Compound heterozygosity in the GALC gene in a late onset Iranian patient with spastic paraparesis,peripheral neuropathy and leukoencephalopathy

Neurological Sciences -     

GM2 gangliosidosis variant B1

Variant B1 is a rare type of GM2 gangliosidosis. Clinically, it shows a wide spectrum of forms ranging from infantile to juvenile. We report the first magnetic resonance imaging (MRI) findings from three patients affected by GM2 gangliosidosis variant B1, two presenting with the infantile form and one with the juvenile form. The MRI appearances of the two patients with the infantile form disease are congruent with those reported for the early-onset type of both Tay-Sachs and Sandhoff diseases, and are characterized by early involvement of the basal ganglia and thalamus with cortical atrophy appearing later. In contrast, the patient with the juvenile form of variant B1 showed progressive cortical and white-matter atrophy of the supratentorial structures and, to a lesser extent, the infratentorial structures. No basal ganglia or thalamic anomalies were observed. Because in the adult forms of both Tay-Sachs and Sandhoff diseases a progressive cerebellar atrophy represents the only abnormality detectable, it appears that an MRI pattern peculiar to GM2 gangliosidosis can be defined. This pattern ranges from the basal ganglia injury associated with the early and severe demyelination process noted in the infantile form of the disease, to cerebellar atrophy with no supratentorial anomalies in the adult form. An “intermediate” MRI picture, with cortical atrophy and mild cerebellar atrophy, but without basal ganglia impairment, can be observed in the juvenile form. In addition, our investigations suggest that MRI abnormalities in GM2 gangliosidosis correlate with the clinical form of the disease rather than with the biochemical variant of the enzymatic defect. Received: 9 January 2002, Received in revised form: 26 June 2002, Accepted: 8 July 2002 Correspondence to Paolo Balestri, M. D.     

Free sialic acid storage disease

Increased amounts of free sialic acid were found in cultured fibroblasts and urine of a 4-year-7-month-old Italian boy with mental retardation, hypotonia, failure to thrive, coarse facial features, convergent strabismus, pale skin and fair hair. Ultramicroscopic examination of conjunctival and skin tissues showed a number of membrane-bound vacuoles containing low-density granular material in the cytoplasm of the fibroblasts. The clinical, biochemical and ultrastructural findings are similar to those described in Salla disease. Neuraminidase activity is normal. The molecular basis of the sialic acid storage disease is not known. Evidence for defective transport of sialic acid across the lysosomal membrane has been demonstrated in the patient's fibroblasts. It is possible that this might represent the metabolic abnormality.     

Chitotriosidase activity in the serum of patients with sarcoidosis and pulmonary tuberculosis

BACKGROUND: Human chitotriosidase is a chitinase selectively expressed by activated macrophages. An increase in chitotriosidase activity was previously described by us in the serum and bronchoalveolar lavage of sarcoidosis patients. OBJECTIVE: The aim of the present study was to analyze serum chitotriosidase activity in a larger number of sarcoidosis patients to verify the reported increase with respect to controls and to compare serum chitotriosidase levels in patients with sarcoidosis and tuberculosis, two granulomatous disorders of different etiology. METHODS: Chitotriosidase activity was measured in the serum of 96 sarcoidosis patients, 15 pulmonary tuberculosis patients and 30 healthy controls. RESULTS: We found significantly higher serum chitotriosidase activity in sarcoidosis patients than controls (p < 0.01) and in sarcoidosis patients than tuberculosis patients (p < 0.01), confirming a striking elevation of chitotriosidase activity (>10 times greater than normal) in pulmonary sarcoidosis patients. This is the first time that chitotriosidase activity has been analyzed in the serum of patients with pulmonary tuberculosis; it was found to be significantly lower than in sarcoidosis patients and not significantly greater than in controls. CONCLUSION: Although the mechanisms leading to the increase in chitotriosidase activity in sarcoidosis are still unknown, this enzyme may be specifically involved in the pathogenesis of the disease. Further studies with a greater number of patients are needed to confirm these results and to determine whether chitotriosidase could be a marker with diagnostic or prognostic value in sarcoidosis.     

