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Histochemistry. (A and B) The muscle biopsy from the vastus lateralis muscle (A = ATPase pH 4.3, B = COX-SDH). There is a preference of atrophy of type 2 fibres (pink in A). Furthermore, COX-negative fibres (arrows in B) can be observed. (C) A semi-thin section (osmium-tetroxide) of the femoral nerve with some swollen (arrow) and degenerating (arrowhead) nerve fibres. (D) A sensory ganglion (haematoxylin and eosin staining) without obvious pathology. (E) A semi-thin section (osmium tetroxide + toluidine blue) from the cervical spinal cord with swollen (arrow) and degenerating (arrowheads) axons in the spinocerebellar tracts. The same type of pathology could be observed in the medial portion of the dorsal tracts. (F) Detail from the cerebellar cortex (Sevier-Munger silver stain) with an axonal torpedo (arrow). Scale bars: A, B and D = 100 mm; C, E and F = 50 mm.
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Spastic paraplegia type 7 is an autosomal recessive neurodegenerative disorder mainly characterized by progressive bilateral lower limb spasticity and referred to as a form of hereditary spastic paraplegia. Additional disease features may also be observed as part of a more complex phenotype. Many different mutations have already been identified, bu...
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... biopsy showed a clear increase in the variation of the muscle fibre diameter with several atrophic fibres ( Fig. 2A and B). Diffusely spread in this biopsy, clumps of pyknotic nuclei were observed, which are indicative of chronic atrophy. Fibre typing (among others with ATPase enzyme-histochemical staining) showed that there was preferential type 2 muscle fibre atrophy, which is often observed in the case of disuse ( Fig. ...
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... with several atrophic fibres ( Fig. 2A and B). Diffusely spread in this biopsy, clumps of pyknotic nuclei were observed, which are indicative of chronic atrophy. Fibre typing (among others with ATPase enzyme-histochemical staining) showed that there was preferential type 2 muscle fibre atrophy, which is often observed in the case of disuse ( Fig. ...
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... it was observed that there was more loss of myelin in the fasciculus gracilis than in the fasciculus cunea- tus and that this was most obvious in the cervical spinal cord. Epon resin slides showed swollen axons in these tracts. Other as- cending tracts such as the spinocerebellar tracts showed some spongiosis and some swollen axons as well (Fig. 2E). On the con- trary, clear loss of fibres from the corticospinal tract was not seen, but in the semi-thin Epon Õ resin slides some swollen axons could be observed. Clear astrogliosis (glial fibrillary acidic protein stain- ing) or microgliosis (CD68, IBA-1 stainings) was not observed in the spinal ...
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... the anterior vermis, there was limited loss of Purkinje cells. This was slightly more severe in the posterior vermis and the cere- bellar hemispheres, where empty baskets as well as axonal torpe- does were observed (Fig. ...
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... et al., 2008). We were able to include a detailed histo- neuropathological evaluation of one of the SPG7 patients with a deviant phenotype of severe visual loss who carried the p.Arg470Gln homozygous mutation. In this patient (Patient 1, Table 1), some COX-negative muscle fibres were found, as described by others (McDermott et al., 2001) (Fig. 2); however, the patient described here was 70 years of age and in normal ageing some COX-negative muscle fibres may be encountered. In the muscle biopsy of our patient, atrophic fibres were found but without clear signs of type-grouping or large group atrophy, which would point in the direction of an ongoing sequence of denervation, ...
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... peripheral neuropathy was less severe than documented in the mouse model (Ferreirinha et al., 2004). On the contrary, we found a severely affected optic system and affected fibres in the ascending spinal tracts (Figs 2 and 3). In the paraplegin-deficient mice, defects of the long tracks in the spinal cord preceded defects of the optic system, a difference that is difficult to ex- plain without further studies in humans and mice. ...
Citations
... Of the 19 mutated genes, five are not formally linked to a dystonia phenotype in OMIM (SPG7, DNM1L, NARS2, OPA1, WFS1). There are however cumulative reports in the literature supporting an association with dystonia for at least 4 of these genes [18][19][20][21]. ...
