Short Report
Journal of
CLINICAL NEUROMUSCULAR DISEASE
1
Volume 16, Number 1 September 2014
Discordant Phenotype in Monozygotic Female Twins With Lys35Thr TTR Familial Amyloidotic Polyneuropathy Katherine Ruzhansky, MD, MS,* Jacqueline Scoon, MD,* Louis H. Weimer, MD,* Mathew S. Maurer, MD,† John L. Berk, MD,‡ and Thomas H. Brannagan, III, MD*
Abstract Familial amyloidotic polyneuropathy is the hereditary form of transthyretin amyloidosis that is rapidly progressive. Discordant expression of Val30Met transthyretin amyloid in monozygotic twins has been reported in the past, in Europe and Asia. We report the first case of discordant expression of Lys35Thr transthyretin amyloid in female monozygotic twins in North America with eye involvement and peripheral neuropathy. Key Words: TTR, FAP, discordant expression, monozygotic twins, Lys35Thr
( J Clin Neuromusc Dis 2014;16:1–6)
amilial amyloidotic polyneuropathy (FAP) is a lethal, autosomal dominant genetic disease mediated by misfolding of transthyretin (TTR). It is caused by mutations in the TTR protein, which are single amino acid substitutions that alter the secondary and tertiary structure of the protein to cause misaggregation and amyloid fibril formation.1 TTR is produced predominantly in the liver and can deposit in peripheral nerve, intestines, heart, and kidney. It is also synthesized in the retina and choroid plexus, which can lead to vitreal and leptomeningeal deposits.2 Peripheral nerves and the heart are the most common targets for amyloid deposition. More than 100 mutations in the TTR protein are known, with Val30Met being the most common neuropathic mutation. Most patients are heterozygous for the TTR mutations, and amyloid deposits consist of both mutant and nonmutant (wild-type) TTR.2
F
FAP is an adult-onset disease that can clinically manifest as early as the second decade of life, but usually after 30 years of age, depending on the mutation. Liver transplantation prolongs survival in Val30Met patients, but its role in nonVal30Met is less certain. In a Japanese study, the probability of survival in those with Val30Met at 10 years is 56.1% compared with 100% in those who have received liver transplant.3 Other treatments include kinetic stabilizers of the TTR tetramer, including tafamidis, which is approved in Europe, and diflunisal, which is found to reduce the rate of progression of neurological impairment after 2 years compared with placebo.4 Another type of anti-amyloid therapy is to inhibit production of mutant and nonmutant TTR by post-transcriptional gene silencing.3 ISIS-TTRRx is a second-generation antisense inhibitor of the molecular target TTR. It is proven to reduce the amount of mutant and wild-type TTR in both the mouse model and in healthy volunteers.5 ALN-TTR01 and ALNTTR02 is a systemically administered formulation of a small interfering RNA targeting wild-type and mutant types of TTR.2 Rapid dose-dependent and durable lowering of both mutant and nonmutant TTR levels is observed.2 These anti-amyloid therapies are currently undergoing further clinical trials.3 Twins and multiples have always intrigued humans and have been subject to many scientific analyses. An increasing number of reports are being published on
From the *Department of Neurology, Peripheral Neuropathy Center, Neurological Institute, College of Physicians and Surgeons, Columbia University, New York, NY; †Division of Cardiology, College of Physicians and Surgeons, Columbia University, New York, NY; and ‡Amyloidosis Center, Department of Medicine, Boston University Medical Center, Boston, MA. The authors report no conflicts of interest. Reprints: Katherine Ruzhansky, MD, MS, Peripheral Neuropathy Center, Neurological Institute, College of Physicians and Surgeons, Columbia University, 710 W 168th St, Box 163, New York, NY 10032 (e-mail: kr2517@ columbia.edu). Copyright © 2014 by Lippincott Williams & Wilkins
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discordant twin pairs, including FAP,6 with epigenetic mechanisms being one possible explanation. Discordant expression of FAP in monozygotic twins is described in patients of Indonesian descent and patients from Majorca, Portugal, Japan, Sweden, and Brazil. A total of 7 cases have been reported to date; all identified with Val30Met mutation. We report monozygotic female twins of Ashkenazi Jewish descent with the first recognized case of discordant presentation of familial amyloid neuropathy associated with the Lys35Thr mutation. We report twin sisters born in New York City, New York, in 1947 who were seen at Columbia University Medical Center. The twins were born to a 42-year-old mother who was in good health of Ashkenazi (Russian and Romanian) Jewish descent. The sisters lived together until age 21. Neither one of the twins smoked, and both drank alcohol socially. No relatives had known amyloidosis; however, one sister reports that