trying to accept their child’s diagnosis was an emotional struggle, they reacted with upset, devastation, anger & shock

Life characterised by uncertainty & ambiguity: life as a roller coaster & living with MPS as a constant battle

Marital relationships markedly strained & fear of siblings becoming side-lined

Fear that comes with increasing evidence of visible clinical features & realisation that the gap would widen as they got older

Frustration & anger comparing to other conditions with treatments available – particularly those parents of children approaching end of life

Parents wanted to be proactive & commonly used reframing strategies

Coping achieved through awareness that there were other children with more severe diagnoses

Collaboration & communication between healthcare professionals, especially during initial diagnostic disclosure

Improved specialist knowledge of rare condition among healthcare professionals to avoid delays in referral, diagnosis & disease management/treatment

Emotionally supportive communication of diagnosis & coping strategies for ongoing challenges of caring for child with progressive condition that has no cure

Streamlined, consistent & equitable access to healthcare resources & supports for their child’s condition. E.g., more responsive physiotherapy, occupational therapy, psychology, & social support services

Frequent & planned reassessment of children & parents psychosocial & mental healthcare needs

Kuratsubo et al. [60]

Correlation between low social status & psychological problems among parents

Many of the parents were seeking psychological counseling

High scores on the BDI-II, suggesting mothers & fathers were in a depressive state. Depression in mothers was serious as compared with previous reports

According to the GHQ60 11/21 mothers were considered to be in a state of neurosis

4/16 fathers & 8/21 mothers showed high levels of anxiety

Younger mothers with young patients with fewer years since diagnosis tended to be more depressed

Tailored support services, including psychological counseling, home nursing care, supports in workplace & community

Early intervention for mental health problems should be provided for younger mothers with few years since the child’s diagnosis

Varvogli et al. [61]

Children had significant developmental & neurological difficulties

Progressive worsening of neurological functioning

Over half patients had 4 + special needs. The most common were dependence on a wheelchair, developmental delays, feedings through a gastrointestinal tube & vision problems

56% of the mothers had scores in the pathological range on three or more scales

Higher MMPI-2 scores were significantly related to the age of mothers, with younger mothers evidencing greater psychopathology

Results from the open-ended interview suggest that the child’s age & the circumstances of the diagnosis did not have an impact on the mother’s personality profile

Psychosocial services tailored to reduce the level of anxiety & stress in mothers

Conjin et al.

Posttraumatic Stress: 22%, (7 mothers & 3 fathers) met the criteria for the diagnosis of PTSD. The prevalence in this study is significantly higher among parents of MPS III patients compared to Dutch general population

Anxiety & Depression: Mothers of MPS III patients reported significantly higher mean levels of anxiety & depression, & more frequently clinically relevant anxiety & depression than mothers in the reference group

Fathers reported more frequently clinically relevant depression compared to fathers in the reference group

Structural monitoring of the psychosocial functioning of MPS III parents

Access to professional psychological & peer support from those in the community

Dermer et al. [57]

The average total stress percentile significantly higher than the median normative sample

Twenty percent of parents had high levels of stress (> 85th percentile), & 11% had clinically significant levels of stress (> 90th percentile)

No significant difference was found between mother & father’s mean total stress score

Mothers’ total stress percentile was significantly higher if their child had behavior difficulties

Tailored parent psychological counseling & support early after the initial diagnosis

Supportive treatments of children with behavioral difficulties

Ammann-Schnell et al. [62]

Time to diagnosis & number of clinicians families visited in attempt to get diagnosis from first onset of symptoms was very distressing

Disease-specific knowledge in parents was high: 71% received disease specific information from clinicians, 51% from other affected families, 46% internet, 14% specific literature Empathic handling of diagnosis, honesty about the severity & comprehensible explanation of the condition was helpful

Disturbing factors were insensitive behaviour towards parents, ignorance of the disease from doctors’ part & passing on of unconfirmed diagnosis

MLD families reported significantly poorer HRQOL than the families with healthy children (Total Impact Score, Parent HRQOL & Family Functioning Summary Scores)

Significantly poorer Family Functioning observed in the late-infantile MLD families compared to the juvenile MLD families

No significant correlations between the severity of the symptoms on the family’s quality of life

Mothers spent an average of 88 h caring for child, more often than fathers missed out on or sacrificed a professional career to be able to care for the child at home

The diagnostic phase/time to diagnosis & the terminal disease stage represents an especially high burden on families

The heavy demands on care, & minimal feedback from the child at that stage are possible reasons for this

Increasing general awareness, about rare diseases including (MLD) among healthcare professionals

Encouraging healthcare professionals to listen to parents who report that they are worried about developmental & behavioral features of their children, they have not known before

A reliable system of easily accessible diagnostic counseling for healthcare professionals & families, which should involve academic centers to promote rapid diagnosis of rare diseases

Bose et al. [48]

Parents of younger children relieved upon receiving diagnosis vs resignation & numbness in older bereaved parents

Range of emotions identified by frequency (overwhelmed, stressed, anxious, exhausted most frequent) & extensiveness (“gut-wrenching”, “devastating”, anger at healthcare professionals & healthcare system – not invested in learning more about rare diseases/lack of coordination)

Stressors; interactions with healthcare professionals / managing multiple needs – feeling of failure, impact on social relationships, highlighting importance of social networks, perceived lack of support contributed to resentment & isolation

Confusion deep sadness & uncertainty for the overall progressive nature of disease/ present & anticipated negative impact on child’s QOL