... On the other hand, declining mitochondrial quality due to impaired biogenesis and mitophagy, as seen with aging [30], may act as "second hit" in a susceptible genetic background [14]. Notably, variants in genes related to mitochondrial dynamics, homeostasis, and quality control (category 3 in our study) are a recurrent cause of monogenic movement disorders with adult onset [18,31,32]. Across different disorders, defects in mitochondrial pathways share common consequences at the cellular level consisting of oxidative stress, iron dysmetabolism and inflammation [30,33,34]. ...
... Mitochondrial-related impairment of axonal transport mainly underlies spastic ataxias, particularly SPG7, in which ataxia and spasticity are often associated to impairment of optic pathway. Signs of cerebellar and extracerebellar oculomotor involvement and PEO are also described in these forms (de Bot et al., 2012;van Gassen et al., 2012;Pfeffer et al., 2014;Synofzik and Schüle, 2017). SPG7 mutations affect the function of Paraplegin, an inner mitochondrial protein which assembles with homologous AFG3L2, to form the oligomeric mAAA protease complex (Casari et al., 1998;Giorgio and Roberto, 2018). ...
... Mitochondrial-related impairment of axonal transport mainly underlies spastic ataxias, particularly SPG7, in which ataxia and spasticity are often associated to impairment of optic pathway. Signs of cerebellar and extracerebellar oculomotor involvement and PEO are also described in these forms (de Bot et al., 2012;van Gassen et al., 2012;Pfeffer et al., 2014;Synofzik and Schüle, 2017). SPG7 mutations affect the function of Paraplegin, an inner mitochondrial protein which assembles with homologous AFG3L2, to form the oligomeric mAAA protease complex (Casari et al., 1998;Giorgio and Roberto, 2018). ...
... SPG7 patients showed increased T2 signal from the dentate nucleus (Hewamadduma et al., 2018), in line with the postmortem data demonstrating neuronal loss in the dentate nucleus (Thal et al., 2015). The most frequently described oculomotor defect in SPG7 patients is the adult onset progressive external ophthalmoplegia and ptosis (CPEO; Klebe et al., 2012;van Gassen et al., 2012). However, cerebellar nystagmus and vertical gaze limitation with slow upward saccades and preserved VOR have also been reported. ...
Autosomal recessive cerebellar ataxias (ARCAs) are a heterogeneous group
of neurodegenerative disorders affecting primarily the cerebellum and/or
its afferent tracts, often accompanied by damage of other neurological or
extra-neurological systems. Due to the overlap of clinical presentation among
ARCAs and the variety of hereditary, acquired, and reversible etiologies that
can determine cerebellar dysfunction, the differential diagnosis is challenging,
but also urgent considering the ongoing development of promising target
therapies. The examination of afferent and efferent visual system may provide
neurophysiological and structural information related to cerebellar dysfunction
and neurodegeneration thus allowing a possible diagnostic classification
approach according to ocular features. While optic coherence tomography
(OCT) is applied for the parametrization of the optic nerve and macular area,
the eye movements analysis relies on a wide range of eye-tracker devices
and the application of machine-learning techniques. We discuss the results of
clinical and eye-tracking oculomotor examination, the OCT findings and some
advancing of computer science in ARCAs thus providing evidence sustaining the
identification of robust eye parameters as possible markers of ARCAs.
... The condition is marked by progressive bilateral lower limb weakness and spasticity. Additionally, one-third of SPG7 cases exhibit cerebellar abnormalities on MRI [66]. Other common symptoms may include spastic dysarthria, dysphagia, ophthalmic findings like nystagmus, strabismus, ptosis, pale optic discs, and urinary sphincter disorders [66]. ...
... Additionally, one-third of SPG7 cases exhibit cerebellar abnormalities on MRI [66]. Other common symptoms may include spastic dysarthria, dysphagia, ophthalmic findings like nystagmus, strabismus, ptosis, pale optic discs, and urinary sphincter disorders [66]. ...
... Among three patients who underwent 123I FP CIT SPECT, one showed bilateral presynaptic denervation, another had mild unilateral denervation, and the third patient's scan was normal [54]. Additional reports described the same clinical features of parkinsonism in patients with SPG7 mutations [66,73]. ...