their father had trouble with his feet and kidney disease; he died of possible underlying heart disease at age 81. Their mother died of pancreatic cancer at age 90. A brother, 14 years their senior had end-stage renal disease and died of a myocardial infarction at age 48. Another brother, 10 years their senior, died suddenly at age 62, presumably of acute renal failure as a complication of diabetes. Twin A was first seen in our neuropathy clinic in 2011, when she was 63 years old. She initially presented with visual impairment and floaters in the left eye at age 58, in 2004. She underwent vitrectomy, and pathology from the vitrectomy confirmed protein aggregates documented as amyloid deposits on Congo Red staining. Neuropathy symptoms started in 2005 as numbness in the left small toe, which then moved to all toes and up her calf. She subsequently developed leg weakness and balance problems. In 2009 to 2011, numbness progressed to involve the hands. She denied orthostatic symptoms or decreased sweating. She was however diagnosed with cyclical vomiting syndrome in 2008. Examination in 2009, found decreased sensation below the © 2014 Lippincott Williams & Wilkins
knees and absent vibration at the toes. Sensorimotor polyneuropathy was diagnosed. Fat pad aspirates exhibited apple green birefringence under polarized light on Congo Red staining, and subsequent testing revealed Lys35Thr gene mutation. Alternate causes of neuropathy were investigated. Her HgA1c was 4.8%; and vitamin B12, B6, and thyroid stimulating hormone (TSH) levels were normal. She was enrolled in a diflunisal study for 18 months but during the trial, her neuropathy symptoms progressed and she suspected that she was on placebo. She was then started on diflunisal 250 mg twice a day regimen as part of the open-label extension of the clinical trial, and felt symptomatic improvement. She did, however, develop elevated creatinine, brain natriuretic peptide (BNP), and troponin. Additionally, she had paroxysmal atrial fibrillation. Because of toxicity concerns, diflunisal was ultimately stopped. She had not received any further anti-amyloid treatment. When she was evaluated at our neuropathy clinic in 2011, her upper extremity examination was notable for 4/5 left wrist extension, 4/5 bilateral interossei and opponens strength, and otherwise 5/5 in all other muscles tested. In the lower extremities, strength was 3+/5 in the tibialis anterior bilaterally, 3+/5 on the right, and 32/5 on the left extensor hallucis longus. Vibratory sensation using the Rydel–Seiffer tuning fork, was absent at the toes and ankles, and 4/8 on the left and 5/8 on the right fingers. Functionally, she was unable to stand on her heels and had trouble standing on her toes. Lower extremity reflexes were absent, and she swayed on Romberg testing, but did not fall. Electrodiagnostic testing revealed the presence of axonal neuropathy. Twin A had a steady decline with several hospitalizations for urinary tract infections secondary to urinary retention from neurogenic bladder. She lost her vision because of a combination of glaucoma, vitreous amyloidosis, and bleeding as a complication of therapeutic anticoagulation. From a neuropathy perspective, she had both weakness and imbalance and was dependent
TABLE 1. Cases of Monozygotic Twins With FAP Reported in the Literature Since 1981 Case Reports 7
Sack et al
MunarQues et al8
Holmgren et al10
www.jcnmd.com
Saporta et al11
Twin
Year of Age of Symptom Gene Birth Onset Mutation
Clinical Manifestations
AOD
NR
NR
N
41
N
48
N Y, 34
63 34
Indonesia
F
1
1947
25
Indonesia
F
2
1947
29
Majorca
M
J
1931
38
Orthostasis, diarrhea (age 33), dysphagia, headache, dizziness, orthostasis NR Sensorimotor syndrome, urinary incontinence, orthostasis, paraplegic by age 39 Val30Met Sensorimotor syndrome
Majorca Portugal
M M
G A
1931 1959
50 30
Val30Met Sensorimotor syndrome Val30Met Sensorimotor syndrome
Portugal Japan
M M
J 1
1959 1971
34 29
Japan
M
2
1971
29
Sweden
M
A1
1941
50
Sweden
M
A2
1941
NA
Sweden Sweden
M M
B1 B2
NR NR
Val30Met Paresthesia and pain in the legs Val30Met None
Y NA
Brazil
M
No symptoms age 63 34 No symptoms 3 years after the onset of brother’s disease 21
Val30Met Sensorimotor syndrome Val30Met Diarrhea, urinary difficulty, impotence, dysautonomia Val30Met Weakness, numbness, diarrhea, urinary disturbance Val30Met Axonal polyneuropathy, diarrhea, orthostatic hypotension, trouble with walking Val30Met None
Twin 1 1980
NR
LT
Val30Met Sensory impairment, steppage gait, urinary retention, sexual impotence, constipation, autonomic dysfunction
COD NR Escherichia coli sepsis NR
NR Peritoneal complications
No
Y
62
Urosepsis
Y
Discordant Phenotype of Lys35Thr FAP in Twins
Ando et al9
Country of Origin Sex
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AOD, age of death; COD, cause of death; LT, liver transplant; NR, not reported; Y, yes; N, no; NA, not applicable.
