Annals of African Medicine
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Year : 2022  |  Volume : 21  |  Issue : 3  |  Page : 296-298  

Novel transthyretin gene mutation in familial amyloid neuropathy in India: Case

1 Department of Neurology, Dr. D.Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth, Pune, Maharashtra, India
2 Department of Neuropathology, NIMHANS, Bengaluru, Karnataka, India

Date of Submission26-Dec-2021
Date of Decision26-Jan-2022
Date of Acceptance29-Jan-2022
Date of Web Publication26-Sep-2022

Correspondence Address:
Furqan Mohd Akram Khan
Department of Neurology, Dr. D.Y. Patil Medical College, Hospital and Research Centre, Pimpri, Pune - 411 018, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aam.aam_260_21

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Familial amyloid polyneuropathy (PN), also known as amyloid transthyretin (TTR)-PN is an autosomal dominant adult-onset fatal disease, if not treated. It occurs due to mutations in (TTR) gene which leads to a faulty TTR protein which folds up to form amyloid and gets deposited mainly on nerves and causes length-dependent PN and autonomic dysfunction. We report a case of a 45-year-old female who presented with symptoms of painful peripheral neuropathy for 5 months, a history of deafness for 5 years, and cardiac pacemaker implantation 2 years ago for complete heart block. She denied any symptoms of autonomic dysfunction. Her brother with similar symptoms died of cardiac arrest at the age of 50 years. Clinical examination was suggestive of symmetrical sensorimotor PN. The nerve conduction study was suggestive of axonal sensorimotor PN. Abdominal fat biopsy was negative for amyloid. Sural nerve biopsy was suggestive of amyloid neuropathy. Genetic analysis showed c. 165G > T mutation encoding amino acid p. Lys55Asn on exon-4 of TTR gene. This mutation has not been reported from India.

   Abstract in French 

La polyneuropathie amyloïde familiale (NP), également connue sous le nom de transthyrétine amyloïde (TTR) -PN, est une maladie mortelle autosomique dominante de l'adulte, si elle n'est pas traitée. Il se produit en raison de mutations du gène (TTR) qui conduisent à une protéine TTR défectueuse qui se replie pour former de l'amyloïde et se dépose principalement sur les nerfs et provoque une PN dépendante de la longueur et un dysfonctionnement autonome. Nous rapportons le cas d'une femme de 45 ans qui présentait des symptômes de neuropathie périphérique douloureuse depuis 5 mois, des antécédents de surdité depuis 5 ans et l'implantation d'un stimulateur cardiaque il y a 2 ans pour un bloc cardiaque complet. Elle a nié tout symptôme de dysfonctionnement autonome. Son frère présentant des symptômes similaires est décédé d'un arrêt cardiaque à l'âge de 50 ans. L'examen clinique évoquait une NP sensorimotrice symétrique. L'étude de la conduction nerveuse était évocatrice d'une NP sensorimotrice axonale. La biopsie de la graisse abdominale était négative pour l'amyloïde. La biopsie du nerf sural était évocatrice d'une neuropathie amyloïde. L'analyse génétique a montré c. Mutation 165G > T codant pour l'acide aminé p. Lys55Asn sur l'exon-4 du gène TTR. Cette mutation n'a pas été signalée en Inde.
Mots clés: Neuropathie amyloïde familiale, tests génétiques, biopsie nerveuse, amylose à transthyrétine

Keywords: Familial amyloid neuropathy, Genetic testing, nerve biopsy, transthyretin amyloidosis

How to cite this article:
Rohatgi S, Nirhale S, Manohar P, Rao P, Naphade P, Khan FM, Dave D, Sravya Kotaru V V, Gupta S, Gitay A, Dubey P. Novel transthyretin gene mutation in familial amyloid neuropathy in India: Case. Ann Afr Med 2022;21:296-8

How to cite this URL:
Rohatgi S, Nirhale S, Manohar P, Rao P, Naphade P, Khan FM, Dave D, Sravya Kotaru V V, Gupta S, Gitay A, Dubey P. Novel transthyretin gene mutation in familial amyloid neuropathy in India: Case. Ann Afr Med [serial online] 2022 [cited 2023 Jun 1];21:296-8. Available from:

