Enrica Bersano

Amyotrophic lateral sclerosis/frontotemporal dementia with predominant manifestations of obsessive-compulsive disorder associated to GGGGCC expansion of the c9orf72 gene.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease involving upper and lower motor neurons. Up to 50 % of ALS cases have cognitive and/or behavioral impairment falling into the spectrum of frontotemporal dementia (FTD) [1]. Approximately 10 % of cases are familial (FALS), while the others are considered sporadic, as their occurrence seems to be random throughout the population. Recently, a GGGGCC hexanucleotide repeat expansion in the first intron of c9orf72 gene on chromosome 9p21 has been related to familial and sporadic cases with ALS, ALS-FTD, or FTD. [2–4]. We describe a 52-year-old man carrying the GGGGCC expansion in the c9orf72 gene. At 50, he developed muscle weakness and wasting at the right hand. Soon after he developed intrusive thoughts of urine loss, not supported by clinical evidence. After a pantoclastic episode characterized by aggressiveness towards objects and auditory hallucinations due to an obsessive impulse to urinary stimuli, he was admitted to our hospital. He had muscle weakness and atrophy of upper limbs (predominantly right) and spasticity of upper and lower limbs, hyperactive deep tendon reflexes, hyperactive jaw jerk, and fasciculations at limbs and trunk muscles. Bulbar and respiratory muscles were spared. Needle EMG showed a diffuse pattern of chronic and active denervation, with normal nerve conduction studies. Motor-evoked potentials demonstrated increased central motor conduction time. Psychiatric evaluation was consistent with obsessive–compulsive disorder (OCD) with predominantly Obsessional Thoughts or Rumination (ICD-10 code F42.0), with psychotic manifestations. The patient’s father died at 42 years old from spinal amyotrophic lateral sclerosis (ALS); he had no cognitive or behavioral impairment. The patient’s sister and a paternal uncle had a depressive disorder. The patient was found to carry a hexanucleotide repeat expansion in c9orf72 gene ([50 repeats); no other mutations of major ALS-FTD related genes were found. Magnetic resonance imaging (MRI) revealed bilateral reduction of fractional anisotropy along the corticospinal tract (predominantly right). Brain positron emission tomography (PET) with FDG presented reduced hypometabolism in the motor cortex bilaterally, in the fronto-mesial cortex bilaterally between the anterior and the middle cingulate gyrus (predominantly right) and in the postero-lateral occipital cortex bilaterally (Fig. 1). The neuropsychological assessment was consistent with a diagnosis of behavioral FTD, associated to OCD, hallucinations, and depressive mood disorder. In the following months, the patient developed dysarthria, dysphagia, tongue atrophy with fasciculations, lower limb weakness and hypotrophy, and worsening of spasticity at the upper and lower limbs. A. Calvo (&) C. Moglia A. Canosa A. Ilardi E. Bersano D. Bertuzzo A. Chio Department of Neuroscience, University of Turin, via Cherasco 15, 10126 Turin, Italy e-mail: andreacalvo@hotmail.com

Chitotriosidase and lysosomal enzymes as potential biomarkers of disease progression in amyotrophic lateral sclerosis: A survey clinic-based study

The aim of this study was to determine if blood chitotriosidase (Chit) activity and lysosomal enzyme levels might represent markers of disease activity and progression in amyotrophic lateral sclerosis (ALS). It is a survey clinic-based study performed in a tertiary ALS centre. Blood samples were obtained from 76 patients with ALS in different stages of the disease and from 106 healthy individuals serving as controls. Chit activity and the levels of acid alpha-glucosidase, acid alpha-galattosidase A, beta-glucocerebrosidase, and alpha-l-iduronidase were detected using the dried blood spots (DBS) technique. The CHIT1 genotype for exon 10 duplication and for the p.G102S variant was also determined. Chit activity was significantly higher in ALS patients than in healthy individuals. This difference was independent of the genotypes at CHIT1 functional variants. Chit were significantly higher in 34 rapidly progressing patients as compared to 42 with slowly progressive disease. Acid alpha-glucosidase was higher than normal and significantly correlated with the severity of the disease. Glucocerebrosidase and alpha-l-iduronidase activity were significantly lower in patients than in the controls. Alpha-galactosidase A was higher than normal only in rapidly progressing patients. We have employed a very simple and affordable laboratory test to measure blood Chit and lysosomal enzymes activity which could be easily included in the screening of ALS patients recruited in clinical trials. Remarkably, high levels of chitinase and alpha-galactosidase A could help to distinguish patients with fast progression from those with slow progression of the disease and possibly to follow the effects of treatments on neuroinflammation and autophagy.

