Giulia Bisogni

Contribution of major amyotrophic lateral sclerosis genes to the etiology of sporadic disease

Objectives: To quantify the overall contribution of mutations in the currently known amyotrophic lateral sclerosis (ALS) genes in a large cohort of sporadic patients and to make genotype–phenotype correlations. Methods: Screening for SOD1, TARDBP, FUS, ANG, ATXN2, OPTN, and C9ORF72 was carried out in 480 consecutive patients with sporadic ALS (SALS) and in 48 familial ALS (FALS) index patients admitted to a single Italian referral center. Results: Mutations were detected in 53 patients, with a cumulative frequency of 11. Seven of them were novel. The highest frequencies of positive cases were obtained in TARDBP (2.7%), C9ORF72 (2.5%), and SOD1 (2.1%). The overall group of mutated patients was indistinguishable from that without mutations as no significant differences were observed with regard to age and site of onset, frequency of clinical phenotypes, and survival. However, by separately evaluating genotype–phenotype correlation in single genes, clinical differences were observed among different genes. Duration of disease was significantly shorter in patients harboring the C9ORF72 expansion and longer in the SOD1 group. A high frequency of predominant upper motor neuron phenotype was observed among patients with TARDBP mutations. Two patients, 1 with C9ORF72 and 1 with SOD1 mutation, had concurrent ANG mutations. Mutations were detected in 43.7% of patients with FALS. Conclusions: A considerable proportion of patients with SALS harbored mutations in major ALS genes. This result has relevant implications in clinical practice, namely in genetic counseling. The detection of double mutations in 2 patients raises the hypothesis that multiple mutations model may explain genetic architecture of SALS. Neurology® 2012;79:66–72

Uncovering amyotrophic lateral sclerosis phenotypes: clinical features and long-term follow-up of upper motor neuron-dominant ALS

Abstract The aim of our study was to analyse the natural history and clinical features of upper motor neuron- dominant (UMN-D) ALS. We studied a large series of sporadic ALS patients admitted in a single referral centre over a 23-year period. UMN-D phenotype was compared with other ALS forms, including classic ALS, flail arm and progressive muscular atrophy. Seven hundred and thirty-four sporadic ALS patients were included of which 163 had UMN-D ALS. The mean age of onset in UMN-D ALS (52 years) was 10 years lower than in classic ALS (61.4 years, p < 0.0001); sex ratio by age groups significantly differed with respect to other phenotypes. The pattern of spread of lower motor neuron signs in UMN-D was characterized by early involvement of upper limb muscles and late impairment of respiratory muscles. Duration of the disease was longer in the UMN-D group (56 months) than in classic ALS (33 months, p < 0.001). The UMN-D phenotype was a strong independent predictor of long survival. In summary, UMN-D ALS showed significant differences in age of onset, sex ratio, pattern of spreading and prognosis with respect to other ALS forms, most probably reflecting biological differences.

TTR-related amyloid neuropathy: clinical, electrophysiological and pathological findings in 15 unrelated patients

Familial amyloid polyneuropathy (FAP) is a rare condition caused by mutations of the transthyretin (TTR) gene and it is generally characterized by a length-dependent polyneuropathy affecting prevalently the small fibers. We reviewed clinical, electrophysiological and pathological findings of 15 unrelated patients with genetically confirmed TTR-FAP. All patients presented a progressive sensory-motor polyneuropathy. Pathological findings were negative for amyloid deposits in about half of the cases. Sequence analysis of TTR gene revealed the presence of three different mutations (p.Val30Met, p.Phe64Leu, and p.Ala120Ser). The p.Val30Met was the most frequently identified mutation and it often occurred in apparently sporadic cases. Conversely, the p.Phe64Leu generally presented in a high percentage of familial cases in patients coming from Southern Italy. Clinicians should consider, to avoid misdiagnosis, the screening for TTR mutations in patients presenting with progressive axonal polyneuropathy of undetermined etiology, including apparently sporadic cases with pathological examinations negative for amyloid deposition.

