Year : 2010 | Volume
: 13 | Issue : 2 | Page : 142--144
Familial amyloidotic polyneuropathy with muscle, vitreous, leptomeningeal, and cardiac involvement: Phenotypic, pathological, and MRI description
DK Prashantha1, Arun B Taly1, Sanjib Sinha1, T Chikkabasavaiah Yasha2, Narayanappa Gayathri2, J. M. E Kovur1, Joy Vijayan1,
1 Departments of Neurology, Neuroimaging and Interventional Radiology, NIMHANS, Bangalore, India
2 Department of Neuropathology, NIMHANS, Bangalore, India
Arun B Taly
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Hosur Road, Bangalore - 560 029
Familial amyloidotic polyneuropathy (FAN type 1) is a rare systemic disease that causes severe and disabling peripheral neuropathy. We describe the phenotypic, radiological, and pathological characteristics of a patient with familial amyloid polyneuropathy type 1 who had evidence of motor-sensory-autonomic neuropathy, ocular vitreous deposits, diffuse leptomeningeal involvement, and hypertrophic cardiomyopathy. Muscle involvement, an infrequently reported feature, was also observed. Early recognition of the disease has significant therapeutic implications.
|How to cite this article:|
Prashantha D K, Taly AB, Sinha S, Yasha T C, Gayathri N, Kovur J, Vijayan J. Familial amyloidotic polyneuropathy with muscle, vitreous, leptomeningeal, and cardiac involvement: Phenotypic, pathological, and MRI description.Ann Indian Acad Neurol 2010;13:142-144
|How to cite this URL:|
Prashantha D K, Taly AB, Sinha S, Yasha T C, Gayathri N, Kovur J, Vijayan J. Familial amyloidotic polyneuropathy with muscle, vitreous, leptomeningeal, and cardiac involvement: Phenotypic, pathological, and MRI description. Ann Indian Acad Neurol [serial online] 2010 [cited 2020 Jul 11 ];13:142-144
Available from: http://www.annalsofian.org/text.asp?2010/13/2/142/64642
Familial amyloidotic polyneuropathy (FAN) is a form of fatal hereditary amyloidosis due to mutations in various genes. Based on the proteins accumulated, there are four types. Type 1, the most common form, is due to a mutation in transthyretin (TTR) and is characterized by peripheral and autonomic neuropathy, as well as vitreous and leptomeningeal involvement.  Primary amyloidosis is more prevalent than FAN but it mainly involves the small fibers of peripheral nerves or causes the carpal tunnel syndrome. 
We report a patient of FAN type 1 with peripheral nerve, autonomic nervous system, muscle, vitreous, leptomeningial, and heart involvement and discuss the diagnostic dilemmas.
A 23-year-old male graduate presented with insidious onset, gradually progressive weakness and numbness of both lower limbs and recurrent vomiting of 16 months' duration. He had had blurring of vision, urgency and hesitancy of micturition, erectile dysfunction, and weight loss over the last 6 months. At the beginning of his illness he had been treated at a peripheral center, where he was investigated for recurrent vomiting with ultrasound of the abdomen and upper gastrointestinal endoscopy. These tests did not reveal any abnormality and his vomiting subsided with antiemetics and proton pump inhibitors. There was no other significant history in the past. He had been born to nonconsanguineous parents and there was no family history of systemic or neurological illness.
The patient weighed 35 kg and had pallor, bilateral pedal edema, and thyromegaly. His vital signs were stable. Ocular examination revealed dilated (8 mm) and nonreactive pupils and vitreous deposits; his visual acuity was 6/24 in both the eyes. The fundi could not be visualized clearly. He had hypotonia in all four limbs, moderate weakness of handgrip and of the intrinsic muscles of the hand on both sides, and profound weakness of the dorsiflexors and plantar flexors of the ankle and toes (MRC: 1/5). Muscle stretch reflexes were normal in the upper extremities. Knee jerks were brisk but ankle jerks were absent. There was no plantar response. He had graded sensory impairment in his lower limbs up to the knee for all sensory modalities. The skin below the knees was dry and shiny, with hair loss. The rest of the examination was unremarkable.
