Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial amyloidotic polyneuropathy type IV, one of the hereditary systemic amyloidoses with an autosomal dominant trait, is clinically characterized by cranial neuropathy and corneal lattice dystrophy. Recent biochemical studies have indicated that the amyloid fibril protein in FAP IV is related to gelsolin, an actin-modulating protein. Cases were clustered in the Finnish population and only a few cases have been reported from other populations. Here we described a large kindred with FAP IV as the first report in Japan. This family comprises 42 members in three generations with 14 affected individuals. We examined 7 patients at the age ranging from 43 to 80 years. All cases have corneal lattice dystrophy type II. The disease begins with slowly progressive facial weakness in the fifth or sixth decade of life and consequently the V, XII, IX and X cranial nerves become involved. Peripheral neuropathy of the extremities remained mild until late of life. Microscopy of skin biopsy samples showed deposits of amyloid around the eccrine glands, sebaceous glands, epidermal-dermal junction and blood vessel walls. Immunohistochemistry of the skin revealed the immunopositive material against a monoclonal antibody to gelsolin in the amyloid deposits. Molecular analysis of the gelsolin gene is now in progress.
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PMID:[Familial amyloidotic polyneuropathy type IV (Finnish type)--the first description of a large kindred in Japan]. 133 23

Among 17 patients with amyloid polyneuropathy type IV in a Japanese family, we found a 72-year-old woman, who showed extraocular symptoms approximately 10 years after the onset of the disease. she developed weakness of the right facial muscles and dysarthria at age 57. She had atrophy and disturbance of movement of the tongue, along with difficulty in swallowing at age 62. At the age of 66, she felt diplopia when she looked toward the left, followed by difficulty of ocular movement. These manifestations progressed and at age 72, she was found to have mild ptopsis, mild to moderate disturbance of almost all extraocular muscles, moderate to severe disturbance of facial, masseter, pharyngeal, tongue and neck muscles. She also had slight weakness and atrophy of the limb and truncal muscles together with slight loss of pain and vibratory sensations in the distal parts of the limbs. FAP IV has sometimes been called cranial amyloidosis, but motor disturbance is limited to the middle and lower cranial nerve territories in the majority of the reported cases, and manifestations of the extraocular muscles are quite rare. According to the present investigation of the world literature, this is the second case of FAP IV with extraocular muscle involvement.
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PMID:[Familial amyloidosis of the Finnish type (FAP) with extraocular muscle involvement]. 856 42

A 64-year-old man has suffered from intractable diarrhea since January 1990. He noticed numbness and weakness in the distal portion of four extremities in the following several months. His symptoms were gradually progressive. In June 1992, neurological examination revealed mild muscular atrophy and weakness in the proximal and distal portions of four extremities. There were paresthesia and severe impairment of superficial sensations in the lower limbs, lower half of the trunk and upper limbs. All deep tendon reflexes were reduced or absent. Autonomic dysfunctions such as orthostatic hypotension, impotence and diarrhea were evident. On sural nerve biopsy, myelinated fibers showing axonal degeneration were predominantly seen, and densities of both myelinated and unmyelinated fibers were markedly decreased. No amyloid deposits were found in the endoneurium. Amyloid deposition was identified in the gastric mucosa by Congo red staining and immunostaining with anti-transthyretin (TTR) antibody. Edman degradation showed one amino acid substitution of Lys for Glu at position 61 in the TTR-peptides from the serum. Direct DNA sequencing revealed a new point mutation in the 61st codon of TTR gene. The same point mutation of TTR gene was identified in the DNAs from his 67-year-old brother and 63-year-old sister and one of the paternal cousins, a 64-year-old woman, although their clinical symptoms and signs were negative. Clinical features such as late onset of the symptoms and signs and presence of carriers in their sixties in this family are unique and atypical as compared with those of more frequent Val30-->Met FAP families. A variant TTR, characterized by a Glu61-->Lys substitution (a basic-for-acidic amino acid substitution) found in this family, has not been reported in the literature. In the case of the examination of the patients with autonomic and sensory symptoms and signs of unknown etiology, amyloidotic polyneuropathies, including FAP even in the absence of the family history, should be differentiated. When FAP is highly suspected, the combination of family study and DNA analysis of a possible variant TTR is indispensable for the establishment of the diagnosis.
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PMID:[A late onset familial amyloidotic polyneuropathy (FAP) with a novel variant transthyretin characterized by a basic-for-acidic amino acid substitution (Glu61-->Lys)]. 897 29

Japanese familial amyloid polyneuropathy (FAP type I) is characterized clinically by autonomic and sensorimotor polyneuropathy. Bulbar palsy or lower cranial amyloid neuropathy has not been reported in this disease. We report a 72-year-old man with senile onset FAP type I, who developed bulbar palsy and sensorimotor polyneuropathy without autonomic failures. He noticed dysesthesia and muscle weakness in the feet at the age of 67 years. Neurological examination showed bulbar signs and sensorimotor polyneuropathy, but not autonomic neuropathy. Electromyography showed denervation in the tongue and extremities. Sural nerve biopsy revealed a profound reduction of myelinated fibers. Neuropathological studies indicated axonal degeneration and transthyretin-amyloid deposits in the peripheral nerves and hypoglossal nerves or roots. DNA analysis demonstrated transthyretinMet30 mutation. We provide the novel possibility that bulbar palsy, due to amyloid neuropathy, can occur in FAP type I. Copyright Rapid Science Ltd
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PMID:Bulbar palsy in senile onset familial amyloid polyneuropathy (30Val-->Met): transthyretin-amyloid deposits in the hypoglossal nerve root. 1021 Aug 34

