Guidelines for the diagnosis, treatment and clinical monitoring of patients with juvenile and adult Pompe disease

Diretriz para o diagnóstico, tratamento e acompanhamento clínico de pacientes com doença de Pompe juvenil e do adulto

ABSTRACT

Pompe disease (PD) is a potentially lethal illness involving irreversible muscle damage resulting from glycogen storage in muscle fiber and activation of autophagic pathways. A promising therapeutic perspective for PD is enzyme replacement therapy (ERT) with the human recombinant enzyme acid alpha-glucosidase (Myozyme^®). The need to organize a diagnostic flowchart, systematize clinical follow-up, and establish new therapeutic recommendations has become vital, as ERT ensures greater patient longevity. A task force of experienced clinicians outlined a protocol for diagnosis, monitoring, treatment, genetic counseling, and rehabilitation for PD patients. The study was conducted under the coordination of REBREPOM, the Brazilian Network for Studies of PD. The meeting of these experts took place in October 2013, at L’Hotel Port Bay in São Paulo, Brazil. In August 2014, the text was reassessed and updated. Given the rarity of PD and limited high-impact publications, experts submitted their views.

Pompe disease; glycogen storage disease type II; acid alpha-glucosidase; muscular weakness; dyspnea; GAA gene; rhGAA

RESUMO

A doença de Pompe (DP) é uma doença grave, potencialmente letal, devida ao depósito de glicogênio na fibra muscular e ativação de vias autofágicas. Tratamento promissor para a DP é a reposição enzimática com a enzima recombinante humana alfa-glicosidase ácida (rhAGA -Myozyme^®). A necessidade de organizar uma propedêutica diagnóstica, sistematizar o seguimento clínico e sedimentar as novas recomendações terapêuticas tornaram-se vitais à medida que o tratamento permite uma maior longevidade aos pacientes. Uma força-tarefa de clínicos experientes no manejo da DP foi constituída para elaborar um protocolo para o diagnóstico, acompanhamento clínico, tratamento, aconselhamento genético, entre outras considerações voltadas ao paciente adulto. O estudo foi realizado sob a coordenação da Rede Brasileira de Estudos da Doença de Pompe (REBREPOM). Diante da raridade da DP e escassez de trabalhos de alto impacto de evidência científica, os especialistas emitiram suas opiniões.

doença de Pompe, doença de depósito de glicogênio tipo II; alfa-glicosidade ácida; debilidade muscular; dispneia; gene GAA; GAA recombinante humana

DATA COLLECTION

This study began in 2013 with a web search on the databases Medline, Embase and LILACS using the following keywords: “Glycogen Storage Disease Type II” [MeSH] OR “Lysosomal Storage Diseases” [MeSH] OR “Pompe Disease” [MeSH] OR “Enzymatic Replacement Therapy” [MeSH]. We obtained 255 studies, 123 for childhood onset (< 18 years old) Pompe Disease (PD) and 132 for adult onset PD. We then selected studies based on their strength of recommendation and quality of evidence. In August 2014, a new search identified 329 studies published between the years 2010 and 2014.

Strength of recommendation and quality of evidence: A. experimental studies or strong observational studies (randomized);B. experimental studies or other observational studies (case-control); C. Case reports (uncontrolled studies); D. expert opinion without critical evaluation, based on consensus, physiological studies or animal models.

PD DEFINITION

Pompe disease (PD) (OMIM # 232300), also known as glycogen storage disease type II, is a rare lysosomal storage disease classified as an inborn error of metabolism¹. It is caused by partial or complete deficiency in the activity of the acid alpha-glucosidase enzyme (GAA) (EC 3.2.1.20), which is essential for the degradation of lysosomal glycogen into glucose. This deficiency causes a progressive accumulation of glycogen in the cells of various tissues, manifesting in multisystem form, predominantly in the skeletal, cardiac and smooth muscle systems¹.

PD has been defined as a low/abnormal activity of the GAA enzyme in asymptomatic or symptomatic individuals and/or presence of two pathogenic mutations in theGAA gene²(B).

EPIDEMIOLOGY

The frequency of PD is quite variable (Table1). Recently, through a blind analysis of 100,000 samples obtained from neonatal screening through mass tandem spectrometry, Scott et al.³ (B) identified, among other lysosomal diseases (Fabry and mucopolysaccharidosis type 1 - MPS I), an incidence of PD about 1/27,800 of the newborns.

On the other hand, a study conducted in 104 muscle biopsies from asymptomatic or oligosymptomatic (fatigue, cramps, myalgia) patients, with increased serum CK, normal physical examination and no statin exposure, PD in juvenile and adults (PDJ-A) was identified in 3.8% of patients⁹ (C). Werneck et al.¹⁰, in a particular study of symptomatic cases, reviewed 4,500 muscle biopsies performed over a period of 33 years in a reference center for neuromuscular diseases in Brazil and identified 19 cases of PD, 10 cases of early onset PD and 9 cases of PDJ-A (C).

PATHOPHYSIOLOGY

PD is an autosomal recessive disease caused by pathogenic mutations in both copies of the gene that encodes the enzyme GAA. Hundreds of mutations have been identified in the GAA gene (http://www.pompecenter.nl/).

PD severity and age of symptom onset are related to the level of residual activity of the GAA enzyme. Early onset infantile PD results from a complete deficiency of the enzyme (activity < 1%), while late onset PD (juvenile or adult) results from partial deficiency of GAA (1-30%). Onset may occur as early in childhood or as late as at the sixth decade of life ¹¹,¹²(B).

The cause of PD is the progressive accumulation of intralysosomal glycogen due to the inability of the cell to breakdown the lysosomal glycogen into glucose. As a result, lysosomal membranes rupture, causing leakage of hydrolytic material into the cytoplasm with impairment of the muscle contractile unit¹. There is also saturation of autophagic pathways during the pathophysiological process¹³(C).

SYMPTOMS AND SIGNS OF JUVENILE AND ADULT POMPE DISEASE (TABLE2)

The clinical manifestations vary according to the patient’s age, the rate of disease progression and the extent of organ involvement, and may result in irreversible motor impairment ¹⁴,¹⁵ (B). The most common manifestation in adults is progressive muscle weakness simulating the muscular dystrophies. Most patients present weakness of the proximal and axial musculature, especially in the lower limbs ¹⁴,¹⁵ (C). Weakness of the paraspinal muscles of the lower back, weak and protruding abdominal muscles, weakness of facial muscles and eyelid ptosis and tongue paralysis reinforce the clinical suspicion¹⁶,¹⁷,¹⁸.

The presence of dysphonia and dysphagia reflects the disease’s bulbar impairment¹⁹, and involvement of the auditory system has also been reported²⁰.