Parkinsonism is a syndrome characterized by bradykinesia in combination with either rest tremor, rigidity, or both. These features are the cardinal manifestations of Parkinson’s disease, the most common cause of parkinsonism, and atypical parkinsonian disorders. However, parkinsonism can be a manifestation of complex neurological and neurodegenerative genetically determined disorders, which have a vast and heterogeneous motor and non-motor phenotypic features. Hereditary dementias, adult-onset ataxias and spastic paraplegias represent only few of this vast group of neurogenetic diseases. This review will provide an overview of parkinsonism’s clinical features within adult-onset neurogenetic diseases which a neurologist could face with. Understanding parkinsonism and its characteristics in the context of the aforementioned neurological conditions may provide insights into pathophysiological mechanisms and have important clinical implications, including diagnostic and therapeutic aspects.
... The ATPase family gene 3-like (AFG3L2) is the catalytic subunit of the m-AAA protease, an ATP-dependent proteolytic complex of the mitochondrial inner membrane that degrades misfolded proteins and regulates ribosome assembly. AFG3L2 assembles into homooligomers and hetero-oligomers with paraplegin, another m-AAA protease subunit encoded by SPG7, and its mutations can cause spastic ataxia [1][2][3]. AFG3L2 is an ATP-dependent protein hydrolysis complex of the inner mitochondrial membrane that is of paramount importance for mitochondrial protein synthesis, ribosome assembly, respiratory complex I and III integrity, and mitochondrial calcium ion homeostasis [3][4][5]. ...
Background:
The most common disease caused by biallelic AFG3L2 mutations is spastic ataxia type 5 (SPAX5). Identification of complex phenotypes resulting from biallelic AFG3L2 mutations has been increasing in recent years.
Methods:
A retrospective analysis was performed on a child with microcephaly and recurrent seizures. The child underwent physical and neurological examinations, laboratory tests, electroencephalography (EEG), and brain magnetic resonance imaging (MRI). Trio-whole-exome sequencing (trio-WES) was performed to identify possible causative mutations.
Results:
We described a child who exhibited early-onset and intractable epilepsy, developmental regression, microcephaly, and premature death. Neuroimaging revealed global cerebral atrophy (GCA) involving the cerebrum, cerebellum, corpus callosum, brainstem, cerebellar vermis, and basal ganglia. On trio-WES, two novel compound heterozygous mutations, c.1834G > T (p.E612*) and c.2176-6T > A in the AFG3L2 gene, were identified in this patient.
Conclusions:
Our findings have expanded the mutation spectrum of the AFG3L2 gene and identified a severe neurodegenerative phenotype of global cerebral atrophy caused by biallelic AFG3L2 mutations.
... SPG7 is the most common autosomal-recessive HSP (about 5%-10% of total cases), and with 39%-57% of all SPG7 patients showing signs of ataxia (van Gassen et al., 2012) also one of the more frequent autosomal-recessive ataxias (up to 5%, (Coutelier et al., 2018;Traschutz et al., 2021;Gama et al., 2022). Disease onset in SPG7 is remarkably later than in most other recessive ataxias and HSPs, with a median disease onset of 36-39 years (range 10-69 years) (Klebe et al., 2012;van Gassen et al., 2012;Pfeffer et al., 2015), and disease usually not starting before age 10-15 years (Klebe et al., 2012;van Gassen et al., 2012). ...
... SPG7 is the most common autosomal-recessive HSP (about 5%-10% of total cases), and with 39%-57% of all SPG7 patients showing signs of ataxia (van Gassen et al., 2012) also one of the more frequent autosomal-recessive ataxias (up to 5%, (Coutelier et al., 2018;Traschutz et al., 2021;Gama et al., 2022). Disease onset in SPG7 is remarkably later than in most other recessive ataxias and HSPs, with a median disease onset of 36-39 years (range 10-69 years) (Klebe et al., 2012;van Gassen et al., 2012;Pfeffer et al., 2015), and disease usually not starting before age 10-15 years (Klebe et al., 2012;van Gassen et al., 2012). After a mean disease duration of 16 years, half of the SPG7 patients used some kind of walking aid, yet with a wide range of 1-70 years (van Gassen et al., 2012). ...