Clinical, neurophysiological and pathological findings of HNPP patients with 17p12 deletion: a single-centre experience

BACKGROUND Classic clinical manifestations of HNPP are characterized by recurrent painless mononeuropathies, but a minority of patients present with an atypical clinical pattern, including CMT-like neuropathy, acute or chronic inflammatory demyelinating neuropathy-like polyneuropathy, and carpal tunnel syndrome. Electrophysiological examination plays a central role in the diagnosis of HNPP, disclosing a non-uniform conduction slowing, more pronounced at entrapment sites. PATIENTS AND METHODS We report clinical, electrophysiological and pathological findings from 73 patients with HNPP, coming from 53 unrelated families, followed at our Institute of Neurology over a 20-year period. RESULTS Typical presentation with recurrent multiple mononeuropathies was observed in 28/64 (44%) patients. In the remaining 36/64 (56%), we observed an atypical clinical presentation, characterized by generalized weakness and cramps, chronic ulnar neuropathy, carpal tunnel syndrome, chronic sensory polyneuropathy, Guillain-Barrè-like presentation, and CMT-like presentation. Nine patients were asymptomatic for neuropathic symptoms. Nerve conduction studies showed in all cases a sensori-motor demyelinating polyneuropathy with conduction abnormalities preferentially localized at common entrapment sites. When performed, sural nerve biopsy disclosed the focal thickening of the myelin sheath in all patients. CONCLUSIONS About half of the patients with HNPP from our cohort showed an atypical clinical presentation. Neurophysiological examination represents the main tool for a proper diagnosis.

Ultrasound evaluation in transthyretin-related amyloid neuropathy

Introduction: Familial amyloid polyneuropathy is a rare condition caused by mutations of the transthyretin gene (TTR). We assessed the pattern of nerve ultrasound (US) abnormalities in patients with TTR‐related neuropathy. Methods: Seven patients with TTR‐related neuropathy (TTR‐N) and 5 asymptomatic TTR‐mutation carriers (TTR‐C) underwent neurological examination, nerve conduction studies, and US evaluation. Results: Multifocal US abnormalities were identified in 6 of 7 TTR‐N patients. A single patient with only a mild sensory polyneuropathy had normal nerves on US evaluation. In the TTR‐C, we only detected an enlarged ulnar nerve at the elbow. Interestingly, disease severity correlated with number of nerves affected on US evaluation. Conclusions: No specific pattern of US abnormalities was identified in this cohort. However, in TTR‐related amyloid neuropathy, US may be a helpful tool in monitoring disease progression, and/or clinical response to pharmacological treatment. Muscle Nerve 50: 372–376, 2014

D11Y SOD1 mutation and benign ALS: A consistent genotype-phenotype correlation☆

We describe three sporadic ALS patients in which a D11Y SOD1 mutation was detected. All three patients disclosed a prolonged survival and a stereotypical distal limbs involvement in the initial stages of the disease. By this report we demonstrate that D11Y SOD1 mutation is associated with a peculiar phenotype and we confirm its probable pathogenetic role.

Matrin 3 variants are frequent in Italian ALS patients

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of motor neurons in the primary motor cortex, brainstem, and spinal cord. Recently, missense variants in MATR3 were identified in familial and sporadic ALS patients, but very few additional ALS patients have been reported so far. The p.S85C MATR3 variant was previously associated to a different phenotype, namely a distal myopathy associated with dysphagia and dysphonia. Here, we assessed the contribution of MATR3 variants in a cohort of 322 Italian ALS patients. We identified 5 different missense MATR3 variants (p.Q66K, p.G153C, p.E664A, p.S707L, and p.N787S) in 6 patients (1.9%). None of our patients showed signs of myopathy at electrophysiological examination. Muscle biopsy, performed in 2 patients, showed neurogenic changes and normal nuclear staining with anti-matrin 3 antibody. Our results confirm that MATR3 variants are associated with ALS and suggest that they are more frequent in Italian ALS patients. Further studies are needed to elucidate the pathogenic significance of identified variants in sporadic and familial ALS.

