Respiratory

Sleep study

A sleep study should be performed when there is an abnormal drop of >10 % in FVC between the upright and supine position, or when there are symptoms suggestive of nocturnal hypoventilation or sleep apnea. If the sleep study demonstrates abnormalities then a pulmonologist with interest in neuromuscular disease should assess the patient for possible bi-level positive airway pressure (BPAP) or other noninvasive ventilator support to improve nocturnal respiration.

Cardiac

Electrocardiography

A study of the clinical spectrum of LOPD patients identified three subjects who suffered from arrhythmias due to Wolff–Parkinson–White syndrome despite no echocardiographic signs of cardiomyopathy [1] and this should therefore be considered during cardiac monitoring of LOPD patients. Some patients may have short PR interval in their electrocardiogram (ECG) secondary to enhanced conduction [42]. Others may have abnormalities reflecting their underlying cardiac disease (e.g. bundle branch block), rather than Pompe disease. As such, ECG should be performed at baseline, and repeated regularly only if clinically indicated.

Echocardiography

Unlike patients with the infantile form, patients with LOPD do not typically develop hypertrophy of the left ventricle (LVH) [37, 42, 78]. In a study of 75 adult patients with hypertrophic cardiomyopathy, none had genetic evidence of Pompe disease [78]. Neither Hagemans et al. nor Soliman et al. found LVH in their series of adult patients with LOPD [37, 42]. Most of the cardiac abnormalities described in patients with LOPD are explained by concurrent underlying diseases, rather than LOPD [42]. ECGs should be performed at baseline, then as clinically indicated.

Gastrointestinal issues

Gastrointestinal motility dysfunction

A 2010 study reported gastrointestinal (GI) symptoms of chronic constipation and GI reflux in four out of six LOPD patients studied at a single institution [44]. At 1 year follow-up, the patients reported a marked improvement of intestinal symptoms. Another study reported three LOPD patients with chronic diarrhea, postprandial bloating, and abdominal pain [79]. Two of the patients reported fecal incontinence while the other reported synchronous vomiting and diarrhea; however all GI symptoms were reported to be resolved within the first 6 months of ERT.

Swallowing dysfunction

A retrospective review of LOPD patients evaluated at the neuromuscular clinic at Duke University Medical Center identified 12 patients, three of whom had symptoms of oropharyngeal dysphagia [41]. This was categorized as mild in two cases and severe in one, with the degree of swallowing impairment appearing to correlate with overall physical strength and function. Moderate or severe lingual weakness was found to be associated with dysphagia, and swallowing difficulties were generally more oral than pharyngeal in nature. It was concluded that screening for symptoms of dysphagia could help reduce morbidity and mortality, while improving understanding of the LOPD phenotype. A recent study has further demonstrated evidence of lingual weakness in LOPD, with a quantitative assessment showing lingual weakness in 80 % of the sample [80].

Diet/Nutrition

At baseline, a study of 17 patients with LOPD undergoing ERT identified increased fat mass in five patients in severe disease stage despite normal body mass index (BMI) [81]. Fat mass was found to correlate inversely, and lean mass directly, with CK, prealbumin, and albumin levels. ERT resulted in significant increases in BMI and fat mass, and a trend towards increased lean mass. Prealbumin and albumin levels increased as early as after the first months of ERT. This study highlighted that BMI may underestimate fat mass in patients in severe stage of disease, due to altered body composition. Furthermore, patients may have a relative protein malnutrition which is reversed by ERT, this reflecting restoration of normal muscle metabolic pathways. The increased BMI may indicate a reduction in energy consumption during exercise or respiration, along with clinical improvement.

High protein diet

A high-protein diet has been shown to have beneficial effects in Pompe patients [82]. A ventilator-dependent Pompe patient fed a general diet supplemented with branched-chain amino acids, which are the principal amino acids involved in muscle protein synthesis and utilization, showed improved respiratory function and muscle strength, resulting in daytime weaning form the ventilator. The potential advantages of a branched-chain amino acids-supplemented liquid diet over a high-protein diet include theoretical sparing of amino acids required for muscle protein synthesis by providing higher concentrations of postprandial branched-chain amino acids in the circulation, and better tolerance by a ventilator-dependent or debilitated patient.

Supplements

Supplementation of LOPD patients with L-alanine reduces protein turnover and catabolism [83]. A study of five subjects found that L-alanine supplementation decreased resting energy expenditure, leucine flux, and leucine oxidation to levels lower than those observed in control subjects. L-alanine has not been studied in combination with ERT.

Gastrostomy tube

In patients where muscular weakness affects the ability to eat or where breathing problems interfere with eating, a gastrostomy tube (G-tube) may be necessary for providing adequate nutrition [84]. These may also be used to improve nutrition in some patients who have normal swallowing function.