GUIDED PHYSICAL EXAMINATION

The physical examination in PDJ-A should focus on the muscular and respiratory systems.

Pain and fatigue are regularly reported symptoms²¹. Diaphragm muscle weakness occurs early on in PD, and may precede limb or axial muscle weakness²² (B).

In a patient that is asymptomatic or has muscle fatigue, the following signs and symptoms may be seen in PDJ-A:

• compensatory rotation of the body to rise from the ground¹⁶(C);

• morning headache; narcolepsy²²(C);

• myopathy with myotonic paroxystic discharges (as seen in EMG) without clinical myotonia²³(C);

• CK levels that do not exceed 15 times the normal value⁹(C);

• increased transaminases without liver disease in asymptomatic or oligosymptomatic individuals²⁴(C);

• vacuolar myopathy assessed by muscular biopsy¹⁰(C);

• MRI imaging with evidence of muscle atrophy or diffusion abnormalities during the process of fat suppression in the posterior thigh, abdominal or paravertebral muscles²⁵(C);

• cardiac arrhythmia associated with skeletal muscle weakness²⁶(C);

• loss or rigidity of aortic compliance and hypertension²⁷(C);

• idiopathic stroke with middle cerebral artery aneurysms²⁸(C);

• post-pubertal adolescent or adult idiopathic scoliosis²⁹(C);

• rigid spine syndrome³⁰(C).

DIFFERENTIAL DIAGNOSIS

Early involvement of respiratory muscles anticipating muscle weakness may differentiate PDJ-A from other neuromuscular diseases²².

Table 3 lists the diseases considered in the differential diagnosis of PDJ-A.

Table 3
Differential diagnosis in Pompe disease a 2 www.musclegenetable.org.

Neuromuscular disorder	Disorder
Muscular dystrophies	Girdle muscular dystrophies
	Duchenne e Becker muscular dystrophies
	Miofibrilar myopathy
	Myotonic Distrophy type 2
Inflammatory myopathies	Polymyositis
Congenital myopathies b	Nemaline myopathy
	Central Core or Multiminicore myopathy
	Centronuclear myopathy
	Danon disease
	X-linked myopathy with na excesso f autophagy
Metabolics myopathies	Glycogen debranching enzyme deficiency (Glycogenosis Type IIIa ou IIIb – Cori or Forbe disease)
	Glycogen branching enzyme deficiency (Glycogenosis Type IV – Andersen Disease)
	McArdle syndrome
	Mitocondrial myopathiesc
Motor neuron disease	Spinal mucular atrophy Types 2 e 3
Neuromuscular junction disease	Miastenia gravis Congenital myastenic syndromesc

• ^a refers primarily to the late onset PD form; ^bcongenital myopathies can simulate either early onset as late onset PD; ^c refers primarily to the early onset PD form.

DIAGNOSTIC LABORATORY METHODS FOR JUVENILE AND ADULT POMPE DISEASE

Dry blood spot on filter paper as a screening test for PD

The introduction of the dry blood spot (DBS) test on filter paper into clinical practice provided a simple and reliable laboratory method for screening patients with suspicion of PD³¹,³²(Table 4).

Table 4
Recommendations for diagnostic tests in Pompe disease in adults31.

Screening Test – DBS – “dried blood spot” on filter paper to perform enzymatic activity analysis of acid α-glucosidase (GAA) a b

“Gold standard” Diagnostic Test – in fibroblasts or muscle tissue for acid α-glucosidase (GAA) enzymatic assay

Diagnostic Test – molecular analysis of theGAA geneb

Diagnostic Test in DBS – GAA activity in lymphocytes and/or leucocytes

• ^a In clinical practice, the definitive diagnosis of Pompe disease is now being based on the molecular analysis of the GAA gene for the presence of two pathogenic allelic mutations (www.pompecenter.nl); ^b Genetic variants of the GAA gene [c. (1726A; 2065A)] have been identified, especially in Asian populations; the combination with a pathogenic GAA allelic pathogenic mutation reduces the GAA enzyme activity on enzymatic assays specially from filter papers, which leads to false positives results considering neonatal screening programs. Such individuals are not diagnosed with PD and are instead classified as being pseudo-deficient individuals for the GAA enzyme.

Whenever the suspicion of PD persists, the test should be repeated, and additional diagnostic methods should be employed (Table 4). As all screening tests, suspected cases require a confirmation by at least one diagnostic test³¹,³²(B;C). DBS pre-analytical problems may result in false-negative and/or false positive screening results³².

Laboratory diagnosis for childhood and adult PD

Upon a positive DBS screening test for PD, additional diagnostic evidence should be obtained by measuring the amount of GAA activity in leukocytes or fibroblasts³¹ and/or by conducting GAA genotyping in search of two pathogenicGAA mutations² (Table 4).

Whenever there is any doubt in the DBS test and clinical suspicion persists, patients with symptoms suggestive of PD should have their GAA activity measured once again by the same laboratory that performed the first analysis. If the patient is negative for the GAA enzyme assay in leukocytes and the possibility of PD persists, diagnosis should proceed with at least one of the following three options:

a) DNA analysis searching for pathogenic mutations in the GAAgene²; or

b) Muscle biopsy evaluation, to assess the presence of abnormal accumulation of glycogen with vacuolar myopathy¹⁰,³⁴ (B), although not specific for PD; or

c) Fibroblast culture from skin biopsy to test for GAAactivity³¹.

GENETIC ASPECTS OF JUVENILE AND ADULT POMPE DISEASE PATIENTS – GENOTYPE-PHENOTYPE CORRELATION AND CRIM STATUS

The enzymatic deficiency in PD is caused by pathogenic mutations in both alleles of the GAA gene. Mutations can be similar (homozygote); or, different (compound heterozygote); however, both within the GAA gene. The most common mutation observed in PDJ-A patients, including Brazilians, is the intronic alteration c.-32-13 T > G (IVS1-13T > G), which is observed in more than two-thirds of the patients worldwide¹²,³⁵. The type and combination of these mutations will determine the amount of residual GAA activity in the cells¹¹,¹².

The combination of two severe mutations leads to a complete lack of GAA protein and, as a consequence, an extremely low residual GAA activity (< 1%); such genotype is associated with the severe early onset PD³⁶. From an immunological point of view, these individuals are classified as CRIM (Cross Reactive Immunological Material) negative patients.CRIM negative individuals who undergo ERT with GAA (rhGAA enzyme) may have severe reactions to the infusion, as well as the production of high titers of IgG antibodies³⁷.(B)

On the other hand, any other combination of mutations, being at least one of then considered a “milder” mutation, such as the classic c. -32-13 T > G, enzyme production will occur, even if abnormally, resulting in different levels of residual GAA activity of up to 30% of the normal value¹¹,¹². Patients with at least one mild mutation constitute most cases of juvenile and late-onset PD and present a clinical phenotype with a slower progression¹,¹². From an immunological standpoint, these patients are classified as CRIM positive³⁶, and generally, will probably not be prone either to severe adverse reactions to Enzyme Replacement Therapy (ERT) with the rhGAA enzyme or sustain high titers of antibodies³⁸ (B).