Sural nerve pathology in ALS patients: a single-centre experience

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of upper and lower motor neurons. Sensory involvement is thought not to be a feature of ALS. We reviewed 17 cases of sural nerve biopsies performed in a large cohort of ALS patients referred to our centre over a 23-year period. More than two-third of biopsies revealed a variable degree of axonal loss. In one case, pathological findings suggested the concomitant presence of an inherited neuropathy, subsequently confirmed by genetic evaluation. In another case, pathological and neurographic data were similar to those of an inflammatory demyelinating neuropathy, but the clinical course corroborated the diagnosis of ALS. Our data confirm that sensory nerve involvement may be found in ALS patients. This finding should prompt physicians to carefully investigate a possible alternative diagnosis, but does not exclude the possibility that the patient may have ALS.

Restless leg syndrome in different types of demyelinating neuropathies: a single-center pilot study

OBJECTIVE to determine the prevalence of restless legs syndrome (RLS) in a cohort of patients with demyelinating neuropathies. METHODS Patients were retrospectively recruited from our cohort of different forms of demyelinating neuropathies, including chronic inflammatory demyelinating neuropathy (CIDP), Charcot-Marie-Tooth 1A (CMT1A), and hereditary neuropathy with liability to pressure palsies (HNPP) referred to our Department of Neurology in a 10-year period. The validated 4-item RLS questionnaire was used for diagnosis of RLS. All patients with RLS who fulfilled criteria underwent a suggested immobilization test to confirm the diagnosis. A group of outpatients referred to the sleep disorders unit and data from published literature were used as controls. RESULTS Prevalence of RLS in demyelinating neuropathy group was higher than prevalence observed in control population (p = 0.0142) or in the literature data (p = 0.0007). In particular, in comparison with both control population and literature data, prevalence of RLS was higher in CIDP group (p = 0.0266 and p = 0.0063, respectively) and in CMT1A group (p = 0.0312 and p = 0.0105, respectively), but not in HNPP (p = 1.000 and p = 0.9320, respectively). CONCLUSIONS our study confirms a high prevalence of RLS in inflammatory neuropathies as CIDP and, among inherited neuropathies, in CMT1A but not in HNPP. Considering that this is only a small cohort from a single-center retrospective experience, the link between RLS and neuropathy remains uncertain, and larger multicenter studies are probably needed to clarify the real meaning of the association between RLS and neuropathy.

Clinical, electrophysiological and pathological findings in a patient with Charcot-Marie-Tooth disease 4D caused by the NDRG1 Lom mutation

Charcot–Marie–Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited peripheral neuropathies [1]. According to electrophysiological findings, CMT is divided into two main subtypes: CMT1, a primarily demyelinating neuropathy with severely reduced motor nerve conduction velocity (NCV ≤ 38 m/s), and CMT2 a primarily axonal neuropathy with normal or slightly reduced NCV [1]. CMT1A is themost common type of demyelinating CMT, caused by a duplication on chromosome 17p12 including the PMP22 gene. Point mutations of genes encoding structural components of the myelin sheath and/or directly involved in the composition of peripheral nerves, including GJB1/Connexin32, MPZ/P0 (myelin protein zero), and PMP22 (peripheral myelin protein 22), are also listed as common causes of CMT1 [1]. Conversely, mutations in regulatory genes, including EGR2 and LITAF/SIMPLE, occur less often (b1%) in CMT1 [1]. The demyelinating forms are usually transmitted in an autosomal dominant fashion (CMT1 or AD-CMT1), while the autosomal recessive types, CMT4 (or AR-CMT1), are most commonly observed in consanguineous populations. In these subtypes, deficits are generally more severe with earlier onset than in the dominant forms. Although several new genes have recently been identified, a large number of recessive cases still cannot be attributed to mutations in the known genes [2]. We report clinical, neurophysiological and pathological findings of a patient with an autosomal recessive CMT4D, also called hereditary motor and sensory neuropathy (HMSN) Lom, due to the p.R148* mutation of N-myc downstream-regulated gene 1 (NDRG1). A 20-year-old girl came to our observation because of walking difficulties, with frequent falls, with onset at the age of 5 years. The patient was of Gypsy origin. No other members of the family were available and no data regarding family history or family origin were known. She had a normal prenatal and neonatal clinical history and normal developmental milestones until the age of 5 years when she started to fall over frequently and she progressively develop bilateral foot drop. On our clinical examination she had