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Physiotherapy for Children with CLN2 Disease

Abstract

CLN2 disease (neuronal ceroid lipofuscinosis type 2) is a rare, genetic, paediatric-onset, neurodegenerative lysosomal storage disorder characterised by seizures, ataxia, rapid loss of motor function and language ability, dementia, visual loss and early death. Physiotherapy plays an important role in the management of CLN2 disease, aiming to maintain the best possible functioning and autonomy of the child, support the child’s participation in everyday life, limit secondary complications and maintain or improve quality of life.

This article discusses the physiotherapeutic treatment of children diagnosed with CLN2 disease. Based on the author’s clinical experience, frequent muscular impairments associated with CLN2 disease, their impact on affected children’s sensorimotor abilities and autonomy, and physiotherapy interventions are described. Common muscular deficits included abnormal muscle tone leading to poor trunk control, difficulty standing upright, often accompanied by equinus contractures and movement disorders such as myoclonus. The use of orthotic and adaptive medical devices that support an erect posture in locomotion and positioning appear to be particularly beneficial for prolonging sensorimotor control, communication and food intake.

In conclusion, early initiation of physiotherapy is recommended and should include the provision of adaptive walking, standing, sitting and positioning aids.

Keywords
CLN2 disease; neuronal ceroid lipofuscinosis type 2; physiotherapy; medical aids; sensorimotor symptoms

Introduction

CLN2 disease (neuronal ceroid lipofuscinosis type 2, OMIM #204500) is a rare, autosomal-recessive, neurodegenerative lysosomal storage disorder. This genetic disorder results from mutations in tripeptidyl peptidase 1 (TPP1), a soluble lysosomal enzyme involved in protein degradation [11. Schulz A, Kohlschütter A, Mink J, et al. NCL diseases - clinical perspectives. Biochim Biophys Acta. 2013;1832(11):1801-1806. doi: 10.1016/j.bbadis.2013.04.008
https://doi.org/10.1016/j.bbadis.2013.04...
,22. Kohlschütter A, Schulz A. CLN2 Disease (Classic Late Infantile Neuronal Ceroid Lipofuscinosis). Pediatr Endocrinol Rev. 2016;13(Suppl 1):682-688. ]. Deficiency in TPP1 enzyme activity results in intracellular accumulation of a protein-rich material called ceroid lipofuscin, which is associated with glial activation and neuronal loss [33. Cooper JD, Tarczyluk MA, Nelvagal HR. Towards a new understanding of NCL pathogenesis. Biochim Biophys Acta. 2015;1852(10 Part B):2256-2261. doi: 10.1016/j.bbadis.2015.05.014
https://doi.org/10.1016/j.bbadis.2015.05...
].

