Novel exon nucleotide deletion causes adrenoleukodystrophy in a Brazilian family.

Adrenoleukodystrophy is a neurodegenerative X-linked recessive disorder. It is characterized by abnormal function of peroxisomes, which leads to an accumulation of very long-chain fatty acids in plasma and tissues, especially in the cortex of adrenal glands and white matter of the central nervous system, causing demyelinating disease and adrenocortical insufficiency (Addison's disease). It is caused by a mutation in the ABCD1 gene (ATP-binding cassette, subfamily D, member 1), which encodes the protein adrenoleukodystrophy that is involved in the transport of fatty acids into the peroxisome for degradation. Variable expression has been recognized in families of patients who have this disease. A Brazilian family from Minas Gerais State, Brazil, was studied. The proband is an adult living in Minas Gerais State, Brazil; he had adrenomyeloneuropathy, adrenocortical insufficiency and a stable cerebral form. DNA was extracted from a blood sample and was sequenced to identify the mutation. The patient's exons were cloned for confirmation. A new mutation was found in exon 5 of the ABCD1 gene (c.1430delA), as well as a single-nucleotide polymorphism in exon 6. The mutation causes a frame shift, resulting in a truncated protein with almost total absence of the ATP binding domain.

Mutation in intron 5 of GTP cyclohydrolase 1 gene causes dopa-responsive dystonia (Segawa syndrome) in a Brazilian family.

Dopa-responsive dystonia (DRD), also known as Segawa syndrome or hereditary progressive dystonia with diurnal fluctuation, is clinically characterized by the occurrence of simultaneous or late Parkinsonism and by an excellent response to treatment with low doses of L-dopa. Diagnosis of DRD is essentially clinical. It is based on clinical history and the response to treatment with low doses of L-dopa. However, due to the low penetrance of the disease, asymptomatic carriers may exist. In these cases, mutational analysis of the GCH1 gene is an alternative to diagnose DRD. In the present study, we investigated a large DRD-carrier family in an attempt to identify the disease-causing mutation. The proband, a young woman diagnosed at the age of 13 years, is the daughter of a healthy non-consanguineous couple with history of several cases, on the maternal side of the family, of tip-toeing, disturbance of gait, Parkinsonism, rigidity and cramps in the lower limbs. Using single strand conformational polymorphism and DNA sequencing techniques to analyze DNA extracted from blood samples, we identified a mutation in the GCH1 gene, IVS5+3insT, which would preclude the formation of the active enzyme due to the formation of truncated peptides.