ENZYME REPLACEMENT THERAPY IN PATIENTS WITH CHILDHOOD AND ADULT POMPE DISEASE

Until recently, treatment for PD consisted only in palliative care. In a natural history study of 255 patients with DPJ-A, disease severity assessed by the need for a wheelchair or dependence on mechanical ventilation showed that progression to wheelchair use increased, on average, 13% each year in patients without ERT treatment³⁹ (B).

In 2007, the commercial use of the rhGAA enzyme was approved for early onset PD patients; and, in 2010, for the late-onset PD presentation. In the 18-month clinical trial conducted with the rhGAA enzyme in the late-onset PD form, there was an increase in the six minute walk test as well as stabilization of their pulmonary function⁴⁰(A).

The goals of rhGAA enzyme therapy depend on the stage of disease progression⁴⁰,⁴¹(B), and include:

• To slow down, stabilize or reverse disease progression;

• To reduce comorbidities and increase survival;

• To improve mobility, preserve motor function, delay the need for walking assistance, and promote motor gains;

• To improve or maintain respiratory function, thus preventing the need for respiratory assistance;

• To improve or preserve patient independence and quality of life.

A systematic review⁴² of the clinical and therapeutic outcomes of ERT with the rhGAA enzyme after one year of treatment in 251 patients with the PD-A presentation and 27 patients with juvenile PD yielded the following findings:

• six-minute walk test: 78% increased the distance covered, 8% maintained the same distance, and 4% decreased the distance;

• Motor Performance: 10% improved, one bedridden patient was able to sit up, three patients in wheelchairs were able to walk a few times a day, and three patients no longer required wheelchairs;

• Forced Vital Capacity (FVC) (127 patients): 53% improved and 33% worsened;

• Ventilatory support (58 patients): 70% improved.

The delay between the first symptoms of the disease, the definitive diagnosis of DPJ-A, and the beginning of ERT, have shown an inverse relationship with the therapeutic prognosis and clinical outcomes desired⁴³.

Practical instructions for enzyme replacement therapy

Currently, there is only one commercially available product for ERT with therhGAA enzyme for PD (Reg MS: 1.2543.0020.001-0.)

Regardless of the PD type, treatment with the rhGAA enzyme should be started at a reference hospital where it would be possible to intervene in the event of any adverse event related to the venous infusion⁴⁴. It is also essential to inform the family about the goals of ERT, the treatment expectations based on the stage of the disease, and the guidelines for clinical follow-up and evaluation³³,⁴⁵.

Health professionals should address the difficulty of predicting the response to long-term ERT treatment and prioritize factors that could potentially influence treatment response, such as respiratory function and muscle involvement. The multidisciplinary team should be instructed regarding these issues. We recommend training the nursing and pharmacy staff on the handling of the drug prior to the first infusion, and provide specific guidance to physicians and the infusion center staff. One should always record the occurrence of any adverse event, whether or not they are associated with ERT. The dose of rhGAAenzyme for ERT should follow the manufacturer’s recommendations. The current standard dose of Myozyme® is a minimum four-hour infusion of 20mg/kg every 15 days.

While adverse events in patients with PDJ-A are considered rare (see Genotype-Phenotype correlation)⁴⁴, infusion-related reactions generally require medical intervention. These reactions are usually mild to moderate and respond positively to a reduction in infusion rate.

The most serious and rarely observed side effects of ERT withrhGAA are life-threatening anaphylactic reactions, serious allergic reactions and immune-mediated reactions. Such events are also rare in late-onset PD because patients are CRIM positive³⁷.

Inclusion and exclusion criteria for enzyme replacement therapy (Table 5)

The heterogeneity of symptoms and signs present in PD patients (Table 2), the intra-familial variability and different stages of PD have led to the characterization of different patient groups and created a clinical dilemma of when to put a patient on ERT withrhGAA. The groups currently are identified as newborns identified via newborn screening⁸; asymptomatic patients with or without clinical signs of the disease⁴⁶; symptomatic PD patients⁴¹ and patients with severe PD¹⁴,¹⁵ (Table 5).

Table 2
Summary of the main clinical features of adults with Pompe disease2,14,15.

Organ or system	Clinical features
Skeletal muscle	Weakness of the pelvic and shoulder girdles Myalgia Exercise intolerance and fatigue Axial muscle weakness: abdominal and lumbar paraspinal muscles Contractures and deformities (“idiopathic” rigid spine)
Other muscles (facial, oral)	Tongue weakness Macroglossia Eyelid ptosis Dysphonia Dysphagia Difficulty in chewing
Lung	Dyspnea on exertion Orthopnea Acute respiratory failure Central and obstructive sleep apnea Sleep disorder - morning headache
Other systems	Hepatomegaly Ectasia of the cerebral arteries with vascular aneurysm Wolf-Parkinson - White syndrome Postprandial pain in the elderly Chronic diarrhea Hyperlordosis and/or scoliosis
Outcomes	Adults with PD have a respiratory disturbance often before the muscle weakness Slow progression of motor weakness Disease progression with stability for long periods Patients with early respiratory insufficiency may have a worse prognosis

Table 5
Summary of recommendations for ERT treatment based on the stage and severity of Pompe disease.

Asymptomatic patients without objective clinical signs
Patients should be examined for proximal muscle weakness and lung function (Pompe registry recommendations, www.registrynxt.com/).
ERT should be considered if:
Symptoms appear
Appearance of proximal muscle weakness and/or > 10% drop in sitting-supine forced vital capacity
Asymptomatic patients with objective clinical signs
ERT should be considered if:
Patient is asymptomatic with muscle weakness detectable by directed examination
Typical vacuolar muscle biopsy
> 10% drop in sitting-supine forced vital capacity
Symptomatic patients
Enzyme replacement therapy should be considered if:
> 10% drop in sitting-supine forced vital capacity; or increased muscular weakness; with or without ventilatory support
Patient has difficulty conducting daily routine tasks
Severe patients
If the patient is confined to a wheelchair and using continuous invasive ventilation:
ERT is recommended for 01 year, followed by evaluations to assess therapy effectiveness
After 01 year of ERT, the multidisciplinary team will review the treatment case-by-case, especially for patients requiring continuous invasive ventilation
ERT will be continued if there is stabilization or improvement of severe signs and symptoms
ERT duration
Annual reassessment to review the effectiveness of treatment
Monitoring
Patients receiving enzyme replacement therapy should have IgG antibody levels monitored every 03 months for up to 02 years, and then annually (www.registrynxt.com)

• ERT: enzyme replacement therapy.