CLN2 disease is a rapidly progressive disorder characterised by language delay, motor and visual deterioration, refractory seizures, and dementia [11. Schulz A, Kohlschütter A, Mink J, et al. NCL diseases - clinical perspectives. Biochim Biophys Acta. 2013;1832(11):1801-1806. doi: 10.1016/j.bbadis.2013.04.008
https://doi.org/10.1016/j.bbadis.2013.04...
,44. Fietz M, AlSayed M, Burke D, et al. Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Expert recommendations for early detection and laboratory diagnosis. Mol Genet Metab. 2016;119(1-2):160-167. doi: 10.1016/j.ymgme.2016.07.011.
https://doi.org/10.1016/j.ymgme.2016.07....
,55. Williams RE, Adams HR, Blohm M, et al. Management Strategies for CLN2 Disease. Pediatr Neurol. 2017;69:102-112. doi: 10.1016/j.pediatrneurol.2017.01.034
https://doi.org/10.1016/j.pediatrneurol....
]. Generally, the disease initially manifests between the ages of 2 and 4 years, most commonly as seizures and/or ataxia, and a history of language delay [11. Schulz A, Kohlschütter A, Mink J, et al. NCL diseases - clinical perspectives. Biochim Biophys Acta. 2013;1832(11):1801-1806. doi: 10.1016/j.bbadis.2013.04.008
https://doi.org/10.1016/j.bbadis.2013.04...
,44. Fietz M, AlSayed M, Burke D, et al. Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Expert recommendations for early detection and laboratory diagnosis. Mol Genet Metab. 2016;119(1-2):160-167. doi: 10.1016/j.ymgme.2016.07.011.
https://doi.org/10.1016/j.ymgme.2016.07....
,55. Williams RE, Adams HR, Blohm M, et al. Management Strategies for CLN2 Disease. Pediatr Neurol. 2017;69:102-112. doi: 10.1016/j.pediatrneurol.2017.01.034
https://doi.org/10.1016/j.pediatrneurol....
]. As the disease progresses, affected children lose voluntary movement, develop movement disorders (e.g. ataxia, myoclonus and spasticity), lose their ability to eat and drink (dysphagia) [66. Kohlschütter A, Riga C, Crespo D, et al. Ethical issues with artificial nutrition of children with degenerative brain diseases. Biochim Biophys Acta. 2015;1852(7):1253-1256. doi: 10.1016/j.bbadis.2015.03.007.
https://doi.org/10.1016/j.bbadis.2015.03...
], become blind and bedridden, and die prematurely [11. Schulz A, Kohlschütter A, Mink J, et al. NCL diseases - clinical perspectives. Biochim Biophys Acta. 2013;1832(11):1801-1806. doi: 10.1016/j.bbadis.2013.04.008
https://doi.org/10.1016/j.bbadis.2013.04...
,44. Fietz M, AlSayed M, Burke D, et al. Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Expert recommendations for early detection and laboratory diagnosis. Mol Genet Metab. 2016;119(1-2):160-167. doi: 10.1016/j.ymgme.2016.07.011.
https://doi.org/10.1016/j.ymgme.2016.07....
,55. Williams RE, Adams HR, Blohm M, et al. Management Strategies for CLN2 Disease. Pediatr Neurol. 2017;69:102-112. doi: 10.1016/j.pediatrneurol.2017.01.034
https://doi.org/10.1016/j.pediatrneurol....
].

Physiotherapy and the use of medical aids plays an important role in the management of CLN2 disease and can help to maintain function and independence for as long as possible and thereby optimise the quality of life of patients and their caregivers [55. Williams RE, Adams HR, Blohm M, et al. Management Strategies for CLN2 Disease. Pediatr Neurol. 2017;69:102-112. doi: 10.1016/j.pediatrneurol.2017.01.034
https://doi.org/10.1016/j.pediatrneurol....
]. Williams et al. recommend two to three physiotherapy sessions per week [55. Williams RE, Adams HR, Blohm M, et al. Management Strategies for CLN2 Disease. Pediatr Neurol. 2017;69:102-112. doi: 10.1016/j.pediatrneurol.2017.01.034
https://doi.org/10.1016/j.pediatrneurol....
]. In the absence of disease-specific studies for this extremely rare disorder, physiotherapeutic approaches developed and tested in patients with similar muscular deficits (e.g. in children with cerebral palsy) can be applied to CLN2 disease (e.g. the Bobath [neurodevelopmental treatment] concept [77. Bobath K. Uma Base Neurofisiológica para o Tratamento da Paralisia Cerebral [A Neurophysiological Basis for the Treatment of Cerebral Palsy]. 2nd ed. São Paulo, Brazil: Manole; 1984. ,88. Vereinigung der Bobath-Therapeuten Deutschlands e.V. [Association of Bobath Therapists of Germany]. Website. http://www.bobath-vereinigung.de/. Accessed January 15, 2018.
http://www.bobath-vereinigung.de/...
] and the Castillo Morales® concept [99. Türk C, Söhlemann S, Rummel H. Das Castillo Morales-Konzept [The Castillo Morales concept]. Stuttgart, Germany: Georg Thieme Verlag KG; 2012. ,1010. Castillo Morales Association. Website. http://www.castillomoralesvereinigung.de/index_e.html. Accessed January 15, 2018.
http://www.castillomoralesvereinigung.de...
]). This article discusses frequently occurring motor impairments (and associated swallowing difficulties) and the use of physiotherapy and adaptive standing and seating equipment in children diagnosed with CLN2 disease. To the best of our knowledge, it is the first paper focusing on the physiotherapeutic management of CLN2 disease.

