Poikilothermia in a 38-year-old Fabry patient

A Fabry patient with poikilothermia is described. Laboratory investigations, neuro-imaging and autonomic function tests did not disclose a cause. Assessment of intra-epidermal nerve fibre density and quantitative sensory testing revealed small fibre neuropathy with a highly impaired cold sensation. We speculate that the poikilothermia is either caused by a vascular lesion in the hypothalamus not visible on MRI or by small fibre neuropathy leading to disturbed body temperature perception and therefore impaired thermoregulation

The cognitive profile of type 1 Gaucher disease patients

BACKGROUND: The absence of neurological symptoms and signs is traditionally considered mandatory for a diagnosis of type 1 Gaucher disease (GD1), but in recent years many reports have emerged on neurological manifestations in GD1 patients. Nevertheless, it has been unclear whether cognitive deficits are part of the disease as well. METHODS: Cognitive function was assessed in a large cohort of GD1 patients with the use of the CDR system, a set of computerised cognitive tests. Testing was performed at baseline and every 6 months thereafter during a two-year study period. RESULTS: Our patient cohort (84 patients, median age 40 years, median time from diagnosis 15 years) showed mild deficits relative to healthy age-matched subjects on the composite scores: power of attention (Z-score (mean ± SD) -0.9 ± 1.37) and speed of memory (Z-score (mean ± SD) -1.39 ± 1.49). No decline in cognitive function was seen during the two-year period. Age correlated with the composite scores variability of attention and quality of working memory. Moreover, severely affected patients (Zimran severity score (SSI) ≥ 15) scored more poorly compared to mildly affected patients (SSI ≤ 5) on the composite measure power of attention, reflecting the ability to concentrate. CONCLUSIONS: GD1 patients exhibit mild deficits in power of attention and speed of memory, reflecting a decreased ability to focus attention and process information, together with a slowing in the speed of retrieval of items from memory. The clinical relevance of these findings is uncertain

Skewed X-inactivation is common in the general female population

X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes (SSR4, REPS2, and SEPT6), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants

Fabry disease: a rare cause of neuropathic pain

Fabry disease is characterized by burning or shooting pains in hands and feet, which have a severe impact on the quality of life of patients. It is therefore of importance that Fabry patients receive adequate diagnosis, counseling, treatment and follow up. This review describes neuropathic pain in classical Fabry disease with the aim to help clinicians to recognize Fabry patients among patients presenting with chronic extremity pain. The diagnostic dilemmas in patients with neuropathic pain and a non-classical disease course are discussed, together with the available diagnostic modalities, pain medication options and the effect of enzyme replacement therapy on small fiber neuropath

Development and clinical consequences of white matter lesions in Fabry disease: a systematic review

Background: Fabry disease (FD) is a rare lysosomal storage disorder that might result in, amongst other complications, early stroke and white matter lesions (WMLs). More insight in WMLs in FD could clarify the role of WMLs in the disease presentation and prognosis in FD. In this systematic review we assessed the prevalence, severity, location and course of WMLs in FD. We also systematically reviewed the evidence on the relation between WMLs, disease characteristics and clinical parameters. Methods: We searched Pubmed, EMBASE and CINAHL (inception to Feb 2018) and identified articles reporting on FD and WMLs assessed with MRI. Prevalence and severity were assessed for all patients combined and divided by sex. Results: Out of 904 studies a total of 46 studies were included in the analyses. WMLs were present in 46% of patients with FD (581 out of 1276 patients, corrected mean age: 38.8 years, range 11.8–79.3) and increased with age. A total of 16.4% of patients (31 out of 189 patients, corrected mean age: 41.1 years, range 35.8–43.3 years) showed substantial confluent WMLs. Men and women showed comparable prevalence and severity of WMLs. However, men were significantly younger at time of WML assessment. Patients with classical FD had a higher chance on WMLs compared to non-classical patients. Progression of WMLs was seen in 24.6% of patients (49 out of 199 patients) during 38.1 months follow-up. Progression was seen in both men and women, with and without enzyme replacement therapy, but at an earlier age in men. Stroke seemed to be related to WMLs, but cerebrovascular risk factors, cardiac and renal (dys)function did not. Pathology in the brain in FD seemed to extend beyond the WMLs into the normal appearing white matter. Conclusions: A significant group of FD patients has substantial WMLs and male patients develop WMLs earlier compared to female patients. WMLs could be used in clinical trials to evaluate possible treatment effects on the brain. Future studies should focus on longitudinal follow-up using modern imaging techniques, focusing on the clinical consequences of WMLs. In addition, ischemic and non-ischemic pathways resulting in WML development should be studied

Miglustat (Zavesca(R)) in type 1 Gaucher disease: 5-year results of a post-authorisation safety surveillance programme

