Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24.

Founder effect and linkage disequilibrium have been successfully exploited to map single gene disorders, and the study of isolated populations is emerging as a major approach to the investigation of genetically complex diseases. In the search for genetic isolates ranging from Pacific islands to Middle East deserts, the 10 million Gypsies resident in Europe have largely escaped the attention of geneticists. Because of their geographical ubiquity, lack of written history and the presumed social and cultural nature of their isolation, Gypsies are construed as not meeting the criteria for a well defined founder population. Gypsy society has a complex structure with subdivisions and stratifications that are incomprehensible to the surrounding populations. Marginalization by the health care systems in most countries results in a lack of information on causes of morbidity and mortality and little is known about hereditary disorders or the population genetic characteristics of Gypsies. This study is the first example of mapping a disease gene in endogamous Gypsy groups. Using lod score analysis and linkage disequilibrium, we have located a novel demyelinating neuropathy to a narrow interval on chromosome 8q24. We show that the disease, occurring in Gypsy groups of different identity and history of migrations, is caused by a single mutation whose origin predates the divergence of these groups.

The importance of serum levels of selected biological parameters in the diagnosis, staging and prognosis of multiple myeloma.

The study aimed at evaluating the relation of 7 parameters associated with the internal biological properties of myeloma cells and the bone marrow microenvironment to multiple myeloma (MM) stages, distinguishing its initial/asymptomatic phase from monoclonal gammopathy of undetermined significance (MGUS) and assessing their relation to myeloma prognosis. In the studied group comprising 286 individuals (89 MGUS and 179 MM patients), statistically significant differences (Mann-Whitney test) between MGUS and MM at the time of diagnosis were found in the serum levels of HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), ICTP (intercellular - carboxy-terminal telopeptide of type I collagen), PINP (procollagen type I N-terminal propeptide), OPG (osteoprotegerin) and syndecan-1/CD138, but not in Fas. Multivariate analysis (logistic regression) revealed an unsatisfactory potential of all the 7 studied indicators to discriminate between MGUS and MM. A deeper analysis showed statistically significant differences between MGUS and the initial/asymptomatic phase of MM (stage 1 according to the International Staging System) only in the cases of syndecan-1 (p=0.001) and Fas (p=0.008). The assessment of initial values of HGF, VEGF, ICTP, PINP, OPG, syndecan-1 and Fas showed a statistically significant relation (log rank test) to the overall survival (OS) in a group of 132 patients treated with conventional chemotherapy only in the cases of syndecan-1 (p=0.0002) and Fas (p=0.018), but in none of the investigated parameters in a group of 74 patients treated with HDT/ASCT (high-dose therapy/autologous stem cell transplantation). The analysis showed that, despite significant differences in serum levels of 6 of the 7 studied parameters found between MGUS and MM, none of the markers may be included in the spectrum of indicators used to distinguish the two conditions. Despite the positive relation, especially of syndecan-1 and, to a lesser extent, of Fas to the OS in patients treated with conventional chemotherapy, these prognostic factors are not applicable to HDT/ASCT.

Diagnosis of diabetic neuropathy using simple somatic and a new autonomic (neuropad) tests in the clinical practice.

AIM: The global spread of diabetes (DM) and the importance of early therapeutic intervention determine the need of simple, inexpensive and sensitive methods for diagnosis of diabetic complications in the general practice. The aim of this study was to assess a new instrument - the plaster Neuropad in diagnosing the sudomotor diabetic dysfunction and to investigate the correlates of Neuropad data with diabetic complications. PATIENTS AND METHODS: In this cross-sectional study participated 264 inpatients (M/F=126/138) with DM type 1/2 (61/203), mean age 55.4+/-12.0 and DM duration of 9.3+/-7.1 years. According to hospital records were registered: anthropometric data; fasting plasma glucose and HbA1c; presence of micro-(retino-, nephro-, neuropathy), and macrovascular (arterial hypertension, coronary artery disease and/or brain vascular disease) complications, and neuropathic symptoms were evaluated. For investigation of somatic DN a modified Neuropathy Disability Score (NDS) and for sudomotor autonomic DN - Neuropad were used. RESULTS: Neuropad showed the highest between-feet correlation of 0.91 compared to all other individual tests and the NDS. Neuropad was able to separate patients in groups with different general risk profile, including age, duration of DM, presence of coronary and/or brain vascular disease, nephropathy, and retinopathy. Moreover, Neuropad differentiated patient groups by their stage of DN, evaluated by symptoms, diagnosis, the individual somatic tests and with the highest significance - by NDS. Most sensitive for detecting DN was NDS > or = 3, followed by Achilles reflexes, vibration perception (128 Hz tuning fork) and Neuropad. A borderline or abnormal result of Neuropad showed sensitivity=76.3/79.3, specificity=56.1/42.9, positive=86.3/62.8 and negative=39.5/63.0 predictive values, and diagnostic accuracy 72.2/62.9%, compared to the indices for presence of somatic DN (NDS > or = 3)/foot at risk (NDS > or = 6) respectively. CONCLUSIONS: Screening for DN must cover somatic and autonomic disturbances. Neuropad is a new sensitive and appropriate for everyday clinical use test for detecting sudomotor DN and identification of patients at higher risk for chronic diabetes complications.

