Anna Sagnelli

Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis

Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid that is produced in the liver and used for treatment of chronic cholestatic liver diseases. Experimental studies suggest that TUDCA may have cytoprotective and anti‐apoptotic action, with potential neuroprotective activity. A proof of principle approach was adopted to provide preliminary data regarding the efficacy and tolerability of TUDCA in a series of patients with amyotrophic lateral sclerosis (ALS).

Mitochondrial dynamics and inherited peripheral nerve diseases.

Peripheral nerves have peculiar energetic requirements because of considerable length of axons and therefore correct mitochondria functioning and distribution along nerves is fundamental. Mitochondrial dynamics refers to the continuous change in size, shape, and position of mitochondria within cells. Abnormalities of mitochondrial dynamics produced by mutations in proteins involved in mitochondrial fusion (mitofusin-2, MFN2), fission (ganglioside-induced differentiation-associated protein-1, GDAP1), and mitochondrial axonal transport usually present with a Charcot-Marie-Tooth disease (CMT) phenotype. MFN2 mutations cause CMT type 2A by altering mitochondrial fusion and trafficking along the axonal microtubule system. CMT2A is an axonal autosomal dominant CMT type which in most cases is characterized by early onset and rather severe course. GDAP1 mutations also alter fission, fusion and transport of mitochondria and are associated either with recessive demyelinating (CMT4A) and axonal CMT (AR-CMT2K) and, less commonly, with dominant, milder, axonal CMT (CMT2K). OPA1 (Optic Atrophy-1) is involved in fusion of mitochondrial inner membrane, and its heterozygous mutations lead to early-onset and progressive dominant optic atrophy which may be complicated by other neurological symptoms including peripheral neuropathy. Mutations in several proteins fundamental for the axonal transport or forming the axonal cytoskeleton result in peripheral neuropathy, i.e., CMT, distal hereditary motor neuropathy (dHMN) or hereditary sensory and autonomic neuropathy (HSAN), as well as in hereditary spastic paraplegia. Indeed, mitochondrial transport involves directly or indirectly components of the kinesin superfamily (KIF5A, KIF1A, KIF1B), responsible of anterograde transport, and of the dynein complex and related proteins (DYNC1H1, dynactin, dynamin-2), implicated in retrograde flow. Microtubules, neurofilaments, and chaperones such as heat shock proteins (HSPs) also have a fundamental role in mitochondrial transport and mutations in some of related encoding genes cause peripheral neuropathy (TUBB3, NEFL, HSPB1, HSPB8, HSPB3, DNAJB2). In this review, we address the abnormalities in mitochondrial dynamics and their role in determining CMT disease and related neuropathies.

Widespread Microstructural White Matter Involvement in Amyotrophic Lateral Sclerosis: A Whole-Brain DTI Study

BACKGROUND AND PURPOSE: The extensive application of advanced MR imaging techniques to the study of ALS has undoubtedly improved our knowledge of disease pathophysiology, even if the actual spread of the neurodegenerative process throughout the central nervous system is not fully understood. The present study aimed to detect WM patterns of microstructural abnormalities to better investigate the pathologic process in ALS, within but also beyond CSTs, in a whole-brain analysis. MATERIALS AND METHODS: DTI was performed in 19 patients with ALS and 20 matched healthy controls, by using whole-brain TBSS and VOI analyses. RESULTS: We observed a significant decrease of FA in the body of CC of the ALS group (P < .05). At the VOI level, both FA decrease and RD increase in the body of CC significantly correlated with the UMN score (P = .003 and P = .02). Additionally, significant voxelwise positive correlations between FA and the ALSFRS-R were detected in the WM tracts underneath the left premotor cortex (P < .05). CONCLUSIONS: The correlations between reduction of FA and increase of RD in the body of CC with the UMN score indicate that the WM degeneration in the CC is strictly related to the ALS pyramidal impairment, while the correlation between FA and ALSFRS-R in the associative tracts underneath the left premotor cortex might reflect the progressive spread of the disease from the motor toward the extramotor areas.

Subclinical leukodystrophy and infertility in a man with a novel homozygous CLCN2 mutation

Mutations in the CLCN2 gene encoding ClC-2, a chloride channel implicated in brain ion and water homeostasis, have been recently associated with a rare autosomal recessive leukoencephalopathy, characterized by specific MRI findings caused by chronic white matter edema.1

Clinical Trials in Spinal and Bulbar Muscular Atrophy-Past, Present, and Future.