Exercise

An uncontrolled prospective study of 34 patients found that compliance to high-protein and low-carbohydrate nutrition and exercise therapy significantly slowed deterioration of muscle function as measured by the Walton scale, and improved the natural history of disease progression [85]. Another study investigated the effect of exercise training on muscular strength and body composition in five patients with LOPD receiving ERT who underwent a 20-week program of supervised aerobic and progressive resistance exercise training. Exercise training resulted in a significant increase in muscular strength and 6-min walking distance despite no change in total and lower extremity lean body mass, highlighting the benefits of exercise training in patients with LOPD on ERT [86].

Studies have also sought to investigate whether exercise training during ERT infusion increases effectiveness of therapy, however in a study of five LOPD patients following a 6-month period of exercise training, no significant functional changes in body composition, isometric strength, or 6-min walking distance were identified [87].

Bone

Low bone mineral density and osteoporosis have been reported in LOPD patients [47]. Studies of the effect of ERT on bone mineral density suggest that ERT administration may moderately improve bone mineral density in some, but not all, LOPD patients [88, 89].

DEXA scan

Due to this bone mineral density component of LOPD, it is recommended that patients are screened at baseline with dual-energy X-ray absorptiometry (DEXA) and then as clinically indicated [6, 47, 52].

Vitamin D plus calcium +/− bisphosphonates

Patients with abnormal DEXA z-scores should be supplemented with vitamin D and calcium [47]. There is insufficient evidence to recommend bisphosphonates as a preventative therapy, however their use in LOPD patients should follow the same guidelines as for the general population [6, 52].

Others

Possible increase in cerebral vascular anomalies

An investigation into cerebrovascular anomalies in six LOPD patients identified brain vascular anomalies, including dolichoectasia of the basilar artery and ectasia of internal carotids, in four out of the six patients [44]. Two patients had clinical signs related to the arteriopathy, including partial paralysis of the third cranial nerve and transient ischemic attacks. ERT at 1 year follow-up was found to have no effect on the size of cerebral vessels and the study concluded that as intracranial artery abnormalities are not infrequent in patients with LOPD, they should be specifically investigated in the presence of unexplained CNS symptoms.

A 2008 case report characterized the thrombotic complications of a basilar artery aneurysm in a young adult with Pompe disease, with the authors concluding that screening of intra-cerebral vessels to potentially diagnose thrombotic and thromboembolic complications may be considered in young adults with Pompe disease [90].

A study published in 2011 reported five LOPD patients with aortic arteriopathy involving primarily the ascending thoracic aorta, highlighting that aneurysmal dilatation of the thoracic aorta is an underreported vascular complication of LOPD [91]. The authors suggested that chest X-ray and echocardiography should be incorporated as initial screening tools for aortic aneurysms in patients with LOPD. Furthermore, contrast-mediated thoracic CT or MRI may be necessary when ectasia is suspected or the ascending aorta is not visualized.

Genetic counseling

As Pompe is an inherited autosomal recessive disease, it is important to undertake genetic counseling with families that are known to be carriers or when there is diagnosis of a new case in a family. The most common inheritance scenario in Pompe disease is where both parents are asymptomatic carriers; in this instance the risk of Pompe disease is 1 in 4 (25 %), the risk that the child will become a carrier is 2 in 4 (50 %), and the risk that the child will be unaffected is 1 in 4 (25 %). As Pompe disease is an autosomal recessive disorder, typically counseling can be performed with an emphasis on prenatal testing and early diagnosis in the newborn.

Pregnancy

Pregnancies in Pompe disease patients, including cases of spinal anesthesia and Cesarean section, have been shown to result in the birth of healthy infants [92], however the pregnancy should be considered high risk. In 2008 it was reported that a 31-year-old patient with known Pompe disease with symptoms and signs of respiratory dysfunction as well as preeclampsia underwent urgent Cesarean section under regional anesthesia, resulting in the birth of a healthy baby girl.

There are limited data on the use of alglucosidase alfa in pregnant women; however studies in animals have shown reproductive toxicity [93]. While safe continuation of ERT during pregnancy and lactation has been reported in a case study [94], the potential risk for humans is unknown and the decision to use alglucosidase alfa during pregnancy needs to be made on an individual basis [93].

A case study reported a primiparous 40-year-old woman diagnosed with Pompe disease whose clinical condition remained fairly stable until the 25th gestational week, after which problems with mobility and respiration were experienced. Fetal growth, as monitored by ultrasound, was reported to be normal and a healthy boy was born at a gestational age of 37 weeks and 5 days by elective Cesarean section. There were no maternal complications and the child developed normally. The mother’s physical condition at 1 year post-partum was similar to prior to her pregnancy. Pharmacokinetic studies following enzyme infusion showed that alglucosidase alfa was secreted into the breast milk, with enzyme activity in the breast milk returning to the pre-infusion level after 24 hrs.

Alglucosidase alfa may be excreted in breast milk and as there are limited data on the effects in neonates exposed to alglucosidase alfa via breast milk, cessation of breastfeeding during use of alglucosidase alfa should be advised [93].