In most cases of PDJ-A, the duration of rhGAA treatment is indefinite. Thus, the treatment goals, the timing of clinical evaluations, and quality of life studies (SF-36 - www.sf-36.org/), may support the multidisciplinary team in clinical management decisions ³³,⁴⁵,⁴⁶. It appears that major improvement of muscle strength and respiratory function with ERT is not common in patients with late-onset Pompe’s disease ⁴⁰. The termination of ERT can be a very difficult task, and there is no consensus regarding this topic except on a case-by-case discussion. The involvement of family members in such decisions is very important³³,⁴⁵. (Table 5).

Monitoring and laboratory tests for enzyme replacement therapy

PD patients on ERT with the rhGAA enzyme will make seroconversion in 95% of cases becoming IgG positive⁴⁴. However, exceptionally high titers of persistent antibodies may occur and this can activate the complement cascade and neutralize the rhGAA enzyme³⁷. In these circumstances, there is a decline of the therapeutic response to ERT (walking, lung function, SF-36) and adverse events associated to ERT may be observed³⁷ (B). Currently, immune modulation and immune suppression protocols, in an attempt to reduce neutralizing antibodies against rhGAA, have been successfully applied in infantile onset PD patients with high sustained IgG antibodies⁴⁷. Patients with PDJ-A are CRIM-positive and therefore are less likely to have such serious immunological reactions³⁷. The concentrations of IgG and IgE antibodies, tryptase and complement activation studies need to be monitored based on the Doctor’s Guide to Clinical Management of Pompe Disease.

Hypersensitivity to the drug should be considered an absolute contraindication to the use of ERT with rhGAA enzyme.

Pregnancy, lactation and enzyme replacement therapy

Since the introduction of ERT, a growing number of women with metabolic diseases have been able to reach reproductive life and become pregnant. Pregnant women with Gaucher, Fabry and (more recently) Pompe disease, are creating a new clinical challenge for obstetricians⁴⁸,⁴⁹.

Until 2014, two cases of pregnant women with PD receiving ERT have been published⁴⁹,⁵⁰. Recently, Karabul et al.⁵¹ collected information on 52 women with PD-A and 125 pregnancies through a retrospective self-administered questionnaire sent to Pompe associations in England and Germany, as well as neuromuscular disease centers in Germany. Pregnant women undergoing ERT not exhibited a reduction in mobility and muscle function, and many asymptomatic patients experienced their first PD symptoms during pregnancy⁵¹. Many pregnant women also used wheelchairs intermittently. A decrease in lung function, as measured by spirometry, was common to all pregnant women, including those undergoing ERT. Nonetheless, the reported experiences were highly favorable to the use of ERT during pregnancy, anesthesia, postpartum, newborn health, lactation and recovery of pre-pregnancy clinical status⁵¹. FDA classification/pregnancy category B (http://www.accessdata.fda.gov).

Pregnant women with neuromuscular diseases and vital capacity < 1l (normal reference = 4.5l) should be warned of the high risk of complications during pregnancy and childbirth. In case of maternal hypoxia with O₂saturation under 85%, the rate of live births is only 12%. The recommendation for pregnant women with PD is a cesarean delivery under local instead of general anesthesia⁵².

MULTIDISCIPLINARY CLINICAL MONITORING

Due to the predominance of muscular signs and symptoms, PDJ-A is primarily a neuromuscular disease. Thus, the neurologist’s role is crucial in coordinating the clinical decisions made by the professional health team²,³³,⁴⁵.

The ICD-10 classification (E74.0) may not accurately describe the functional impairment and disability associated with PD, since these patients vary in their degree of functionality. The International Classification of Functioning, Disability and Health (ICF) (WHO, 2001) provides more meaningful information and data for clinical purposes (Table 6).

Table 6
Classification of functioning, disability and health (ICF) for adult Pompe disease (2003) (www.who.int/classification/icf).

Code	Domain
b134	Sleep functions
b3100	Voice production
b445; s430	Respiratory muscle functions; structure of the respiratory tract
b455	Exercise tolerance functions
b510	Food intake functions
b525	Defection functions
b530	Weight maintenance functions
b730	Muscle strength functions
d230	Performing daily routines
d450	Walking
d460	Moving through different locations
d598	Self-care
d640	Performing household chores
e120	Products and technologies to facilitate mobility and/or transport the person indoors and outdoors

A study of 210 adults with PD using the Quality of Life Scale (SF-36) survey³⁹ highlights the impact of the disease on patients’ ability to work, perform household activities and move independently outside of their home. Progressive disability also increases the dependence of family members and other supportive care in the management of PD patients.

We recommend using disability scales (the Rotterdam study), visual analog scales for measuring pain, and the SF-36.

Functional rehabilitation of skeletal muscles

Skeletal muscle involvement in PD is characterized by progressive weakness, poor posture and compensatory movement patterns. Table 7 lists the main recommendations for patients with PDJ-A regarding the maintenance of functional muscle activity.

Table 7
Summary of recommendations for the evaluation and rehabilitation of the musculoskeletal system in juvenile and adult patients with Pompe Disease.

Include the patient in the International Pompe Registry (www.registrynxt.com/)
Physical examination and evaluations
Evaluation by a cardiologist and pulmonologist prior to physical therapy and aerobic exercise
Baseline 6-minute walk test (ATM Statement, 2002; www.registrynxt.com).
Annual densitometry (DEXA) (even for patients in wheelchairs)
PD patients with reduced bone density: assessment by specific tests and endocrinologist
Walking assistance equipment to reduce falls
Physical/occupational therapy
Physical therapy program including walking, treadmill, bicycle, hydrotherapy, swimming, muscle strengthening for neuromuscular diseases;
Avoid extreme exercise, excessive fatigue and immobility
Emphasis on aerobic exercises
Incorporate into daily functional activities
Instruct the patient to monitor heart rate and breathing during exercise
Daily exercise regime for the prevention of contractures
Managing contractures
Orthotic devices to prevent joint contractures with posture assessments while the patient is in the wheelchair and support for when he/she stands
Surgical intervention
Surgical intervention for scoliosis when the Cobb angle is between 30° and 40°
Vitamin and Mineral supplements
Vitamin D, calcium and bisphosphonates following the osteoporosis manual

The assessment of skeletal muscle function, strength and structure should include:

• Timed functional tests and mobility scales: 6-minute walk test; 4-step ascent and descent staircase test⁴⁵,⁵³;

• Manual or quantified evaluation of muscles strength (MRC scale)⁵³;

• Evaluation of tongue strength¹⁸;

• Magnetic resonance imaging of the skeletal muscle, including tongue, paraspinal and thighs²⁵.