Methods

This is a descriptive review of muscular impairments associated with CLN2 disease, their impact on affected children’s sensorimotor abilities and autonomy, and physiotherapy interventions from a single centre. Sixteen patients aged between four and eleven years who were diagnosed with CLN2 disease were managed at the Paediatric Physiotherapy Practice in Hamburg, Germany between February 2014 and July 2018. Individually tailored physiotherapy was performed 2 or 3 times a week for 30-40 minutes according to the Bobath and the Castillo-Morales concepts [99. Türk C, Söhlemann S, Rummel H. Das Castillo Morales-Konzept [The Castillo Morales concept]. Stuttgart, Germany: Georg Thieme Verlag KG; 2012. ,1010. Castillo Morales Association. Website. http://www.castillomoralesvereinigung.de/index_e.html. Accessed January 15, 2018.
http://www.castillomoralesvereinigung.de...
], in collaboration with therapists in the individual children’s school, kindergarten or hospice.

Results

Physiotherapeutic Goals

The objectives of physiotherapeutic treatment for children with CLN2 are to support children’s ability to participate in everyday life activities, by promoting their ability to walk, stand and sit, as well as to communicate and eat and drink with minimal external intervention for as long as possible. This includes early intervention such as the implementation of augmentative and alternative communication methods in anticipation of language loss to help the children express their thoughts/wishes (e.g. through the use of voice-output communication aids) and continued support over the course of the disease. Importantly, even with the most severe symptoms, regular standing or sitting (e.g. at the table with the family) can be achieved with standing devices or therapy chairs.

The physiotherapeutic interventions seek to: maximise functional independence/participation in daily activities, with early use of medical aids (e.g. standing devices); improve food intake/safe swallowing by educating parents on the most appropriate supportive body positioning; reduce the risk of patients developing secondary complications (e.g. respiratory infections following aspiration of food into the lungs or joint contractures resulting from spasticity/immobility); enable children to maintain upright positions in order to support the above goals; and set functional goals with the patients’ families and counsel them on treatment and care options throughout the course of the disease.

Prevalent Sensorimotor Symptoms

The 16 children with CLN2 disease demonstrated recurrent muscular dysfunctions and compensation patterns. In terms of functional limitations, conspicuous features of CLN2 disease were the rapid loss of the ability to walk, difficulty concentrating and the effects of muscle dysfunction on orofacial function impacting the ability to eat. Common neuromuscular disorders included abnormal muscle tone and movement disorders (e.g. hypo/hypertonia, spasticity, myoclonus and dystonia); these are listed in Table 1. The muscular deficits described in Table 1 influence each other. For example, hypertonia in the back of the legs results in a forward displacement of the torso (see Figure 1), which existing hypotonia in the torso is increasingly unable to overcome. Muscle reactions such as hypotonia, myoclonus and dystonia also occur in the orofacial area; this results in an inability to close the jaw. The tongue may also exhibit myoclonic muscle jerks or twitches, such as lateral and rotating motions, or dystonic activities, exerting intermittent pressure on the palate.

Table 1
Prevalent sensorimotor symptoms associated with CLN2 disease and their effect on patients observed at the Paediatric Physiotherapy Practice in Hamburg, Germany.

Figure 1
Children with CLN2 disease who developed equinus contractures, typically compensated for this foot deformity by hyperextension of the knees, backward displacement of the pelvis, forward displacement of the trunk and hyperextension of the neck. As a result, their ability to stand and walk became severely restricted and independent standing and walking rapidly became impossible. The equinus position can be corrected with the help of orthoses. As a result, the child can assume a more favourable upright position, which greatly supports standing and walking. Positive effects may also be observed on communication, independence and contracture prophylaxis.

Significance of an Upright Posture for Sensorimotor Abilities and Communication

Optimising the childrens’ ability to move and/or adopt age-appropriate positions (e.g. standing upright) strengthened their mental alertness and motivation to utilise motor abilities. Even if part of the musculature could no longer sustain an upright posture (e.g. increased trunk instability), the child could still walk alone with an adaptive walking device (e.g. with torso support). The ability of a child to independently control his/her legs and determine the direction to walk represents an expansion in independence. In light of the early loss of a child’s ability to walk as CLN2 disease progresses, it is necessary to support and maintain the ability to stand and sit upright for as long as possible. In this way children with CLN2 disease can obtain postural control with relatively little effort and motivation, adapting an optimal position from which to engage in functional activities such as communicating, eating and playing (Table 1). Being at the same eye level as other children or parents when communicating and eating promoted these functions and thereby could greatly improve their quality of life.

