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An Italian family with Ala-47 transthyretin mutation associated with cardiomyopathy and polyneuropathy
Neuromuscular Disorders 10 (2000) 52±55
Case report
www.elsevier.com/locate/nmd
An Italian family with Ala-47 transthyretin mutation associated with cardiomyopathy and polyneuropathy C. Solaro a,*, A. Schenone a, A. Di Sapio b, L. Pradotto b, G.L. Mancardi a, A. Primavera a, A. Mauro b a
Department of Neurological Sciences and Rehabilitation, University of Genoa, Via De Toni 5, 16132 Genoa, Italy b Department of Neurosciences, University of Turin, Turin, Italy Received 11 November 1998; received in revised form 14 May 1999; accepted 21 May 1999
Abstract We describe two Italian ®rst cousins with familial amyloidotic polyneuropathy associated with transthyretin variant consisting of the substitution of alanine for glycine at codon 47 (TTR Ala-47), from a family with a history of cardiac failure. The 40-year-old patient presented with autonomic dysfunction and the 44-year-old cousin with congestive heart failure. Both developed sensorimotor and autonomic polyneuropathy. Since a similar clinical picture has been described in another Italian family, the cardiac involvement must be regarded as a salient and early feature of the TTR Ala-47 mutation. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Familial amyloidotic polyneuropathy; Cardiomyopathy; Italian family
1. Introduction Familial amyloidotic polyneuropathy (FAP) is a fatal autosomal dominant disease characterized by amyloid deposition in various organs and tissues, such as in peripheral nerves, heart and kidney [1]. The protein, deposited as amyloid, is a mutant form of transthyretin (TTR), a tetrameric plasma protein formerly known as prealbumin [2]. Since the ®rst TTR variant associated with FAP was described, i.e. substitution of methionine for valine at codon 30 (TTR Met-30), over 60 different point mutations have been identi®ed [3,4]. However, different TTR mutations may regulate the phenotype expression and overall clinical outcome. Symptoms usually begin in the third or fourth decade of life and the most frequent clinical features are sensorimotor neuropathy, autonomic dysfunction and cardiomyopathy. Other organs such as the eye, with vitreous opacities, and kidney may be occasionally affected [4]. At least eight different TTR mutations associated with FAP have been described in Italian subjects, with Met-30 mutation being the most frequent variant, representing approximately 50% of TTR mutations [5], indicating a signi®cant allelic heterogeneity in this country. In 1994, Ferlini et al. [6], identi®ed a new TTR variant in an Italian family with FAP consisting of the substitution of * Corresponding author. Tel.: 139-10-353-7057; fax: 139-10-3538631. E-mail address: [email protected] (C. Solaro)
alanine for glycine at codon 47 (TTR Ala-47). We report clinical, pathological and molecular ®ndings in a second Italian FAP family (Fig. 1A) with TTR Ala-47 mutation, apparently unrelated to the one previously described.