Homocystein and carotid atherosclerosis in chronic renal failure.

BACKGROUND: Since total homocysteine (Hcy) is markedly elevated in patients with chronic renal failure (CRF), it has been presented as potential factor contributing to the high risk of cardiovascular disease (CVD) in CRF. The aim of the study was to examine the significance of elevated Hcy and other cardiovascular risk factors for carotid atherosclerosis in patients with CRF. MATERIAL AND METHODS: Fifty six patients 16-M, 40-F, average age 58+/-14.55, creatinine clearance 39.19+/-10.11 ml/min were examined. In addition, 20 control healthy subjects were examined. The association of Hcy levels and classic risk factors for atherosclerosis with common carotid intima-media thickness (IMT) was examined. B-mode ultrasound measurement of carotid IMT was performed in 56 hypertensive pts with CRF (glomerular filtration rate>20 ml/min and <90 ml/min), 44 hypertensive pts with normal renal function and 20 healthy volunteers. The mean duration of hypertension was 145.12 years. RESULTS: IMT in all examined hypertensive pts was increased above normal clinical value and significantly higher then in healthy controls (0.75+/-0.006/0.60+/-0.1, p<0.001). The carotid IMT was similar between hypertensive pts with CRF and hypertensive pts with normal renal function (0.74+/-0.1/0.76 +/-0.1, p>0.05). Significant predictors for IMT were age (r=0.358, p<0.04), duration of hypertension (r=0.395, p=0.023), diabetes duration (r=0.343, p<0.02), as well as duration of CRF (r=0.324, p<0.006). There was a negative correlation between IMT and glomerular filtration rate assessed by creatinine clearance (r=-0.303, p<0.003). Renal function, described by creatinine clearance was the strongest determinant for Hcy levels (r=-0.332, p<0.008). Increased IMT was estimated in pts with CRF compared to healthy controls (0.74+/-0.10 vs 0.59+/-0.10, p<0.001). We found association between Hcy and carotid IMT ( r=0.344, p<0.015). No consistent association was found between IMT and other specific for CRF cardiovascular risk factors. CONCLUSION: The study suggests that patients with mild renal failure have increased IMT of the common carotid artery and that elevated plasma Hcy level in CRF is associated with carotid intima- media thickening.

Hereditary motor and sensory neuropathy--Lom, a novel demyelinating neuropathy associated with deafness in gypsies. Clinical, electrophysiological and nerve biopsy findings.

A previously unrecognized neuropathy was identified in Bulgarian gypsies, and was designated hereditary motor and sensory neuropathy-Lom (HMSNL) after the town where the initial cases were found. It was subsequently identified in other gypsy communities. The disorder, which is of autosomal recessive inheritance, was mapped to chromosome 8q24. It begins consistently in the first decade of life with gait disorder followed by upper limb weakness in the second decade and, in most subjects, by deafness which is most often first noticed in the third decade. Sensory loss affecting all modalities is present, both this and the motor involvement predominating distally in the limbs. Skeletal deformity, particularly foot deformity, is frequent. Severely reduced motor nerve conduction velocity indicates a demyelinating basis, which was confirmed by nerve biopsy. The three younger patients biopsied showed a hypertrophic 'onion bulb' neuropathy. The hypertrophic changes were not evident in the oldest individual biopsied and it is likely that they had regressed secondarily to axon loss. In the eight cases in which brainstem auditory evoked potentials could be recorded, the results suggested demyelination in the eighth cranial nerve and also abnormal conduction in the central auditory pathways in the brainstem. As no myelin genes are known to be located at chromosome 8q24, the disorder may involve a gene for a novel myelin protein or be due to an abnormality of axon-Schwann cell signalling.

Congenital cataracts facial dysmorphism neuropathy syndrome, a novel complex genetic disease in Balkan Gypsies: clinical and electrophysiological observations.

During a study of hereditary motor and sensory neuropathy-Lom in Bulgaria, a previously unrecognized neurological disorder was encountered, mainly in Wallachian Gypsies, who represent a relatively recent genetic isolate. The disorder has been termed the congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome to emphasize its salient features. Fifty individuals from 19 extended pedigrees were identified and examined clinically and electrophysiologically. At least 1 patient from each family was admitted to the hospital in Sofia for full investigation. Pedigree analysis indicates autosomal recessive inheritance. The disorder is recognized in infancy by the presence of congenital cataracts and microcorneas. A predominantly motor neuropathy beginning in the lower limbs and later affecting the upper limbs develops during childhood and leads to severe disability by the third decade. Associated neurological features are a moderate nonprogressive cognitive deficit in most affected individuals together with pyramidal signs and mild chorea in some. Accompanying nonneurological features include short stature, characteristic facial dysmorphism, and hypogonadotrophic hypogonadism. Nerve conduction studies suggest a hypomyelinating/demyelinating neuropathy, confirmed by nerve biopsy. The CCFDN syndrome is thus a pleomorphic autosomal recessive disorder displaying a combination of neurological and nonneurological features.