Intraspinal stem cell transplantation for amyotrophic lateral sclerosis: Ready for efficacy clinical trials?

Intraspinal stem cell (SC) transplantation represents a new therapeutic approach for amyotrophic lateral sclerosis (ALS) clinical trials. There are considerable difficulties in designing future efficacy trials, some related to the field of ALS and some that are specific to SCs or the mode of delivery. In October 2015, the most controversial points on SC transplantation were addressed during an international workshop intended to bring together international SC and ALS researchers in a public discussion on a topic for which expertise is limited. During the meeting, a discussion was started on the basic structure of the ideal clinical trial testing the efficacy and safety of SC transplantation. The current document includes a number of consensus points reflecting the design of phase II/III clinical trials.

Secular Trends of Amyotrophic Lateral Sclerosis: The Piemonte and Valle d’Aosta Register

Importance This study reports the long-term epidemiologic trends of amyotrophic lateral sclerosis (ALS) based on a prospective register. Objective To examine the 20-year epidemiologic trends of ALS in the Piemonte and Valle d’Aosta regions of Italy. Design, Setting, and Participants The Piemonte and Valle d’Aosta Register for ALS (PARALS) is an epidemiologic prospective register that covers 2 Italian regions (population of 4 476 931 inhabitants according to the 2011 census) from January 1, 1995, through December 31, 2014. Case ascertainment is based on multiple sources (neurologic departments, hospital discharge archives, and mortality records). Incidence rates are age and sex standardized for the Italian population of the 2011 census. Age-period-cohort (APC) analysis was performed using a Poisson regression model. Main Outcomes and Measures The primary study outcomes were long-term incidence and prevalence rates of ALS using a prospective design and their determinants. Results During the study period, a total of 2702 patients (mean [SD] age at onset, 65.7 [11.1] years; 1246 [46.1%] female and 1456 [53.9%] male) received a diagnosis of ALS between 1995 and 2014, corresponding to a crude annual incidence rate of 3.03 per 100 000 population (95% CI, 2.85-3.23) and an adjusted incidence rate of 2.78 per 100 000 population (95% CI, 2.57-2.96). The age-adjusted incidence rate increased in the 2 decades of the study (1995-2004: 2.66; 95% CI, 2.50-2.83; 2005-2014: 2.89; 95% CI, 2.71-3.07; P = .04), mostly in women. The adjusted rate ratio of men to women decreased from 1.27:1 (1995-2004) to 1.17:1 (2005-2014). The analysis of deviance for the APC regression models indicated that the drift variable is relevant in explaining the variation of ALS incidence rates over time in the overall population (change in deviance, 4.6553; P = .03) and in women (change in deviance, 3.8821; P = .05) but not in men (change in deviance, 0.77215; P = .38). A total of 479 patients with ALS were alive and had not undergone tracheostomy at the prevalence day (December 31, 2014), corresponding to a crude prevalence rate of 10.54 per 100 000 population (95% CI, 9.64-11.52). Conclusions and Relevance During the 1995 to 2014 period, the crude and adjusted incidences of ALS increased in Piemonte and Valle d’Aosta, mostly in women. The APC model revealed that the increase of ALS incidence is attributable to a birth cohort effect in women, with a peak in the 1930 cohort. The different increase of ALS incidence in men and women points to an effect of exogenous factors with a differential effect on the 2 sexes, acting on a genetic background.