Active physical activity

Recent evidence shows that people with carbohydrate processing disorders can benefit from light exercise⁵⁴(C). People who are physically fit are better able to use alternative sources of fuel for energy. Excessive strain in PDJ-A can cause muscle injuries; therefore, all exercise programs should be supervised by a professional familiar with PD (Table 6).

Therapeutic exercise should start lightly, be interspersed with rest periods, and follow a gradual increase in intensity until it reaches 60-75% of maximum effort in three to five days per week⁵⁴ (B). Strenuous or eccentric physical therapy exercises should be avoided, especially in proximal muscles, flexors and abductors of the lower limbs (Nascimento, Siqueira and Barone, personal observation, 2014).

Optimization of the biomechanical advantages of movement:

• Provide positioning and support to increase biomechanical advantage;

• Save energy;

• Optimize the effects of gravity;

• Consider positions that improve the muscle length-tension relationship

• Minimize muscle contracture.

Prevention of secondary musculoskeletal deficits (Table 7)

Secondary musculoskeletal impairments can be prevented by following the principles of biomechanics to counteract deforming forces. This is done by applying light pressure, stretching, practicing posture correction, performing orthotic interventions, and using seating and support systems⁵⁵.

Recent studies show that the mobilization and utilization of fat and carbohydrates in skeletal muscles during exercise are normal in PD. In fact, the reduction in exercise capacity results from muscle weakness and wasting and not from a reduction of muscle glycogenolysis, even with ERT therapy⁵⁵(B).

Pulmonology

Respiratory failure is a major cause of mortality and morbidity in PDJ-A¹⁵,¹⁶,²²(B). Approximately 60% of individuals with PDJ-A show a slight decrease in vital capacity (less than 80% of normal) and 30-40% show a moderate decrease (less than 60% of normal)¹⁵,¹⁶(C). Observational studies have shown average annual declines in FVC of 1.7% to 4.6%¹⁶(B).

As PDJ-A progresses, muscles weaken and lung volume is reduced. Consequently, cough can become harmful, blood-gas values become abnormal, and respiratory conditions may disrupt sleep⁵⁶,⁵⁷.

The guidelines for monitoring and treating pulmonary aspects of PD include⁵⁶,⁵⁷(C):

• Clinical evaluation of respiratory status by a pulmonologist experienced in the clinical management of patients with neuromuscular diseases;

• Evaluation of pulmonary function and blood gas analysis at diagnosis, annually, at each medical visit, or as changes occur in the course of the disease;

• Update the immunization record, including influenza and pneumococcus;

• Frequent removal of secretions from the lung airways (cough devices, aspiration);

• Assess the use of the cough-assist device and train/educate patients and families about its use and muscle inhalation techniques;

• Evaluation of respiratory function during sleep if the patient feels sleepy during the day, presents with unexplained fatigue, sleep apnea, morning headaches, or when his/her vital capacity falls below 40-50% of normal;

• Treat sleep disorders with positive airway pressure (CPAP) or with non-invasive nocturnal ventilation (BiPAP);

• In the absence of sleep studies, consider BiPAP ventilation if P_CO2is ≥ 45 mm Hg, or supine forced vital capacity < 50% of predicted, or negative forced inspiration < 60 cm H₂O, or oxygen saturation is < 88% for more than 05 continuous minutes during sleep;

• Aggressive treatment against all lung infections, and concomitant diseases sucah as asthma and cardiomyopathy;

• Consider enzyme replacement therapy with recombinant human GAA.

For pregnant PD women clinical caution is vital regarding the pulmonary and muscle functions (see 7.4 Pregnancy, lactation and enzyme replacement therapy).

Nutritional and gastrointestinal evaluation and treatment

PD patients have difficulty swallowing and eating. Factors contributing to this difficulty include facial hypotonia, macroglossia, weakened tongue muscles, and impairment of oral movements. Patients have difficulty dealing with saliva and secretions usually accumulate on the vocal cords, which can also lead to respiratory complications. They experience fatigue of the jaw muscles as well as difficulty chewing and eating certain foods. For these reasons, patients with PD often consume low amounts of vitamins, minerals and energy, resulting in malnutrition and the compensatory use of muscle proteins, in addition to increased risk of microaspirations and aspiration pneumonia by vomiting or regurgitation. Also, nutritional problems arising from gastrointestinal muscle weakness may also be present, including dysphagia, gastroesophageal reflux, gastroparesis, and decreased bowel movements leading to constipation.

Patients should be assisted by a group of professionals that includes: a speech therapist, a stomal therapist, a psychologist, a dietitian and a nutrition specialist (preferably with experience in metabolic diseases) to ensure proper nutritional care. Diets and food consistency should be reassessed regularly.

For patients with PDJ-A, the main goal of the diet - other than adequate nutrition - is to control glycogen accumulation and the processing of amino acids. We recommend a high protein diet (20-25% of total energy intake from protein, 30-35% from carbohydrates and 35-40% from lipids), with special attention to vitamins and minerals, and modification of food consistency. Diets rich in protein and/or L-alanine and low in carbohydrates have shown positive results in PDJ-A. Supplement with 1.4 g of L-Alanine up to 04 times a day is indicated if the recommended protein content associated with 4% (500 ml) of branched-chain amino acids cannot be met. Results are optimized with training and physical activity. Body composition measurements include body mass index (kg/m²) calculation, waist circumference and/or plicometry and Dual-energy X-ray absorptiometry (DXA).

Approaches to gastrointestinal problems include postural swallowing techniques, swallowing maneuvers to improve facial muscle coordination (supraglottic, Mendelsohn maneuver), environmental modifications, and oral sensory awareness techniques. The use of a feeding tube (nasal tube, gastrostomy or gastrojejunostomy tube) should also be considered.

Swallowing

In PD patients with dysphagia, positive results have been obtained with a soft diet consisting of purees and similar preparations, and including the use of thickeners.

Percutaneous endoscopic gastrostomy (PEG) is a surgical endoscopic procedure that aims to provide extended food access for patients with an intact and functional gastrointestinal tract, but who are unable to maintain adequate oral energy intake⁵⁹. PEG is indicated for PDJ-A patients with severe dysphagia, aspiration risk, weight loss ( >10% in one year) and FVC < 40%⁵⁹. The Brazilian Ministry of Health established (Portaria GM/MS No. 343e No. 120) mechanisms for the implementation of assistance centers and high complexity reference centers for nutritional therapy as part of SUS (Sistema Único de Saúde), and established their technical and operational requirements (procedure code 98.003.02-0). Gastrostomy involves a laparotomy and often general anesthesia, which limits its use in patients with severe PDJ-A (seeAnesthesia/Surgery). The main indication of PEG in daily clinical practice is for long-term enteral nutrition for patients with dysphagia⁵⁹.