Lys35Thr Carpal tunnel syndrome, sensory complaints, although had vitrectomy age 64 without path evidence of amyloid 66 1947 F United States
B
57 1947 F Present Case 2014
United States
A
N
66 N
N. Awaiting at the time of case report
Val30Met Neuropathic pain, erectile dysfunction, but later on developed muscle atrophy, sensory impairment, neuropathic pain and episodes of diarrhea Lys35Thr Vitreous infiltration, severe sensorimotor syndrome, cardiac failure, gastroparesis 25 Twin 2 1980 Brazil
M
Twin Case Reports
Country of Origin Sex
Year of Age of Symptom Gene Birth Onset Mutation
Clinical Manifestations
LT
AOD
COD
Unknown
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TABLE 1 (Continued )
4
on a walker for ambulation, but was not ambulatory, however, due to visual impairment and medical illness. She has evidence of heart failure. Her echocardiogram results in 2012 were consistent with advanced amyloid cardiomyopathy as evidenced by a normal chamber size (43 mm) but an increased septal and posterior wall thickness of 17 mm and 14 mm, respectively, reduced ejection fraction of 25% to 30%, low tissue Doppler velocities, right ventricular hypertrophy, and advanced diastolic dysfunction. There was also bilateral atrial enlargement and left ventricular hypokinesis. She had atrial fibrillation treated with dabigatran, which was discontinued 3 months prior to her death. Her troponin, pro-BNP, and BNP were elevated. She has never had a cardiac magnetic resonance imaging because of claustrophobia. Her cyclical vomiting syndrome diagnosis had been revised in the past year to gastroparesis, and she was being treated with botulinum toxin injections. Diflunisal was being considered for treatment, prior to death but with close monitoring due to elevated baseline creatinine. She died in her sleep at age 66, in 2014. Twin B presented to our neuropathy clinic at age 66 for evaluation of familial amyloid neuropathy given her sister’s medical history. She reported right hand tingling and pain at night for over 10 years. Additionally, she described having a leathery feeling on the bottom of her feet, as well as numbness that has developed a few months before presentation. On examination, she has mild interossei and toe extensor weakness, as well as mild distal sensory and vibratory loss. She denied shortness of breath or palpitations, but noted lightheadedness upon standing. She denied dry eyes or dry mouth. Of note, she had vitrectomy for ocular hypertension at age 64. Vitreous fluid had a lattice-like appearance but Congo Red staining of extracted vitreous aggregates did not document amyloid deposits. Electrodiagnostic testing revealed mild-to-moderate chronic axonal sensorimotor polyneuropathy and severe right and moderately severe left median mononeuropathies at the wrist
Discordant Phenotype of Lys35Thr FAP in Twins
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CLINICAL NEUROMUSCULAR DISEASE Volume 16, Number 1 September 2014
TABLE 2. Summary of Affected Individuals With Lys35Thr Mutation and Their Clinical Phenotypes Patient Age of Onset 1 2 3 4 5 6 7 8 Twin A Twin B
Mid-fourth decade Mid-fourth decade Mid-fourth decade 48 50 40 43 40 57 66
Clinical Phenotype Radiculopathy, vitreous amyloid Radiculopathy, vitreous amyloid Radiculopathy, vitreous amyloid Vitreous amyloid, radiculopathy Vitreous amyloid, radiculopathy Vitreous amyloid Radiculopathy Normal Vitreous amyloid, severe sensorimotor syndrome, cardiac failure, gastroparesis Carpal tunnel syndrome, sensorimotor polyneuropathy, although had vitrectomy age 64 without path evidence of amyloid
Patients 1 through 8 as reported by Long et al.12
consistent with Carpal tunnel syndrome. Autonomic testing, which includes heart rate variability at rest and cyclic deep breathing, Valsalva maneuver blood pressure and heart rate response, and tilt-table testing revealed mild-to-moderate parasympathetic cardiovagal and minimal to no evidence of peripheral sympathetic vasoconstrictor dysfunction and no neurogenic orthostatic hypotension. Laboratory testing showed the presence of positive anti-nuclear antibody with a 1:160 titer speckled pattern, elevated Gliadin IgG antibodies and normal Gliadin IgA and transglutaminase IgA antibodies, low B6 level, and a borderline B12 and random urine protein. Myelin-associated glycoprotein, dsDNA, urine protein electrophoresis, serum protein electrophoresis, copper, quantitative immunoglobulins, and TSH levels were normal. She has no history of diabetes or impaired glucose tolerance, and her random glucose was 96 mg/dL and HgA1C 5.1%. Her troponin and BNP were normal. Echocardiography showed grade I diastolic dysfunction with a normal systolic and valve function and an EF of 60%. Genetic testing revealed the same Lys35Thr TTR mutation as twin A and fat pad aspirates exhibited apple green birefringence under polarized light. Although discordant presentation of TTR has been reported in monozygotic twins
