Genotype-phenotype associations in familial Mediterranean fever: a study of 500 Egyptian pediatric patients.

INTRODUCTION: Familial Mediterranean fever (FMF) is the most prevalent monogenic autoinflammatory disease, caused by recessively inherited MEFV gene mutations. The most frequent MEFV mutations differ in penetrance and disease severity. We investigated the genotype-phenotype associations of the three most frequent MEFV gene mutations (M680I, M694V, and V726A) in Egyptian FMF children, regarding clinical features, severity, and colchicine response. METHODS: We conducted a retrospective analysis of the medical registries of 500 FMF pediatric patients from Metropolitan Cairo between 2010 and 2015. The diagnosis was based on the Tel-Hashomer clinical diagnostic criteria. Clinical data and baseline investigations were collected. Mutation analysis was performed by the amplification-refractory mutation system (ARMS)-PCR method. RESULTS: Males represented 54% and ages ranged from 2 to 18 years. The most frequent symptoms were abdominal pain, fever, and arthralgia. Clinical features mostly associated with M694V mutation either homozygous or heterozygous whether simple, double, or triple. Of the patients, 94.6% completely responded to colchicine. Among patients benefiting from colchicine, 42.5% had M694V/V726A, 21.6% had M694V/V726A/M680I, and 21.1% had M694V genotype. Simple heterozygous M694V or V726A mutations conveyed a moderate phenotype in 57.1% and 50% of cases, respectively. Homozygous M694V mutation showed moderate and severe phenotypes in 21.7% and 65.2% of cases, respectively. Compound M694V/V726A mutation associated with moderate or severe disease in 48.3% and 33.8% of cases, respectively. CONCLUSION: This study encompasses the largest group of Egyptian pediatric FMF up to date to explore their genotype-phenotype associations. Our results support the notion that the genotype influences the phenotype as regards clinical manifestations, disease severity, and colchicine response. KEY POINTS: • This study encompasses the largest group of Egyptian pediatric patients affected by FMF up to date to explore their genotype-phenotype associations. • Our results support the notion that the genotype influences the phenotype as regards the clinical manifestations, the disease severity, and the response to colchicine treatment.

Reversal of life-threatening hepatopulmonary syndrome in Gaucher disease by imiglucerase enzyme replacement therapy.

Advanced liver disease complicated by hepatopulmonary syndrome is a recognized complication of Gaucher disease. Macrophage-targeted, recombinant enzyme replacement therapy is effective in reversing clinical manifestations attributed to the accumulation of glycolipid-laden macrophages but it is not known whether advanced fibrotic features of the disease can be ameliorated. We describe a splenectomized patient with Gaucher disease who developed massive hepatomegaly, cirrhosis of the liver and life-threatening hepatopulmonary syndrome. Treatment with Imiglucerase enzyme replacement therapy resulted in dramatic reversal of hepatopulmonary syndrome and liver disease. Our report suggests that Gaucher disease pathology involving advanced fibrosis and life-threatening complications can be reversed by imiglucerase enzyme therapy. SYNOPSIS: Effect of imiglucerase enzyme replacement therapy on Hepatopulmonary Syndrome in Gaucher Disease.

A multicenter, open-label, phase III study of Abcertin in Gaucher disease.

BACKGROUND: Gaucher disease (GD) is caused by a deficiency in the lysosomal enzyme glucocerebrosidase. Enzyme replacement therapy (ERT) is recommended for clinical improvement. METHODS: The efficacy and safety of a new imiglucerase, Abcertin, were assessed in 7 Egyptian patients with treatment-naïve type 1 GD. Each patient was administered a biweekly 60 U/kg dose of Abcertin for 6 months. The primary endpoint was the change in hemoglobin concentration. The secondary endpoints were changes from baseline in platelet counts, spleen and liver volumes, biomarker levels, skeletal parameters, and bone mineral density. RESULTS: The hemoglobin concentration increased by a mean of 1.96 ±â€Š0.91 g/dL (range 1.11-2.80 g/dL) or 20.6% (P = .001). Statistically significant increases in the platelet count and decreases in the spleen volume and biomarker levels were also observed. There were no severe drug-related adverse events. One patient developed anti-imiglucerase antibodies without neutralizing activity. CONCLUSION: Our study results demonstrate the efficacy and safety of Abcertin in patients with type 1 GD. This suggests that Abcertin can be an alternative ERT option for type 1 GD.