Spinal and Bulbar Muscular Atrophy (SBMA), also known as Kennedys disease, is a rare adult-onset lower motor neuron disorder with a classic X-linked inheritance pattern. It is caused by the abnormal expansion of the CAG-repeat tract in the androgen receptor gene. Despite important progress in the understanding of the molecular pathogenesis and the availability of a broad set of model organisms, successful translation of these insights into clinical interventions remains elusive. Here we review the available information on clinical trials in SBMA and discuss the challenges and pitfalls that impede therapy development. Two important factors are the variability of the complex neuro-endocrinological phenotype and the comparatively low incidence of the disease that renders recruitment for clinical trials demanding. We propose that these challenges can be and need to be overcome by fostering closer collaborations between clinical research centers, the patient communities and the industry and non-industry sponsors of clinical trials.

X-linked Charcot-Marie-Tooth type 1: Stroke-like presentation of a novel GJB1 mutation

X‐linked Charcot‐Marie‐Tooth type 1 (CMTX1) is the second most common type of CMT and is caused by mutations in the Gap‐Junction Beta‐1 gene (GJB1), encoding connexin 32 which is expressed in Schwann cells as well as in oligodendrocytes. More than 400 GJB1 mutations have been described to date. Many mutation‐carrier males have subclinical central nervous system (CNS) involvement, a few show mild CNS clinical signs, whereas only rarely overt though transient CNS dysfunction occurs. We report a 29‐year‐old man with CMTX1 who, at 16 years, showed short‐lived CNS symptoms with transitory white matter abnormalities on cerebral magnetic resonance imaging (MRI) as first clinical presentation of a novel GJB1 mutation (p.Gln99_His100insGln). He had three consecutive episodes of right hemiparesis, together with sensory loss in the paretic limbs and expressive aphasia, all lasting a few hours, over a 2‐day period, with concurrent white matter hyperintensity on MRI. These “stroke‐like” episodes occurred just after arriving at sea level, after travelling from home at 700 m of altitude. Only a few years later did symptoms of peripheral neuropathy appear. In conclusion, CMTX1 should be included in the differential diagnosis of diseases characterized by transient CNS symptoms and white matter abnormalities on MRI.

Amyotrophic lateral sclerosis and multiple sclerosis overlap: a case report.

The concurrence of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) is extremely rare. We reported the case of a 33-year-old woman with a past history of paresthesias at the right hand, who developed progressive quadriparesis with muscular atrophy of limbs and, finally, bulbar signs and dyspnea. Clinical and neurophysiologic investigations revealed upper and lower motor neuron signs in the bulbar region and extremities, suggesting the diagnosis of ALS. Moreover, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis demonstrated 3 periventricular and juxtacortical lesions, hyperintense in T2 and FLAIR sequences, and 3 liquoral immunoglobulin G (IgG) oligoclonal bands, consistent with diagnosis of primary progressive MS (PPMS). This unusual overlap of ALS and MS leads to the discussion of a hypothetical common pathological process of immunological dysfunction in these two disorders, although the role of immune response in ALS remains ambivalent and unclear.

Clinical features and lifestyle of patients with amyotrophic lateral sclerosis in Campania: brief overview of an Italian database

BACKGROUND Physical activity and occupational exposures appeared to play a relevant role in pathogenesis of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of unknown origin. MATERIALS AND METHODS We aimed to make an overview of the clinical characteristics and lifestyle (occupation and sport) of a population of 395 patients with ALS from Campania, in southern Italy. RESULTS ALS onset resulted anticipated of about 11 years in industry workers, whilst the more frequent site of onset among farmers was upper limbs. Compared to non-athletes, athletes, particularly soccer players, showed a 7 years anticipation of ALS onset, with higher mortality after 5 years. DISCUSSION AND CONCLUSIONS We suggest that subjects genetically prone to abnormal response to hypoxia during strenuous physical activity or exposed to neurotoxic agents, such as athletes, farmers or industry workers, might present increased risk to develop ALS. Future case-control and follow-up studies on our population should be implemented to deepen the present results.