A rare case of conjugal amyotrophic lateral sclerosis

We report a case of conjugal amyotrophic lateral sclerosis (ALS) encountered in our tertiary ALS Centre. Family trees, possible environmental factors, and all known ALSassociated genes have been studied. The incidence of sporadic ALS ranges from 1.33 to 3.22 per 100,000, and the prevalence in Italy is 5.2 to 8.0 per 100,000 inhabitants [1]. Our patients lived in the Piedmont Region, in Northern Italy, where the incidence is 2.90/100,000 population, and the prevalence is 7.89 to 8.00/100,000 [2]. Since ALS is such a rare disease, chances of conjugal ALS are extremely low, estimated to be about 1 in 510,000 couples. To our knowledge only 20 cases have been reported of both spouses suffering from ALS [3–5]. In 2005, a 63-year-old man was diagnosed with spinal onset ALS after presenting with a two-year history of widespread fasciculations and progressive gait impairment. On neurological examination we found diffuse spontaneous fasciculations, moderate atrophy and weakness of limbs, with tendon hyperreflexia and Babinski sign. Electromyography (EMG) revealed diffuse fasciculation potentials and motor unit action potentials on voluntary activation, with complex and unstable morphology in all sampled upper and lower limb muscles. Transcranial magnetic stimulation detected a delay of the central motor conduction time in upper and lower limbs. The patient was a blacksmith, but serum and urinary heavy-metal concentrations were normal. Endocrine, paraneoplastic, autoimmune, and infective panels and cerebral spinal fluid results were also normal. He died of respiratory failure five years after initial presentation. Three years later, his 68-year-old non-consanguineous wife presented to our clinic with dysphonia, dyspnea at rest, and orthopnea. She was a saleswoman and had no contact with the husband’s workshop. Neurological examination demonstrated mild wasting and fasciculations of the tongue, and neck weakness. Widespread fasciculations were detected also in the limbs. Deep tendon reflexes were increased. The patient’s laboratory tests and MRI of the brain and spinal cord were normal. EMG showed diffuse involvement of the lower motor neuron in the limb and bulbar muscles, while electroneurography was normal. Pulmonary function was assessed, revealing a forced vital capacity of 45 %. The diagnosis of ALS with bulbar onset was confirmed, and she is still alive with noninvasive ventilation support. The patients were born in the same town of about 20,000 inhabitants, located in a rural area of the Piedmont region, and they lived there together for 30 years. In this area no cases of familiar ALS have been reported, and the incidence of the disease does not differ from that in other areas of the Piedmont region. Family trees of both patients, built from the second generation back (Fig. 1), established that the two subjects were not related and that no relative was ever affected by neurodegenerative disease. Both patients were screened for known ALS-associated genes (C9orf72; SOD1; TDP_43; FUS; Ataxin-2; uBQN2 ex4; PFN), and no mutations were detected. No common exposures were identified in regard to exogenous and environmental toxins such as radiation, food-borne pathogens, cosmetics, drugs, pesticides in agricultural environments; nor were there exposure risks from smoking, intense physical activity, or trauma. E. Bersano (&) S. Servo R. Cantello L. Mazzini Department of Neurology, ALS Center, Eastern Piedmont University, Maggiore della Carita Hospital, Novara, Italy e-mail: enricabersano@gmail.com

Monomelic amyotrophy is not always benign: a case report.

Abstract Monomelic amyotrophy (MA) is a variant of motor neuron disease (MND), characterized by muscle weakness and atrophy restricted to one limb. We describe the case of a 56-year-old Italian patient who developed a segmental muscular atrophy limited to the lower left limb. After 11 years of clinical stability he developed progressive spread of the disease to all limbs and to bulbar and respiratory muscles. The patient died from respiratory failure 15 years after disease onset. This case demonstrates that monomelic amyotrophy may rarely evolve to a diffuse fatal MND, even after more than a decade of clinical stability. Our findings support the idea that MA is part of the clinical continuum of MND.

