REGISTRO DOI:10.69849/revistaft/ra10202502122308
Andreia Lira de Oliveira¹
Maria de Lourdes de Souza Galvão¹
ABSTRACT: Pompe disease is a genetic disorder inherited in an autosomal recessive manner, related to dysfunction of the enzyme acid alpha-glucosidase. It presents in two classical forms: the infantile-onset form, for patients who develop symptoms before the age of 2, and the late-onset form, for those who begin to show symptoms after this age. The childhood onset tends to be more severe and fatal, whereas the late-onset form manifests a myopathic phenotype, with axial and respiratory involvement. Diagnosis should be established by the evidence of acid alpha-glucosidase dysfunction in blood samples or through genetic testing. Enzyme replacement therapy is the current pharmacological treatment for this condition. In this article, we describe the case of an elderly woman who developed weakness in the lower limbs in the 7th decade of life, and after etiological investigation, a compound heterozygous mutation in the gene encoding acid alpha-glucosidase (GAA) was demonstrated. This highlights the need for awareness of metabolic causes of myopathies in elderly patients who present late-onset proximal limb weakness, with respiratory involvement.
KEYWORDS: Late-onset Pompe disease, GAA, myopathy.
INTRODUCTION:
Pompe disease, also known as glycogen storage disease type II, is a genetic disorder inherited in an autosomal recessive manner, associated with homozygous or compound heterozygous mutations in the GAA gene, located on chromosome 17q25, which encodes the enzyme acid alpha-glucosidase, also known as acid maltase [1]. The acid alpha-glucosidase enzyme is responsible for hydrolyzing glycogen into glucose, a process that occurs in the lysosomes. As a result, its deficiency leads to the accumulation of glycogen in the lysosomes and cytoplasm of various tissues, including smooth, skeletal, and cardiac muscle [2].
There are two classical forms of presentation of the disease: infantile-onset Pompe disease, in which symptoms begin before the age of 2, and late-onset Pompe disease, in which symptoms appear after this period [3]. The age and phenotype of presentation vary according to the associated genetic mutation [4]. To date, more than 600 mutations in the GAA gene have been identified.
The infantile form of the disease develops within the first weeks or months of life and is characterized by generalized muscle weakness, associated with hypotonia, as well as hypertrophic cardiomyopathy and respiratory dysfunction. This form of the disease progresses to death within 2 years if left untreated. On the other hand, the late-onset form may begin between the 2nd and 7th decades and is characterized by proximal weakness, with axial involvement, as well as varying degrees of respiratory dysfunction and absence of cardiac involvement [2]. Macroglossia has also been reported as a possible complication of late-onset Pompe disease [5, 6]. The late-onset form of the disease constitutes an important differential diagnosis of myopathies in adults, particularly when there is diaphragmatic involvement, reduced forced vital capacity, and refractoriness to the use of immunosuppressors and glucocorticoids [7].
Pompe disease is a rare condition, with an incidence of 1 case per 40,000 inhabitants, with 1 case per 138,000 inhabitants for the infantile form and 1 case per 57,000 inhabitants for the late-onset form [2]. Diagnosis can be established by confirming enzymatic dysfunction through enzymatic assay in blood samples, as well as through the detection of pathogenic mutations [8].
The development of enzyme replacement therapy has revolutionized the treatment of this condition. Currently, three enzyme replacement therapies are approved by regulatory agencies: alglucosidase alfa, avalglucosidase alfa, and cipaglucosidase alfa associated with miglustat. In Brazil, the Clinical Protocol and Therapeutic Guidelines (PCDT) for Pompe disease recommends the use of alglucosidase alfa at a dose of 20mg/kg every 15 days. To date, no gene therapy has been authorized for use by regulatory agencies [8].
CASE REPORT:
A 79-year-old female patient, who at the age of 71 began experiencing weakness in the lower limbs, presenting with difficulty walking, as well as difficulty climbing ramps and stairs. After two years, she developed a sensation of a heavy tongue, which impaired her speech. She underwent a thorough investigation with Rheumatology and Orthopedics, but no diagnosis was found.
She was referred for a consultation with a neurologist, who, at that time, identified the presence of dysarthria associated with macroglossia, as well as symmetric, flaccid, and areflexic paraparesis, predominantly proximal, with a muscle strength of grade 4 in hip flexion and leg extension, requiring unilateral support to walk. She had a history of systemic arterial hypertension, dyslipidemia, and hiatal hernia. There was no family history of similar cases.
A myopathy was suspected, and diagnostic investigation was initiated. Complementary exams confirmed the hypothesis of myopathy and ruled out the diagnosis of inflammatory myopathies and other forms of acquired myopathies. Subsequently, next-generation sequencing for neuromuscular diseases was performed, which identified the presence of two pathogenic mutations in heterozygosity in the GAA gene: Chr17:80.104.542 T>G and Chr17:80.118.271 C>T. The test did not indicate whether these mutations were on the same allele or on distinct alleles; however, due to the clinical compatibility with the patient’s presentation and the possibility of compound heterozygosity, a diagnosis of Pompe disease was considered.
The patient began treatment with enzyme replacement therapy, using alglucosidase alfa. After the sixth infusion of the medication, she noticed a reduction in macroglossia and less difficulty articulating speech. Additionally, she started rehabilitation therapy with daily hydrotherapy, motor physiotherapy twice a week, respiratory physiotherapy twice a week, and speech therapy weekly. At the time of the last evaluation, she had not exhibited signs of respiratory discomfort, although spirometry demonstrated a reduction in forced vital capacity and FEV1.
DISCUSSION:
The etiological diagnosis of myopathies in the elderly typically raises suspicion for acquired causes, such as inflammatory diseases and paraneoplastic syndromes; however, the possibility of a hereditary disease with late-onset symptoms should also be considered. In this context, when faced with a myopathic condition characterized by proximal weakness, ventilatory involvement, and macroglossia, the hypothesis of Pompe disease should be considered, and diagnostic evaluation for this condition should be performed.
In the case presented, the patient does not have a known family history of Pompe disease or any symptoms consistent with the condition in her relatives, suggesting a recessive inheritance pattern. Next-generation sequencing for neuromuscular diseases did not show the presence of a biallelic mutation; however, it did reveal two mutations that may be located on different alleles, indicating compound heterozygosity. Compound heterozygosity is also a genetic mutation compatible with the autosomal recessive inheritance pattern.
As a result, enzyme replacement therapy with alglucosidase alfa was initiated, and after 3 months of evaluation, the patient showed less difficulty in speech articulation, a change also noted by her family members. Therefore, the importance of this diagnostic suspicion is emphasized, as it is a disease that can become disabling but has an available treatment through enzyme replacement therapy, potentially leading to improved survival and functionality in these patients.
CONCLUSION:
Pompe disease is a rare hereditary condition inherited in an autosomal recessive manner, which can present with late-onset manifestations, even in the 7th and 8th decades of life. Therefore, in the presence of late-onset myopathy with axial involvement, ventilatory dysfunction, and macroglossia, this condition should be suspected. It is a condition with an established pharmacological treatment, through enzyme replacement therapy, and the absence of diagnosis can lead to negative impacts on the patient’s life.
REFERENCES:
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1Hospital Universitário Getúlio Vargas – Universidade Federal do Amazonas