2. Case report 2.1. Patient I (III/2) A 40-year-old male presented with impotence, orthostatic hypotension, diarrhea with progressive weight loss requiring hospitalization in internal care where a rectal biopsy was negative for amyloid deposition. At the age of 42, he developed paraestesiae and burning pain of lower limbs. Neurological examination revealed loss of thermal sensation with mild distal weakness and atrophy of lower limbs; tendon re¯exes were symmetrically lost. No skin lesions or trophic changes were noticed. There were no macroglossia nor hepatosplenomegaly. Renal function was mildly impaired (creatinine clearance 30 ml/min) without proteinuria at urinalysis. Cerebrospinal ¯uid total proteins were increased (78 mg/dl, normal value 51.5 mg/dl). EMG signs of chronic denervation and mild slowing in sensory nerve conduction velocity (NCV) of the median (42 m/s) and ulnar (44 m/s) nerves were found at neurophysiological examination. Amplitude of the sensory action potential (SAP) at the ulnar nerve was 3.3 mV. Motor NCV and amplitude were normal. No vitreous opacities were detected. An electrocar-
0960-8966/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S09 60-8966(99)0006 2-0
C. Solaro et al. / Neuromuscular Disorders 10 (2000) 52±55
diogram demonstrated signs of an inferior and distal septal previous necrosis and right bundle branch block; Holter monitoring evidenced supra-infra ventricular hyperkinetic arrhythmias. A two-dimensional echocardiogram showed the presence of an hypokinetic area at apical region and dilatative cardiomyopathy (left ventricular posterior wall (LVPW): 9 mm, LV telediastolic diameter (LVTD): 58 mm). An endomyocardial biopsy specimen taken from left ventricular was positive for extracellular, but negative for intracellular, amyloid deposition. Ten months later the patient underwent liver transplantation; the post-operative course was satisfactory but he was unable to feed himself and remained con®ned to a wheelchair due to severe orthostatic hypotension. Three weeks after transplantation a gastric biopsy demonstrated the presence of abundant amyloid deposits. After 3 months he died due to sepsis. 2.2. Patient 2 (III/3) The patient, ®rst cousin of patient 1, was asymptomatic until the age of 44, when he presented in the emergency room for heart failure promptly resolved with diuretics; in the following year he began to complain of diffuse muscle weakness, acral parestheasiae and subjective distal hypoesthesia, initially con®ned to lower limbs. At the age of 45 autonomic failure developed, consisting in mild bladder and bowel dysfunction and impotence. Neurological examination revealed a bilateral sensorimotor polyneuropathy con®rmed by electrophysiological studies (slowing in sensory and motor NCV, reduced amplitude of SAPs). An electrocardiogram revealed right bundle branch block. Twodimensional echocardiogram showed hypokinetic dilatative cardiomyopathy with prevalently right heart failure (LVPW: 8 mm, LVTD: 59 mm). The heart failure and the polyneuropathy progressively deteriorated and chronic renal failure appeared. Extracellular amyloid deposits were present at nerve and myocardial biopsies while gastric and rectal mucosa biopsies were negative. The cardiac, renal and nervous dysfunction worsened and the patient was enrolled to have cardiac transplantation. He died at the age of 47 while awaiting the heart transplant.
53
2.4. Genetic analysis High molecular weight DNA was isolated from peripheral blood leukocytes of all members of the third generation. Exons 2, 3 and 4 of the TTR gene were ampli®ed by polymerase chain reaction using 500 ng of DNA and the following oligonucleotides as primers: 1. 5 0 -CGTGTCTTCTCTACACCCAG-3 0 and 5 0 -AAGTCCTGTGGGAGGGTTCT-3 0 for exon 2; 2. 5 0 -CAGACTTTCACACCTTATAG-3 0 and 5 0 -TCGAAGGTCTGTATACTCAC-3 0 for exon 3; 3. 5 0 -GGATCTGTCTGTCTTCTCTC-3 0 and 5 0 -CATGAAATCCCATCCCTCGT-3 0 for exon 4. The ampli®ed DNA fragments containing the entire length of each exon were cloned in a Bluescript vector (Stratagene) and subjected to nucleotide sequence by the Sanger method. Nucleotide sequence (Fig. 2) of the exon 2 of the TTR gene from patients 1 and 2 revealed the presence of a G to C transversion in the second nucleotide of codon 47, causing the Ala-47 mutation previously described [6]. The presence of Ala-47 mutation was con®rmed in both patients by MwoI (New England Biolabs) digestion of exon 2 PCR products (Fig. 1B). On the contrary MwoI digestion of TTR exon 2 amplicons from the healthy members of the third generation showed only uncut fragments, indicating unmutated alleles (Fig. 1B). The two patients of the second generation were not observed by us, but the analysis of clinical data indicates
2.3. Neuropathological study Both patients underwent a diagnostic sural nerve biopsy. A portion of the nerve was ®xed in 4% paraformaldehyde overnight, embedded in paraf®n and stained with E/E and Congo red. Myelinated ®bers density was mildly reduced with a selective involvement of smaller and middle size ®bers. A slight loss of unmyelinated ®bers was also seen at the electron microscopy. Teased ®bers examination revealed several ®bers undergoing active axonal degeneration. Large deposits of amyloid were observed in the endonevrium.