   Introduction Top

Familial amyloid neuropathy is an inherited, adult-onset, progressive disease caused by mutations in the transthyretin (TTR) gene. It is characterized by the extracellular deposition of insoluble amyloid fibrils in the peripheral nervous system. It typically presents as progressive, length-dependent, mixed sensory, and motor peripheral polyneuropathy (PN) with variable autonomic disturbances. The diagnosis can be confirmed by demonstration of amyloid deposits in biopsy specimens, but identification of an amyloidogenic TTR variant by gene sequencing is the diagnostic gold standard.[1] Negative biopsies remain a frequent cause of diagnostic delay. The sensitivity of biopsy depends on multiple factors, such as pathologist experience, biopsied tissue, and patient's age. A negative biopsy does not rule out the diagnosis because amyloid fibrils have a patchy distribution in tissues which may result in a negative biopsy and may require multiple biopsies for diagnosis from different sites in some cases.[2]

We report a case of a 45-year-old female, who presented with progressive painful symmetric PN, complete heart block, and sensorineural hearing loss. She was diagnosed as a case of familial amyloid PN (FAP) based on the findings of sural nerve biopsy and gene sequencing.

   Case Report Top

A 45-year-old female presented with history of deafness for 5 years and progressively increasing burning pain and paresthesia in both lower limbs followed by the upper limbs for the past 1 year. She had a history of pacemaker implantation 2 years ago for complete heart block. She denied any history of autonomic symptoms at the time of presentation. There was no history of diabetes, exposure to any drugs or toxins, skin rash, mucosal ulcers, or joint pains. Her elder brother had similar symptoms and died of sudden cardiac arrest at the age of 55 years.

General examination was unremarkable. There was no postural hypotension or organomegaly. She had moderate sensorineural hearing loss in both ears.

Neurological examination revealed normal bulk of muscles, there was distal symmetrical weakness (Grade 4/5 at ankle and 4+/5 at wrists). Glove and stocking types of sensory loss were present. Ankle jerks were absent bilaterally. Peripheral nerves were not thickened. Nerve conduction study was suggestive of axonal sensorimotor PN, more in lower limbs. A differential diagnosis of hereditary sensorimotor neuropathy (axonal) or vasculitic neuropathy was made. Pure-tone audiometry was suggestive of bilateral severe sensorineural hearing loss. Routine hematological and biochemical investigations were normal. Antinuclear antibodies, anti-neutrophilic cytoplasmic antibodies, HIV, and hepatitis B and C were negative. Echocardiogram revealed normal ejection fraction and no diastolic dysfunction. Cardiac magnetic resonance imaging (MRI) was attempted but because of pacemaker artifacts, it was unsatisfactory. Ultrasound abdomen was normal. Abdominal fat pad biopsy was negative for amyloid. Sural nerve biopsy [Figure 1] revealed amyloid deposition in the vessel wall and interstitium consistent with amyloid PN. Genetic analysis showed a likely pathogenic heterozygous c.168G >T mutation in the TTR gene located at exon-4 on chromosome 18q, altering the encoded amino acid, p. Lys55Asn. Another heterozygous mutation in exon-2 c.268C >G encoding amino acid (p. Leu90Val) was detected which is associated with nonsyndromic hearing loss. The prognosis was discussed with the patient and was given the option of liver transplant or injection patisiran, but she could not afford it. She was also advised genetic analysis of offspring.
Figure 1: Sural nerve biopsy (a) cross-section of nerve fascicle shows amorphous homogeneous eosinophilic amyloid deposits (arrow) in the endoneurial vessel wall (v); (b) the deposits displayed characteristic apple-green birefringence (arrow) on polarized light; and (c) significant loss of small diameter fibers. (a: H and E; b: Congo red stain under cross-polarized light; c: Kulchitsky Pal stain [scale bars – 20 microns])

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   Discussion Top

There are three main types of FAP depending on the precursor protein of amyloid: TTR, apolipoprotein A-1, and gelsolin.[3] The clinical spectrum in TTR gene mutation includes familial amyloidotic PN, familial amyloidotic cardiomyopathy, and familial leptomeningeal amyloidosis.

The global prevalence of TTR amyloid PN is estimated at 38,000 cases.[4] The exact prevalence in India is not known but few case reports from India have been published.[5],[6]

The age of presentation is always in adulthood and variable.[7] Early-onset is in the third decade mostly in endemic regions and the fifth to sixth decade in nonendemic regions. Usual presentation is length-dependent PN with autonomic dysfunctions and/or cardiac involvement. Patients with early-onset presentation have rapid progression with autonomic dysfunction. While in patients with a late-onset, the PN progresses slowly, with cardiac involvement but with less autonomic dysfunction.