Regret & guilt for time lost spent on unaffected siblings

Coping (cognitive & behavioural strategies employed to address these emotional experiences) redefining expectations, acceptance of difference in parent experiences to help cope with challenges & limitations of the disease, advocating for child’s needs, becoming involved in promoting disease awareness

Collaborative, transparent & consistent healthcare community fosters trust & respect which positively impacted parents

Simple, targeted approaches focusing on improved communication between healthcare professionals & parents

Resources for emotional support & counseling to support redefining parent expectations & to promote acceptance

Social support system & healthcare community (e.g. advocacy organisations to enhance knowledge & ability to address child’s needs effectively) crucial element in managing overall emotional experience

Killian et al. [63]

Increasing child & parent age associated with decreased parent PCS & increased MCS

Parents of children who were older at diagnosis showed poorer parent PCS & improved MCS

Greater time period beyond age of regression was associated with poorer parent PCS & improved MCS

More severe disease associated with poorer PCS but improved MCS

Feeding problems & seizure severity adversely impacted both PCS & MCS

Multivariate predictors: a longer interval beyond regression was associated with poorer PCS

Parents who felt limited in the amount of time for their own needs also had poorer PCS, as did parents who sensed tension or conflict at home

For parent MCS, increased child’s age was associated with an improved score

Feeding problems were associated with poorer MCS. Finally, CHQ items associated with personal worry, lack of time & poor family dynamics described a relationship between increasing severity & poorer MCS

For Rett syndrome, clinical severity, as measured by the CSS, associated with poorer PCS but with improved MCS

Access to appropriate psychosocial resources to reduce parent emotional distress, worry & to improve family dynamics

Time allocated to cater for parents own needs, especially among parents of children with severe clinical features (child feeding problems & seizure severity) to improve parent quality of life

Supports for child feeding problems & seizure severity

Rozensztrauch et al. [54]

75% of children aged 1–2 years experienced a significant regression in acquired skills, with developmental deterioration, severe dementia, with loss of speech, autistic features, & stereotypies

Malnutrition (78% of children), epilepsy (43%), impaired mobility (40%), scoliosis (13%), respiratory problems (87%), hyperventilation 22%

Average age when symptoms were first noticed was 1 year

Child’s average age at diagnosis was 3.5

Malnutrition & feeding difficulties significantly affect family functioning in family relationships dimension

Parents were not satisfied with the effects of rehabilitation

Children living in urban areas had better access to healthcare professionals than those living in towns & villages

Access to specialists & rehab centres offering early diagnostic services, especially for families living in rural areas

Psychological support for parents, especially in early diagnosis stage

Assistance with feeding difficulties to improve family relationships

Identification of child’s need & targeted assistance with individual problems

Healthcare professionals’ help with making appropriate decisions for patient care

Lamb et al. [64]

Parents who shared more of the caregiving responsibilities with other family members had more effective family functioning

Less effective functioning was associated with having more than one child with RS & having children who were older when symptoms of RS emerged (more years asymptomatic)

3 key variables were significantly correlated with family functioning: parental self-efficacy, problem-focused coping & emotion focused coping

4 key variables were significantly correlated with adaptation: parental self-efficacy, problem-focused & emotion focused coping, & family functioning

Mediation: family functioning is a significant partial mediator of the relationships between adaptation & three key variables: parental self-efficacy, problem-focused coping & emotion focused coping

Interventions to strengthen parent competence in their role to enhance parent adaptation, to increase parental self-efficacy, employing appropriate coping strategies, & facilitating greater family functioning

Parent education about importance of family dynamics, to facilitate effective communication about roles & responsibilities, & to encourage other members of the family to provide support for the primary caregiver

Referral pathways to support groups & other resources to promote adaptation

Palacios-Ceña et al. [27]

Genetic diagnosis experienced as a pilgrimage: looking for answers, seeking diagnosis: as confirmation of their suspicions & fears as early as possible to avoid delaying treatment

Information seeking from specialist healthcare professionals & internet

Non-pharmacological therapies (speech therapy, physio) necessary basic pillars for parents to fight illness on another front as they attempt to decrease the physical & cognitive disability of the child

Symptoms: manifold, arising at irregular intervals, leading to a state of alert in the caregivers, which affected their initial feelings of joy after giving birth

Challenges managing day-to-day life: integrating treatments & care into daily life & family routine

Appointments short with limited number of sessions, difficult & expensive to access continuous therapies in public system

Learning to care; with ever-changing problems without a fixed pattern (nutritional problems, bowel problems, sleeping disorders, respiratory disorders, epileptic seizures & stereotypical movements)

Sleep, stress & anxiety impact the whole family & parent who experience distress that they are unable to care for their child

High impact on family economic resources, direct & indirect indispensable costs associated with hospital care, work readjustments resulting in decreased economic income. In addition, cost of sanitary supplies is considered abusive; no regulations

Economic support & resources for direct & indirect indispensable caregiving costs

Equitable access to genetic testing & diagnoses across geographical / residential locations

Social support networks to loan or buy second-hand materials

Mori et al. [65]

Living in a remote area, the child being a teenager at baseline, frequent sleep disturbances or behavioural problems, & the type of MECP2 gene mutation were each associated with later poorer parental physical well-being

Being a single parent or on a low income was also associated with later poorer physical well-being

Child being enterally fed was associated with later poorer emotional well-being

Both the physical & emotional well-being of the parent improved when the child was living in out-of-home care

Healthcare professionals being alert to the possibility & need for management of a child’s sleep or emotional disturbance

Additional support for parents as child moves through adolescence into early adulthood, including additional physical supports (hoists, modified vehicle)

Respite for coping with care demands & facilitating parents’ social life

Additional supports for single parents & families showing poor functioning