A nationwide study of CMT and FAP has been performed. In FAP TTR Met30 families with late onset, neuropathy showed male preponderance, low penetrance, little relationship to endemic foci, sensorimotor symptoms beginning distally in the lower extremities with disturbance of both superficial and deep sensation, and relatively mild autonomic symptoms, consistent with pathological findings. In contrast, families with early onset showed higher penetrance, concentration in endemic foci, predominant loss of superficial sensation, severe autonomic dysfunction. Demyelinating versus axonal phenotypes are major issues in CMT. CMT1A duplication caused mainly demyelinating phenotype, while axonal features were variably present. In CMT1B, two distinctive phenotypic subgroups were present: one showed exclusively axonal features; and another was exclusively demyelinating. CMTX showed intermediate slowing of MCV, predominantly axonal features, and relatively mild demyelinating pathology. Differing from CMT1B, these axonal and demyelinating features were concomitantly present in individual patients in variable extent. Median nerve MCVs were well maintained independently of age, disease duration, and severity of clinical and pathologic abnormalities. Amplitude of CMAPs was correlated significantly with distal muscle strength, indicating that clinical weakness results from reduced numbers of functional large axons, not from demyelination. CMT patients with demyelinating and/or axonal features, together with FAP patients with axonal feature and scattered distribution, are supposed to increase according to the development of genetic diagnosis for hereditary neuropathy that verifies late-onset, de novo and asymptomatic patients.
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PMID:[Clinical phenotype of Charcot-Marie-Tooth disease (CMT) and familial amyloid polyneuropathy (FAP)]. 1515 60

Transthyretin familial amyloid polyneuropathies (TTR-FAPs) are autosomal dominant neuropathies of fatal outcome within 10 years after inaugural symptoms. Late diagnosis in patients who present as nonfamilial cases delays adequate management and genetic counseling. Clinical data of the 90 patients who presented as nonfamilial cases of the 300 patients of our cohort of patients with TTR-FAP were reviewed. They were 21 women and 69 men with a mean age at onset of 61 (extremes: 38 to 78 years) and 17 different mutations of the TTR gene including Val30Met (38 cases), Ser77Tyr (16 cases), Ile107Val (15 cases), and Ser77Phe (5 cases). Initial manifestations included mainly limb paresthesias (49 patients) or pain (17 patients). Walking difficulty and weakness (five patients) and cardiac or gastrointestinal manifestations (five patients), were less common at onset. Mean interval to diagnosis was 4 years (range 1 to 10 years); 18 cases were mistaken for chronic inflammatory demyelinating polyneuropathy, which was the most common diagnostic error. At referral a length-dependent sensory loss affected the lower limbs in 2, all four limbs in 20, and four limbs and anterior trunk in 77 patients. All sensations were affected in 60 patients (67%), while small fiber dysfunction predominated in the others. Severe dysautonomia affected 80 patients (90%), with postural hypotension in 52, gastrointestinal dysfunction in 50, impotence in 58 of 69 men, and sphincter disturbance in 31. Twelve patients required a cardiac pacemaker. Nerve biopsy was diagnostic in 54 of 65 patients and salivary gland biopsy in 20 of 30. Decreased nerve conduction velocity, increased CSF protein, negative biopsy findings, and false immunolabeling of amyloid deposits were the main causes of diagnostic errors. We conclude that DNA testing, which is the most reliable test for TTR-FAP, should be performed in patients with a progressive length-dependent small fiber polyneuropathy of unknown origin, especially when associated with autonomic dysfunction.
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PMID:Diagnostic pitfalls in sporadic transthyretin familial amyloid polyneuropathy (TTR-FAP). 1842 77