The diagnosis requires demonstration of amyloid deposits in biopsy specimens, but the diagnostic gold standard is the identification of an amyloidogenic TTR variant by gene sequencing. Biopsy of abdominal subcutaneous fat is the first-line investigation in the suspected case, and it has sensitivity of approximately 50%. Conversely, nerve biopsy is usually considered a second-line investigation, has a higher sensitivity cited as high as 80%.[2] As in our case, the abdominal subcutaneous fat biopsy was negative, and the sural nerve biopsy demonstrated amyloid deposits. Highlighting the importance of nerve biopsy in diagnosis, which should be done in all suspected cases of amyloid PN with negative abdominal subcutaneous fat biopsy.

More than 100 genotypes have been identified in TTR gene across 40 countries, mainly in Portugal, Sweden, Japan, China, Taiwan, and South Korea. The most common mutation is Val30Met in TTR gene followed by Gly83Arg2. There is wide heterogeneity in phenotypes in one genotype regarding the age of onset and expression of amyloid TTR gene.[4] There is only one article with series of four cases where genetic analysis showed mutations on TTR gene on different codons and different amino acid substitutions.[8]

This is the first report of p. Lys55Asn mutation in TTR gene reported from India. This variant has been classified as “likely pathogenic” in the ClinVar database.[9]

Our patient had a second heterozygous mutation at exon-2 of GJB3 gene c.268>G encoding p. Ley90Val which is associated with nonsyndromic hearing loss.[10]

Our case had a positive family history, short history of neuropathy, complete heart block, and deafness without autonomic involvement. She was diagnosed very early in the course of disease. She may develop symptoms of autonomic involvement in future.

Liver transplant is the first-line therapy to remove the production of mutant TTR. Patisiran binds to the TTR protein and prevents its deformation through RNA interference. It helps in reducing the level of TTR protein made in the liver and the resultant amyloid deposits in the tissues. It is available in India. Tafamidis and diflunisal stabilize TTR and delay the progression of disease in the early stages.

This case highlights the importance of nerve biopsy and genetic analysis in all suspected cases of axonal neuropathy with positive family history.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Adams D, Ando Y, Beirão JM, Coelho T, Gertz MA, Gillmore JD, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol 2021;268:2109-22.  Back to cited text no. 1
Luigetti M, Romozzi M, Bisogni G, Cardellini D, Cavallaro T, Di Paolantonio A, et al. hATTR pathology: Nerve biopsy results from Italian referral centers. Brain Sci 2020;10:780.  Back to cited text no. 2
Plante-Bordeneuve V. Update in the diagnosis and management of transthyretin familial amyloid polyneuropathy. J Neurol 2014;261:1227-33.  Back to cited text no. 3
Waddington-Cruz M, Schmidt H, Botteman MF, Carter JA, Stewart M, Hopps M, et al. Epidemiological and clinical characteristics of symptomatic hereditary transthyretin amyloid polyneuropathy: A global case series. Orphanet J Rare Dis 2019;14:34.  Back to cited text no. 4
Venkatesh P, Selvan H, Singh SB, Gupta D, Kashyap S, Temkar S, et al. Vitreous amyloidosis: Ocular, systemic, and genetic insights. Ophthalmology 2017;124:1014-22.  Back to cited text no. 5
Nagappa M, Sinha S, Mahadevan A, Bindu PS, Krishnan KA, Ray S, et al. Genetically established familial amyloidotic polyneuropathy from India: Narrating the diagnostic “Odyssey” and a mini review. Neurol India 2020;68:1084-91.  Back to cited text no. 6
[PUBMED]  [Full text]  
Ikeda S. Transthyretin Val30Met familial amyloid polyneuropathy: A considerably different clinical picture and natural course in endemic and non-endemic areas. J Neurol Neurosurg Psychiatry 2012;83:121.  Back to cited text no. 7
Sekijima Y, Ueda M, Koike H, Misawa S, Ishii T, Ando Y. Diagnosis and management of transthyretin familial amyloid polyneuropathy in Japan: Red-flag symptom clusters and treatment algorithm. Orphanet J Rare Dis 2018;13:6.  Back to cited text no. 8
Available from:[Last accessed on 12 Dec 2021].  Back to cited text no. 9
Aliazami F, Farhud D, Zarif-Yeganeh M, Salehi S, Hosseinipour A, Sasanfar R, et al. Gjb3 gene mutations in non-syndromic hearing loss of bloch, kurd, and turkmen ethnicities in Iran. Iran J Public Health 2020;49:2128-35.  Back to cited text no. 10


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