... SPG7 is the most common autosomal-recessive HSP (about 5%-10% of total cases), and with 39%-57% of all SPG7 patients showing signs of ataxia (van Gassen et al., 2012) also one of the more frequent autosomal-recessive ataxias (up to 5%, (Coutelier et al., 2018;Traschutz et al., 2021;Gama et al., 2022). Disease onset in SPG7 is remarkably later than in most other recessive ataxias and HSPs, with a median disease onset of 36-39 years (range 10-69 years) (Klebe et al., 2012;van Gassen et al., 2012;Pfeffer et al., 2015), and disease usually not starting before age 10-15 years (Klebe et al., 2012;van Gassen et al., 2012). After a mean disease duration of 16 years, half of the SPG7 patients used some kind of walking aid, yet with a wide range of 1-70 years (van Gassen et al., 2012). ...
Degenerative ataxias and hereditary spastic paraplegias (HSPs) form a continuous, often overlapping disease spectrum sharing not only phenotypic features and underlying genes, but also cellular pathways and disease mechanisms. Mitochondrial metabolism presents a major molecular theme underlying both multiple ataxias and HSPs, thus indicating a heightened vulnerability of Purkinje cells, spinocerebellar tracts, and motor neurons to mitochondrial dysfunction, which is of particular interest for translational approaches. Mitochondrial dysfunction might be the primary (upstream) or secondary (downstream) result of a genetic defect, with underlying genetic defects in nuclear-encoded genes being much more frequent than in mtDNA genes in both, ataxias and HSPs. Here, we outline the substantial number of ataxias, spastic ataxias and HSPs caused by mutated genes implicated in (primary or secondary) mitochondrial dysfunction, highlighting several key "mitochondrial" ataxias and HSPs which are of particular interest for their frequency, pathogenesis and translational opportunities. We then showcase prototypic mitochondrial mechanisms by which disruption of these ataxia and HSP genes contributes to Purkinje cells or corticospinal neuron dysfunction, thus elucidating hypotheses on Purkinje cells and corticospinal neuron vulnerability to mitochondrial dysfunction.
... For instance, ataxia is a major clinical presentation in patients with SPG7 mutations [6,7]. Parkinsonism-sometimes l-dopa responsive-and dystonia have been described in SPG11 [2,[8][9][10][11] and SPG15 [12,13], while cervical dystonia, spasmodic dysphonia, and limb dystonia have been reported in SPG7 [14][15][16]. Myoclonus is a rare feature of HSP [17]. While these previous studies have started to delineate associations between specific SPG loci and movement disorders, a large but focused effort is needed to draw stronger, more accurate, and potentially predictive correlations. ...
Background:
Hereditary spastic paraplegia (HSP) is a rare genetic disorder associated with mutations in > 80 loci designated SPG (SPastic parapleGia). The phenotypic spectrum of HSP can extend to include other neurologic features, including movement disorders. Our aim was to investigate genotype-phenotype associations in HSP with a focus on movement disorders.
Methods:
We performed a systematic review and individual participant data (IPD)-level meta-analysis by retrieving publications from Medline/EMBASE/Web of Science on HSP with a SPG genotype. Studies were included only if individual-level information was accessible and at least one patient with a movement disorder was reported for that genotype. Out of 21,957 hits, 192 manuscripts with a total of 1413 HSP cases were eligible. Data were compared between two HSP groups: manifested with (HSP-MD, n = 767) or without (HSP-nMD, n = 646) a movement disorder.
Results:
The HSP-MD group had an older age of onset (20.5 ± 16.0 vs. 17.1 ± 14.2 yr, p < 0.001) and less frequent autosomal dominant inheritance (7.6% vs. 30.1%, p < 0.001) compared to HSP-nMD. SPG7 (31.2%) and SPG11 (23.8%) were the most frequent genotypes in the HSP-MD group. HSP-MD with SPG7 had higher frequency of later onset during adulthood (82.9% vs. 8.5%), ataxia (OR = 12.6), extraocular movement disturbances (OR = 3.4) and seizure (OR = 3.7) compared to HSP-MD with SPG11. Conversely, SPG11 mutations were more frequently associated with consanguinity (OR = 4.1), parkinsonism (OR = 7.8), dystonia (OR = 5.4), peripheral neuropathy (OR = 26.9), and cognitive dysfunction (OR = 34.5).
