Absence of genetic linkage of Charcot-Marie-Tooth disease (HMSN Ia) with chromosome 1 gene markers.

We previously reported a large Charcot-Marie-Tooth family not linked to the Duffy blood group marker, supporting the existence of genetic heterogeneity in this neuropathy. In order to investigate the possibility of another disease locus on chromosome 1, we analyzed this family further, using DNA polymorphisms of 6 genes. Absence of linkage makes a second disease locus on chromosome 1 unlikely.

Absence of linkage with the Duffy blood group in a family with Charcot-Marie-Tooth neuropathy.

We report a large Belgian family with Charcot-Marie-Tooth disease (CMT) or hereditary motor and sensory neuropathy type I (HMSN-I). The pedigree consists of 5 generations with 350 family members comprising 42 patients. The disease is transmitted according to an autosomal dominant inheritance pattern. Several HMSN-I families have been reported to be closely linked to the Duffy blood group marker on chromosome 1. These families were designated HMSN-Ib families, opposed to the HMSN-Ia families which do not show evidence for such a linkage. Therefore we examined our family for the Duffy linkage relationship. We found no evidence for a strong linkage of the disease to the Duffy blood group locus, indicating that this family is of genetic subtype Ia.

Cadmium: a possible etiological factor in peripheral polyneuropathy.

Uncovering the exact cause of polyneuropathies seems to be impossible in up to 24% of the cases. Experimental studies have shown that cadmium (Cd), which is a well-known occupational and environmental hazard, can be a potent neurotoxicant for the peripheral nervous system. Moreover, Cd has a half-life of more than 15 years in humans. We hypothesize that older workers may be more susceptible to an increased Cd body burden, and may develop a peripheral polyneuropathy (PNP) over time. A blinded epidemiological survey was performed in 13 retired, long-term Cd-exposed workers and 19 age-matched controls. Historical Cd biomonitoring data were available over the last two decades. A neurological clinical examination, nerve conduction studies, and needle EMG were performed, and a standardized questionnaire was given to evaluate polyneuropathy complaints. If two of the following four criteria, i.e. complaints of polyneuropathy, neurophysiological changes compatible with polyneuropathy, distal symmetrical areflexia, or distal symmetrical anesthesia for vibration sense, temperature or blunt-sharp discrimination were present, the diagnosis of PNP was made. Two (11%) of the control and seven (54%) of the retired Cd workers met the PNP criteria OR: 9.92 (95%CI 1.60-61.6), Fisher exact test p=0.015. The existence of a polyneuropathy was related to the level of the Cd body burden as reflected by urinary Cd multiple logistic regression p=0.016, OR=1.26, (95%CI, 1.04-1.51), but not to blood lead (p=0.352). Our findings favour the hypothesis of a promoting role of increased cadmium body burden in the development of PNP at older age.

Adipose tissue cellularity in patients with amyotrophic lateral sclerosis.

The subcutaneous mean fat-cell volumes as measured in 20 patients suffering from amyotrophic lateral sclerosis (ALS) were definitely larger than those measured in a control group. In contrast with the control subjects, the mean fat-cell volume in patients with ALS appeared to be independent of body weight. The noted disturbances in carbohydrate-insulin metabolism in patients with ALS and the increase in serum triglycerides as observed in some patients may be related to the enlarged fat cells. The possibility that the enlargement of the fat-cells may, at least partially, have a neurogenic basis cannot be ignored. The hypothesis is put forward that in patients with ALS there is not only a lesion of the anterior horn, but also an involvement of sympathic structures responsible for the innervation of adipose tissue vessels. This involvement may lead to an inhibition of the lipolysis, and consequently to an enlargemnt of the fat cell. Interaction between the interference with metabolic and neurogenic factors may be at play.

[Familial amytrophic lateral sclerosis. A study of a family suffering from this disease for three generations]. / Sclérose latérale amyotrophique familiale. Etude d'une famille atteinte sur trois générations

The authors describe nine cases of amytrophic lateral sclerosis running through the same family for three successive generations. The transmission is autosomal dominant with complete penetrance. The clinical picture comprises specific characteristics, amongst which the age of onset and the absence of Achilles reflexes. The course of the disease is fatal before long.

Adult ceroid-lipofuscinosis: diagnostic value of biopsies and of neurophysiological investigations.

In a sibship of ten, three brothers presented with an adult form of ceroid-lipofuscinosis. The diagnosis was confirmed by necropsy of the first patient and was made by electron microscopy of eccrine sweat glands and of skeletal muscles in the two others. Somatosensory evoked potentials were characterised by biphasic, nearly monophasic, very high voltage complexes totally unlike those found in normal controls. Similar sensory evoked potentials were however recorded in other types of ceroid-lipofuscinosis. While electron microscopy of easily available tissues gives fairly specific results, sensory evoked potentials can bring supportive diagnostic evidence in adult ceroid-lipofuscinosis.

Neurobehavioural effects of occupational exposure to cadmium: a cross sectional epidemiological study.