Management of Muscular Limitations

To delay development or reduce the severity of movement disorders associated with CLN2 disease, early initiation of physical therapy and the use of medical aids are recommended. Therapeutic and medical aids, such as sensorimotor inserts, rotation bandages, orthoses and adaptive standing devices, and a description of their function are listed in Table 2.

Table 2
Description of the main tools used, effects observed, and challenges encountered at the Paediatric Physiotherapy Practice in Hamburg, Germany.

Physiotherapeutic techniques, such as muscle stretching and stabilising pressure toward the joint can temporarily help regulate hypertonia, such as spasticity. Position correction and medical aids can also reduce muscular hypertonia when in use. When extensor hypertonia causes equinus deformity, orthoses can be used to hold the foot in a normal, plantigrade position and enable weight bearing; this allows temporary normalisation of muscle tone (Figure 1). The children with CLN2 disease generally appeared to tolerate orthoses well during physical activity such as standing and walking without any apparent discomfort or pain. Orthoses must not be applied if they cause pain. For existing myoclonus, appropriate positioning of the child (e.g. on the more severely impaired side of the child’s body) allows the body weight to exert a regulating effect on muscle tone, which reduces myoclonic muscle activity (Table 2). These therapeutic interventions allow the child to be supported in his/her proprioception, enabling adoption of physiologic postures and enhancing the implementation of physiologic movement patterns. However, because CLN2 disease is progressive, eventually appropriate positioning will not be able to overcome the deficits caused by the disease.

As part of the treatment of orofacial dysfunction according to the Castillo-Morales concept, parents are instructed to support their child’s independent food intake for as long as possible. To achieve this goal, caregivers are educated about how their child can achieve optimal swallowing through postural management (with positioning aids that support trunk stability and head position) and the use of utensils (e.g. adapted cups).

The most physiologic position with a straight neck that is achievable offers a good basis for the functions of swallowing and speaking. Depending on the severity of the limitations, postural support is provided by the parents/caregivers or by adaptive equipment.

Passive standing devices and frames can provide long-term benefits even in the later stages of the disease, when the child can no longer sit or stand on his/her own. Starting in a lying position and being supported based on his/her abilities (if necessary, complete leg, hip, trunk and head support), the child can be tilted into an erect posture permitting him/her to feel and bear his/her own body weight. Standing normalises the tone of and stretches the muscles, which may prevent contractures, and positively affects respiratory and gastrointestinal functions.

Special Considerations in the Physiotherapeutic Treatment of the Child with CLN2 Disease

Factors complicating the treatment of a child with CLN2 disease are the complexity of the symptoms, which include cognitive, sensorimotor and communication deficits and rapid disease progression. Physiotherapy must be tailored to the individual needs of the child and the disease stage. Thus, the degenerative nature of CLN2 disease dictates that the therapeutic goal evolves from maintaining function in early-stage disease to maintaining quality of life in spite of loss of function in later stages [55. Williams RE, Adams HR, Blohm M, et al. Management Strategies for CLN2 Disease. Pediatr Neurol. 2017;69:102-112. doi: 10.1016/j.pediatrneurol.2017.01.034
https://doi.org/10.1016/j.pediatrneurol....
]. In addition to the progressive worsening of sensorimotor functions due to neurodegeneration, physical impairments can be temporarily exacerbated by emotional situations or fatigue (e.g. side effects of medications for seizure control).

These fluctuations in the physical and emotional health of the child require constant observation and therapeutic adjustments. It may also be necessary to change the location where therapy is provided and treat the child at his/her home. This reduces the burden on the child and family and allows for implementation of a practical therapy plan that is relevant to the patient’s everyday life. To ensure the best possible management of the child, a properly functioning interdisciplinary team of doctors, therapists, psychologists, orthopaedic technicians, dieticians, health insurers, etc. is necessary, so that in conjunction with the family, changes can be made quickly to respond to the child’s needs.

Discussion

Physical therapy has a beneficial effect on children diagnosed with CLN2 disease. The early initiation of therapy tailored to individual children’s needs and the early use of medical aids are recommended [55. Williams RE, Adams HR, Blohm M, et al. Management Strategies for CLN2 Disease. Pediatr Neurol. 2017;69:102-112. doi: 10.1016/j.pediatrneurol.2017.01.034
https://doi.org/10.1016/j.pediatrneurol....
]. The use of medical aids allows the child to be as self-sufficient as possible as the disease progresses. Adjustable standing devices and postural aids can be used long term across the different disease stages. In comparison, mobility aids (e.g. walkers) can be used for shorter periods of time. It is also important to educate, enable and support the patient’s parents. Effective management of children with CLN2 disease requires good communication and close interdisciplinary collaboration among the medical, social, psychological and therapeutic team and the patient’s family/caregivers. All parties need to work together to effectively address the multifaceted and complex problems occurring in children with CLN2 disease. This interdisciplinary and long-term care can be coordinated for example through a socio-educational centre.

