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Background Zellweger spectrum disorder is an autosomal recessively inherited multisystem disorder caused by one of the 13 different PEX gene defects resulting in defective peroxisomal assembly and multiple peroxisomal enzyme deficiencies. We report a new patient with late-onset Zellweger spectrum disorder mimicking X-linked adrenoleukodystrophy. Patient Description This 8.5-year-old boy with normal development until 6.5 years of age presented with bilateral sensorineural hearing loss during a school hearing test. He then developed acute-onset diplopia, clumsiness, and cognitive dysfunction at age 7 years. Magnetic resonance imaging of the brain revealed symmetric leukodystrophy, although without gadolinium enhancement. Elevated plasma very long chain fatty acid levels were suggestive of X-linked adrenoleukodystrophy, but his ABCD1 gene had normal coding sequence and dosage. Additional studies of cultured skin fibroblasts were consistent with Zellweger spectrum disorder. Molecular testing identified disease-causing compound heterozygous mutations in the PEX6 gene supporting the Zellweger spectrum disorder diagnosis in this patient. Conclusions We describe a new patient with late-onset Zellweger spectrum disorder caused by PEX6 mutations who presented with an acute neurodegenerative disease course mimicking X-linked adrenoleukodystrophy. This finding provides an additional reason that molecular confirmation is important for the genetic counseling and management of patients with a clinical and biochemical diagnosis of X-linked adrenoleukodystrophy. [ABSTRACT FROM AUTHOR]

We report the prenatal findings of severe cerebellar growth arrest in two siblings with POLG1 mutations. The first presented with seizures and lactic acidosis immediately after premature birth and was diagnosed with mitochondrial disease on muscle biopsy. Molecular DNA analysis confirmed homozygous missense mutation in the POLG1 gene. The pregnancy of the second sibling was monitored closely by repeat fetal ultrasounds since the parents declined invasive testing. A detailed fetal ultrasound at 19 weeks gestation showed a small cerebellum with transcerebellar diameter (TCD) on axial cranial imaging, measuring below the 5th centile for gestational age. Molecular analysis confirmed the same homozygous familial mutation in the POLG1gene. This report further delineates the phenotypic features of the POLG related disorders and expands it to the prenatal era. Subsequent pregnancies were monitored by molecular analysis, using chorionic villus sampling (CVS). [ABSTRACT FROM AUTHOR]

Abstract: X-linked adrenoleukodystrophy (X-ALD) is a progressive peroxisomal disorder affecting adrenal glands, testes and myelin stability that is caused by mutations in the ABCD1 (NM_000033) gene. Males with X-ALD may be diagnosed by the demonstration of elevated very long chain fatty acid (VLCFA) levels in plasma. In contrast, only 80% of female carriers have elevated plasma VLCFA; therefore targeted mutation analysis is the most effective means for carrier detection. Amongst 489 X-ALD families tested at Kennedy Krieger Institute, we identified 20 cases in which the ABCD1 mutation was de novo in the index case, indicating that the mutation arose in the maternal germ line and supporting a new mutation rate of at least 4.1% for this group. In addition, we identified 10 cases in which a de novo mutation arose in the mother or the grandmother of the index case. In two of these cases studies indicated that the mothers were low level gonosomal mosaics. In a third case biochemical, molecular and pedigree analysis indicated the mother was a gonadal mosaic. To the best of our knowledge mosaicism has not been previously reported in X-ALD. In addition, we identified one pedigree in which the maternal grandfather was mosaic for the familial ABCD1 mutation. Less than 1% of our patient population had evidence of gonadal or gonosomal mosaicism, suggesting it is a rare occurrence for this gene and its associated disorders. However, the residual maternal risk for having additional ovum carrying the mutant allele identified in an index case that appears to have a de novo mutation is at least 13%. [Copyright &y& Elsevier]