The various forms of hereditary motor neuron disorders and their historical descriptions.

Motor neuron disorders comprise a clinically and pathologically heterogeneous group of neurologic diseases characterized by progressive degeneration of motor neurons (including both sporadic and hereditary diseases), affecting the upper motor neurons, lower motor neurons, or both. Hereditary motor neuron disorders themselves represent a vast and heterogeneous group, with numerous clinical and genetic overlaps that can be a source of error. This narrative review aims at providing an overview of the main types of inherited motor neuron disorders by recounting the stages in their historical descriptions. For practical purposes, this review of the literature sets out their various clinical characteristics and updates the list of all the genes involved in the various forms of inherited motor neuron disorders, including spinal muscular atrophy, familial amyotrophic lateral sclerosis, hereditary spastic paraplegia, distal hereditary motor neuropathies/neuronopathies, Kennedy's disease, riboflavin transporter deficiencies, VCPopathy and the neurogenic scapuloperoneal syndrome.

Detailed clinical, physiological and pathological phenotyping can impact access to disease-modifying treatments in ATTR carriers.

BACKGROUND: Hereditary transthyretin amyloidosis is a life-threatening autosomal dominant systemic disease due to pathogenic TTR variants (ATTRv), mostly affecting the peripheral nerves and heart. The disease is characterised by a combination of symptoms, organ involvement and histological amyloid deposition. The available disease-modifying ATTRv treatments (DMTs) are more effective if initiated early. Pathological nerve conduction studies (NCS) results are the cornerstone of large-fibre polyneuropathy diagnosis, but this anomaly occurs late in the disease. We investigated the utility of a multimodal neurological and cardiac evaluation for detecting early disease onset in ATTRv carriers. METHODS: We retrospectively analysed a cohort of ATTRv carriers with normal NCS results regardless of symptoms. Multimodal denervation and infiltration evaluations included a clinical questionnaire (Lauria and New York Heart Association (NYHA)) and examination, intra-epidermal nerve fibre density assessment, autonomic assessment based on heart rate variability, Sudoscan, meta-iodo-benzyl-guanidine scintigraphy, cardiac biomarkers, echocardiography, MRI and searches for amyloidosis on skin biopsy and bone scintigraphy. RESULTS: We included 130 ATTRv carriers (40.8% men, age: 43.6±13.5 years), with 18 amyloidogenic TTR gene mutations, the majority of which was the late-onset Val30Met variant (42.3%). Amyloidosis was detected in 16.9% of mutation carriers, including 9 (6.9%) with overt disease (Lauria>2 or NYHA>1) and 13 asymptomatic carriers (10%) with organ involvement (small-fibre neuropathy or cardiomyopathy). Most of these patients received DMT. Abnormal test results of unknown significance were obtained for 105 carriers (80.8%). Investigations were normal in only three carriers (2.3%). CONCLUSIONS: Multimodal neurological and cardiac investigation of TTRv carriers is crucial for the early detection of ATTRv amyloidosis and initiation of DMT.

Skin amyloid deposits and nerve fiber loss as markers of neuropathy onset and progression in hereditary transthyretin amyloidosis.

BACKGROUND AND PURPOSE: This study was undertaken to assess skin biopsy as a marker of disease onset and severity in hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN), a treatable disease. METHODS: In this single center retrospective study, skin Congo red staining and intraepidermal nerve fiber density (IENFD) were evaluated in symptomatic ATTRv-PN patients and asymptomatic TTR gene mutation carriers between 2012 and 2019. Non-ATTRv subjects with suspected small fiber neuropathy who underwent skin biopsy during the same timespan were used as controls. RESULTS: One hundred eighty-three symptomatic ATTRv-PN patients, 36 asymptomatic carriers, and 537 non-ATTRv patients were included. Skin biopsy demonstrated amyloid depositions in 80% of the 183 symptomatic cases. Skin amyloid deposits were found in 75% of early stage ATTRv-PN patients, and in 14% of asymptomatic carriers. All 183 symptomatic and 34 of 36 asymptomatic patients displayed decreased ankle IENFD with a proximal-distal gradient distribution, and reduced IEFND correlated with disease severity and duration. CONCLUSIONS: Our study demonstrates skin amyloid deposits are a marker of ATTRv-PN disease onset, and decreased IENFD a marker of disease progression. These results are of major importance for the early identification of ATTRv-PN patients in need of disease-modifying treatments.

E-TAN, a technology-enhanced platform with tangible objects for the assessment of visual neglect: A multiple single-case study.

Visual neglect is a frequent and disabling consequence of right brain damage. Traditional paper-and pencil tests of neglect have limited sensitivity and ecological validity. The Baking Tray Task (BTT), instead, approaches real-life situations, because it requires participants to place 16 physical objects on a board. The number of objects placed on the left and right portions of the board provides a clinical index of visual neglect. Here we present E-TAN, a technology-enhanced platform for BTT (E-BTT). E-BTT automatically determines the object locations on the board, and also records the sequence and timing of their placement. We used E-BTT to test 9 patients with right hemisphere damage and compared their performance with that obtained by 115 healthy participants. To this end, we developed a new method of analysis of participants' performance, based on the use of the convex hull described by the objects on the board. This measure provides an estimate of the portion of space processed by each participant and can effectively discriminate neglect patients from patients without neglect. E-TAN allows clinicians to assess visuospatial performance by using a convenient, fast, and relatively automatized procedure, that patients can even perform at home to follow-up the effects of rehabilitation.

Inherited Thrombotic Thrombocytopenic Purpura Revealed by Recurrent Strokes in a Male Adult: Case Report and Literature Review.

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy related to a severe deficiency of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13). In this article, we describe the first case of a young male adult suffering from a hereditary TTP revealed by recurrent strokes, relapsing despite antiplatelet and anticoagulant therapy. Because of the persistent moderate thrombocytopenia, plasmatic ADAMTS13 activity was investigated and was found lower than 5% in the absence of anti-ADAMTS13 IgG. Direct sequencing of ADAMTS13 gene led to the diagnosis of Upschaw-Schulman syndrome (USS). Inherited TTP or USS is a rare autosomal recessive inherited disease leading to a severe deficiency of ADAMTS13 mostly beginning in childhood or in young female adult during pregnancy. Our patient was treated with fresh frozen plasma every 2 weeks. One year after diagnosis, he was free of neurological symptoms. Around 12 cases of inherited TTP diagnosed in adults (outside pregnancy) are described in literature. Only 4 of them exhibited a stroke. This case is the first late onset genetic TTP revealed by recurrent strokes, moderate thrombocytopenia without anemia.