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Neurogenetics

Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disease affecting 1/20000 males either as cerebral ALD in childhood or as adreno-myeloneuropathy (AMN) in adulthood. Recently, a candidate gene for ALD was identified by positional cloning.
A 36-year-old male patient presented with AMN, biochemical studies showed elevated plasma concentration of saturated very-long-chain fatty acids (VLCFA). Three women in his family had increased plasma concentration of VLCFA, suggesting carrier status of ALD. A single nucleotide substitution in exon six within the ALD gene (C1930T) was detected by mutational screening of the patient's DNA predicting the replacement of serine to phenylalanine at position 515 (Ser515Phe) in the deduced amino acid sequence of the ALD
protein sequence. The Ser515Phe mutation could additionally be detected in a heterozygous manner in the 3 female relatives of the patient, who also showed elevated VLCFA-levels, but not in the unaffected father.
A 42-year-old male patient had clinical and biochemical evidence of AMN. Molecular genetic analysis in the patient detected a 9-base pair deletion in exon 1 of the ALD gene (967del9). This mutation predicts the replacement of aspartic acid 194 by valine (D194) and deletion of the three following amino acids in the deduced ALD protein.
In the patient's family detection of this mutation allowed identification of a heterozygous carrier of ALD/AMN and exclusion of the ALD/AMN carrier status for one possible heterozygous female.
Mutation screening in ALD families is of practical importance, to confirm or rule out carrier status, particularly when biochemical parameters are inconclusive.

Headings
Adrenoleukodystrophy (ALD)
adreno-myeloneuropathy (AMN)

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