Influence of arterial hypertension, type 2 diabetes and cardiovascular risk factors on ALS outcome: a population-based study

Abstract Objective: To assess the prognostic influence of pre-morbid type 2 diabetes mellitus, arterial hypertension and cardiovascular (CV) risk profile on ALS phenotype and outcome in a population-based cohort of Italian patients. Methods: A total of 650 ALS patients from the Piemonte/Valle d’Aosta Register for ALS, incident in the 2007–2011 period, were recruited. Information about premorbid presence of type 2 diabetes mellitus, arterial hypertension was collected at the time of diagnosis. Patients’ CV risk profile was calculated according to the Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice (JBS2). Results: At the univariate analysis, the presence of pre-morbid arterial hypertension was associated with a higher age at onset of ALS and a shorter survival, and patients with a high CV risk profile had a worse prognosis than those with a low CV risk profile. The Cox multivariable analysis did not confirm such findings. Type 2 diabetes mellitus did not modify either the phenotype or the prognosis of ALS patients. Conclusions: This study performed on a large population-based cohort of ALS patients has demonstrated that arterial hypertension, type 2 diabetes and CV risk factors, calculated using the Framingham equation, do not influence ALS phenotype and prognosis.

The multistep hypothesis of ALS revisited: The role of genetic mutations.

Objective Amyotrophic lateral sclerosis (ALS) incidence rates are consistent with the hypothesis that ALS is a multistep process. We tested the hypothesis that carrying a large effect mutation might account for ≥1 steps through the effect of the mutation, thus leaving fewer remaining steps before ALS begins. Methods We generated incidence data from an ALS population register in Italy (2007–2015) for which genetic analysis for C9orf72, SOD1, TARDBP, and FUS genes was performed in 82% of incident cases. As confirmation, we used data from ALS cases diagnosed in the Republic of Ireland (2006–2014). We regressed the log of age-specific incidence against the log of age with least-squares regression for the subpopulation carrying disease-associated variation in each separate gene. Results Of the 1,077 genetically tested cases, 74 (6.9%) carried C9orf72 mutations, 20 (1.9%) had SOD1 mutations, 15 (1.4%) had TARDBP mutations, and 3 (0.3%) carried FUS mutations. In the whole population, there was a linear relationship between log incidence and log age (r2 = 0.98) with a slope estimate of 4.65 (4.37–4.95), consistent with a 6-step process. The analysis for C9orf72-mutated patients confirmed a linear relationship (r2 = 0.94) with a slope estimate of 2.22 (1.74–2.29), suggesting a 3-step process. This estimate was confirmed by data from the Irish ALS register. The slope estimate was consistent with a 2-step process for SOD1 and with a 4-step process for TARDBP. Conclusion The identification of a reduced number of steps in patients with ALS with genetic mutations compared to those without mutations supports the idea of ALS as a multistep process and is an important advance for dissecting the pathogenic process in ALS.

Ptosis and bulbar onset: an unusual phenotype of familial ALS?

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder of upper and lower motor neurons that usually spare the oculomotor nerves. Here, we describe a case of two siblings with a familial bulbar-onset ALS both with ptosis manifested at the onset of the disease.

A case of late-onset OCD developing PLS and FTD

Abstract We describe a 64-year-old woman, suffering from late-onset obsessive–compulsive disorder (OCD) from the age of 57, who developed dysarthria and dysphagia, spastic diplegic, and proximal muscles weakness. Needle electromyography showed no active denervation. Neuropsychological evaluation showed intact cognitive functioning. We diagnosed upper motor neuron disease (MND), with no known genetic correlates. Brain magnetic resonance (MRI) detected bilateral hippocampal atrophy with sclerosis of right hippocampus. 18F-FDG positron emission tomography (PET) showed moderate right temporal cortex thinning. Six months later, motor and behavioral symptoms worsened. Neuropsychological examination revealed long-term memory deficit and executive dysfunction. MRI and PET evidenced severe worsening of atrophy in temporal and frontal lobes. Four years later a definitive diagnosis of primary lateral sclerosis (PLS) and FTD was made. To our knowledge, this is the first report of PLS and FTD with OCD at onset.