Screening of growth hormone deficiency in short thalassaemic patients and effect of L-carnitine treatment.

INTRODUCTION: Evaluation of growth hormone (GH) in short thalassaemic patients and effect of L-carnitine therapy in those with hormone deficiency. MATERIAL AND METHODS: The study included 30 ß-thalassaemic patients aged 13.8 ±1.7 years and 30 children with constitutional short stature as controls. Anthropometric measurements (basal and after 6 months), thyroid profile, insulin-like growth factor-1 (IGF-1) and GH provocation by 2 tests were carried out. Eight patients with inadequate GH response to both clonidine and ITT were given L-carnitine treatment for 6 months. They were re-evaluated (clinically, anthropometrically and in the laboratory by doing GH stimulation test) after 6 months of therapy. RESULTS: Twelve (40%) patients had sub-clinical hypothyroidism and 10 (33.3%) had growth hormone deficiency (GHD). Peak GH and growth velocity (cm and standard deviation score [SDS]) were significantly lower while weight (SDS) and weight/height SDS were significantly higher than in patients with constitutional short stature (p < 0.05). A significant positive correlation was found between height and target height (cm). Haemoglobin levels, peak GH, IGF-1 and growth velocity (cm & SDS) were significantly higher and the number of blood transfusions was significantly lower in GH deficiency patients after L-carnitine treatment (p < 0.05). Delta changes were higher in height (cm & SDS), estimated mature height and sitting height and lower in target height - height (SDS and cm) six months after L-carnitine treatment in ß-thalassaemic patients with GHD (p < 0.05). CONCLUSIONS: Growth hormone deficiency is an aetiological factor in thalassaemic patients with short stature. L-carnitine can promote GH secretion and growth.

The effect of freezing on the recovery and expansion of umbilical cord blood hematopoietic stem cells.

OBJECTIVES: Cell populations residing in waste tissues (cord blood, umbilical cord, and placenta) may be collected without any medical or ethical contraindications concerning the mother or newborn baby. Cord blood hematopoietic stem cells are routinely used for clinical transplants; however, the low cell dose of the graft limits their therapeutic efficacy as it is associated with increased delayed or failed engraftment. The cell dose can be increased, and the efficacy of cord blood transplant potentially improved, by ex vivo expansion before transplant. MATERIALS AND METHODS: Twelve umbilical cord blood samples were included. The effect of cord blood storage at -80 degrees C on CD34+ cell count (mean -/+ standard deviation [SD]), cell viability (mean -/+ SD percent), and cell cycle status (percent quiescent versus dividing) was estimated. Ex vivo culture of cord blood mononuclear cells was done before storage, and after 1 week of freezing, and after 2 weeks of freezing. Ex vivo liquid culture was performed with media supplemented with stem cell factor, interleukin-3 (IL-3), and both. RESULTS: The count of CD34+ cells in pre-expansion aliquots decreased from 15.00 +/- 9.96 x 106 cells before freezing to 7.70 -/+ 3.20 x 106 cells after 2 weeks of freezing (P = .024). Cell viability in pre-expansion aliquots decreased from 99.5% -/+ 1.0% before freezing, to 52.5% -/+ 27.5% after 1 week of freezing (P = .013) and to 32.5% -/+ 9.5% after 2 weeks of freezing (P = .001). Mean fold of cell expansion and proportion of quiescent versus dividing cells did not change significantly from before to after freezing, and was not significantly different for culture with stem cell factor, IL-3, or both. CONCLUSION: Although freezing decreased cell count and viability, it did not impair the expansion potential of cord blood hematopoietic cells. Whether IL-3 or stem cell factor should be considered as essential components of expansion media is uncertain.