PURPOSE: Miglustat (Zavesca(R)) is an orally-available substrate reduction therapy (SRT) for treatment of mild-to-moderate type 1 Gaucher disease (GD1) in adult patients unsuitable for enzyme replacement therapy (ERT). Miglustat has not been evaluated in children with GD1, and is not used during pregnancy and breast-feeding. A non-interventional, prospective, web-based safety surveillance programme was initiated at the time of the European launch of miglustat in 2003, and is ongoing. We report the first 5 years of collected data, focusing on neurological manifestations. METHODS: Data were collected on 122 GD1 patients between March 2003 and April 2008, representing 244 patient-years cumulative miglustat post-authorisation experience. The electronically-captured data collected from participating physicians includes patient demographics, prior and current therapies, baseline disease manifestations and concurrent conditions, disease severity, duration of miglustat exposure, and safety-relevant information. RESULTS: Mean (SD) age at baseline was 46.1 (16.5) years. At baseline, bone disease and neurological manifestations were reported in 55.6 and 28.6% of patients, respectively; the latter included peripheral neuropathy (7.2%) and a wide variety of neurological symptoms and signs. In addition, 23.2% had other health conditions relevant to neurological status. During the reporting period, new neurological manifestations were reported in 23 (18.9%) patients, principally tremor. Thirty-five (28.7%) patients discontinued treatment, predominantly for gastrointestinal (GI) disturbances (11.5%), two-thirds of which occurred during the first 6 months. CONCLUSION: The safety profile of miglustat in GD1 patients included in the safety surveillance programme is overall consistent with that reported in the registration and other clinical trials, and no new safety finding was identified. Copyright (c) 2009 John Wiley & Sons, Lt

The Mini Mental State Examination does not accurately screen for objective cognitive impairment in Fabry Disease

Fabry disease (FD) patients may suffer from objective cognitive impairment (OCI). This study assessed the accuracy of the Mini Mental State Examination (MMSE) to screen for OCI in FD patients. Presence or absence of OCI was established using a neuropsychological test battery. For different MMSE cutoffs sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and clinical utility index (CUI) to identify OCI were calculated. Eighty-one patients were included (mean age 44.5 ± 14.3, 35% men, 74% classical phenotype) of which 13 patients (16%) had OCI. The median MMSE score was 29 (range: 25-30). MMSE cutoffs ≤28 and ≤29 had the highest sensitivity and specificity, with higher specificity reached at cutoff ≤28 (sensitivity: .46, specificity: .73) and higher sensitivity at cutoff ≤29 (sensitivity: .92, specificity: .40). PPV was low for both cutoffs (PPV ≤28: .25, PPV ≤29: .23) resulting in a low positive CUI (case finding ability). The results of our study indicate that the MMSE does not accurately screen for OCI in FD, with poor sensitivity-specificity trade-off at all cutoffs. The low PPV shows that the majority of FD patients that score below the cutoffs do not suffer from OCI. Administering the MMSE as a screening test will lead to unnecessary referrals for neuropsychological testing, which is time consuming and burdensome. Screening tools designed to accurately detect mild (executive) impairment might prove more appropriate to screen for OCI in FD

Effects of Alternaria alternata f.sp. lycopersici Toxins at Different Levels of Tomato Plant Cell Development

Since the host-specific toxins of Alternaria alternata f. sp. lycopersici play an important role in pathogenesis, they potentially could be applied as selective agents in in vitro selection at the cellular level for disease resistance. Prerequisite for this is that sensitivity to the Alternaria alternata f.sp. lycopersici pathotoxins is manifest at the cellular level. To gain insight into cellular effects of AAL-toxins and into the mechanisms of plant insensitivity to AAL-toxins, effects of AAL-toxins on leaves, leaf discs, roots, calli, suspension cells, minicalli and protoplasts of susceptible and resistant tomato genotypes were studied. In leaves of susceptible genotypes, toxins cause severe necrosis, while in leaves of resistant genotypes necrosis was never observed. Inhibition effects of toxins were observed at all other levels in susceptible and resistant genotypes: toxins inhibited shoot induction on leaf discs, root growth and growth of calli, suspension cells and protoplasts. This indicates a cellular site for AAL-toxins. Differences in sensitivity to AAL-toxins between susceptible and resistant genotypes were observed in leaves and roots, but were not observed during shoot induction on leaf discs, in calli, suspension cells and protoplasts. However, differences in sensitivity to AAL-toxins in roots were at least 20 times less than in leaves. Therefore insensitivity seems related to a higher level of tomato plant differentiation and is most pronounced in leaves.

Small fiber neuropathy in Fabry disease

Previous studies have explicitly shown that small nerve fibers are affected in Fabry disease which is assumed to cause the severe neuropathic pain that patients may have from childhood on. Neuropathic pain and small fiber neuropathy characteristics have therefore been considered as appropriate study endpoints in studies on the efficacy of enzyme replacement therapy. However, the relationship between small fiber neuropathy characteristics and pain, as well as the course of small fiber neuropathy in Fabry disease is still uncertain. In this article a comprehensive overview of the existing literature on small nerve fiber function and structure and the relationship with pain, age and disease severity is presented supplemented with data from the Dutch Fabry cohort, with the aim to identify consensus as well as controversies and to propose a hypothesis on the evolution of neuropathy in Fabry disease. (C) 2012 Elsevier Inc. All rights reserve