Case history 1

A full-term female was born after an uneventful pregnancy. She had an abnormally high respiratory rate of 100 per minute during the first day. Her liver was palpable 2 cm below the costal margin. No other physical abnormalities were noted. A chest X -ray performed on day 2 postpartum revealed cardiomegaly; echocardiography was performed and a non-obstructive hypertrophic cardiomyopathy of both ventricles was demonstrated. Initially, diabetes gravidarum of the mother was suspected to be the cause of the cardiomyopathy, and the child was discharged. After 9 weeks, however, the child started to develop feeding difficulties and was re-admitted to the hospital for further evaluation. At that time, generalized hypotonia was noted and the child showed very little spontaneous movement. Otherwise, the girl presented as a normal baby without dysmorphic features. She had neither facial muscle weakness nor a protruding tongue as sometimes seen in patients with classic-infantile Pompe disease.

Additional tests revealed slightly elevated levels of: AST (182 U/L; normal 0–88), ALT (97 U/L; normal 0–59), and CK (456 U/L; normal 0–230). LDH (955 U/L; normal 0—1,099) was normal. The Glc₄ content of the urine was elevated. A muscle biopsy of the quadriceps femoris showed pathological changes with characteristic staining of lysosomal glycogen by Periodic Acid Schiff (PAS) reagent and lysosomes by increased acid phosphatase activity (Figure 13.1). The acid α-glucosidase activity in leukocytes was far below the normal range and fully deficient in cultured fibroblasts. Two pathogenic GAA mutations were identified in the patient’s DNA: one was also identified in DNA from the mother and the other in paternal DNA, confirming the diagnosis.

Case history 2

A 23-year-old Caucasian man complained of difficulty in cycling and climbing stairs. After an uneventful childhood he had experienced difficulties with lifting heavy objects from the age of 14 years. From the age of 20 years he could no longer run due to progressive limb-girdle weakness. Neurological examination showed weakness of the proximal upper and lower extremities (MRC scores of 4/4 and 3/4, respectively). Sensation and tendon reflexes were normal. The patient had atrophy of the pectoral muscles, pseudo-hypertrophy of the calves, a lumbar hyperlordosis and scapular winging (Figure 13.2). Furthermore, he had a waddling gait, and positive Trendelenburg and Gower signs. Blood tests revealed an elevated CK of 1,304 (normal < 200 U/L). Pulmonary examination showed an FVC of 75% in the sitting position and 65% in the supine position. The acid α-glucosidase activity in leukocytes was 4% of average normal, as measured with 4-MU-glucopyranoside in the presence of acarbose, and 13% of average normal in fibroblasts as measured with the same substrate. The muscle biopsy showed PAS positive inclusions in 3–12% of the muscle fibres and a punctated staining pattern of acid phosphatase. DNA analysis demonstrated heterozygosity for two pathogenic GAA mutations, c.-32-13 T > G and c.309 C > A, each located on a different allele.

Case history 3

A 6-year-old boy with atrophy of the shoulder muscles was referred to our “Pompe Centre” for a second opinion. The finding of an elevated plasma CK of 561 U/L (vs 0–200 U/L normal) and a reduced acid α-glucosidase activity in leukocytes of 0 nmole/mg.h (vs 33–160 nmole/mg.h normal) were the main reasons for his referral. Facioscapulohumeral muscular dystrophy (FSHD) had been excluded. He had started to walk at the age of 18 months. Dislocation of the shoulders had been noted at the age of 2.5 years. He had been under the care of an orthopaedic surgeon and a paediatrician, but no specific diagnosis had been made. At the age of 6 years a paediatric neurologist saw him because of his hanging shoulders. Clinical examination in our Centre revealed no weakness of the lower limbs, the hips, the paraspinal muscles, the abdominal muscles, the facial muscles or the respiratory muscles. We concluded that the clinical picture was not typical for a child with Pompe disease. No vacuolated lymphocytes were found in a PAS-stained blood smear. The Glc₄ level in urine was normal, and repeat enzyme analysis in leukocytes also did not confirm the diagnosis. The activity for glycogen substrate was 39 nmole/mg.h (normal range: 40–250) and for MU substrate 6.3 nmole/mg.h (normal range 6.7–27); both activities were measured in the presence of acarbose. DNA analysis revealed heterozygosity for the novel missense mutation c.1190 C > T (p.P397L) in the GAA gene. Mutation analysis by site-directed mutagenesis and transient expression showed p.P397L to cause loss of acid α-glucosidase function. A second mutation was not detected. Based on the combination of all findings, the diagnosis of Pompe disease was rejected.

Figure 13.1 Muscle biopsy of a patient with Pompe disease. Routine staining with haematoxylin-eosin does not always reveal the pathologic abnormality but staining the lysosomes for acid phosphatase activity, as in this muscle biopsy specimen, usually reveals intensive staining (reddish colour).

Figure 13.2Extreme scapular winging in a patient with adultonset Pompe disease.