Early-onset progressive spastic paraplegia caused by a novel TUBB4A mutation: brain MRI and FDG-PET findings.

A 21-year-old man was evaluated in 2010 because of a sporadic childhood-onset slowly progressive spastic paraplegia complicated by mild learning difficulties. Examination showed spastic gait with no need of support, lower limb spastic hypertonia, diffusely increased deep tendon reflexes, bilateral Babinski sign, equinovarus deformity of the feet, and mild intellectual disability (WAIS total IQ score = 60) which did not prevent him from having a nearnormal life. Brain MRI showed relatively diffuse, slight white matter T2-hyperintensity in combination with normal T1-weighted signal (Fig. 1a–c), unmodified on two repeat MRI scans 3 and 5 years apart, at age 24 and 26 (not shown). Hence, we suspected a hypomyelinating leukodystrophy (HLD). A bilateral globus pallidus hypointensity on T2*-weighted images, which was above the normal range for the age [2], suggested pathologic iron deposition (Fig. 1d). At last evaluation, in 2015, the patient was still able to walk without support, and brain FDG-PET principally showed hypometabolism in the central grey nuclei and cerebellum (Fig. 2). A genetic screening for HLDs identified a novel heterozygous c.1064A[T (p.Asp355Val) mutation in exon 4 of the TUBB4A (tubulin, beta 4A class IVa) gene. The mutation was absent in the parents and in his sister (suggesting that this is a de novo mutation), as well as in the 1000 Genomes Project, Exome Variant Server, and dbSNP databases, and it was predicted to be pathogenic by in silico analysis (see Electronic Supplementary Material for details). TUBB4A-related disorders encompass a wide clinical and neuroradiological spectrum, ranging from dystonia type 4 (DYT4) disease, which is characterized by adultonset dystonia and normal brain MRI [4], to hypomyelination with atrophy of the basal ganglia and cerebellum (HABC) disease, which is clinically characterized by earlyonset extrapyramidal movement abnormalities and other variable neurological features including spasticity, ataxia, cognitive impairment, and seizures [5]. The major findings of our report are as follows: first, our patient presented with a progressive spastic paraplegia complicated only by mild intellectual disability, as recently reported in a consanguineous Roma/Gypsy kindred [6]. No overt extrapyramidal sign was found even after a long history of disease, providing further evidence that the extrapyramidal movement abnormalities, which have been considered the core feature of the TUBB4A-related disorders [5, 7], can be absent. Second, brain MRI showed that: (1) basal ganglia were of normal size [8, 9], and white matter abnormalities were not so diffuse as usually found, in agreement with the relatively mild clinical phenotype [6]; (2) there was an unexpected iron deposition in the globi pallidi, which is likely an epiphenomenon of neurodegeneration [10]. Third, brain FDG-PET revealed cerebellar hypometabolism (in agreement with the presence of mild cerebellar atrophy on MRI), but also bilateral putamen hypometabolism. The latter suggests that subtle pathological changes are present in this region (which expresses high levels of TUBB4A [4]) also when no Electronic supplementary material The online version of this article (doi:10.1007/s00415-016-8020-8) contains supplementary material, which is available to authorized users.

Hereditary gelsolin amyloidosis (HGA): a neglected cause of bilateral progressive or recurrent facial palsy.

We report the first Italian family affected by hereditary gelsolin amyloidosis (HGA), a rare autosomal dominant disease characterized by adult‐onset slowly progressive cranial neuropathy, lattice corneal dystrophy, and cutis laxa. The index case was a 39‐year‐old male with a 9‐year history of progressive bilateral facial nerve palsy. His mother had two episodes of acute facial palsy, and his maternal aunt and grandfather were also affected. Electrophysiological studies confirmed bilateral facial nerve involvement, without signs of peripheral polyneuropathy, and ophthalmological examination showed bilateral lattice corneal dystrophy, in both the index case and his mother. Gelsolin‐gene sequencing revealed the heterozygous c.640G>A mutation (p.Asp187Asn) in the proband, his mother and aunt and also in three apparently asymptomatic relatives. The majority of HGA patients come from Finland, although several cases have been reported from other countries. HGA should be considered in the differential diagnosis of progressive or recurrent bilateral facial neuropathy.