Interpretation of Test Results

The majority of mutations in ABCD1 are missense mutations (58.4%), with frameshifts and nonsense mutations accounting for 23.9% and 9.1% of mutation alleles, respectively, and amino acid insertions and deletions and whole exon deletions accounting for 4.6% and 4%, respectively. A recent study of the effects of missense mutations on ALDP stability demonstrated that approximately 70% resulted in absent or reduced ALDP, indicating that most mutations in ABCD1 result in complete loss of protein function (Figure 8-3).29 These findings are consistent with the observed lack of genotype-phenotype correlation and lend support to the existence of additional genetic and environmental factors that modify the X-ALD phenotype.

Figure 8-3. A hypothetical model of ALDP is shown. Individual amino acids are represented by circles. Missense mutations may affect the stability of ALDP. The effect of missense mutations on the stability of ALDP has been investigated for 52 independent missense mutations. Of these 52 amino acid substitutions, 31% do not affect ALDP stability and the cells have normal ALDP levels (green circles). Eleven percent of missense mutations result in reduced amounts of ALDP (orange circles). However, at 2 of these 6 positions,missense mutations have been reported that destabilize ALDP and are marked in red. Fifty eight percent of missense mutations result in no detectable ALDP (red circles). Overall, 69% of all missense mutations result in reduced or absent ALDP activity.29 All other mutations, including in-frame amino acid deletions and truncations near the carboxy terminus, result in the absence of detectable levels of ALDP. (Reproduced from the Web site http://www.x-ald.nl/, with permission © J. Berger and S. Kemp.)

Figure 8-3. A hypothetical model of ALDP is shown. Individual amino acids are represented by circles. Missense mutations may affect the stability of ALDP. The effect of missense mutations on the stability of ALDP has been investigated for 52 independent missense mutations. Of these 52 amino acid substitutions, 31% do not affect ALDP stability and the cells have normal ALDP levels (green circles). Eleven percent of missense mutations result in reduced amounts of ALDP (orange circles). However, at 2 of these 6 positions,missense mutations have been reported that destabilize ALDP and are marked in red. Fifty eight percent of missense mutations result in no detectable ALDP (red circles). Overall, 69% of all missense mutations result in reduced or absent ALDP activity.29 All other mutations, including in-frame amino acid deletions and truncations near the carboxy terminus, result in the absence of detectable levels of ALDP. (Reproduced from the Web site http://www.x-ald.nl/, with permission © J. Berger and S. Kemp.)

LEUKODYSTROPHIES (CANAVAN DISEASE)

The leukodystrophies are a group of degenerative metabolic diseases that involve the white matter of the brain, resulting predominately from disruption in the synthesis, transport, or catabolism of myelin. Examples include Krabbe disease and metachromatic leukodystrophy (MLD), which affect lysosomal function and degradation of myelin, and Pelizaeus-Merzbacher disease, which is due to the abnormal synthesis of proteolipid protein. Another example, discussed in detail below, is Canavan disease, characterized by loss of axonal myelin sheaths and spongi-form degeneration of the brain. Neurological deterioration in most leukodystrophies occurs after a period of normal development, and therapy is usually limited to the alleviation of symptoms.

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