Claudia Stancanelli

Transthyretin‐related familial amyloidotic polyneuropathy: description of a cohort of patients with Leu64 mutation and late onset

Transthyretin‐related familial amyloidotic polyneuropathy (TTR‐FAP) usually presents itself as a progressive sensorimotor polyneuropathy with severe autonomic dysfunction and cardiomyopathy. Eighteen patients carrying the Leu64 mutation underwent a series of regular follow‐ups, including: neurological examination, electroneurography, electromyography, electrocardiography and echocardiography, blood analysis, a questionnaire on autonomic symptoms, cardiovascular autonomic tests and a 99mTc‐DPD examination study. A late onset of a slowly progressive disease which reached its terminal stage after about 10  years was observed. The onset was mainly a length‐dependent sensory neuropathy, although a focal onset with carpal tunnel syndrome was detected in three patients. At the onset of the disease, autonomic dysfunction was present in a small number of patients, but, within a few years, this had manifested in all members of the sample group. The only extra‐neurological manifestations were cardiac related. It is reasonable to consider Southern Italy as an endemic focus of TTR‐FAP. An underestimation of disease prevalence could be caused by a late onset of FAP, which can manifest in patients up to their late 70s. Follow‐up of asymptomatic individuals may permit the early detection of symptoms and signs, allowing a detailed record of the natural history of the disease from the beginning and facilitating prompt treatment.

Charcot–Marie–Tooth 2F: phenotypic presentation of the Arg136Leu HSP27 mutation in a multigenerational family

Abstract Mutations in the small heat-shock protein HSP27 gene are associated with distal hereditary motor neuropathy and with the axonal form of Charcot–Marie–Tooth disease type 2. We present the clinical and electrophysiological data on a multigenerational family with the p.Arg136Leu HSP27 mutation. Atypical features such as deafness and pyramidal signs were present in our cases adding new data to the large spectrum of HSP27-related phenotype.

Transthyretin-Related Familial Amyloid Polyneuropathy (TTR-FAP): A Single-Center Experience in Sicily, an Italian Endemic Area

Abstract Background: Familial amyloid polyneuropathy related to transthyretin gene (TTR-FAP) is a life-threatening disease transmitted as an autosomal dominant trait. Val30Met mutation accounts for the majority of the patients with large endemic foci especially in Portugal, Sweden and Japan. However, more than one hundred other mutations have been described worldwide. A great phenotypic variability among patients with late- and early-onset has been reported. Objective: To present a detailed report of TTR-FAP patients diagnosed in our tertiary neuromuscular center, in a 20-year period. Methods: Clinical informations were gathered through the database of our center. Results: The study involved 76 individuals carrying a TTR-FAP mutation. Three phenotypes were identified, each corresponding to a different TTR variant, homogeneous within and heterogeneous between each other: i) Glu89Gln mutation, characterised by 5th – 6th decade onset, neuropathy as presenting symptoms, early heart dysfunction, cardiomyopathy as major cause of mortality followed by dysautonomia and cachexia; ii) Phe64Leu mutation, marked by familiarity reported in one-half of cases, late onset, severe peripheral neuropathy, moderate dysautonomia and mild cardiomyopathy, death for wasting syndrome; iii) Thr49Ala mutation, distinguished by onset in the 5th decade, autonomic disturbances as inaugural symptoms which may remain isolated for many years, moderate polyneuropathy, cachexia as major cause of mortality followed by cardiomyopathy. Conclusions: This survey highlighted a prevalence of 8.8/1,000,000 in Sicily Island. Good knowledge of the natural history of the disease according to different TTR mutations allow clinicians to optimise multiprofessional care for patients and to offer carriers a personalized follow-up to reveal first signs of the disease.

Unusual features of central nervous system involvement in CMTX associated with a novel mutation of GJB1 gene

In this study, we report a novel connexin 32 (CX32) mutation associated with cognitive impairment and a differential degree of peripheral nerve involvement. We present clinical, electrophysiological, and neuroimaging data on a family with X‐linked Charcot‐Marie‐Tooth disease caused by a 41A>G mutation of the gap junction protein beta 1 (GJB1) gene. The proband and her sister presented with a severe neuropathy with subclinical cognitive impairment; the probands brother showed severe cognitive impairment and a mild neuropathy. This family report confirms that Charcot‐Marie‐Tooth type X is a clinically heterogeneous group, with great variability of phenotypes, possible severe involvement in females and clinical signs of cognitive impairment. Thus, this novel mutation should be added to the group of CX32 mutations with a central nervous system phenotype.