Case histories

Confusing nomenclature

Unfortunately, the nomenclature used to cover the clinical spectrum of Pompe disease is confusing. Originally, Pompe disease or glycogenosis type II referred to infants with onset of symptoms shortly after birth, and the following characteristics: generalized hypotonia, cardiomegaly, and a life expectancy of less than one year. Later, “muscular variants” were described without cardiac involvement. In 1963, acid α-glucosidase deficiency was discovered as the very first lysosomal enzyme deficiency and as causative for Glycogen Storage Disease type II (Pompe disease). In 1968, the term Acid Maltase Deficiency became established among neurologists to describe adult, i.e. late-onset, variants of Pompe disease. Childhood and juvenile became widely accepted adjectives to bridge the gap between infantile-onset and late-onset disease.

The confusion started when, for the purpose of clinical trials of enzyme replacement therapy, patients with hypertrophic cardiomyopathy and onset of symptoms under the age of 1 year were said to have infantile-onset Pompe disease, and all with onset of symptoms above the age of 1 year to have late-onset disease. At present, veterans in the field adhere to the historic definition that late-onset Pompe disease, or Acid Maltase Deficiency, is typically a disease of adulthood. Others have adopted the new definition that late-onset Pompe disease is defined by onset of symptoms above the age of 1 year, and yet others argue that late-onset Pompe disease can manifest even before the age of 1 year.

Key message: information contained in publications on late-onset Pompe disease should be interpreted according to the definition of late-onset disease as set forth in that particular publication. Publications about patients with infantile onset Pompe disease may include patients who do not have the classic-infantile phenotype.

Epidemiology

Accurate numbers on the prevalence of rare diseases are difficult to obtain. Based on the birth prevalence of three common mutations in the Dutch population, an estimated frequency of 1:40,000 was obtained in the Netherlands, divided between 1:138,000 for the classic-infantile phenotype and 1:57,000 for the less progressive phenotypes. A study in the New York population based on a larger number of then known mutations came to a similar estimate. An Australian study counting the actual number of diagnosed and registered cases in that country indicated a much lower prevalence of 1:146,000. The birth prevalence of Pompe disease derived from two recently conducted newborn screening activities in Taiwan and Austria was 1:20,000 and 1:9,000, respectively.

Pompe disease is pan-ethnic. Certain pathogenic GAA sequence variations prevail in certain ethnic communities, and some are interestingly linked to migration patterns of people around the globe.

Genetic basis

The acid α-glucosidase gene (GAA ref seq Y00839/M34424) is located on chromosome 17 q25.3 and encodes a protein of 952 amino acids that is glycosylated at seven different sites. As at June 2012, the Pompe Disease Mutation Data at www/pompecenter.nl lists 310 pathogenic sequence variations and 93 non-pathogenic variations. c.-32-13 T > G is by far the most common pathogenic sequence variation in the Caucasian population. The nonsense mutation c.2560 C > T (p.Arg854X) is the most common mutation in Afro-Americans, and c.1935 C > A (p.Asp645Glu) is widely encountered in Taiwanese, Chinese, and other Asian populations excluding the Japanese. In addition, a number of mutations are known to be more frequent in some countries than in others. Knowledge of the frequencies of mutations in ethnic populations has lost significance for diagnostic purposes, as it is presently more efficient and almost equally costly to perform whole gene sequencing than to selectively screen for specific mutations.

Pathophysiology

The acid α-glucosidase deficiency is genetically determined and almost always equally severe in all cell types. Consequently, the lysosomal glycogen storage manifests in all cell types. It is remarkable that symptoms related to central nervous system dysfunction do not dominate the clinical picture since massive glycogen storage has been demonstrated in motor neurons of severely affected infants. With regard to the preferential muscle pathology, some evidence has been presented that the muscle weakness followed by muscle wasting is brought about by the expanding lysosomal system within the muscle fibre. It hampers linear force transduction and ultimately damages the delicate organization of the contractile elements. Circumstantial evidence has been presented that genetic and non-genetic factors can modify the clinical course; patients with the same GAA genotype can have a widely different age of onset and rate of disease progression, provided that acid α-glucosidase is not fully deficient.

Clinical presentation

For practical reasons it is best to describe the disease by age category. Patients with classic-infantile Pompe disease present shortly after birth as floppy babies. They all have cardiac hypertrophy, feeding difficulties, and they do not achieve major developmental milestones including sitting, standing and walking. They typically succumb before the age of 1 year due to cardio-respiratory insufficiency. Severely affected infants with early-onset but without cardiac involvement survive longer. They usually develop a childhood phenotype characterized by progressive skeletal muscle weakness affecting their pulmonary function and leading to ventilator dependency. There are also patients who are diagnosed in infancy, mostly based on poor motor development, but who progress very slowly and continue into adulthood without medical intervention. Using the historic nomenclature, adult-onset or late-onset cases of Pompe disease are typically diagnosed in early or late adulthood with an age range from 20 to 70 years at the time of diagnosis. They present with proximal muscle weakness, most prominently in the limb-girdle region, leading to a rather characteristic waddling gate and a Gower sign. Pulmonary function is usually compromised, especially when measured in the supine position. Some patients present with shortage of breath. Extreme fatigue or muscle cramps can also be the first sign of Pompe disease. Thus, Pompe disease patients may present to a range of clinical specialities in very different age categories (Box 13.1).

Only gold members can continue reading. Log In or Register to continue