Global developmental delay, osteopenia and ectodermal defect: a new syndrome

Global developmental delay is a serious social problem. It is often unrecognized and the phenotypes are inadequately studied. To investigate the phenotypes of children with aspecific central nervous system (CNS) impairment (poor speech, maladaptive behavioral symptoms such as temper tantrums, aggressiveness, poor concentration and attention, impulsiveness, and mental retardation). SETTING: Tertiary care hospital. PATIENTS: Three children (two male siblings, and one unrelated girl). METHODS: We used the results from clinical neurological evaluations; imaging and electrodiagnostic studies; metabolic and genetic tests; skin biopsies and bone mineral densitometry. All three children suffered from (A) global developmental delay, (B) osteopenia, and (C) identical skin defects. The skin ultrastructural abnormalities were abnormal keratin differentiation, consisting of hyperkeratosis and granular layer thickening; sweat gland abnormalities, consisting of focal, cytoplasmic clear changes in eccrine secretory cells; and melanocyte abnormalities, with both morphological changes (reduced number and size without evident dendritic processes), and functional changes (defects in the migration of melanosomes in the keratinocytes). These patients present a previously unrecognized syndrome. We retain useful to report this new association, to be recognized, in the next future, as a specific key-sign of a well-defined genetic defect.     

A second MNGIE patient without typical mitochondrial skeletal muscle involvement

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease caused by mutations in the gene encoding thymidine phosphorylase (TYMP). Clinically, MNGIE is characterized by gastrointestinal dysmotility, cachexia, ptosis, ophthalmoparesis, peripheral neuropathy and leukoencephalopathy. Most MNGIE patients have signs of mitochondrial dysfunction in skeletal muscle at morphological and enzyme level, as well as mitochondrial DNA depletion, multiple deletions and point mutations. A case without mitochondrial skeletal muscle involvement and with a TYMP splice-acceptor site mutation (c. 215–1 G>C) has been reported. Here, we describe an Italian patient with the same mutation and without mitochondrial skeletal muscle involvement, suggesting a possible genotype–phenotype correlation.     

Biochemical diagnosis of Canavan disease

Canavan disease (CD) is a rare autosomal recessive disorder characterized by macrocephaly and progressive leukodystrophy. Up to now biopsy or necropsy were required to define the diagnosis. Recently the disease has been related to N-acetylaspartic aciduria and deficiency of aspartoacylase, an enzyme possibly involved in the myelin synthesis. These biochemical findings have provided a diagnostic marker for the disease. We report a new case of infantile CD in which the demonstration of N-acetylaspartic aciduria and a marked deficiency of aspartoacylase activity confirmed the diagnosis.     

Pathogenic mechanism, prophylaxis, and therapy of symptomatic acidosis induced by acetazolamide.

BACKGROUND: Acetazolamide, a noncompetitive carbonic anhydrase inhibitor, can produce symptomatic acidosis and bone marrow suppression by a mechanism that is still unknown. This presentation occurs in the elderly, patients with renal or liver failure, people with diabetes, and newborns. The objective of this study was to understand the pathogenic mechanism of these adverse effects and to propose a possible prophylaxis and therapy. METHODS: Four human clinical cases were studied, and one animal experiment was performed. Four preterm newborns with posthemorrhagic ventricular dilation developed severe metabolic acidosis after treatment with acetazolamide. The acidosis suddenly disappeared after a packed red blood cell transfusion. Metabolic studies were performed in one patient and in newborn guinea pigs treated with 200 mg/kg acetazolamide. RESULTS: Acetazolamide can produce severe lactic acidosis with an increased lactate-to-pyruvate ratio, ketosis with a low beta-hydroxybutyrate-to-acetoacetate ratio, and a urinary organic acid profile typical of pyruvate carboxylase deficiency. The acquired enzymatic injury resulting from the inhibition of mitochondrial carbonic anhydrase V that provides bicarbonate to pyruvate carboxylase can produce tricarboxylic acid cycle damage. We demonstrate that the dramatic disappearance of metabolic acidosis and normalizing metabolism after blood transfusion were due to the citrate contained in the packed red blood cell bag. This hypothesis was confirmed by animal experimentation. We argue that the metabolic disorder and bone marrow suppression may be related. CONCLUSION: We demonstrate how acetazolamide can lead to symptomatic metabolic acidosis and probably to bone marrow suppression. We suggest citrate as a possible prophylaxis and treatment for these adverse reactions.