Conclusion:
This systematic IPD-level meta-analysis provides the largest data on genotype-phenotype associations in HSP-MD. Several clinically relevant phenotypic differences were found between various genotypes, which can possibly facilitate diagnosis in resource-limited settings.
... Heterozygous relatives may present impaired balance and mild cerebellar atrophy, occurring later than homozygous carriers do [10]. Some variants seem to be associated with dominant cases, as p.Arg485_ Glu487del [43]. However, for these cases, the presence of pathogenic variant in another gene cannot be excluded. ...
This narrative review aims at providing an update on the management of inherited cerebellar ataxias (ICAs), describing main clinical entities, genetic analysis strategies and recent therapeutic developments. Initial approach facing a patient with cerebellar ataxia requires family medical history, physical examination, exclusions of acquired causes and genetic analysis, including Next-Generation Sequencing (NGS). To guide diagnosis, several algorithms and a new genetic nomenclature for recessive cerebellar ataxias have been proposed. The challenge of NGS analysis is the identification of causative variant, trio analysis being usually the most appropriate option. Public genomic databases as well as pathogenicity prediction software facilitate the interpretation of NGS results. We also report on key clinical points for the diagnosis of the main ICAs, including Friedreich ataxia, CANVAS, polyglutamine spinocerebellar ataxias, Fragile X-associated tremor/ataxia syndrome. Rarer forms should not be neglected because of diagnostic biomarkers availability, disease-modifying treatments, or associated susceptibility to malignancy. Diagnostic difficulties arise from allelic and phenotypic heterogeneity as well as from the possibility for one gene to be associated with both dominant and recessive inheritance. To complicate the phenotype, cerebellar cognitive affective syndrome can be associated with some subtypes of cerebellar ataxia. Lastly, we describe new therapeutic leads: antisense oligonucleotides approach in polyglutamine SCAs and viral gene therapy in Friedreich ataxia. This review provides support for diagnosis, genetic counseling and therapeutic management of ICAs in clinical practice.
... The clinical characteristics, laboratory test results, imaging, gene mutation status, treatment and follow-up data of patients were collected, and the correlations between genotype and clinical phenotype were analyzed. We hypothesized that mutations resulting in defective protein products may have different phenotypic effects from mutations resulting in complete protein deletions (van Gassen et al., 2012). Mutations that may not produce a protein product or produce a severely truncated protein product were classified as class 1. ...
Purpose: This study reports the clinical and genetic features of Brown-Vialetto-Van Laere syndrome (BVVL) type 2 in a case of uniparental disomy of chromosome 8 in mainland China and analyzes the genotype-phenotype correlation through a review of the literature of BVVL type 2 cases.
Methods: The clinical characteristics, treatment, and follow-up data of the patient were summarized, and the etiology was identified by whole-exome sequencing and gene chip analysis. Correlations between the genotype and phenotype were analyzed by collecting clinical and genetic data of published cases and our patient.
Results: We identified a homozygous mutation in SLC52A2 (NM_001253815.2 c.1255G>A) by trio-WES. Sanger sequencing confirmed that his father was heterozygous and his mother was wild type. Subsequently, paternal uniparental disomy of chromosome 8 [UPD (8)pat] was confirmed by chromosomal microarray analysis.The patient received long-term oral riboflavin treatment (7 mg/kg.d) and was followed up for 40 months by which time the child’s bulbar palsy, ataxia, and motor function had improved. A review of the literature and statistical analysis found that the symptoms of BVVL type 2 appear at the earliest shortly after birth and at the latest at 10 years of age. The median age of onset was 2.5 years, but the overall delay in diagnosis was a median of 5.6 years. The most common symptoms were hearing loss (83.9%), followed by muscle weakness (80.6%), visual impairment (64.5%), and ataxia (61.3%). To date, a total of 32 mutations in the SLC52A2 gene have been reported, with the most common being a missense mutation. Mutations occur throughout the length of the gene apart from at the N-terminus. In patients with missense mutations, homozygous pattern was more likely to present with ataxia as the first symptom (p < 0.05), while compound heterozygous pattern was more likely to develop respiratory insufficiency during the course of disease (p < 0.001). Moreover, patients with one missense mutation located in inside the transmembrane domain were more likely to have respiratory insufficiency than those with mutations both inside and outside the domain (p < 0.05). Riboflavin supplementation was an important factor in determining prognosis (p < 0.001).
