RECURRENCE OF POMPE DISEASE IN FIRST COUSINS.

Summary: Recurrence of Pompe disease infirst cousins: We report on the cases of two first-degree non-consanguineous cousins with infantile-onset Pompe disease, a rare autosomal recessive disease. The first patient developed cardiorespiratory failure at age I year. When she was 4 her male cousin developed hypotonia during his first month of life. Both infants had cardiac hypertrophy at diagnosis and shared the c.I927G>A missense mutation. Since a first degree cousin of an affected patient has 50 times the risk of developing the disease compared with unrelated infants and since cardiac hypertrophy is constant in affected infants, the combination of cardiac symptoms with a history of Pompe disease in a first degree cousin leads to a very high probability of having the condition. Clinically oriented screening based on simple diagnostic procedures such as echocardiogram and anamnesis could accelerate the initiation of enzyme replacement therapy of the deficient acid a-glucosidase which is critical to restoring cardiac function in affected infants.Key-words: Pompe disease - Infant - Recurrence - Lysosomal disease.INTRODUCTIONPompe disease is a rare autosomal recessive disease in which a deficiency in acid a-glucosidase (GAA) activity leads to glycogen accumulation in the lysosomes. Progressive muscle damage and organ failure follow (3). Several phenotypes can be individualized according to the age at symptom onset, the extent of organ involvement and the progression-to-death rate (3). In the infantile-onset form, massive glycogen deposits in the heart and skeletal muscles result in quickly progressing cardiomyopathy, generalized muscle weakness and hypotonia. Death from cardiac or respiratory failure usually occurs within the first year after birth (3). We report on two cousins with the infantile-onset form of Pompe disease.PATIENTS' PRESENTATIONPatient 1 is a first-born full term girl, who weighed 3430 g at birth. She was able to maintain sitting position at age 10 months but suffered from bronchiolitis at the same age. At age 12 months she developed flaccid tetraparesis and severe cardiac and respiratory failure leading to tracheotomy. An echocardiogram showed an enlargement of the left ventricle, which also appeared to be concentrically hypertrophied. The left ventricular ejection fraction (LVEF) was initially low (20%) but quickly improved with treatment. Pompe disease was diagnosed in a muscle biopsy sample. Genotyping identified two mutations of the acid a-glucosidase locus (GAA): c.1655T>L (p.L552P) and c,1927G>A (p.G643R). Between ages 12 and 19 months successive echocardiograms showed left ventricular hypertrophy with preserved LVEF. At age 17 months the patient was able to grasp objects with her hands and to feed herself (supplemented with enteral nutrition through gastrostomy). An enzyme replacement therapy (ERT) with alglucosidase alfa was started at age 19 months (20 mg/kg every other week). After 4 months of treatment, myocardial structure and function improved. She was then able to move her left arm normally and regain extension of her right arm. However, she suffered from several pulmonary infections. At the age of 4 years, and after 13 months of ERT, she remains wheelchair-bound but her respiratory status is stabilized. The left ventricular function is normal and the left ventricular hypertrophy is mild, but stable.Patient 2 is a first-born full term boy, who weighed 3500 g at birth. His mother is patient 1 's mother's sister (Fig. 1). During his first month he showed axial hypotonia and mild polypnea. An echocardiogram showed hypertrophy of both ventricles with preserved LVEF. He also had a mild hepatosplenomegaly and myolysis, as well as absent acid a-glucosidase activity. Genotyping identified a deletion of exon 18 (Delta 18) and a c.1927G>A (p.G643R) missense mutation. Enzyme replacement therapy was started (alglucosidase alfa 20 to 21 mg/kg every other week) at the age of 2 months. …