BACKGROUND: A patient with unexplained minor behavioural changes associated with an axonal sensorimotor polyneuropathy had a history of chronic occupational exposure to cadmium (Cd). Although animal studies have shown that Cd is a potent neurotoxicant, little is known about its toxicity for the human central nervous system. The aim of this study was to investigate the toxic potential of chronic occupational exposure to Cd on neurobehavioural functions. METHODS: A cross sectional epidemiological study was conducted ina group of Cd workers and an age matched control group. Eighty nine adult men (42 exposed to Cd and 47 control workers) were given a blinded standardised examination that consisted of computer assisted neurobehavioural tests (neurobehavioural examination system), a validated questionnaire to assess neurotoxic complaints (neurotoxicity symptom checklist--60, NSC-60), and a standardised self administered questionnaire to detect complaints consistent with peripheral neuropathy and dysfunction of the autonomic nervous system. Historical and current data on biomonitoring of exposure to Cd, either the highest value of Cd in urine (CdU in microgram Cd/g creatinine) of each Cd worker during work (CdUmax) or the current value (CdUcurrent) of each control, were available as well as data on microproteinuria. RESULTS: Cd workers (CdUmax: mean (range), 12.6 (0.4-38.4)) performed worse than the controls (CdUcurrent: mean (range), 0.7 (0.1-2.0)) on visuomotor tasks, symbol digit substitution (p = 0.008), and simple reaction time to direction (p = 0.058) or location (p = 0.042) of a stimulus. In multiple linear regression analysis, symbol digit substitution, simple direction reaction time test, and simple location reaction time test were significantly related to CdUmax, (beta = 0.35 (p < 0.001), beta = 0.25 (p = 0.012), and beta = 0.23 (p = 0.021) respectively). More complaints consistent with peripheral neuropathy (p = 0.004), complaints about equilibrium (p = 0.015), and complaints about concentration ability (p = 0.053) were found in the group exposed to Cd than in the control group, and these variables correlated positively with CdUmax (peripheral neuropathy: beta = 0.38, p < 0.001; equilibrium: beta = 0.22, p = 0.057; concentration ability: beta = 0.27, p = 0.020). CONCLUSION: Slowing of visuomotor functioning on neurobehavioural testing and increase in complaints consistent with peripheral neuropathy, complaints about equilibrium, and complaints about concentration ability were dose dependently associated with CdU. Age, exposure to other neurotoxicants, or status of renal function could not explain these findings. The present study also indicates that an excess of complaints may be detected in Cd workers before signs of microproteinuria induced by Cd occur.

Localization of the mutation in an extended family with Charcot-Marie-Tooth neuropathy (HMSN I).

Hereditary motor and sensory neuropathy type I (HMSN I) or Charcot-Marie-Tooth (CMT) disease is an autosomal dominant peripheral neuropathy. In some CMT families linkage has been reported with either the Duffy blood group or the APOA2 gene, both located on chromosome 1q. More recently, linkage has been found in six CMT families with two chromosome 17p markers. We extensively analyzed a multi-generation Charcot-Marie-Tooth family by using molecular genetic techniques in order to localize the CMT gene defect. First, we constructed a continuous linkage group of 11 chromosome 1 markers and definitely excluded chromosome 1 as the site of mutation. Second, we analyzed the family for linkage with chromosome 17. The two-point lod scores obtained with D17S58 and D17S71 proved that this Charcot-Marie-Tooth family is linked to chromosome 17. Moreover, multipoint linkage results indicated that the mutation is most likely located on the chromosome 17p arm, distal of D17S71.

Exclusion analysis of Charcot-Marie-Tooth neuropathy (CMT1) with chromosome 1p markers.

We previously described a large five-generation family with autosomal dominant inheritance of hereditary motor and sensory neuropathy type I, or Charcot-Marie-Tooth disease (CMT1). The genetic defect in this family was not linked to the Duffy blood group. We investigated the possibility of a disease locus on the short arm of chromosome 1 using 12 anonymous DNA markers. Two markers, D1S2 and D1S22, showed positive linkage, suggesting the existence of a CMT1 locus on 1p. D1S2 and D1S22 are clustered in the 1p31----p22 region. However, multipoint linkage analysis, including additional DNA markers from this chromosome region, excluded a possible CMT1 locus in this part of chromosome 1.

Assignment of the Charcot-Marie-Tooth neuropathy type 1 (CMT 1a) gene to 17p11.2-p12.

Charcot-Marie-Tooth disease type 1a (CMT 1a) is an autosomal dominant peripheral neuropathy linked to the DNA markers D17S58 and D17S71, located in the pericentromeric region of the chromosome 17p arm. We analyzed an extended 5-generation Belgian family, multiply affected with CMT 1a, for linkage with eight chromosome 17 markers. The results indicated that the CMT 1a mutation is localized in the chromosomal region 17p11.2-p12 between the marker D17S71 and the gene for myosin heavy polypeptide 2 of adult skeletal muscle.