Immune responses to alglucosidase in infantile Pompe disease: recommendations from an Italian pediatric expert panel.

BACKGROUND: Classic infantile onset of Pompe disease (c-IOPD) leads to hypotonia and hypertrophic cardiomyopathy within the first days to weeks of life and, without treatment, patients die of cardiorespiratory failure in their first 1-2 years of life. Enzymatic replacement therapy (ERT) with alglucosidase alfa is the only available treatment, but adverse immune reactions can reduce ERT's effectiveness and safety. It is therefore very important to identify strategies to prevent and manage these complications. Several articles have been written on this disease over the last 10 years, but no univocal indications have been established. METHODS: Our study presents a review of the current literature on management of immune responses to ERT in c-IOPD as considered by an Italian study group of pediatric metabolists and immunologists in light of our shared patient experience. RESULTS: We summarize the protocols for the management of adverse reactions to ERT, analyzing their advantages and disadvantages, and provide expert recommendations for their optimal management, to the best of current knowledge. However, further studies are needed to improve actual management protocols, which still have several limitations.

Muscle MRI of classic infantile pompe patients: Fatty substitution and edema-like changes.

INTRODUCTION: The aim of this study was to evaluate the muscle MRI pattern of 9 patients (median age: 6.5 ± 2.74 years) affected by classic infantile-onset Pompe disease who were treated with enzyme replacement therapy. METHODS: We performed and qualitatively scored T1-weighted (T1-w) sequences of the facial, shoulder girdle, paravertebral, and lower limb muscles and short-tau inversion recovery (STIR) sequences of the lower limbs using the Mercuri and Morrow scales, respectively. RESULTS: On T1-w images, mild (grade 1) or moderate (grade 2) involvement was found in the tongue in 6 of 6 patients and in the adductor magnus muscle in 6 of 9. STIR hyperintensity was detected in all areas examined and was categorized as limited to mild in 5 of 8 patients. CONCLUSIONS: On T1-w sequences, mild/moderate adipose substitution in the adductor magnus and tongue muscles was documented. STIR edema-like alterations of thigh and calf muscles are novel findings. Correlations with biopsy findings and clinical parameters are needed to fully understand these findings. Muscle Nerve 55: 841-848, 2017.

Glycogen storage disease type Ia (GSDIa) but not Glycogen storage disease type Ib (GSDIb) is associated to an increased risk of metabolic syndrome: possible role of microsomal glucose 6-phosphate accumulation.

BACKGROUND: In GSDIa, glucose 6-phosphate (G6P) accumulates in the endoplasmic reticulum (ER); in GSDIb, G6P levels are reduced in ER. G6P availability directly modulates the activity of 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1), an ER-bound enzyme playing a key role in the development of the metabolic syndrome (MS). OBJECTIVE: To evaluate the prevalence of MS and Insulin Resistance (IR) in GSDIa and GSDIb patients. PATIENTS AND METHODS: This was a prospective study. All the enrolled patients were followed at the Department of Pediatrics "Federico II" University of Naples for 10 years. Clinical and biochemical parameters of MS and the presence of IR were recorded. The results were correlated with the biochemical parameters of GSDI-related metabolic control. 10 GSDIa patient (median age 12.10 ± 1.50), 7 GSDIb patients (median age 14.90 ± 2.20 were enrolled in the study. They were compared to 20 and 14 age and sex matched controls, respectively. 10 GSDIa patients (median age 24.60 ± 1.50) and 6 GSDIb patients (median age 25.10 ± 2.00) completed the 10-year-follow-up. At the end of the study the patients' data were compared to 10 and 6 age and sex matched controls, respectively. RESULTS: At study entry, 20 % GSDIa patients had MS and 80 % showed 2 criteria for MS. GSDIa patients showed higher HOMA-IR than controls and GSDIb patients (p < 0.001, p < 0.05), respectively. Baseline ISI was lower in GSDIa than controls (p < 0.001). QUICKI was significantly lower in GSDIa than in controls (p < 0.001). At the end of the study 70 % of GSDIa patients had MS and 30 % showed 2 criteria for MS. HOMA-IR was higher in GSDIa than controls (p < 0.01). Baseline ISI was higher in GSDIb than controls (p < 0.005) and GSD1a (p < 0.05). QUICKI was lower in GSD1a patients than in controls (p < 0.03). VAI was higher in GSDIa patients than controls (p < 0.001) and GSDIb patients (p = 0.002). CONCLUSIONS: Our data showed high prevalence of IR and MS in GSDIa patients. We speculate a possible role of 11ßHSD1 modulation by G6P availability. We suggest a routine metabolic assessment in GSDIa patients.

Mental retardation, congenital heart malformation, and myelodysplasia in a patient with a complex chromosomal rearrangement involving the critical region 21q22.

The region 21q22 is considered crucial for the pathogenesis of both Down syndrome (DS) and the partial monosomy 21q syndrome. Haploinsufficiency of the RUNX-1 gene, mapping at 21q22 is responsible for a platelet disorder and causes predisposition to myelodysplastic syndrome (MDS). We describe a 3-year-old girl with mental retardation, congenital heart malformation, and subtle dysmorphic facial features. The patient developed thrombocytopenia when she was 2 years old. Bone marrow smear led to the diagnosis of myelodysplasia. Prenatal karyotyping had shown chromosome 21 pericentric inversion. Postnatally the array-CGH revealed duplication at bands 21q11.2-21q21.1 and a simultaneous deletion involving the region 21q22.13-21q22.3. RUNX-1 mRNA levels analyzed in patient's skin fibroblasts were reduced. In this child the monosomy of the region 21q22 likely had the main role in determining the phenotype. Although the RUNX-1 gene is localized outside the deleted region, we speculate that RUNX-1 reduced expression, is probably due to the deletion of regulatory factors and caused the hematologic disorder in the patient. The present report underlines also the importance of array-CGH in characterizing patients with a complex phenotype.