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

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Authors: Cecilia Marelli MD, Mustafa A. Salih MD, Karine Nguyen MD, Martial Mallaret MD, Nicolas Leboucq MD, Hamdy H. Hassan MD, Nathalie Drouot MSc, Pierre Labauge MD, PhD and Michel Koenig MD, PhD

Article first published online:  18 FEB 2015 | DOI: 10.1002/mdc3.12118

 


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 FA2Hmutations without evidence of iron accumulation, and we present a review of the literature with particular focus on neuroimaging findings.

Case Series

Genetic Analysis

SNP Genotyping

Genome-wide homozygosity mapping technique was performed in 97 consanguineous families primarily presenting with ataxia,[6] using the GeneChip Mapping Mapping 50K Xba 240 Array containing 58.102 single-nucleotide polymorphisms (SNPs; Affymetrix Inc., Santa Clara, CA). SNP genotypes were obtained by the Affymetrix protocol for the GeneChip Mapping Array (Mapping 100K Assay Manual [P/N701684 Rev.3]). Homozygous regions were identified with the HomoSNP software developed by Plewniak and Muller (available on request from jmuller@igbmc.fr).

Microsatellite Marker Analysis

Microsatellite markers from chromosome 16q were designed from the University of California San Francisco Human genome database (http://genome.ucsc.edu; March 2006 release) and analyzed on an a ABI Prism 3100 genetic analyzer with allele sizes determined using the ABI PRISM1 Genotyper software package (Applied Biosystems, Foster City, CA).[7]

Mutational Analysis

Sequencing of FA2H was undertaken as previously reported.[7] Amplified polymerase chain reaction (PCR) products were purified on Montage PCR96 Cleanup Plates (Millipore, Bedford, MA) and bidirectionally sequenced using BigDye Terminator chemistry implemented on an ABI Prism 3100 Genetic Analyzer. Sequences were aligned and compared with consensus sequences from the human genome databases (http://genome.ucsc.eduhttp://www.ncbi.nlm.nih.gov) using the software package, Seqscape (Version 2.5; ABI).

Genetic, Clinical, and Neuroimaging Findings

Shared homozygosity over the chromosome 16q interval containing FA2H was identified among the affected patients of two unrelated consanguineous families with ataxia and spastic paraplegia. Sequencing of FA2H revealed 2 novel homozygous mutations (Supporting Fig. 1). Genetic analysis was performed after signature of a written informed consent approved by the local ethics committee.

Family 1

In a multiconsanguineous family of Moroccan origin, 2 of 5 siblings were affected and harbored a homozygous p.R269H mutation in theFA2H gene. Their mother presented the same clinical phenotype, and because of multiconsanguinity, a pseudodominant inheritance pattern was suspected; however, no DNA was available for molecular confirmation. The 2 sisters had a normal psychomotor development; at the age of, respectively, 16 and 12 years, they presented with progressive spasticity and ataxia, associated with cognitive decline and incontinence (see Video). Ability of walking was lost approximately 15 (subject 1) and 9 (subject 2) years after disease onset. At the last neurological assessment (mean follow-up: 17.5 years), disability stage was scored at 6/7 for the 2 sisters. Sensation and nerve conduction were normal (2/2), although central somatosensory evoked potential were not recordable (2/2). They presented with a bilateral optic atrophy without retinopathy, confirmed by altered visual evoked potential (VEP) and optical-coherence tomography as well as normal electroretinogram (ERG) (2/2).

Initial MRI, at, respectively, 7 and 6 years from onset, showed cerebellar atrophy (2/2), mild posterior periventricular WMH (2/2), and thin CC (1/2); no iron accumulation was evident on T2-weighted sequences. A second MRI performed 18 years after disease onset in subject 1 and 14 years after disease onset in subject 2 (Table 1) showed progression of cerebral and cerebellar atrophy, brainstem atrophy, and extension of WMH to the centrum semiovale and to the subcortical and perirolandic regions. Nevertheless, no cerebral iron accumulation was evident on T2-weighted (2/2) or T2 gradient-echo (T2*) and susceptibility-weighted images (SWI) (1/1) sequences (Fig. 1). Spinal MRI showed marked spinal atrophy (2/2).

Table 1. Neuroimaging findings in FA2H-mutated patients from the present report and from the literature
Article Subject Mutation Cortical Atrophy Cerebellar Atrophy Thin CC Pallidal Iron Deposition WMH Brainstem Atrophy MRI Follow-up (Years) Dystonia
  1. a

    Homozygous mutations.