Fig. 1. (A) Pedigree of the family with the TTR Ala47; black boxes indicate affected patients. (B) Electrophoresis of the MwoI digestion products of PCR ampli®ed TTR exon 2. Lanes correspond to subjects of third generation. The small cleavage fragment of 27 bp is not shown. Lanes 2 and 3 are heterozygotes for normal and mutated allele, while lanes 1, 4 and 5 are normal homozygotes.
54
C. Solaro et al. / Neuromuscular Disorders 10 (2000) 52±55
Fig. 2. Sequence analysis of TTR exon 2 from patient III-2 shows the G to C transversion at position 1731.
that they died at age of 40 (II-1) and 45 (II-2) years, from cardiac failure and presented clinical pictures suggestive of lower limbs sensorimotor polyneuropathy, autonomic dysfunction and heart involvement. The other third generation individuals have not shown any evidence of disease at ages of 45 (III/1), 47 (III/4) and 56 years (III/5). 3. Discussion FAP is a dominantly autosomal inherited disease with extracellular deposition of amyloid (mutant TTR), in various organs and tissues such as peripheral nerves and the heart [7,8]. The course was fatal in 7±15 years until the liver transplantation strategy provided the only potential cure for FAP [9], although the impact of transplantation on the natural history of the disease is still unknown [8]. So far, more than 60 point mutations in the TTR gene are described associated with deposition of amyloid material [3]. In Italy the most common mutation is TTR Met-30 but at least eight different variants have been observed. A point mutation in position 47 with substitution of Gly with Ala has been recently described in another Italian family apparently unrelated to our cases [6]. Although aplotype analysis was not performed, the origin of the two families appeared unrelated arising from different Italian regions (our family was living in Livorno, Tuscany, for at least ®ve generations, while the previously reported family was living in Abruzzi). Age of onset (42±45 years) and disease presentation and duration (4±5 years) are similar in all the affected members of our family. Moreover, in three patients cardiac dysfunction was the ®rst manifestation and in the remaining one (patient III/2) it was present at the time of diagnosis. Heart failure was the cause of death in all four. Our observation con®rm that cardiac involvement may
represent the ®rst sign of the FAP associated with Ala-47 substitution, and the cause of death. Echocardiographic data are suggestive of dilatative cardiomyopathy in patients III/2 and III/3, a typical pattern of cardiac involvement in amyloid cardiomyopathy due to autonomic disorder. Autonomic disturbances, such as orthostatic hypotension, diarrhea and impotence, were present in both patients. We suggest that cardiac dysfunction was due to the impairment of the heart conduction system and not directly related to amyloid deposition in the cardiac muscle. Liver transplantation, in FAP patients, seems to arrest further deposition of the mutant protein in tissues and results in signi®cant palliation of the underlying symptoms. A possible exception are those patients with pre-existing cardiac dysfunction, who fail to improve after receiving a transplant [10,11]. Liver transplantation has revealed insuf®cient to stop the disease progression in our patient (III/2), maybe due to the severity of cardiac involvement. Although it can only be hypothesized that combined liver and heart transplantation life expectancy would have been extended. Moreover, the limited follow-up period of our patient hampers any conclusion about the possible effect of liver transplantation on dilatative cardiomyopathy related to the autonomic dysfunction [12]. Sural nerve biopsy was diagnostic for amyloidosis in both patients, although they were performed 2 years after symptoms onset. On the contrary, rectal biopsy was negative for amyloid in both patients and resulted in a delayed diagnosis. Our data indicate that TTR Ala-47 mutation causes a prevalent distribution of amyloid deposits in heart and peripheral nerves, producing signs and symptoms of autonomic disturbances at disease onset. The observation that some patients, described by Ferlini et al. [6], in an apparently unrelated family carrying the same TTR mutation, showed heart involvement due to autonomic dysfunction at disease onset, suggests that the diagnosis of FAP Ala-47 should be considered in relatively young patients of Italian origin with congestive heart failure or arrhythmia, even in the absence of evident signs of polyneuropathy. References [1] Andrade C. A peculiar form of peripheral neuropathy: familial atypical generalized amyloidosis with special involvement of the peripheral nerve. Brain 1952;75:408±427. [2] Costa PP, Figuera AS, Bravo FR. Amyloid ®bril protein related to prealbumin in familial amyloidotic polyneuropathy. Proc Natl Acad Sci USA 1978;75:4499±4503. [3] Petersen RB, Goren H, Cohen M, et al. Transthyretin amyloidosis: a new mutation associated with dementia. Ann Neurol 1997;41:307± 313. [4] Kyle RA, Dyck PJ. Amyloidosis and neuropathy. In: Dick PJ, Thomas PK, editors. Peripheral Neuropathy, third ed., 1993. pp. 1294±1309. [5] Benson MD. Leptomeningeal amyloid and variant transthyretins. Am J Pathol 1996;148:351±354. [6] Ferlini A, Patrosso MC, Repetto M, et al. A new mutation (TTR Ala47) in the transthyretin gene associated with hereditary amyloidosis. Hum Mutat 1994;4:61±64.