Anesthesia/surgery

The medical staff must carefully attend to a series of considerations when indicating surgery to patients with PD, because the increase risk of complications involving anesthesia⁶⁰(B/C).

Patients with neuromuscular diseases due to metabolic causes may have a higher risk of adverse events to general anesthetics, especially the combination of halothane and succinylcholine⁶⁰.

The following guidelines are recommended for surgery procedures in PDJ-A:

• Conduct anesthetic procedures only when necessary;

• Consolidate all surgical procedures requiring anesthesia to reduce the risk of exposure to the anesthetic;

• Avoid tracheal intubation and, if indicated, make sure it is performed by an experienced professional;

• Conduct rigorous intraoperative supervision;

• Use inhalation agents in non-severe patients;

• Avoid depolarizing agents due to the risk of severe hyperkalemia;

• Monitor circulating fluid volume;

• Whenever possible, perform surgery in centers with professionals experienced with PD.

Family history and genetic counseling

PD is an autosomal recessive disease caused by pathogenic mutations in both alleles of the GAA gene¹,¹². Parents of individuals with PD are healthy obligatory heterozygotes with a risk of PD recurrence in their future offspring of approximately 25%. Therefore, once an individual is diagnosed with PD, it is essential for parents to receive genetic counseling. The diagnosis of an individual with PD justifies the active search of the disease among his/her siblings. Asymptomatic or mildly symptomatic cases are often identified due to the intrafamilial clinical variability observed between two siblings with PD. Laboratory screening and diagnostic methods are the same as for the index case (Table 4).

Individuals with PDJ-A have benefited from ERT, with increased survival rates. As a result, some of them may have families once they reach reproductive age, especially those who are mildly symptomatic or diagnosed with late PD. An individual with PD can have an affected child if his/her partner is heterozygous for mutations in the gene that causes the disease. Pregnant women with PD require intensive supervision (see Pregnancy).

Table 1
Pompe disease incidence in different populations.

Population (Year)	Incidence	Reference
Afro-Americans (2001)	1: 14,000	1
Dutch (1999)	1: 40,000 combined 1: 138,000 early onset 1: 57,000 adults	4
Americans (1998)	1: 40,000 combined	5
European Descendents (1998)	1:100,000 early onset 1: 60,000 adults	5
Australia (1999)	1: 145,000	6
Portugal (2004)	1: 600,000	7
Taiwan (2014)*	1:18.221 combined 1:52.538 early onset 1:27.866 late onset	8

• *neonatal screening.

ACKNOWLEDGES

The authors would like to acknowledge Genzyme, Sanofi Company, for the organization of the participants’ logistics, as travel and accommodations, what make this work possible. The authors have full responsibility for the information contained in this text, with total exemption of the sponsors.

