Linda Richfield

Three-dimensional face shape in Fabry disease.

Facial dysmorphology is an important feature in several lysosomal storage disorders. Although in Fabry disease facial dysmorphism is not a prominent sign, minor facial abnormalities have been previously reported. By analysing three-dimensional images of faces, we quantified facial dysmorphology in a cohort of both male and female Fabry patients. Morphometric analysis of different regions of the face revealed significant differences in face shape in male patients and to a lesser extent in female patients. In male patients, the most prominent abnormalities were located in the peri-orbital region. Pattern recognition techniques achieved a discrimination accuracy of up to 85% for male patients compared with healthy controls. The discrimination accuracy in female patients achieved only 67%. This objective method for facial dysmorphology assessment provided evidence for significant differences in face shape in both male and female Fabry patients compared with controls. However, because discrimination from healthy controls is too low, no key role in the diagnostic process can be expected.

Clinical prodromes of neurodegeneration in Anderson-Fabry disease

Objective: To estimate the prevalence of prodromal clinical features of neurodegeneration in patients with Anderson-Fabry disease (AFD) in comparison to age-matched controls. Methods: This is a single-center, prospective, cross-sectional study in 167 participants (60 heterozygous females and 50 hemizygous males with genetically confirmed AFD, 57 age-matched controls) using a clinical screening program consisting of structured interview, quantitative tests of motor function, and assessments of cognition, depression, olfaction, orthostatic intolerance, pain, REM sleep behavior disorder, and daytime sleepiness. Results: In comparison to age-matched controls (mean age 48.3 years), patients with AFD (mean age 49.0 years) showed slower gait and transfer speed, poorer fine manual dexterity, and lower hand speed, which was independent of focal symptoms due to cerebrovascular disease. Patients with AFD were more severely affected by depression, pain, and daytime sleepiness and had a lower quality of life. These motor and nonmotor manifestations significantly correlated with clinical disease severity. However, patients with AFD did not reveal extrapyramidal motor features or signs of significant cognitive impairment, hyposmia, orthostatic intolerance, or REM sleep behavior disorder, which commonly precede later neurodegenerative disease. In our cohort, there were no differences in neurologic manifestations of AFD between heterozygous females and hemizygous males. Conclusions: Aside from cerebrovascular manifestations and small fiber neuropathy, AFD results in a distinct neurologic phenotype comprising poorer motor performance and specific nonmotor features. In contrast to functional loss of glucocerebrosidase in Gaucher disease, α-galactosidase deficiency in AFD is not associated with a typical cluster of clinical features prodromal for neurodegenerative diseases, such as Parkinson disease.

Haemorheology in Gaucher disease

Abstract:  In Gaucher disease, a deficiency of glucocerebrosidase results in the accumulation of glucocerebroside within the lysosomes of the monocyte–macrophage system. Prior to the availability of enzyme replacement therapy (ERT), splenectomy was often indicated for hypersplenism. Haemorheological abnormalities could be expected in view of the anaemia and abnormal lipid metabolism in these patients and the role of the spleen in controlling erythrocyte quality. Objectives: To investigate the effect of Gaucher disease on blood and plasma viscosity, erythrocyte aggregation and erythrocyte deformability, and to determine whether observed rheological differences could be attributed to splenectomy. Methods: Haematological and haemorheological measurements were made on blood collected from 26 spleen‐intact patients with Gaucher disease, 16 splenectomised patients with Gaucher disease, 6 otherwise healthy asplenic non‐Gaucher disease subjects and 15 healthy controls. Results: No haemorheological differences could be demonstrated between spleen‐intact patients with Gaucher disease and the control group. Compared to controls, both asplenic Gaucher disease and asplenic non‐Gaucher disease study groups had a reduced MCHC (P = 0.003 and 0.005, respectively) and increased whole blood viscosity at 45% haematocrit (Hct), relative viscosity and red cell aggregation index – all measured at low shear (P < 0.05 for all). Additionally, asplenic patients with Gaucher disease alone showed an increased MCV (P = 0.006), an increased whole blood viscosity at 45% Hct measured at high shear (P = 0.019), and a reduced relative filtration rate (P = 0.0001), compared to controls. Conclusion: These observations demonstrate a direct and measurable haemorheological abnormality in Gaucher disease only revealed when there is no functioning spleen to control erythrocyte quality.

Pregnancy and associated events in women receiving enzyme replacement therapy for late-onset glycogen storage disease type II (Pompe disease).

Glycogen storage disease type II (GSD II or Pompe disease; OMIM; 232 300) is a rare autosomal recessive lysosomal storage disorder resulting from deficiency of α‐glucosidase and accumulation of glycogen in muscle. Clinical symptoms include weakness of skeletal and respiratory muscles and, in infants, cardiomyopathy. Patients with GSD II receive infusions of recombinant α‐glucosidase (enzyme replacement therapy; ERT), which slow the progression of the disease. ERT is given to male and female patients of all ages but as yet little is documented on the effects of continuing ERT during pregnancy. The aim of this case series was therefore to ascertain the pregnancy outcomes of women with GSD II on ERT and to describe adverse events associated with pregnancy, delivery and therapy.

Facilitation of suction termination using extra-amniotic prostaglandins in gel.

Extra-amniotic prostaglandin E2 (PGE2) suspended in a slow release gel (Tylose) was instilled in 35 patients prior to a planned surgical termination in an attempt to dilate the cervix, minimize cervical trauma, and reduce the possible risk of cervical trauma, and reduce the possible risk of cervical incompetence and its sequelae. Dilatation occurred in all patients to a minimum of 8 mm and 74% aborted before surgical evacuation performed 6 to 24 hours after injection. No serious side effects occurred. Extra-amniotic PGE2 in gel should be considered as a primary procedure when the cervix is obviously immature on examination. If the cervix is found to be tight and unyielding at surgical dilatation, the latter procedure should be dicontinued and PGE2 in gel injected.

Limitations of a single extra-amniotic injection of prostaglandins in viscous gel to induce midtrimester abortion.

A dose-response study using PGE2 in a viscous gel has been undertaken for induction of midtrimester abortion. A direct relationship was found between the time to abortion and the dose administered. However, even using PGE2 3.5 mg induced uterine activity was noticed to subside in a significant number of women after approximately 6 h. For routine management it is suggested that PGE2 3.5 mg be injected and followed by repeat doses 6 h later with removal of the injecting catheter on each occasion.

Therapy – home versus hospital? A questionnaire survey in patients with Fabry and Gaucher diseases

clearance compared with other drug products or proteins provides support for mannose-6-phosphate (M6P) receptor clearance of agalsidase alfa. The percentage of administered agalsidase alfa found in a patient’s liver decreased as the dose increased on a mg/ kg basis. At the two lowest doses, 0.007 and 0.014 mg/ kg, the percentage of agalsidase alfa recovered in the liver 44 hours after dosing was approximately 25–30%. In contrast, at 0.11 mg/kg, only 14% of administered agalsidase alfa was found in the liver. Saturation of liver uptake of agalsidase alfa occurred when maximum drug product concentrations exceeded the Kd for the M6P receptor (2 £ 10¡ mol/l). Conclusions: Based on these results, the estimated amount of the commercial dose of agalsidase alfa (Replagal2; 0.2 mg/kg) taken into the liver is approximately 2–3 mg for a 75 kg patient. The remainder of the dose (12–13 mg) is available for uptake into key organs affected by Fabry disease.