Non-coding variants contribute to the clinical heterogeneity of TTR amyloidosis

Coding mutations in TTR gene cause a rare hereditary form of systemic amyloidosis, which has a complex genotype–phenotype correlation. We investigated the role of non-coding variants in regulating TTR gene expression and consequently amyloidosis symptoms. We evaluated the genotype–phenotype correlation considering the clinical information of 129 Italian patients with TTR amyloidosis. Then, we conducted a re-sequencing of TTR gene to investigate how non-coding variants affect TTR expression and, consequently, phenotypic presentation in carriers of amyloidogenic mutations. Polygenic scores for genetically determined TTR expression were constructed using data from our re-sequencing analysis and the GTEx (Genotype-Tissue Expression) project. We confirmed a strong phenotypic heterogeneity across coding mutations causing TTR amyloidosis. Considering the effects of non-coding variants on TTR expression, we identified three patient clusters with specific expression patterns associated with certain phenotypic presentations, including late onset, autonomic neurological involvement, and gastrointestinal symptoms. This study provides novel data regarding the role of non-coding variation and the gene expression profiles in patients affected by TTR amyloidosis, also putting forth an approach that could be used to investigate the mechanisms at the basis of the genotype–phenotype correlation of the disease.

Autonomic involvement in subacute and chronic immune-mediated neuropathies.

Autonomic function can be impaired in many disorders in which sympathetic, parasympathetic, and enteric arms of the autonomic nervous system are affected. Signs and symptoms of autonomic involvement are related to impairment of cardiovascular, gastrointestinal, urogenital, thermoregulatory, sudomotor, and pupillomotor autonomic functions. Availability of noninvasive, sensitive, and reproducible tests can help to recognize these disorders and to better understand specific mechanisms of some, potentially treatable, immune-mediated autonomic neuropathies. This paper describes autonomic involvement in immune-mediated neuropathies with a subacute or chronic course.

Considerable post-partum worsening in a patient with CMT2E.

Mutations in neurofilament light polypeptide gene (NEFL) have been reported to cause autosomal dominant (AD) axonal CMT2 (CMT2E), AD demyelinating CMT1 (CMT1F) [1] and autosomal recessive CMT2 [2]. We report clinical, neurophysiological and pathological findings of a patient belonging to a three-generational family that carries the p.Glu396Lys mutation in NEFL gene. Other members of the family (mother and uncle) have been previously described [3]; they presented a moderate to severe sensory–motor neuropathy, with onset between the first and the second decade, and prominent sensory ataxia with hearing loss in the female patient. Our patient is a 32-year-old woman who has complained of mild balance impairment since childhood without any clinical evidence of progression until 3 years ago when, since the 5th week of her first pregnancy, she noticed a rapid worsening with severe walking difficulty and balance impairment. In fact, she started to walk with a stick, especially outdoor. She also had distal numbness and paraesthesias at the four limbs. Neurological examination at the 14th week of her pregnancy revealed ataxic gait with bilateral foot-drop and positive Romberg’s test, along with moderate distal wasting of upper and lower limbs, and bilateral pes cavus. In upper limbs, there was mild weakness of wrist extensors (MRC 4) and severe weakness in hand muscles (MRC grade 1–3). In lower limbs, weakness of ankle dorsiflexion (MRC 3) and severe weakness of extensor hallucis longus (EHL) (MRC 1) was seen, and the patient was areflexic. Sensory examination showed reduction of pinprick sensation below wrists and knees, and reduction of vibration sense below wrists and ankles. Joint position sense was reduced at the toes. Nerve conduction study showed an intermediate sensory-motor neuropathy, with motor conduction velocity which ranged from 27 m/s in the median nerve to 42 m/s in the ulnar, and absent motor action potential in lower limbs. Sensory action potentials were diffusely absent. Normal or negative results were found for haematological and biochemical tests, including ANA, ANCA, C3, C4, hepatitis C markers, glucose tolerance test and thyroid hormones. Similar to other members of this pedigree, there was a delay in BAEP and MEP central components. Due to atypical progression, sural nerve biopsy was performed, to rule out inflammatory processes, and moderate loss of myelinated fibres was seen. There were neither amyloid deposits nor the presence of inflammatory cells. A moderate endoneurial and perineurial edema was seen. Sequencing of the NEFL gene confirmed the same mutation (p.Glu396Lys) as the patient’s mother. Neurological improvement started a few months after delivery even if she continued to complain of moderate weakness at lower limbs with slight difficulty in walking. Previous studies have shown that mutations in NEFL gene can cause a high-variety of peripheral neuropathy phenotype, with clinical impairment ranging from mild to severe and with electrophysiological features that make classification in a specific CMT type (CMT1, CMT2) difficult [1]. Similarly to the family previously described with L. Gentile (&) M. Russo C. Stancanelli A. Mazzeo Department of Neurosciences, Psychiatry and Anesthesiology, AOU ‘‘G. Martino’’, Messina, Italy e-mail: lucagentile84@yahoo.it