The perceived effectiveness of supported standing in children with CLN2 disease is consistent with the findings of a systematic review on paediatric supported standing programs examining 30 high-quality research studies in children with atypical development, with or without a neuromuscular diagnosis, including cerebral palsy [1111. Paleg GS, Smith BA, Glickman LB. Systematic review and evidence-based clinical recommendations for dosing of pediatric supported standing programs. Pediatr Phys Ther. 2013;25(3):232-247. doi: 10.1097/pep.0b013e318299d5e7
https://doi.org/10.1097/pep.0b013e318299...
]. This review found moderate to strong evidence for a beneficial effect of supported standing on lower-extremity range of motion, lower-leg spasticity or tone, muscle power, interaction with peers and the environment, functional activities (e.g. walking, activities of daily living, transfers) and, in high-dose programs of supported standing, on bone mineral density [1111. Paleg GS, Smith BA, Glickman LB. Systematic review and evidence-based clinical recommendations for dosing of pediatric supported standing programs. Pediatr Phys Ther. 2013;25(3):232-247. doi: 10.1097/pep.0b013e318299d5e7
https://doi.org/10.1097/pep.0b013e318299...
]. Furthermore, case report and survey evidence supports a possible positive impact on bowel function and reflux, hip stability, alertness and well-being [1111. Paleg GS, Smith BA, Glickman LB. Systematic review and evidence-based clinical recommendations for dosing of pediatric supported standing programs. Pediatr Phys Ther. 2013;25(3):232-247. doi: 10.1097/pep.0b013e318299d5e7
https://doi.org/10.1097/pep.0b013e318299...
]. A survey of 319 paediatric and adult patients with various congenital or acquired disabilities (e.g. cerebral palsy, syndromes, multi-disabilities, spina bifida, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, virus, tumours) who used standing devices confirmed that the users (or their caregivers) perceived a positive impact on well-being and quality of life [1212. Nordström B, Naslund A, Eriksson M, et al. The impact of supported standing on well-being and quality of life. Physiother Can. 2013;65(4):344-352. doi: 10.3138/ptc.2012-27
https://doi.org/10.3138/ptc.2012-27...
]. Similarly, the recommendation to use adaptive seating equipment in children with CLN2 disease is supported by findings from a systematic review that concluded that special-purpose adaptive seating systems may be able to improve self-care and play behaviour at home among children with severe cerebral palsy [1313. Angsupaisal M, Maathuis CG, Hadders-Algra M. Adaptive seating systems in children with severe cerebral palsy across International Classification of Functioning, Disability and Health for Children and Youth version domains: a systematic review. Dev Med Child Neurol. 2015;57(10):919-930. doi: 10.1111/dmcn.12762
https://doi.org/10.1111/dmcn.12762...
].

Conclusions

While physiotherapy is a valuable factor in the palliative management of patients with CLN2 disease, it is not possible to draw firm conclusions from case analyses. However, the use of physiotherapy and assistive equipment described appears to contribute to the maximisation of positioning and functioning, ability to undertake daily activities, social interaction and well-being in children with CLN2 disease. Further research is needed to measure and compare the effect of the current and alternative physiotherapeutic concepts and assistive technology devices on functioning, activities of daily living, social participation, quality of life and ease of care in children with CLN2 disease. Such studies will need to overcome challenges relating to the heterogeneous and complex clinical presentation of CLN2 disease, the application of many interventions at the same time, the highly individualised physiotherapy approach and the degenerative nature of the disease (goal to slow worsening rather than improve outcomes). In addition, studies need to account for the impact of the motivation and skill level of caregivers as well as the impact of enhanced therapeutic environments on children with CLN2 disease.

Acknowledgements

I would like to thank the patients and their families. Medical writing support was provided by Susanne Vidot, PhD, Excel Medical Affairs, Horsham, UK, and supported by BioMarin Pharmaceutical Inc.