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a fatal clinical disorder characterized by extracellular deposition of abnormal fibrils derived from misfolded, normally soluble transthyretin (TTR) molecules. The disease is most commonly caused by a point mutation within the TTR gene inherited in an autosomal dominant fashion. Over 100 of such mutations have been identified, leading to destabilization of the physiological TTR tetramer. As a result, many monomers originate with a tendency for spontaneous conformational changes and self-aggregation. The main clinical feature of TTR-FAP is progressive sensorimotor and autonomic neuropathy. In the beginning, this polyneuropathy predominantly involves small unmyelinated nerve fibers with the result of dissociated sensory loss disproportionately affecting sensation of pain and temperature. Autonomic neuropathy typically accompanies sensory deficits early in the disease course. The symptoms include orthostatic hypotension, constipation alternating with diarrhea, erectile dysfunction, anhydrosis, and urinary retention or incontinence. Later, involvement of motor fibers causes rapidly progressive weakness and gait disturbances. In addition to the peripheral nervous system, the heart and the gut are frequently affected. Onset of symptoms is bimodal, with one peak at age 33 years (early onset) and another distinct peak in the sixth decade of life (late onset). The course of TTR-FAP is uniformly progressive and fatal. Death occurs an average of 10.8 years after the onset of symptoms in Portuguese patients, and 7.3 years in late-onset Japanese patients. Common causes include cachexia, cardiac failure, arrhythmia, and secondary infections. Liver transplantation is the standard therapy for patients who are in a clinical condition good enough to tolerate this intervention because it stops progression of neuropathy by removing the main source of mutant TTR. Recently, orally administered tafamidis meglumine has been approved by European authorities for treatment of FAP. The substance has been shown to stabilize the TTR tetramer, thereby improving the outcome of patients with TTR-FAP. Various other strategies have been studied in vitro to prevent TTR amyloidosis, including gene therapy, immunization, dissolution of TTR aggregates, and free radical scavengers, but none of them is ready for clinical use so far.
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PMID:Familial amyloidotic polyneuropathy: current and emerging treatment options for transthyretin-mediated amyloidosis. 2377 79

Protein stabilization and oligonucleotide therapies are being tested in transthyretin amyloid polyneuropathy (TTR FAP) trials. From retrospective analysis of 97 untreated TTR FAP patients, we test the adequacy of Neuropathy Impairment Score+7 tests (NIS+7) and modifications to comprehensively score impairments for use in such therapeutic trials. Our data confirms that TTR FAP usually is a sensorimotor polyneuropathy with autonomic features which usually is symmetric, length dependent, lower limb predominant and progressive. NIS+7 adequately assesses weakness and muscle stretch reflexes without ceiling effects but not sensation loss, autonomic dysfunction or nerve conduction abnormalities. Three modifications of NIS+7 are suggested: 1) use of Smart Somatotopic Quantitative Sensation Testing (S ST QSTing); 2) choice of new autonomic assessments, e.g., sudomotor testing of distributed anatomical sites; and 3) use of only compound muscle action potential amplitudes (of ulnar, peroneal and tibial nerves) and sensory nerve action potentials of ulnar and sural nerve - than the previously recommended attributes suggested for the sensitive detection of diabetic sensorimotor polyneuropathy. These modifications of NIS+7 if used in therapeutic trials should improve characterization and quantification of sensation and autonomic impairment in TTR FAP and provide better nerve conduction tests.
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PMID:Retrospective study of a TTR FAP cohort to modify NIS+7 for therapeutic trials. 2501 80

A 76-year-old woman was admitted to our hospital because of transthyretin-related familial amyloid polyneuropathy (TTR-FAP). She had developed bilateral vitreous opacity at the age of 58 and paroxysmal atrial fibrillation at the age of 62. She suffered gait disturbance and dysesthesia of the limbs at the age of 68 and was diagnosed with FAP involving a homozygous Val30Met mutation in the amyloidogenic transthyretin (ATTR) gene after a genetic test. Her parents were cousins, and her aunt's medical history included pacemaker implantation and polyneuropathy. At the age of 74, the patient developed gait disturbance and dysesthesia of her extremities. A neurological examination revealed visual loss, hearing impairment, distal muscle weakness, dysesthesia, and decreased sensation in all modalities in her extremities. She could neither walk nor remain standing without support. Brain magnetic resonance imaging (MRI) revealed a low intensity lesion on the surface of the cerebellum on T2*-weighted images and susceptibility-weighted images. A low intensity pattern that was indicative of the classical type of superficial siderosis was detected. At the age of 76, when she was admitted to our hospital because of the deterioration of her gait disturbance and dysesthesia, brain MRI showed that the patient's cerebellar atrophy and hemosiderin deposition had worsened. Some reports suggest that FAP patients that are homozygous for the ATTR Val30Met mutation are more likely to develop central nervous involvement than those that are heterozygous for the mutation. Superficial siderosis may be responsible for the central nervous involvement.
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PMID:Familial amyloid polyneuropathy involving a homozygous Val30Met mutation in the amyloidogenic transthyretin gene presenting with superficial siderosis: a case report. 2721 78

We herein report the case of an 84-year-old woman with transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP-ATTR Val30Met), representing a very old case. The patient had muscle weakness and sensory disturbances in her extremities caused by severe peripheral neuropathy. She also had vitreous opacity and orthostatic hypotension, and pyrophosphate scintigraphy showed a myocardial accumulation. Esophagogastroduodenoscopy revealed mucosal amyloid deposits, positive in anti-TTR antibody staining. A TTR gene analysis isolated the Val30Met mutation. More than a few cases of FAP-ATTR develop late, like our own, and their familial histories are often obscure in non-endemic areas, which might make a diagnosis difficult.
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PMID:Late-onset Transthyretin (TTR)-familial Amyloid Polyneuropathy (FAP) with a Long Disease Duration from Non-endemic Areas in Japan. 3033 6


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