Conclusion: We report the first UPD(8)pat with SLC52A2 homozygous pathogenic mutation case in BVVL type 2, which expand the mutation spectrum of gene.
... It was also found in French patients, both in compound heterozygous and homozygous states [32]. In a Dutch cohort of 60 SPG7 patients, one patient presenting with HSP and ataxia syndrome was a compound heterozygous for p.Leu78* with another SPG7 mutation [34]. One Romani patient in a Spanish cohort was found to carry the nonsense p.Leu78* mutation in a heterozygous state, while his mother and aunt were homozygous for this mutation. ...
Hereditary spastic paraplegia (HSP) is among the most genetically diverse of all monogenic diseases. The aim was to analyze the genetic causes of HSP among adult Serbian patients. The study comprised 74 patients from 65 families clinically diagnosed with HSP during a nine-year prospective period. A panel of thirteen genes was analyzed: L1CAM (SPG1), PLP1 (SPG2), ATL1 (SPG3A), SPAST (SPG4), CYP7B1 (SPG5A), SPG7 (SPG7), KIF5A (SPG10), SPG11 (SPG11), ZYFVE26 (SPG15), REEP1 (SPG31), ATP13A2 (SPG78), DYNC1H1, and BICD2 using a next generation sequencing-based technique. A copy number variation (CNV) test for SPAST, SPG7, and SPG11 was also performed. Twenty-three patients from 19 families (29.2%) had conclusive genetic findings, including 75.0% of families with autosomal dominant and 25.0% with autosomal recessive inheritance, and 15.7% of sporadic cases. Twelve families had mutations in the SPAST gene, usually with a pure HSP phenotype. Three sporadic patients had conclusive findings in the SPG11 gene. Two unrelated patients carried a homozygous pathogenic mutation c.233T>A (p.L78*) in SPG7 that is a founder Roma mutation. One patient had a heterozygous de novo variant in the KIF5A gene, and one had a compound heterozygous mutation in the ZYFVE26 gene. The combined genetic yield of our gene panel and CNV analysis for HSP was around 30%. Our findings broaden the knowledge on the genetic epidemiology of HSP, with implications for molecular diagnostics in this region.
... In SPG7, there are studies describing a lower motor neuropathy. The frequency is variable between 0 % reported by Karle et al. up to approximately 30 % of cases according to van Gassen [27,28]. ...
Spinal diffusion tensor imaging (sDTI) is still a challenging technique for selectively evaluating anatomical areas like the pyramidal tracts (PT), dorsal columns (DC), and anterior horns (AH) in clinical routine and for reliably quantifying white matter anisotropy and diffusivity. In neurodegenerative diseases, the value of sDTI is promising but not yet well understood.The objective of this prospective, single-center study was to evaluate the long fiber tract degeneration within the spinal cord in normal aging (n = 125) and to prove its applicability in pathologic conditions as in patients with molecular genetically confirmed hereditary spastic paraplegias (HSP; n = 40), a prototypical disease of the first motor neuron and in some genetic variants with affection of the dorsal columns. An optimized monopolar Stejskal-Tanner sequence for high-resolution, axial sDTI of the cervical spinal cord at 3.0 T with advanced standardized evaluation methods was developed for a robust DTI value estimation of PT, DC, and AH in both groups.After sDTI measurement at C2, an automatic motion correction and an advanced semi-automatic ROI-based, standardized evaluation of white matter anisotropy and diffusivity was performed to obtain regional diffusivity measures for PT, DC, and AH. Reliable and stable sDTI values were acquired in a healthy population without significant decline between age 20 and 65. Reference values for PT, DC, and AH for fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were established.In HSP patients, the decline of the long spinal fiber tracts could be demonstrated by diffusivity abnormalities in the pyramidal tracts with significantly reduced PTFA (p