References

  • 1. Schulz A, Kohlschütter A, Mink J, et al. NCL diseases - clinical perspectives. Biochim Biophys Acta 2013;1832(11):1801-1806. doi: 10.1016/j.bbadis.2013.04.008
    » https://doi.org/10.1016/j.bbadis.2013.04.008
  • 2. Kohlschütter A, Schulz A. CLN2 Disease (Classic Late Infantile Neuronal Ceroid Lipofuscinosis). Pediatr Endocrinol Rev 2016;13(Suppl 1):682-688.
  • 3. Cooper JD, Tarczyluk MA, Nelvagal HR. Towards a new understanding of NCL pathogenesis. Biochim Biophys Acta 2015;1852(10 Part B):2256-2261. doi: 10.1016/j.bbadis.2015.05.014
    » https://doi.org/10.1016/j.bbadis.2015.05.014
  • 4. Fietz M, AlSayed M, Burke D, et al. Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Expert recommendations for early detection and laboratory diagnosis. Mol Genet Metab 2016;119(1-2):160-167. doi: 10.1016/j.ymgme.2016.07.011.
    » https://doi.org/10.1016/j.ymgme.2016.07.011
  • 5. Williams RE, Adams HR, Blohm M, et al. Management Strategies for CLN2 Disease. Pediatr Neurol 2017;69:102-112. doi: 10.1016/j.pediatrneurol.2017.01.034
    » https://doi.org/10.1016/j.pediatrneurol.2017.01.034
  • 6. Kohlschütter A, Riga C, Crespo D, et al. Ethical issues with artificial nutrition of children with degenerative brain diseases. Biochim Biophys Acta 2015;1852(7):1253-1256. doi: 10.1016/j.bbadis.2015.03.007.
    » https://doi.org/10.1016/j.bbadis.2015.03.007
  • 7. Bobath K. Uma Base Neurofisiológica para o Tratamento da Paralisia Cerebral [A Neurophysiological Basis for the Treatment of Cerebral Palsy]. 2nd ed. São Paulo, Brazil: Manole; 1984.
  • 8. Vereinigung der Bobath-Therapeuten Deutschlands e.V. [Association of Bobath Therapists of Germany]. Website. http://www.bobath-vereinigung.de/ Accessed January 15, 2018.
    » http://www.bobath-vereinigung.de/
  • 9. Türk C, Söhlemann S, Rummel H. Das Castillo Morales-Konzept [The Castillo Morales concept]. Stuttgart, Germany: Georg Thieme Verlag KG; 2012.
  • 10. Castillo Morales Association. Website. http://www.castillomoralesvereinigung.de/index_e.html Accessed January 15, 2018.
    » http://www.castillomoralesvereinigung.de/index_e.html
  • 11. Paleg GS, Smith BA, Glickman LB. Systematic review and evidence-based clinical recommendations for dosing of pediatric supported standing programs. Pediatr Phys Ther 2013;25(3):232-247. doi: 10.1097/pep.0b013e318299d5e7
    » https://doi.org/10.1097/pep.0b013e318299d5e7
  • 12. Nordström B, Naslund A, Eriksson M, et al. The impact of supported standing on well-being and quality of life. Physiother Can 2013;65(4):344-352. doi: 10.3138/ptc.2012-27
    » https://doi.org/10.3138/ptc.2012-27
  • 13. Angsupaisal M, Maathuis CG, Hadders-Algra M. Adaptive seating systems in children with severe cerebral palsy across International Classification of Functioning, Disability and Health for Children and Youth version domains: a systematic review. Dev Med Child Neurol 2015;57(10):919-930. doi: 10.1111/dmcn.12762
    » https://doi.org/10.1111/dmcn.12762

Publication Dates

  • Publication in this collection
    04 Nov 2019
  • Date of issue
    2019

History

  • Received
    30 July 2019
  • Reviewed
    05 Sept 2019
  • Accepted
    11 Sept 2019
Latin American Society Inborn Errors and Neonatal Screening (SLEIMPN); Instituto Genética para Todos (IGPT) Rua Ramiro Barcelos, 2350, CEP: 90035-903, Porto Alegre, RS - Brasil, Tel.: 55-51-3359-6338, Fax: 55-51-3359-8010 - Porto Alegre - RS - Brazil
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