  2. b

    MRI results are not available for the other FA2H-mutated subjects reported in these papers.

  3. nr, not reported.

Present report I.1 p.R269Ha Yes Yes Yes No Yes Yes 18 No
I.2 p.R269Ha Yes Yes Yes No Yes Yes 14 No
II.1 p.H336Na No Yes No No Yes No 2.5 No
II.2 p.H336Na No No No No Yes No 2.5 No
II.3 p.H336Na No No No No Yes No 2.5 No
Cao et al.[10] I.1 p.P323Q; p.G326S; p.E230K Yes Yes Yes Yes Yes Yes nr Yes
I.2 p.P323Q; p.G326S; p.E230K Yes Yes Yes Yes Yes Yes nr Yes
Dick et al.[1]b VII. 2 p.R235Ca nr nr nr nr Yes nr 3 Yes
IV.8 p.R53_I58dela Yes Yes Yes Borderline Yes Yes 19 Yes
Donkervoort et al.[12] I.1 p.Y170Xa No Yes Yes No Yes Yes 8 No
I.2 p.Y170Xa No Yes No No Yes No 5 No
Edvardson et al[2]b I.1 Skipping of exons 5 and 6a nr No No No Yes nr nr Yes
I.2 Skipping of exons 5 and 6a nr Yes Yes nr Yes Yes 12 Yes
I.3 Skipping of exons 5 and 6a nr Yes Yes nr Yes nr nr Yes
II.1 Skipping of exons 5 and 6a nr Yes Yes nr Yes nr nr Yes
II.2 Skipping of exons 5 and 6a nr No No nr Yes nr nr Yes
II.3 Skipping of exons 5 and 6a nr No No nr Yes nr nr Yes
II.4 Skipping of exons 5 and 6a nr No No Yes Yes nr 3 Yes
III.2 p.D35Y No No No No No No nr No
Garone et al.[8] I.1 Frameshift after exon 1a No Yes Yes Yes Yes Yes 13 No
I.2 Frameshift after exon 1a No Yes Yes Yes Yes Yes 10 No
Kruer et al.[3] I.1 p.R154Ca Yes Yes Yes Yes Yes Yes Approximately 13 Yes
I.2 p.R154Ca Yes Yes Yes Yes Yes Yes nr Yes
I.3 p.R154Ca Yes Yes Yes Yes Yes Yes nr Yes
II.1 p.Y170Xa nr Yes Yes Yes Yes Yes >10 Yes
II.2 p.Y170Xa nr Yes Yes Yes Yes Yes nr Yes
Pierson et al.[9] I.1 p.F236S; deletion of exons 3 to 7 No Yes Yes Borderline Yes Yes >7 Yes
Rupps et al.[11] I.1 p.S70L; p.P323L No No No No Yes nr 1 No
Tonelli et al.[4] I.1 p.Y170Ca Yes Yes Yes Yes No nr 10 No
II.2 p.Y170Ca Yes Yes Yes No No nr 9 No
Pensato et al.[13] I.1 p.Y34C; p.T207M Yes Yes Yes No Yes No nr No
I.2 p.Y34C; p.T207M Yes Yes Yes No Yes No nr No
II.1 p.G46Da Yes Yes Yes No Yes No nr No
 
MRI findings of family 1 and 2.

Figure 1. MRI findings of family 1 and 2. (A, B, C) Cerebral MRI of patient 1 from family 1 showing no pallidal iron accumulation (A, T2* axial image), WMH (B, T2-weighted axial image, white arrow), and cerebellar, brainstem, and CC atrophy (C, T1-weighted sagittal image). (D, E, F) Cerebral MRI from family 2 showing no pallidal iron accumulation in patients 1 and 3 (D and F, T2-weighted axial image) and in patient 2 (E, T2* axial image).

 
 
Family 2

This is a consanguineous family from Saudi Arabia harboring the homozygous p.H336N mutation in the FA2H gene. A pair of twin brother and sister (subjects 1 and 2) and another female (subject 3) of 4 siblings were affected. After a normal psychomotor development, they presented with progressive spasticity and ataxia with a mean age of onset of 4 years, without cognitive decline. They were still able to walk at a mean of 4.5 years from onset. Neurophysiological examination showed normal nerve conduction (3/3), normal ERG (2/2), and altered VEP (1/2). Cerebral MRI, at a mean of 2.5 years from disease onset, showed periventricular WMH (3/3) and cerebellar atrophy (1/3). No cerebral iron accumulation was found on T2-weighted (3/3) and T2* (1/1) sequences (Fig. 1).

