To determine the values of iron accumulation in the basal ganglia of healthy volunteers of different ages with R2* and raw signal intensity measurements from T1-weighted magnetic resonance (MR) images, supported by voxel-based relaxometry (VBR), and to compare them with previously reported iron concentrations found in autopsy material. The ethics committee approved the study, and the participants or their parents gave written informed consent. Eighty subjects (41 female and 39 male subjects; age range, 1-80 years) were examined at 1.5 T. For each subject, R2* values were calculated. Curves for R2* versus age were obtained for globus pallidus (GP), putamen, caudate nucleus, substantia nigra (SN), and frontal white matter (FWM). To highlight possible differences in iron concentration among the age decades, VBR was applied. Signal intensity values were estimated on T1-weighted fast low-angle shot images, and regions of interest were drawn in each nucleus. R2* values were also compared with iron concentrations reported in a postmortem study. Statistical analysis was performed (t test), and a difference with P < .05 (FDR corrected) was significant. The curves for R2* versus age showed an exponential increase with increasing age in all the basal ganglia. VBR demonstrated significant differences (P < .05, corrected) in the comparison between the 2nd and the following decades for lenticular nuclei. Good correlation coefficients were found for GP (R(2) = 0.64), putamen (R(2) = 0.51), and SN (R(2) = 0.53) when compared with findings in the postmortem study. Signal intensity curves were similar to the R2* curves. R2* measurements can be used to quantify brain iron accumulation and thus may allow better evaluation of neurodegenerative diseases associated with iron deposition.

Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders with progressive extrapyramidal signs and neurological deterioration, characterized by iron accumulation in the basal ganglia. Exome sequencing revealed the presence of recessive missense mutations in COASY, encoding coenzyme A (CoA) synthase in one NBIA-affected subject. A second unrelated individual carrying mutations in COASY was identified by Sanger sequence analysis. CoA synthase is a bifunctional enzyme catalyzing the final steps of CoA biosynthesis by coupling phosphopantetheine with ATP to form dephospho-CoA and its subsequent phosphorylation to generate CoA. We demonstrate alterations in RNA and protein expression levels of CoA synthase, as well as CoA amount, in fibroblasts derived from the two clinical cases and in yeast. This is the second inborn error of coenzyme A biosynthesis to be implicated in NBIA.

Hereditary spastic paraplegias are a heterogeneous group of neurodegenerative disorders, clinically classified in pure and complex forms. Genetically, more than 70 different forms of spastic paraplegias have been characterized. A subgroup of complicate recessive forms has been distinguished for the presence of thin corpus callosum and white matter lesions at brain imaging. This group includes several genetic entities, but most of the cases are caused by mutations in the KIAA1840 (SPG11) and ZFYVE26 genes (SPG15). We studied a cohort of 61 consecutive patients with complicated spastic paraplegias, presenting at least one of the following features: mental retardation, thin corpus callosum and/or white matter lesions. DNA samples were screened for mutations in the SPG11 /KIAA1840, SPG15/ ZFYVE26, SPG21 /ACP33 , SPG35 /FA2H , SPG48 /AP5Z1 and SPG54 /DDHD2 genes by direct sequencing. Sequence variants were found in 30 of 61 cases: 16 patients carried SPG11/ KIAA1840 gene variants (26.2%), nine patients carried SPG15 /ZFYVE26 variants (14.8%), three patients SPG35 /FA2H (5%), and two patients carried SPG48/ AP5Z1 gene variants (3%). Mean age at onset was similar in patients with SPG11 and with SPG15 (range 11–36), and the phenotype was mostly indistinguishable. Extrapyramidal signs were observed only in patients with SPG15, and epilepsy in three subjects with SPG11. Motor axonal neuropathy was found in 60% of cases with SPG11 and 70% of cases with SPG15. Subjects with SPG35 had intellectual impairment, spastic paraplegia, thin corpus callosum, white matter hyperintensities, and cerebellar atrophy. Two families had a late-onset presentation, and none had signs of brain iron accumulation. The patients with SPG48 were a 5-year-old child, homozygous for a missense SPG48/ AP5Z1 variant, and a 51-year-old female, carrying two different nonsense variants. Both patients had intellectual deficits, thin corpus callosum and white matter lesions. None of the cases in our cohort carried mutations in the SPG21 /ACP33 and SPG54/ DDH2H genes. Our study confirms that the phenotype of patients with SPG11 and with SPG15 is homogeneous, whereas cases with SPG35 and with SPG48 cases present overlapping features, and a broader clinical spectrum. The large group of non-diagnosed subjects (51%) suggests further genetic heterogeneity. The observation of common clinical features in association with defects in different causative genes, suggest a general vulnerability of the corticospinal tract axons to a wide spectrum of cellular alterations. * Abbreviations : ALS : amyotrophic lateral sclerosis SNP : single nucleotide polymorphism SPG : spastic paraplegia