C. Solaro et al. / Neuromuscular Disorders 10 (2000) 52±55 [7] Benson MD. Amyloidosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D. editors. The metabolic basis of inherited disease, seventh ed., 1995. pp. 4159±4191. [8] Hesse A, Altland K, Linke RP, et al. Cardiac amyloidosis: a review and report of a new transthyretin (prealbumin) variant. Br Heart J 1993;70:111±115. [9] Holmgren G, Ericzon BG, Groth CG, et al. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 1993;341:1113±1116. [10] Pomfret EA, Lewis WD, Jenkins RL, et al. Effect of orthotopic liver
55
transplantation on the progression of familial amyloidotic polyneuropathy. Transplantation 1998;65:918±925. [11] Stangou AJ, Hawkins PN, Heaton ND, et al. Progressive cardiac amyloidosis following liver transplantation for familial amyloid polyneuropathy. Transplantation 1998;66:229±233. [12] Suhr OB, Wiklund U, Ando Y, Ando E, Olofsson BO. Impact of liver transplantation on autonomic neuropathy in familial amyloidotic polyneuropathy: an evaluation by spectral analysis of heart rate variability. J Intern Med 1997;242:225±229.
Case report
www.elsevier.com/locate/nmd
An Italian family with Ala-47 transthyretin mutation associated with cardiomyopathy and polyneuropathy C. Solaro a,*, A. Schenone a, A. Di Sapio b, L. Pradotto b, G.L. Mancardi a, A. Primavera a, A. Mauro b a
Department of Neurological Sciences and Rehabilitation, University of Genoa, Via De Toni 5, 16132 Genoa, Italy b Department of Neurosciences, University of Turin, Turin, Italy Received 11 November 1998; received in revised form 14 May 1999; accepted 21 May 1999
Abstract We describe two Italian ®rst cousins with familial amyloidotic polyneuropathy associated with transthyretin variant consisting of the substitution of alanine for glycine at codon 47 (TTR Ala-47), from a family with a history of cardiac failure. The 40-year-old patient presented with autonomic dysfunction and the 44-year-old cousin with congestive heart failure. Both developed sensorimotor and autonomic polyneuropathy. Since a similar clinical picture has been described in another Italian family, the cardiac involvement must be regarded as a salient and early feature of the TTR Ala-47 mutation. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Familial amyloidotic polyneuropathy; Cardiomyopathy; Italian family
1. Introduction Familial amyloidotic polyneuropathy (FAP) is a fatal autosomal dominant disease characterized by amyloid deposition in various organs and tissues, such as in peripheral nerves, heart and kidney [1]. The protein, deposited as amyloid, is a mutant form of transthyretin (TTR), a tetrameric plasma protein formerly known as prealbumin [2]. Since the ®rst TTR variant associated with FAP was described, i.e. substitution of methionine for valine at codon 30 (TTR Met-30), over 60 different point mutations have been identi®ed [3,4]. However, different TTR mutations may regulate the phenotype expression and overall clinical outcome. Symptoms usually begin in the third or fourth decade of life and the most frequent clinical features are sensorimotor neuropathy, autonomic dysfunction and cardiomyopathy. Other organs such as the eye, with vitreous opacities, and kidney may be occasionally affected [4]. At least eight different TTR mutations associated with FAP have been described in Italian subjects, with Met-30 mutation being the most frequent variant, representing approximately 50% of TTR mutations [5], indicating a signi®cant allelic heterogeneity in this country. In 1994, Ferlini et al. [6], identi®ed a new TTR variant in an Italian family with FAP consisting of the substitution of * Corresponding author. Tel.: 139-10-353-7057; fax: 139-10-3538631. E-mail address: [email protected] (C. Solaro)
alanine for glycine at codon 47 (TTR Ala-47). We report clinical, pathological and molecular ®ndings in a second Italian FAP family (Fig. 1A) with TTR Ala-47 mutation, apparently unrelated to the one previously described.