 

Discussion

We present a series of 5 novel FA2H-mutated patients without evidence of cerebral iron accumulation. They showed a progressive spastic-ataxia syndrome without dystonia; disease onset was in adolescence in family 1 (mean 14 yr) and in childhood in family 2 (mean, 4 years).

Patients from family 1 presented with the full spectrum of FA2H-related MRI alterations, but iron deposition (Fig. 1). In family 2, isolated WMH without iron deposition was a constant finding, with additional cerebellar atrophy in 1 subject.

Our 5 patients presented with symmetrical T2-weighted and fluid attenuated inversion recovery WMH, predominantly in the posterior, but also in the anterior periventricular regions; sometimes WMH extended to the centrum semiovale and to the subcortical and perirolandic regions; no tract-specific pattern of white matter involvement was observed. Given that FA2H is primarily involved in myelin metabolism and given that WMH could be an early and isolated finding, as in family 2, these alterations are probably a direct consequence of the disease.

None of our patients showed pallidal iron accumulation on T2-weighted sequences; T2* and SWI sequences were additionally performed in patient 1, from family 1, and T2* imaging was also available for patient 2, from family 2. Although T2* and SWI sequences are more sensitive in the detection of cerebral iron deposition, pallidal iron accumulation in NBIA is often also detected as a symmetrical, homogeneous hypointensity on T2-weighted sequences.[5] In previously reported SPG35 cases,[1-4, 8-13] cerebral iron deposition was almost always examined with T2-weighted sequences; in the sole patient with iron deposition and available T2* sequences, the hypointensity was already evident on T2-weighted images.[4]

Although SPG35 was included among the causes of NBIA, the exact frequency of cerebral iron accumulation is still unknown. We therefore performed a review of the literature,[1-4, 8-13] and, after inclusion of the 5 patients described in the present study, a total of 33 FA2H-mutated patients were available for comparison of cerebral MRI data (Table 1): iron accumulation was definitively present in only 11 of 33 patients (33%; stated as mild in 2 of 11), was present with borderline features in 2 of 33 (6%),[1, 9] and absent or not mentioned in 20 of 33 (61%); pallidal iron deposition was more frequently reported in patients with longer disease duration (Table 1).

Notably, according to the literature, other neuroimaging findings were more constantly present: WMH (30 of 33 patients; 91%), cerebellar atrophy (24 of 32; 75%), thin CC (22 of 32; 69%), and brainstem atrophy (15 of 23; 65%); finally, cortical atrophy was reported in 13 of 23 patients (56%). One patient had normal cerebral MRI.[3] Isolated cerebral iron accumulation was never detected in FA2H-mutated patients.

The two families reported on here were identified from a group of patients mainly selected on the basis of the presence of ataxic signs and absence of predominant extrapyramidal presentation[6]; this could constitute a bias with respect to the presence of iron deposition. However, no FA2H mutations were detected in two different cohorts of 43 and 46 PANK2- and PLA2G6-negative NBIA patients, defined by the presence of movement disorders and MRI evidence of iron deposition in the basal ganglia, confirming that FA2H mutations are a rare cause of NBIA.[3, 14] On the contrary, mutations in PLA2G6, also causing cerebellar atrophy, WMH, and basal ganglia iron accumulation, were detected in 20 of 105 NBIA patients (19%) of one of the two cohorts,[14] and pallidal iron accumulation was detected in 50%[15] to 80%[16] of the PLA2G6-mutated patients.

Literature-reported FA2H-mutated patients showed a well-defined progression of WMH and brain atrophy according to disease evolution.[4, 8, 9] The inconsistency of iron accumulation was explained as a tardive finding, possibly appearing mainly in later disease stages.[3]However, in the 2 patients from family 1, subsequent MRI showed a clear progression of brain atrophy and WMH and no iron deposition in T2 and T2* sequences, even after 18 years of disease duration, clearly indicating that at least some patients are not prone to develop iron deposition. Of note, FA2H is primarily and directly involved in metabolism of the myelin; the pathophysiological mechanism of iron accumulation is less clear and may be a possible indirect consequence.[3]

In conclusion cerebral iron accumulation is a very inconstant finding in SPG35, particularly in the initial and intermediate stages of the disease. Its absence should not discourage one from evoking this diagnosis. Notably, iron deposition does not seem to be always dependent on disease duration.

 

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