Neurodegenerative disease and iron storage in the brain

PURPOSE OF REVIEW: Iron is very important for normal regulation of various metabolic pathways. Neurons store iron in the form of ferrous ion or neuromelanin. In specific disorders the axonal transport of iron is impaired, leading to iron deposition which in the presence of reactive oxygen species results in neurodegeneration. RECENT FINDINGS: Recent developments in genetics, including the finding of mutations in the pantothenate kinase gene and ferritin light chain gene, have demonstrated a direct relationship between the presence of a mutation in the iron-regulatory pathways and iron deposition in the brain resulting in neurodegeneration. These two disorders now add to our understanding of the mechanism of disease due to dysfunction of iron-regulatory pathways. In addition to these disorders there may be several other mutations of iron-regulatory genes or related genes that are yet to be found. The animal models of disease have also added value to this area. SUMMARY: In this review we provide a summary of recent developments in the field of movement disorders with abnormalities in iron transport, and the current evidence in neurodegenerative disorders such as Parkinson's disease.     

Acute panmyelosis with myelofibrosis: clinical, immunophenotypic and cytogenetic study of twelve cases

The clinical, cytogenetic, and immunophenotypic features in 12 adult patients with acute panmyelosis with myelofibrosis (APMF; ICD-0-3: 9931/3; C42.1) are reported (median age: 57 years; f/m = 1.4). The white cell count (WBC) was normal in 3 patients; 9 had leucopenia. The median hemoglobin value was 64.5 g/l, and median platelet count 12 x 10(9)/l. Bone marrow biopsy showed a hypercellular marrow in 10/12 patients with a significant infiltration of pathological blasts (range: 30 - 60%). All the cases had marked reticulin fibrosis. Immunophenotyping of bone marrow blast cells showed the expression of early (CD34) and lineage-unspecified antigens (HLA-DR) in 6/7, and 7/7 patients, respectively. "Early" myeloid antigens (CD13, CD33) were seen in 6/7 and 4/6 patients respectively. Monocyte antigen (CD14) was expressed in 3/7 patients. Megakaryocyte antigen (CD61) and erythroid cell antigen (GpA) were each expressed in only 1 patient. Two patients had expression of CD34, HLA-DR and "early" myeloid antigens by their bone marrow blast cells and 1 of these also had a co-expression of the antigens from a differentiated monocytic cell proliferation (lysozyme+, CD68+). Nonspecific chromosomal aberrations were recorded in 8/10 patients. The median survival was 2 months. These findings suggest an immature myeloid phenotype of blast cells in APMF. In 6/9 patients a leukemic cell differentiation into monocytic, megakaryocytic or erythroid lineage was also demonstrated.     

Rates of nucleotide substitution,mutation at a locus,and the "beanbag" gene number in man

We estimated the number of different human genes by relating the patterns of spontaneous mutation at the population and individual level. A geometric distribution model of mutation was used in which the average rates of nucleotide replacement (P) and mutation at a locus (p), obtained by experiment, were used to determine the estimate of the physical size of the coding genome (n) in man. The probabilistic relation used, P = (1 −p) ⁿ⁻¹ p, integrates two different referential time scales of mutation, that of a nucleotide and year and that of a coding gene and generation. The estimates of n, for different values of P and p, are compatible with the experimentally determined genome sizes. The size of the coding portion of the genome appears to be evolutionarily constrained by an interplay between the rate of nucleotide replacement and the pattern of mutation at the level of the individual locus. The evolution of the size of the coding genome may be more dependent on the number of generations than on time. Received: October 26, 2001 / Accepted: January 16, 2002     

Transient neonatal diabetes mellitus in a child with paternal uniparental disomy of chromosome 6

We report a male infant with transient neonatal diabetes mellitus (TNDM; MIM 601410), macroglossia, hypertelorism, umbilical hernia, inguinoscrotal hernia and onychomycosis. Diabetes mellitus was diagnosed 10 days after birth and resolved after 6.5 months of treatment. Genetic investigation indicated the presence of paternal uniparental disomy of chromosome 6 (UPD 6). The finding of paternal UPD 6 allows prediction of a transient, rather than permanent NDM, and no increased recurrence risk of TNDM in subsequent pregnancies. Therefore, finding of NDM should be a strong indicator for genetic testing.     

Premonitory sensory phenomenon in Tourette's syndrome.

