Reported are the clinical, neuroradiologic, and molecular findings in 18 patients with megalencephalic leukoencephalopathy and subcortical cysts (MLC) syndrome. Marked clinical intrafamilial and interfamilial variability in mutation-proven cases was found. A broad spectrum of pathogenetic mutations (missense, splice site, insertion, and deletions) were identified in the MLC1 gene, enlarging the spectrum of allelic variants without a straightforward genotype-phenotype correlation. Five patients did not harbor mutations in MLC1, supporting the existence of at least one other MLC locus.
Leigh syndrome (LS) is a neurodegenerative disorder usually starting before 1 year of age and leading to death within months or years. 1 In most patients, LS is caused by defects of mitochondrial oxidative phosphorylation (OXPHOS), the most common involving pyruvate dehydrogenase complex (PDH), cytochrome c oxidase (complex IV), and NADH-ubiquinone oxidoreductase (complex I). 1 Complex I consists of at least 45 subunits, 2 7 of which are encoded by the mitochondrial genome, and is the largest and the most complex in terms of function and structure among the OX-PHOS complexes. Recent focus on the culprit role of nuclear genes encoding the majority of the structural subunits of complex I was the effect of the discovery of autosomal recessive mutations in several patients with LS or Leigh-like phenotypes. More recently, the 12706TϾC and the 13513GϾA mutations in the ND5 gene, one of seven subunits of complex I encoded by mitochondrial genome (mtDNA), were identified in patients with LS. 3,4 Thus, both nuclear gene defects and mtDNA mutations are possible in patients with LS with complex I deficiency.Here we report on an additional child with LS harboring the 13513G3 A mutation.Case report. A 4-year-old Italian boy, born to unrelated parents, was the product of uncomplicated pregnancy and delivery. He had a normal neonatal period but parents became concerned about his development at age 12 months because of acute onset ataxia. Physical examination at 17 months showed failure to thrive (weight 9.2 kg, height 74 cm), ataxia, bilateral ptosis, and convergent strabismus. Urinary organic acids showed increased lactate and 3-OH-butyrate. Serum lactate was also elevated (4.1 mmol/L, normal values Ͻ2). Brain MRI showed hyperlucencies in the medial thalamus (see supplementary figure E-1 at www. neurology.org), subthalamus, periaqueductal midbrain, dorsal mesencephalon, and substantia nigra in T2-weighted images (figure, A) and in fluid-attenuated inversion recovery, suggesting a diagnosis of LS. Routine histochemical analyses in muscle biopsy showed mitochondrial proliferation with no clear ragged-red fibers. Spectrophotometric analyses of OXPHOS complexes showed a reduction of the activity of complex I in muscle (25% of normal values) and in cultured skin fibroblasts (30% of normal). At age 4 years, the child remains ambulant; ptosis and ataxia have improved. However, he shows a progressive dystonic posturing in his feet. A recent brain MRI showed bilateral hyperintensities in the putamen (figure, B, and supplementary figure E-2 at www.neurology.org).Direct sequencing of PDH-E1␣ subunit and of nuclear genes of complex I (NDUFV1-3, NDUFS1-4, NDUFS7, NDUFS8, ND-FUA1, NDUFA8, NDUFA9, NDUFB6) had normal results. Analysis of a large part of the mitochondrial genome, including the seven ND genes, identified a 13513G3 A transition in ND5 (see the figure). Using a reported PCR-restriction fragment length polymorphism analysis, 5 we quantitated the mutation in tissues from the patient (75%, 82%, and 70% mutant genomes in skin fibrobl...
A homozygous POLG1 mutation might explain PEO with mitochondrial abnormalities in skeletal muscle in our propositus, and it might have aggravated his axonal and hypomyelinating sensory-motor neuropathy. Most likely, his cousin had an axonal polyneuropathy with CMT phenotype of still unknown etiology.
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