2. Case report 2.1. Patient I (III/2) A 40-year-old male presented with impotence, orthostatic hypotension, diarrhea with progressive weight loss requiring hospitalization in internal care where a rectal biopsy was negative for amyloid deposition. At the age of 42, he developed paraestesiae and burning pain of lower limbs. Neurological examination revealed loss of thermal sensation with mild distal weakness and atrophy of lower limbs; tendon re¯exes were symmetrically lost. No skin lesions or trophic changes were noticed. There were no macroglossia nor hepatosplenomegaly. Renal function was mildly impaired (creatinine clearance 30 ml/min) without proteinuria at urinalysis. Cerebrospinal ¯uid total proteins were increased (78 mg/dl, normal value 51.5 mg/dl). EMG signs of chronic denervation and mild slowing in sensory nerve conduction velocity (NCV) of the median (42 m/s) and ulnar (44 m/s) nerves were found at neurophysiological examination. Amplitude of the sensory action potential (SAP) at the ulnar nerve was 3.3 mV. Motor NCV and amplitude were normal. No vitreous opacities were detected. An electrocar-
0960-8966/00/$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S09 60-8966(99)0006 2-0
C. Solaro et al. / Neuromuscular Disorders 10 (2000) 52±55
diogram demonstrated signs of an inferior and distal septal previous necrosis and right bundle branch block; Holter monitoring evidenced supra-infra ventricular hyperkinetic arrhythmias. A two-dimensional echocardiogram showed the presence of an hypokinetic area at apical region and dilatative cardiomyopathy (left ventricular posterior wall (LVPW): 9 mm, LV telediastolic diameter (LVTD): 58 mm). An endomyocardial biopsy specimen taken from left ventricular was positive for extracellular, but negative for intracellular, amyloid deposition. Ten months later the patient underwent liver transplantation; the post-operative course was satisfactory but he was unable to feed himself and remained con®ned to a wheelchair due to severe orthostatic hypotension. Three weeks after transplantation a gastric biopsy demonstrated the presence of abundant amyloid deposits. After 3 months he died due to sepsis. 2.2. Patient 2 (III/3) The patient, ®rst cousin of patient 1, was asymptomatic until the age of 44, when he presented in the emergency room for heart failure promptly resolved with diuretics; in the following year he began to complain of diffuse muscle weakness, acral parestheasiae and subjective distal hypoesthesia, initially con®ned to lower limbs. At the age of 45 autonomic failure developed, consisting in mild bladder and bowel dysfunction and impotence. Neurological examination revealed a bilateral sensorimotor polyneuropathy con®rmed by electrophysiological studies (slowing in sensory and motor NCV, reduced amplitude of SAPs). An electrocardiogram revealed right bundle branch block. Twodimensional echocardiogram showed hypokinetic dilatative cardiomyopathy with prevalently right heart failure (LVPW: 8 mm, LVTD: 59 mm). The heart failure and the polyneuropathy progressively deteriorated and chronic renal failure appeared. Extracellular amyloid deposits were present at nerve and myocardial biopsies while gastric and rectal mucosa biopsies were negative. The cardiac, renal and nervous dysfunction worsened and the patient was enrolled to have cardiac transplantation. He died at the age of 47 while awaiting the heart transplant.
