3 Rare Cases Link Atypical Symptoms, New Genetic Mutations to Juvenile-onset Pompe Disease

New genetic mutations and uncommon clinical symptoms, including skeletal alterations and developmental delay, were linked to juvenile-onset Pompe disease in three rare cases, making early recognition of these anomolies an important step to providing the best care for these patients, a study says.

The cases were described by researchers from Venezuela and Spain in a study, titled “Skeletal alterations, developmental delay and new mutations in juvenile-onset Pompe disease,” and published in the journal Neuromuscular Disorders.

Pompe disease is a genetic disorder characterized by impaired production or function of the acid alpha-glucosidase (GAA) enzyme and consequent accumulation of glycogen in tissues and organs.

Clinical reports have demonstrated that the same GAA genetic mutation can give rise to different clinical symptoms. Pompe disease can manifest with different degrees of severity, age of onset, and organ involvement. This variability suggests that the disease may result from the interaction of other genetic and non-genetic factors, making the diagnosis process a challenge.

The researchers in the study reported three cases with some unusual clinical features which would not normally lead to suspicion of Pompe disease.

The first case was of an adolescent boy, 14, who developed generalized fatigue and had difficulties in performing daily activities, such as running and playing sports. He also had muscle cramps and weakness, with reduced muscular strength mainly affecting his limbs. He began experiencing symptoms at 12.

An initial physical examination confirmed that his general condition was within normal standards for his age, with the exception of generalized reduced muscle mass and loss of strength in his lower limbs but with normal deep tendon reflexes.

He had pectus excavatum and was found to have a restrictive ventilation disorder. No cardiac function alterations were detected. Imaging analysis of his abdomen did not revealed any masses or structural organ changes.

The second patient was a 7-year-old boy who complained of fatigue while walking and climbing stairs. He had fallen several times without reason. He also showed signs of general clumsiness while performing basic daily activities.

He had weakness and reduced muscular strength, and pain in his limbs, without any obvious physical or neurological alteration that could help explain these symptoms. He was also found to have winged scapulae (abnormally protruding shoulder blades).

The last case was of a 6-year-old boy who, similar to the others, had generalized fatigue, with difficulty running and playing sports at the onset of his symptoms, which evolved to fatigue in performing daily activities. He showed signs of weakness and pain in his limbs, which had gradually started two years before. No respiratory or cardiac alterations were noted.

In all cases, the boys’ families had no history of metabolic or neurological diseases. Still, they all showed some developmental delay during early infancy, taking slightly longer to achieve developmental milestones such as walking and sitting.

Blood analyses were within normal range in all patients for several important biochemical parameters related to the immune system, kidney and liver functions, sugar levels, and electrolytes balance.

However, they showed clear signs of muscle damage, as determined by increased blood levels of lactate dehydrogenase (LDH), creatine kinase (CPK), and the muscle variant of creatine kinase (M-CPK).

Based on the patients’ clinical symptoms and these biochemical findings, the team decided to analyze the activity of GAA enzyme, which was found to be decreased in 6- and 7-year-old boys, and almost absent in the 14-year-old patient.

Evaluation of muscle tissue biopsies confirmed the accumulation of glycogen inside muscle fibers, not affecting the muscle’s nerve responsiveness.

The team performed a genetic analysis of the GAA gene to find out if the boys had Pompe disease.

The 14-year-old was found to have two new GAA mutations that had not been previously described, and were determined to be causing the patient’s symptoms. The younger boys were also found to have mutations in the GAA gene, which are associated with Pompe disease.

“Our case series adds new clinical evidence regarding symptoms, signs, and genetic variants in juvenile-onset Pompe disease, which may vary considerably among patients and could mimic a spectrum of other neuromuscular disorders,” the researchers wrote.

Recognizing these uncommon skeletal alterations and developmental delay features, as well as novel associated genetic mutations, can “offer clinicians an additional background to suspect Pompe disease when the clinical picture of patients does not fully match with classical presentation of this (disease),” they said.