References

• ¹
  Hirschhorn R, Reuser AJ. Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In:Scriver CR, Beaudet A, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill; 2001. p. 3389-420.
• ²
  American Association of Neuromuscular & Electrodiagnostic Medicine. Diagnostic criteria for Late-Onset (Childhood and Adult) Pompe Disease. Muscle Nerve. 2009;40(1):149-60. doi:10.1002/mus.21393
• ³
  Scott CR, Elliott S, Buroker N, Thomas LI, Keutzer J, Glass M et al. Identification of infants at risk for developing Fabry, Pompe, or mucopolysaccharidosis-I from newborn blood spots by tandem mass spectrometry. J Pediatr. 2013;163(2):498-503. doi:10.1016/j.jpeds.2013.01.031
• ⁴
  Ausems MG, Verbiest J, Hermans MP et al. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur J Hum Genet. 1999;7(6):713-6. doi:10.1038/sj.ejhg.5200367
• ⁵
  Martiniuk F, Chen A, Mack A et al. Frequency for glycogen storage disease type II in New York and estimates of affected individuals born with the disease. Am J Med Genet. 1998;79(1):69-72. doi:10.1002/(SICI)1096-8628(19980827)79:1<69::AID-AJMG16>3.0.CO;2-K
• ⁶
  Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281(3):249-54. doi:10.1001/jama.281.3.249
• ⁷
  Pinto R, Caseiro C, Lemos M, Lopes L, Fontes A, Ribeiro H et al. Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet. 2004;12(2):87-92. doi:10.1038/sj.ejhg.5201044
• ⁸
  Fernandez C, Paula AM, Figarella-Branger D, Krahn M, Giorgi R, Chabrol B et al. Diagnostic evaluation of clinically normal subjects with chronic hyperCKemia. Neurology. 2006;66:1585-7. doi:10.1212/01.wnl.0000216144.69630.6e
• ⁹
  Liao HC, Chiang CC, Niu DM, Wang CH, Kao SM, Tsai FJ et al. Detecting multiple lysosomal storage diseases by tandem mass spectrometry: a national newborn screening program in Taiwan. Clin Chim Acta. 2014;431:80-6.
• ¹⁰
  Werneck LC, Lorenzoni PJ, Kay CSK, Scola RH. Muscle biopsy in Pompe disease. Arq. Neuropsiquiatr. 2013;71(5):284-9. doi:10.1590/0004-282X20130022
• ¹¹
  Ploeg AT, Reuser AJ. Pompe’s disease. Lancet. 2008;372(9646):1342-53. doi:10.1016/S0140-6736(08)61555-X
• ¹²
  Kroos M, Hoogeveen-Westerveld M, Ploeg A, Reuser AJJ. The genotype–phenotype correlation in Pompe disease. Am J Med Genet C Semin Med Genet. 2012;160C(1):59-68. doi:10.1002/ajmg.c.31318
• ¹³
  Raben N, Ralston E, Chien YH, Baum R, Schreiner C, Hwu WL et al. Differences in the predominance of lysosomal and autophagic pathologies between infants and adults with Pompe disease: implications for therapy. Mol Genet Metab. 2010;101(4):324-33. doi:10.1016/j.ymgme.2010.08.001
• ¹⁴
  Van der Beek NA, Hagemans ML, Reuser AJ, Hop WC, Van der Ploeg AT, Van Doorn PA et al. Rate of disease progression during long-term follow-up of patients with late-onset Pompe disease. Neuromuscul Disord. 2009;19:113-7. doi:10.1016/j.nmd.2008.11.007
• ¹⁵
  Güngör D, Vries JM, Hop WC, Reuser AJ, Doorn PA, Ploeg AT et al. Survival and associated factors in 268 adults with Pompe disease prior to treatment with enzyme replacement therapy. Orphanet J Rare Dis. 2011;6(1):34. doi:10.1186/1750-1172-6-34
• ¹⁶
  Alejaldre A, Diaz-Manera J, Ravaglia S, Tibaldi EC, D’Amore F, Morís G et al. Trunk muscle involvement in late-onset Pompe disease: Study of thirty patients. Neuromuscul Disord. 2012;22(Suppl 2):S148-54. doi:10.1016/j.nmd.2012.05.011
• ¹⁷
  Ravaglia S, Moglia A, Garaghani KS, Danesino C. Ptosis in Pompe disease: common genetic background in infantile and adult series. J Neuroophthalmol. 2010;30(4):389-90. doi:10.1097/WNO.0b013e3181f9a923
• ¹⁸
  Dubrovsky A, Corderi J, Lin M, Kishnani PS, Jones HN. Expanding the phenotype of late-onset pompe disease: tongue weakness: a new clinical observation. Muscle Nerve. 2011;44(6):897-901. doi:10.1002/mus.22202
• ¹⁹
  Hobson-Webb LD, Jones HN, Kishnani PS. Oropharyngeal dysphagia may occur in late-onset Pompe disease, implicating bulbar muscle involvement. Neuromuscul Disord.. 2013;23:319-23. doi:10.1016/j.nmd.2012.12.003
• ²⁰
  Beek NA, Verschuure H, Reuser AJ, Ploeg AT, Doorn PA, Poublon RM. Hearing in adults with Pompe disease. J Inherit Metab Dis. 2012;35:335-41. doi:10.1007/s10545-011-9396-3
• ²¹
  Güngör D, Schober AK, Kruijshaar ME, Plug I, Karabul N, Deschauer M et al. Pain in adult patients with Pompe disease: a cross-sectional survey. Mol Genet Metab. 2013;109(4):371-6. doi:10.1016/j.ymgme.2013.05.021
• ²²
  Fuller DD, ElMallah MK, Smith BK et al. The respiratory neuromuscular system in Pompe disease. Respir Physiol Neurobiol. 2013;189:241-9. doi:10.1016/j.resp.2013.06.007
• ²³
  Müller-Felber W, Horvath R, Gempel K et al. Late onset Pompe disease: Clinical and neurophysiological spectrum of 38 patients including long-term follow-up in 18 patients. Neuromuscul Disord. 2007;17(9-10):698-706. doi:10.1016/j.nmd.2007.06.002
• ²⁴
  Hoeksma M, Boon M, Niezen-Koning KE, Overbeek-van Gils L, Spronsen FJ. Isolated elevated serum transaminases leading to the diagnosis of asymptomatic Pompe disease Eur J Pediatr. 2007;166:871-4. doi:10.1007/s00431-006-0315-9
• ²⁵
  Carlier RY, Laforet P, Wary C, Mompoint D, Laloui K, Pellegrini N et al. Whole-body muscle MRI in 20 patients suffering from late onset Pompe disease: Involvement patterns. Neuromuscul Disord. 2011;21:791-9. doi:10.1016/j.nmd.2011.06.748
• ²⁶
  Forsha D, Li JS, Smith PB, Ploeg AT, Kishnani P, Pasquali SK. Cardiovascular abnormalities in late-onset Pompe disease and response to enzyme replacement therapy. Genet Med. 2011;13(7):625-31. doi:10.1097/GIM.0b013e3182142966
• ²⁷
  Wens SC, Kuperus E, Mattace-Raso FUS, Kruijshaar ME, Brusse E, Montfort KC et al. Increased aortic stiffness and blood pressure in non-classic Pompe disease. J Inherit Metab Dis. 2014;37(3):391-7. doi:10.1007/s10545-013-9667-2
• ²⁸
  Sacconi S, Bocquet JD, Chanalet S, Tanant V, Salviati L, Desnuelle C. Abnormalities of cerebral arteries are frequent in patients with late-onset Pompe disease. J Neurol. 2010;257(10):1730-3. doi:10.1007/s00415-010-5618-0
• ²⁹
  Roberts M, Kishnani PS, Ploeg AT, Müller-Felber W, Merlini L, Prasad S et al. The prevalence and impact of scoliosis in Pompe disease: lessons learned from the Pompe Registry. Mol Genet Metab. 2011;104(4):574-82. doi:10.1016/j.ymgme.2011.08.011
• ³⁰
  Laforêt P, Doppler V, Caillaud C, Laloui K, Claeys KG, Richard P et al. Rigid spine syndrome revealing late-onset Pompe disease. Neuromuscul Disord. 2010;20(2):128-30. doi:10.1016/j.nmd.2009.11.006
• ³¹
  Pompe Disease Diagnostic Working Group, Winchester B, Bali D et al. Methods for a prompt and reliable laboratory diagnosis of Pompe disease: report from an international consensus meeting. Mol Genet Metab. 2008;93(3):275-81. doi:10.1016/j.ymgme.2007.09.006
• ³²
  Müller KB, Rodrigues MD, Pereira VG, Martins AM, D’Almeida V. Reference values for lysosomal enzymes activities using dried blood spots samples: a Brazilian experience. Diagn Pathol. 2010;5(1):65-9. doi:10.1186/1746-1596-5-65