53
2.4. Genetic analysis High molecular weight DNA was isolated from peripheral blood leukocytes of all members of the third generation. Exons 2, 3 and 4 of the TTR gene were ampli®ed by polymerase chain reaction using 500 ng of DNA and the following oligonucleotides as primers: 1. 5 0 -CGTGTCTTCTCTACACCCAG-3 0 and 5 0 -AAGTCCTGTGGGAGGGTTCT-3 0 for exon 2; 2. 5 0 -CAGACTTTCACACCTTATAG-3 0 and 5 0 -TCGAAGGTCTGTATACTCAC-3 0 for exon 3; 3. 5 0 -GGATCTGTCTGTCTTCTCTC-3 0 and 5 0 -CATGAAATCCCATCCCTCGT-3 0 for exon 4. The ampli®ed DNA fragments containing the entire length of each exon were cloned in a Bluescript vector (Stratagene) and subjected to nucleotide sequence by the Sanger method. Nucleotide sequence (Fig. 2) of the exon 2 of the TTR gene from patients 1 and 2 revealed the presence of a G to C transversion in the second nucleotide of codon 47, causing the Ala-47 mutation previously described [6]. The presence of Ala-47 mutation was con®rmed in both patients by MwoI (New England Biolabs) digestion of exon 2 PCR products (Fig. 1B). On the contrary MwoI digestion of TTR exon 2 amplicons from the healthy members of the third generation showed only uncut fragments, indicating unmutated alleles (Fig. 1B). The two patients of the second generation were not observed by us, but the analysis of clinical data indicates
2.3. Neuropathological study Both patients underwent a diagnostic sural nerve biopsy. A portion of the nerve was ®xed in 4% paraformaldehyde overnight, embedded in paraf®n and stained with E/E and Congo red. Myelinated ®bers density was mildly reduced with a selective involvement of smaller and middle size ®bers. A slight loss of unmyelinated ®bers was also seen at the electron microscopy. Teased ®bers examination revealed several ®bers undergoing active axonal degeneration. Large deposits of amyloid were observed in the endonevrium.
Fig. 1. (A) Pedigree of the family with the TTR Ala47; black boxes indicate affected patients. (B) Electrophoresis of the MwoI digestion products of PCR ampli®ed TTR exon 2. Lanes correspond to subjects of third generation. The small cleavage fragment of 27 bp is not shown. Lanes 2 and 3 are heterozygotes for normal and mutated allele, while lanes 1, 4 and 5 are normal homozygotes.
54
C. Solaro et al. / Neuromuscular Disorders 10 (2000) 52±55
Fig. 2. Sequence analysis of TTR exon 2 from patient III-2 shows the G to C transversion at position 1731.
that they died at age of 40 (II-1) and 45 (II-2) years, from cardiac failure and presented clinical pictures suggestive of lower limbs sensorimotor polyneuropathy, autonomic dysfunction and heart involvement. The other third generation individuals have not shown any evidence of disease at ages of 45 (III/1), 47 (III/4) and 56 years (III/5). 3. Discussion FAP is a dominantly autosomal inherited disease with extracellular deposition of amyloid (mutant TTR), in various organs and tissues such as peripheral nerves and the heart [7,8]. The course was fatal in 7±15 years until the liver transplantation strategy provided the only potential cure for FAP [9], although the impact of transplantation on the natural history of the disease is still unknown [8]. So far, more than 60 point mutations in the TTR gene are described associated with deposition of amyloid material [3]. In Italy the most common mutation is TTR Met-30 but at least eight different variants have been observed. A point mutation in position 47 with substitution of Gly with Ala has been recently described in another Italian family apparently unrelated to our cases [6]. Although aplotype analysis was not performed, the origin of the two families appeared unrelated arising from different Italian regions (our family was living in Livorno, Tuscany, for at least ®ve generations, while the previously reported family was living in Abruzzi). Age of onset (42±45 years) and disease presentation and duration (4±5 years) are similar in all the affected members of our family. Moreover, in three patients cardiac dysfunction was the ®rst manifestation and in the remaining one (patient III/2) it was present at the time of diagnosis. Heart failure was the cause of death in all four. Our observation con®rm that cardiac involvement may
