The phenotype of 16 members of a family affected by a late-onset, dominant, progressive, motor and autonomic disorder is described. The VAPB (Pro56Ser) mutation was detected in Brazilian families with different phenotypes of motor neuron disorders. In this family, proximal and axial muscle weakness and atrophy, associated with abdominal protrusion, defined the motor phenotype. Death occurred in 10-15 years due to respiratory insufficiency. Tone and tendon reflexes were decreased and a distal tremor was common. Sensation was preserved. Autonomic abnormalities were also present, including choking, chronic intestinal constipation, sexual dysfunction, and sudomotor abnormalities, and on nerve morphology there was involvement of unmyelinated fibers. Electromyography disclosed ongoing denervation and reinnervation. Isolated dysfunction of motor and autonomic neurons is unusual among the spinal muscular atrophies. On this basis, this condition seems to represent a new category of disease.

Pompe disease (glycogen storage disease type II or acid maltase deficiency) is an inherited autosomal recessive deficiency of acid alpha-glucosidase (GAA), with predominant manifestations of skeletal muscle weakness. A broad range of studies have been published focusing on Pompe patients from different countries, but none from Brazil. We investigated 41 patients with either infantile-onset (21 cases) or late-onset (20 cases) disease by muscle pathology, enzyme activity and GAA gene mutation screening. Molecular analyses identified 71 mutant alleles from the probands, nine of which are novel (five missense mutations c.136T> G, c.650C > T, c.1456G > C, c.1834C > T, and c.1905C > A, a splice-site mutation c.1195-2A > G, two deletions c.18_25del and c.2185delC, and one nonsense mutation c.643G > T). Interestingly, the c.1905C > A variant was detected in four unrelated patients and may represent a common Brazilian Pompe mutation. The c.2560C > T severe mutation was frequent in our population suggesting a high prevalence in Brazil. Also, eight out of the 21 infantile-onset patients have two truncating mutations predicted to abrogate protein expression. Of the ten late-onset patients who do not carry the common late-onset intronic mutation c.-32-13T > G, five (from three separate families) carry the recently described intronic mutation, c.-32-3C > A, and one sibpair carries the novel missense mutation c.1781G > C in combination with known severe mutation c.1941C > G. The association of these variants (c.1781G > C and c.-32-3C > A) with late-onset disease suggests that they allow for some residual activity in these patients. Our findings help to characterize Pompe disease in Brazil and support the need for additional studies to define the wide clinical and pathological spectrum observed in this disease.

The objective of the present study was to investigate whether creatine (Cr) could attenuate the deleterious effects of high doses of dexamethasone (Dexa) on body mass, exercise performance, and respiratory variables of rodents. Forty-four Wistar rats performed incremental maximal exercise tests. They were then assigned to four groups: G1: subcutaneous (s.c.) and intraperitoneal (i.p.) saline; G2: s.c. saline and i.p. Cr (250 mg x kg(-1) x day(-1)); G3: s.c. Dexa (7.5 mg x kg(-1) x day(-1)) and i.p. saline; G4: s.c. Dexa and i.p. Cr. New exercise tests and analysis of the respiratory pattern under resting conditions and after stimulation with doxapram (2 mg/kg i.p.) were performed after 18 days. Post- minus pretreatment differences were compared between groups. G3 and G4 showed a significant impairment in body mass gain compared with G1 and G2 (P < 0.05) (G1: 65.3 +/- 26.1, G2: 93.1 +/- 27.4, G3: -18.4 +/- 20.1, G4: 9.8 +/- 23.1 kg x 10(-3)). Similar results were observed for maximal oxygen consumption (G1: 9.5 +/- 8.5, G2: 25.8 +/- 14.5, G3: -25.5 +/- 6.0, G4: -4.8 +/- 9.5 ml x kg(-1) x min(-1)) and test duration (G1: 43.0 +/- 45.0, G2: 72.0 +/- 59.5, G3: -165.0 +/- 60.6, G4: -48.0 +/- 48.5 s). Simultaneous use of Cr significantly attenuated the Dexa-induced impairment of the last two variables. Cr attenuated Dexa-induced gastrocnemius and diaphragm muscle weight losses and the atrophy of gastrocnemius type IIb fibers. Cr supplementation had only small effects on Dexa-induced respiratory changes. These results suggest that Cr may play a role in the prophylaxis or treatment of steroid-induced myopathy.

No abstract

Compound forms of Charcot-Marie-Tooth (CMT) disease have been recently associated with unusually severe neuropathies, an observation that prompted the proposition that the additive effects of two mutations should be searched in patients whose clinical severity falls outside the common CMT phenotypes. In this report, we present a father and a daughter with a very mild and unusual disease that segregates with two mutations in PMP22 gene, the 17p11.2-p12 duplication and a Ser72Leu point mutation. We propose that the deleterious effects of each mutation are partially compensated by the functional effect of the other.