Additional Investigation After the Muscle Biopsy Diagnosis

The acid alpha-1,4 glucosidase (GAA) gene sequencing for Pompe disease was positive for compound heterozygous mutations described as c.-32-13 T > G and c.213 T > C.

Final Diagnosis

Pompe Disease (Acid Maltase Deficiency)

Patient Follow-up

The patient was started on the enzyme replacement therapy (ERT) with Lumizyme every 2 weeks. Her motor function had stabilized and even improved over 5 years on the treatment. Respiratory function had also improved with better FVC. Her mild-to-moderate hearing loss was treated with a hearing aid.

Discussion

Pompe disease , also referred to as acid maltase deficiency or type II glycogen storage disease, is an autosomal recessive disease caused by mutations in the gene encoding lysosomal acid alpha-1,4 glucosidase (GAA) leading to a deficiency of the acid alpha glucosidase or acid maltase enzyme with secondary accumulation of glycogen in lysosomes [1]. The estimated incidence of GAA deficiency was 1 in 40,000 [2]. Deficiency of the enzyme leads to glycogen accumulation in lysosomes and cytoplasm, resulting in tissue destruction [3, 4]. The classic infantile form presents with hypertrophic cardiomyopathy, generalized hypotonia, and elevated CK. In the juvenile and adult forms, clinical features are widely variable. There is usually a slowly progressive myopathy with eventual respiratory muscle involvement . Children have delayed gross motor milestones with diaphragm involvement, sleep-disordered breathing and limb girdle muscle weakness. Adults also have limb girdle weakness and have diaphragm involvement relatively early. The heart is less involved with adult onset. Differential diagnosis consists of fatty oxidation disorders, mitochondrial disorders, other glycogen storage disorders, and muscular dystrophies. Initial diagnostic evaluation includes serum CK level and NCS/EMG. Patients can have neurogenic findings on EMG probably due to the co-existing motor neuron involvement, as the results from early autopsy investigations showed that spinal cord anterior horn cells, motor nuclei of the brain stem, and spinal ganglia were susceptible particularly in infantile Pompe disease [5–7]. In this clinic setting , the diagnosis of Pompe disease can be challenging, and a muscle biopsy is helpful as seen in our case. Measuring GAA enzyme activity in white blood cells or dried blood spots can be used to screen patients. Diagnostic confirmation is made through sequencing of the GAA gene. GAA gene encodes lysosomal acid alpha-1,4 glucosidase located at chromosome 17q25.2-q25.3 [1].

Pompe disease defers from all other types of glycogen storage diseases as the enzyme is located within lysosomes. Acid maltase deficiency results in glycogen accumulation within lysosomes that are positive for both acid phosphatase stain, which detects lysosomes, and PAS stain, which detects glycogen. Vacuolar changes are usually prominent in the infantile-onset form; however, they can be quite subtle or absent in selected muscle groups in patients with the late-onset disease (see Chap. 16). The most sensitive finding in a mildly affected muscle is diffusely increased sarcoplasmic punctate acid phosphatase reactivity, or in some cases, increased lipofuscin particles [8]. However, these findings are not specific. Main differential considerations include other lysosomal vacuolar myopathies associated with Danon disease , X-linked myopathy with excessive autophagy (XMEA) , myotoxicities of drugs such as chloroquine, hydroxychloroquine (see Chap. 19) and colchicine, vitamin E deficiency [9] and aging. On the other hand, a muscle biopsy with normal histology does not exclude the possibility of acid maltase deficiency, especially in the late-onset cases. Mild denervation changes are relatively common in muscle biopsies from patients with acid maltase deficiency, likely due to motor neuron involvement.

Treatment of Pompe disease is ERT with alglucosidase alfa. With the advent of ERT, prognosis of Pompe disease has improved. Adverse effects of ERT include hypersensitivity reactions and development of antibodies to alglucosidase alfa [10]. Other genetic therapies are on the preclinical stages or early clinical phases [11, 12].

Pearls