represent the ®rst sign of the FAP associated with Ala-47 substitution, and the cause of death. Echocardiographic data are suggestive of dilatative cardiomyopathy in patients III/2 and III/3, a typical pattern of cardiac involvement in amyloid cardiomyopathy due to autonomic disorder. Autonomic disturbances, such as orthostatic hypotension, diarrhea and impotence, were present in both patients. We suggest that cardiac dysfunction was due to the impairment of the heart conduction system and not directly related to amyloid deposition in the cardiac muscle. Liver transplantation, in FAP patients, seems to arrest further deposition of the mutant protein in tissues and results in signi®cant palliation of the underlying symptoms. A possible exception are those patients with pre-existing cardiac dysfunction, who fail to improve after receiving a transplant [10,11]. Liver transplantation has revealed insuf®cient to stop the disease progression in our patient (III/2), maybe due to the severity of cardiac involvement. Although it can only be hypothesized that combined liver and heart transplantation life expectancy would have been extended. Moreover, the limited follow-up period of our patient hampers any conclusion about the possible effect of liver transplantation on dilatative cardiomyopathy related to the autonomic dysfunction [12]. Sural nerve biopsy was diagnostic for amyloidosis in both patients, although they were performed 2 years after symptoms onset. On the contrary, rectal biopsy was negative for amyloid in both patients and resulted in a delayed diagnosis. Our data indicate that TTR Ala-47 mutation causes a prevalent distribution of amyloid deposits in heart and peripheral nerves, producing signs and symptoms of autonomic disturbances at disease onset. The observation that some patients, described by Ferlini et al. [6], in an apparently unrelated family carrying the same TTR mutation, showed heart involvement due to autonomic dysfunction at disease onset, suggests that the diagnosis of FAP Ala-47 should be considered in relatively young patients of Italian origin with congestive heart failure or arrhythmia, even in the absence of evident signs of polyneuropathy. References [1] Andrade C. A peculiar form of peripheral neuropathy: familial atypical generalized amyloidosis with special involvement of the peripheral nerve. Brain 1952;75:408±427. [2] Costa PP, Figuera AS, Bravo FR. Amyloid ®bril protein related to prealbumin in familial amyloidotic polyneuropathy. Proc Natl Acad Sci USA 1978;75:4499±4503. [3] Petersen RB, Goren H, Cohen M, et al. Transthyretin amyloidosis: a new mutation associated with dementia. Ann Neurol 1997;41:307± 313. [4] Kyle RA, Dyck PJ. Amyloidosis and neuropathy. In: Dick PJ, Thomas PK, editors. Peripheral Neuropathy, third ed., 1993. pp. 1294±1309. [5] Benson MD. Leptomeningeal amyloid and variant transthyretins. Am J Pathol 1996;148:351±354. [6] Ferlini A, Patrosso MC, Repetto M, et al. A new mutation (TTR Ala47) in the transthyretin gene associated with hereditary amyloidosis. Hum Mutat 1994;4:61±64.
C. Solaro et al. / Neuromuscular Disorders 10 (2000) 52±55 [7] Benson MD. Amyloidosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D. editors. The metabolic basis of inherited disease, seventh ed., 1995. pp. 4159±4191. [8] Hesse A, Altland K, Linke RP, et al. Cardiac amyloidosis: a review and report of a new transthyretin (prealbumin) variant. Br Heart J 1993;70:111±115. [9] Holmgren G, Ericzon BG, Groth CG, et al. Clinical improvement and amyloid regression after liver transplantation in hereditary transthyretin amyloidosis. Lancet 1993;341:1113±1116. [10] Pomfret EA, Lewis WD, Jenkins RL, et al. Effect of orthotopic liver
55
transplantation on the progression of familial amyloidotic polyneuropathy. Transplantation 1998;65:918±925. [11] Stangou AJ, Hawkins PN, Heaton ND, et al. Progressive cardiac amyloidosis following liver transplantation for familial amyloid polyneuropathy. Transplantation 1998;66:229±233. [12] Suhr OB, Wiklund U, Ando Y, Ando E, Olofsson BO. Impact of liver transplantation on autonomic neuropathy in familial amyloidotic polyneuropathy: an evaluation by spectral analysis of heart rate variability. J Intern Med 1997;242:225±229.