The complete hemogram revealed anemia (Hb: 9 gm/dl) and a rapid ESR (74 mm in the 1 st hour). Routine analysis of urine was normal. Serum biochemistry showed a low serum albumin (3.3 gm/dl; normal > 3.5 gm/dl), while glucose, renal and liver function tests, and electrolytes were normal. ELISA test for HIV and investigations for vasculitis, including serum ANA, ANCA, dsDNA, LE cell, and RA factor, were negative. The cerebrovascular fluid (CSF) was acellular, with elevated protein of 170 mg/dl (normal:  These investigations could not be carried out in our case due to lack of facilities. TTR is a normal tetrameric protein that is involved in the transport of thyroxine and retinol-binding protein. It is located in chromosome 18 and is produced mainly in the liver, retinal pigment epithelium, choroid plexus, and yolk sac. It has an autosomal dominant pattern of inheritance, and a family history may not be present in more than 50% of cases.  More than 100 causative mutations have been described, with the commonest being FAP ATTR V30M.  Familial amyloidosis was first described in 1929 by DeBruyn and Stern and constitutes about 2-4% of all patients of amyloidosis.  There are four major types of FAN, depending on the type of aberrant proteins accumulated (e.g., TTR, ApoA1, or gelsolin). Type 1 FAN is the commonest and presents with peripheral and autonomic neuropathy, and vitreous and leptomeningeal involvement. Type 2 is the restricted form of type 1 and manifests with carpal tunnel syndrome, but no autonomic involvement. Type 3 is characterized by duodenal ulcers and early renal involvement. Type 4 manifests with cranial nerve involvement and corneal dystrophy.  Our patient had features of type 1 FAN.
TTR-related FAN was first described from Japan and certain European countries. It is an invariably progressive disease, with a mean age of onset of 35.3 years; it reaches the terminal stage in around 10 years.  The dominant phenotype shows sensory disturbances (100%), motor weakness and wasting (80%), autonomic dysfunction (>80%), and leptomeningeal and ocular involvement (20%).  Cerebral involvement is rare but, when present, manifests with cerebral infarction and hemorrhage, dementia, hydrocephalus, seizures, and pyramidal signs.  This might be due to amyloid deposits in the leptomeningeal and cerebral vessels causing ischemia and impaired autoregulation.  These patients have evidence of multisystem involvement, including cardiac and renal involvement, which often leads to early death. Survival is for 10-15 years. MRI studies in these patients have shown enhancement of the leptomeninges, labyrinth, dentate ligament, and vitreous body following gadolinium administration. , The present case did have extensive enhancement of leptomeninges and vitreous. Liver transplantation has been tried to halt the progression of the disease.
Our patient had demonstrable amyloid deposition in nerve, muscle, conjunctiva, and vitreous. Spuler et al. (1998) studied 13 adults with muscle weakness of 3 months' to 4 years' duration with a diagnosis of systemic amyloidosis and demonstrated congophilic deposits around blood vessels and muscle fibers in all the muscle specimens. The authors stressed the importance of fluorescent Congo red stain as a routine procedure in the diagnosis of amyloidosis.  Muscle involvement was also studied in another series of 35 patients with amyloid neuropathy, and 9 of the 25 patients of FAN had muscle involvement.  Amyloid myopathy in a 62-year-old man with progressive proximal weakness has been reported. This diagnosis should always be a consideration in adults with progressive neuromuscular weakness of uncertain cause.  Neuropathy is attributed to preferential deposition of amyloid in the sensory and autonomic ganglia, which causes axonal degeneration. Also, there is endoneurial edema due to the amyloid, resulting in ischemia. Nerve biopsy in the early stages may reveal a relatively greater reduction of small myelinated and unmyelinated fibers. In the advanced stages of the illness, large myelinated fibers also decrease. The largest and most numerous amyloid deposits are seen within the nerve fascicles.
This is one of only two case reports of FAN from India with ocular, skeletal muscle, cardiac, and leptomeningeal involvement; the other case, reported from north India, was that of a lady presenting with sensory/motor neuropathy, without any systemic involvement.  A high index of suspicion, with careful attention to clinical clues and histological characteristics are essential for accurate diagnosis. Genetic analysis is essential for confirmation. Symptomatic treatment for dysautonomia and visual disturbances, along with rehabilitative measures, can improve the quality of life in these patients.
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