C19orf12 and FA2H Mutations Are Rare in Italian Patients With Neurodegeneration With Brain Iron Accumulation

Panteghini, Celeste; Zorzi, Giovanna; Venco, Paola; Dusi, Sabrina; Reale, Chiara; Brunetti, Dario; Chiapparini, Luisa; Zibordi, Federica; Siegel, Brigitte; Garavaglia, Barbara; Simonati, Alessandro; Bertini, Enrico; Nardocci, Nardo; Tiranti, Valeria

doi:10.1016/j.spen.2012.03.006

Cited by 37 publications

(35 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Until now, 67 MPAN patients have been described in the literature (Deschauer et al, 2012;Dezfouli et al, 2013;Dogu et al, 2012;Goldman et al, 2013;Hartig et al, 2011;Hogarth et al, 2013;Panteghini et al, 2012;Schottmann, Stenzel, Lutzkendorf, Schuelke, & Knierim, 2013;Schulte et al, 2013). A compilation of all these cases shows that MPAN leads to a distinctive phenotype with prominent pyramidal and extrapyramidal signs, cognitive decline, neuropsychiatric abnormalities, optic atrophy, and motor axonal neuropathy (Table 3.1).…”

Section: Clinical Findingsmentioning

confidence: 99%

“…In addition to iron accumulation, generalized brain atrophy and/or cerebellar atrophy is found in a fraction of MPAN patients. Compilation of patients from references (Deschauer et al, 2012;Dezfouli et al, 2013;Dogu et al, 2012;Goldman et al, 2013;Hartig et al, 2011;Hogarth et al, 2013;Panteghini et al, 2012;Schottmann et al, 2013;Schulte et al, 2013).…”

Section: Neuroimagingmentioning

confidence: 99%

“…Seven of clinically typical MPAN patients had a mutation in just one of the two copies of the c19orf12 gene. Four out of five of these mutations were frameshift or nonsense mutations located at the C-terminal part of the protein (p.G69R, p.Q86X, p.A94CfsX8, p.A120GfsX32, and p.L99fs102) Panteghini et al, 2012). Given that in the case of autosomal recessive inheritance a pathogenic alteration should affect both alleles, incomplete mutation detection might be one possible explanation.…”

Section: Geneticsmentioning

confidence: 99%

“…Given that in the case of autosomal recessive inheritance a pathogenic alteration should affect both alleles, incomplete mutation detection might be one possible explanation. In order to increase sensitivity of genetic testing, deletion screening and sequencing of promoter regions has been performed in some of these cases, but no second mutation was identified Panteghini et al, 2012;Hartig, unpublished). In one family with only one heterozygous mutation detected (p.A120GfsX32), family history pointed to possible autosomal-dominant inheritance.…”

Section: Geneticsmentioning

confidence: 99%

“…The percentage of NBIA patients carrying mutations in C19orf12 vary in the literature, ranging from 5% to 30% (Hartig et al, 2011;Hogarth et al, 2013;Panteghini et al, 2012). The corresponding phenotype was named mitochondrial membrane protein-associated neurodegeneration (MPAN, NBIA 4, MIM# 614298) due to the subcellular localization of the C19orf12 protein.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN)

Hartig

Prokisch

Meitinger

et al. 2013

International Review of Neurobiology

View full text Add to dashboard Cite

Section: Clinical Findingsmentioning

confidence: 99%

Section: Neuroimagingmentioning

confidence: 99%

Section: Geneticsmentioning

confidence: 99%

Section: Geneticsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN)

Hartig

Prokisch

Meitinger

et al. 2013

International Review of Neurobiology

View full text Add to dashboard Cite

Cerebral Iron Accumulation Is Not a Major Feature of FA2H/SPG35

Marelli

Salih

Nguyen³

et al. 2015

Movement Disord Clin Pract

View full text Add to dashboard Cite

Mutations in the fatty-acid 2-hydroxylase (FA2H) gene cause an autosomal recessive spastic paraplegia (SPG35), often associating with cerebellar ataxia; cerebral MRI may show iron accumulation in the basal ganglia, leading to the inclusion of SPG35 among the causes of neurodegeneration with brain iron accumulation. This finding was initially considered strongly relevant for diagnosis, although its frequency is not yet established. We found 5 novel patients (from two families) with mutations in the FA2H gene: none of them showed cerebral iron accumulation (T2-weighted images performed in all; T2 gradient-echo in 2); notably, in 1 case, iron accumulation was absent even after 18 years from disease onset on both T2 gradientecho and susceptibility-weight MRI sequences. Cerebral iron accumulation is not a prominent feature in SPG35 and is not always dependent on disease duration; its absence should not discourage from evoking this diagnosis.Mutations in the fatty-acid 2-hydroxylase (FA2H) gene (OMIM #612319) cause a rare autosomal recessive spastic paraplegia (SPG35) with a complex phenotype, variably associating ataxia, dystonia, cognitive decline, optic atrophy, and epilepsy.1 A large spectrum of cerebral MRI alterations can be observed, consisting of cerebellar atrophy, brainstem atrophy, thin corpus callosum (CC), white matter hyperintensities (WMH), and cerebral iron accumulation, notably in the pallidum and, to a lesser degree, in the SN. 2-5 These clinical and radiological manifestations are collectively designated as fatty acid hydroxylase-associated neurodegeneration. Given that cerebral iron accumulation was a clear-cut and obligatory feature in one of the first series of patients, 3 FA2H was included among the causes of neurodegeneration with brain iron accumulation (NBIA) and significant relevance was initially given to this feature in orienting diagnosis. However, further descriptions of FA2H patients showed that cerebral iron accumulation was not universally present and was milder than in other forms of NBIA, although the exact frequency of this finding is not yet established. We report on 5 patients with novel FA2H mutations without evidence of iron accumulation, and we present a review of the literature with particular focus on neuroimaging findings.

show abstract