We administered a questionnaire designed to probe for premonitory sensations associated with motor tics to 50 patients with Tourette's syndrome (TS). Premonitory sensations were reported by 46 (92%) patients, and the most common sensation was an urge to move and an impulse to tic ("had to do it"). Intensification of premonitory sensations, if prevented from performing a motor tic, was reported also in 37 patients (74%), 36 patients (72%) reported relief of premonitory sensations after performing the tic, and 27 of 40 (68%) described a motor tic as a voluntary motor response to an involuntary sensation, rather than a completely involuntary movement. The "just right" sensation correlated with the presence of co-morbid obsessive-compulsive disorder. We conclude that premonitory sensations are an important aspect of motor tics and some patients perceive motor tics as a voluntary movement in response to an involuntary sensation.     

Choosing dopamine agonists in Parkinson's disease

Dopamine agonists (DAs) have been shown to be effective as monotherapy in early stages of Parkinson's disease (PD) and as an adjunctive treatment to levodopa in advanced PD. Since bromocriptine, an ergot compound, was introduced as the first commercially available DA more than 25 years ago, additional DAs have become available for clinical use. There is a remarkable paucity of data, however, that would guide clinicians in their decision process to select the most appropriate DAs. We discuss the theoretical basis for comparing the various DAs, and provide a concise analysis and summary of comparative trials of DAs in PD.     

Psychogenic hemifacial spasm

Facial spasms that distort facial expression are typically due to facial dystonia, tics, and hemifacial spasm (HFS). Psychogenic facial spasms, however, have not been well characterized. The authors sought to 1) determine prevalence of psychogenic facial spasm in patients referred for evaluation of HFS and 2) draw attention to clinical characteristics and potential diagnostic pitfalls. Among 210 consecutive patients referred for evaluation of HFS, 5 (2.4%) received diagnoses of psychogenic facial spasm. All patients were female; mean age was 34.6 years (range 26-45) and mean symptom duration 1.1 years (range 2 wk-2 yr). Onset was left-sided in 3 patients, and the lid was the initial site affected in 2 patients. This series of patients shows that facial spasms, although usually of neurovascular etiology, may be the initial or only manifestation of a psychogenic movement disorder, often associated with an underlying depression.     

Treating severe bruxism with botulinum toxin

BACKGROUND: Locally administered botulinum toxin, or BTX, is an effective treatment for various movement disorders. Its usefulness in treating bruxism, however, has not been systematically evaluated. SUBJECTS AND METHODS: The authors studied 18 subjects with severe bruxism and whose mean duration of symptoms was 14.8 +/- 10.0 years (range three-40 years). These subjects audibly ground their teeth and experienced tooth wear and difficulty speaking, swallowing or chewing. Medical or dental procedures had failed to alleviate their symptoms. The authors administered a total of 241 injections of BTX type A, or BTX A, in the subjects' masseter muscles during 123 treatment visits. The mean dose of the BTX A was 61.7 +/- 11.1 mouse units, or MU (range 25-100 MU), per side for the masseter muscles. RESULTS: The mean total duration of response was 19.1 +/- 17.0 weeks (range six-78 weeks), and the mean peak effect on a scale of 0 to 4, in which 4 is equal to total abolishment of grinding, was 3.4 +/- 0.9. Only one subject (5.6 percent) reported having experienced dysphagia with BTX A. CONCLUSION: The results of this study suggest that BTX administered by skilled practitioners is a safe and effective treatment for people with severe bruxism, particularly those with associated movement disorders. It should be considered only for those patients refractory to conventional therapy. Future placebo-controlled studies may be useful in further evaluating the potential of BTX in the treatment of bruxism.     

Primary MALT lymphoma of the kidney

A primary mucosa associated lymphoid tissue tumor (MALT) of the kidney in a 50-year-old man who suffered from on therapy resistant high blood pressure over 15 years period is presented. A mass in the right kidney (6x5x3 cm) during routine check up was discovered on ultrasonography and confirmed on CT scan and NMR. The patient was submitted to nephrectomy. A mass involving kidney, pyelon and upper part of the ureter was found. Histology showed low grade non-Hodgkin B-cell lymphoma of MALT type. The neoplastic cells were positive for monoclonal antibodies CD20, CD79alpha, surface and cytoplasmic and IgM immunoglobulins and showed light chain restriction (kappa+). After histology was available, a careful staging was performed. The disease was not found anywhere else. It was concluded that the patient belonged to the stage IE of primary kidney MALT lymphoma. Gastroscopy showed signs of chronic superficial gastritis. Urease test was positive and IgG antibodies against Helicobacter pylori in titer 421 were found as well. Except for Helicobacter pylori no additional therapy was given.