• ³³
  Llerena Jr JC, Horovitz DDG, Marie SKN, Porta G, Giuglian R, Muños Rojas MV et al. The Brazilian consensus on the management of Pompe disease. J. Pediatrics. 2009;155(4):S47-56. doi:10.1016/j.jpeds.2009.07.006
• ³⁴
  Vissing J, Lukacs Z, Straub V. Diagnosis of Pompe disease: muscle biopsy vs blood-based assays. JAMA Neurol. 2013;70(7):923-7. doi:10.1001/2013.jamaneurol.486
• ³⁵
  Oba-Shinjo SM, Silva R, Andrade FG, Pamer RE, Pomponio RJ, Ciociola KM et al. Pompe disease in a Brazilian series: clinical and molecular analyses with identification of nine new mutations. J Neurol. 2009;256(11):1881-90. doi:10.1007/s00415-009-5219-y
• ³⁶
  Bali DS, Goldstein JL, Banugaria S, Dai J, Mackey J, Rehder C et al. Predicting cross-reactive immunological material (CRIM) status in Pompe disease usingGAA mutations: Lessons learned from 10 years of clinical laboratory testing experience. Am J Med Genet C Semin Med Genet. 2012;160C(1):40-9. doi:10.1002/ajmg.c.31319
• ³⁷
  Kishnani PS, Goldenberg PC, DeArmey SL, Heller J, Benjamin D, Young S et al. Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants. Mol Genet Metab. 2010;99(1):26-33. doi:10.1016/j.ymgme.2009.08.003
• ³⁸
  Patel TT, Banugaria SG, Case LE, Wenninger S, Schoser B, Kishnani PS. The impact of antibodies in late-onset Pompe disease: a case series and literature review. Mol Genet Metab. 2012;106(3):301-9. doi:10.1016/j.ymgme.2012.04.027
• ³⁹
  Hagemans ML, Winkel LP, Hop WC, Reuser AJ, Van Doorn PA, Van der Ploeg AT et al. Disease severity in children and adults with Pompe disease related to age and disease duration. Neurology. 2005;64(12):2139-41. doi:10.1212/01.WNL.0000165979.46537.56
• ⁴⁰
  Ploeg AT, Clemens PR, Corzo D, Escolar DM, Florence J, Groeneveld GJ et al. A randomized study of alglucosidase alfa in late-onset Pompoe disease. N Engl J Med. 2010;362(15):1396-406. doi:10.1056/NEJMoa0909859
• ⁴¹
  Güngör D, Kruijshaar ME, Plug I, D’Agostino RB, Hagemans ML, Doorn PA et al. Impact of enzyme replacement therapy on survival in adults with Pompe disease: results from a prospective international observational study Orphanet J Rare Dis. 2013;8(1):49. doi:10.1186/1750-1172-8-49
• ⁴²
  Toscano A, Schoser B. Enzyme replacement therapy in late-onset Pompe disease: a systematic literature review. J Neurol. 2013;260(4):951-9. doi:10.1007/s00415-012-6636-x
• ⁴³
  Vries JM, Beek NAME, Hop WCJ, Karstens FPJ, Wokke JH, Visser M et al. Effect of enzyme therapy and prognostic factor in 69 adults with Pompe disease: an open label single-center study. Orphanet J Rare Dis. 2012;7(1):73. doi:10.1186/1750-1172-7-73
• ⁴⁴
  Desnick RJ, Schuchman EH. Enzyme replacement therapy for lysosomal diseases: lessons from 20 years of experience and remaining challenges. Annu Rev Genomics Hum Genet. 2012;13(1):307-35. doi:10.1146/annurev-genom-090711-163739
• ⁴⁵
  Cupler EJ, Berger KI, Leshner RT et al. Consensus treatment recommendations for late-onset Pompe disease. Muscle Nerve. 2012;45(3):319-33. doi:10.1002/mus.22329
• ⁴⁶
  Wang RY, Bodamer OA, Watson MS, Wilcox WR, ACMG Work Group on Diagnostic Confirmation of Lysosomal Storage Diseases. Lysosomal storage diseases: diagnostic confirmation and management of presymptomatic individuals. Genet Med. 2011;13(5):457-84. doi:10.1097/GIM.0b013e318211a7e1
• ⁴⁷
  Messinger YH, Mendelsohn NJ, Rhead W, Dimmock D, Hershkovitz E, Champion M et al. Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease. Genet Med. 2012;14(1):135-42. doi:10.1038/gim.2011.4
• ⁴⁸
  Politei JM. Treatment with agalsidase beta during pregnancy in Fabry disease. J Obstet Gynaecol Res. 2010;36(2):428-9. doi:10.1111/j.1447-0756.2009.01164.x
• ⁴⁹
  Vries JM, Brugma JD, Ozkan L, Steegers EA, Reuser AJ, Doorn PA et al. First experience with enzyme replacement therapy during pregnancy and lactation in Pompe disease. Mol Genet Metab. 2011;104(4):552-5. doi:10.1016/j.ymgme.2011.09.012
• ⁵⁰
  Zagnoli F, Leblanc A, Blanchard C. Pregnancy during enzyme replacement therapy for late-onset acid maltase deficiency. Neuromuscul Disord. 2013;23(2):180-1. doi:10.1016/j.nmd.2012.11.006
• ⁵¹
  Karabul N, Berndt J, Kornblum C et al. Pregnancy and delivery in women with Pompe disease. Mol Genet Metab. 2014;112(2):148-53. doi:10.1016/j.ymgme.2014.03.010
• ⁵²
  Norwood F, Rudnick-Schöneborn S. 179th ENMC International Workshop: pregnancy in woman with neuromuscular disorders 5-7 November, Naarden, The Netherlands. Neuromuscul Disord. 2012;22(2):183-90. doi:10.1016/j.nmd.2011.05.009
• ⁵³
  Angelini C, Semplicini C, Ravaglia S, Moggio M, Comi GP, Musumeci O et al. New motor outcome function measures in evaluation of late-onset Pompe disease before and after enzyme replacement therapy. Muscle Nerve. 2012;45(6):831-4. doi:10.1002/mus.23340
• ⁵⁴
  Terzis G, Dimopoulos F, Papadimas GK et al, Effect of aerobic and resistance exercise training on late-onset Pompe disease patients receiving enzyme replacement therapy. Mol Genet Metab. 2011;104(3):279-83. doi:10.1016/j.ymgme.2011.05.013
• ⁵⁵
  Case LE, Kishnani PS. Physical therapy management of Pompe disease. Genet Med. 2006;8(5):318-27. doi:10.1097/01.gim.0000217789.14470.c5
• ⁵⁶
  Mellies U, Stehling F, Dohna-Schwake C, Ragette R, Teschler H, Voit T. Respiratory failure in Pompe disease: treatment with noninvasive ventilation.. Neurology. 2005;64(8):1465-7. doi:10.1212/01.WNL.0000158682.85052.C0
• ⁵⁷
  Mellies U, Lofaso F. Pompe disease: a neuromuscular disease with respiratory muscle involvement. Respir Med. 2009;103(4):477-84. doi:10.1016/j.rmed.2008.12.009
• ⁵⁸
  Bernstein DL, Bialer MG, Mehta L, Desnick RJ. Pompe disease: dramatic improvement in gastrointestinal function following enzyme replacement therapy. A report of three later-onset patients. Mol Genet Metab. 2010;101(2-3):130-3. doi:10.1016/j.ymgme.2010.06.003
• ⁵⁹
  Gauderer MW. Percutaneous endoscopic gastrostomy and the evolution of contemporary long-term enteral access. Clin Nutr. 2002;21(2):103-10. doi:10.154/chu.2001.0533
• ⁶⁰
  Lehberger J, Roth R, Weingärtner K, Heesen M. Pompe disease: anesthesiological special features. Anaesthesist;.2012;61(3):229-33. doi:10.1007/s00101-012-1998-0

• Erratum

  Arquivos de Neuro-Psiquiatria. 2016;74(2):166-76. doi:10.1590/0004-282X20150194
  The citation numbers and the references were modified, as shown below:
  

  
  
  Excluded references:
  4 to 8 and 58.
  New reference:
  48. World Health Organization. International classification of functioning, disability and health. Geneva: World Health Organization; 2001.

Publication Dates

• Publication in this collection
  22 Dec 2015
• Date of issue
  Feb 2016

History

• Received
  12 May 2015
• Reviewed
  05 Sept 2015
• Accepted
  25 Sept 2015