in the past, this is the first case of TTR Lys35Thr in Ashkenazi Jewish sisters living in the United States and causing peripheral neuropathy as part of the phenotype. Table 1 outlines the findings of previously reported twin cases. Discordant presentation in twin pairs ranged from 4 to 13 years after the onset of symptoms of the more severely affected twin. Although initial symptoms varied, dysautonomia tended to be an initial presentation for many. Most of the twin pairs eventually developed neuropathy and dysautonomia, but the time to onset of symptoms varied. TTR Lys35Thr has been identified as a cause of radiculopathy and vitreous amyloid in a family in China.12 Of the 8 family members with the gene mutation, 7 had evidence of disease at the time of the report. The clinical phenotype was vitreous amyloid and radiculopathy in 5/8, vitreous amyloid in 1/8, and radiculopathy in 1/8. Peripheral neuropathy is not reported in the previously published cases. Our case is therefore atypical for this particular gene mutation. As in our case, the reported patients with this gene mutation have late-onset disease, mean age being between 40 and 50 years old for this mutation. Table 2 summarizes the clinical phenotype of the individuals reported by www.jcnmd.com
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Long et al and the clinical phenotype of twin A and twin B. Although it is conceivable that one of the twins’ brothers was affected with TTR given his early death, there is no definitive evidence that other family members were affected, and this could be a de novo mutation in these twins. Twin B had vitreous that did not stain for amyloid, but it was noted to be abnormal with a lattice-like appearance that could have been the initial TTR amyloid symptom in this patient, making the age of initial presentation 64, or 6 years after twin A’s presentation. Given the progression of twin A’s disease is much more rapid, other factors likely play a role in the clinical phenotype of the affected individual. It has been reported that in the case of the Val30Met mutation, the onset of symptoms may be modulated by an interval downstream of TTR on the accompanying noncarrier chromosome (microsatellites D18S457 and D18S456). It is possible that a similar mechanism has a role in the Lys35Thr.13 REFERENCES 1. Benson MD. Liver transplantation and transthyretin amyloidosis. Muscle Nerve. 2013;47:157–162. 2. Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369:819–829. 3. Adams D, Theaudin M, Cauquil C, et al. FAP neuropathy and emerging treatments. Curr Neurol Neurosci Rep. 2014;14:435.
© 2014 Lippincott Williams & Wilkins
4. Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013;310:2658–2667. 5. Ackermann EJ, Guo S, Booten S, et al. Clinical development of an antisense therapy for the treatment of transthyretin-associated polyneuropathy. Amyloid. 2012;19(suppl 1):43–44. 6. Zwijnenburg PJ, Meijers-Heijboer H, Boomsma DI. Identical but not the same: the value of discordant monozygotic twins in genetic research. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:1134– 1149. 7. Sack GH Jr, Dumars KW, Gummerson KS, et al. Three forms of dominant amyloid neuropathy. Johns Hopkins Med J. 1981;149:239–247. 8. Munar-Ques M, Pedrosa JL, Coelho T, et al. Two pairs of proven monozygotic twins discordant for familial amyloid neuropathy (FAP) TTR Met 30. J Med Genet. 1999;36:629–632. 9. Ando Y, Ohtsu Y, Terazaki H, et al. Japanese monozygotic twins with familial amyloidotic polyneuropathy (FAP) (ATTR Val30Met). Amyloid. 2000;7:133–136. 10. Holmgren G, Wikstrom L, Lundgren HE, et al. Discordant penetrance of the trait for familial amyloidotic polyneuropathy in two pairs of monozygotic twins. J Intern Med. 2004;256:453–456. 11. Saporta MA, Plante-Bordeneuve V, Misrahi M, et al. Discordant expression of familial amyloid polyneuropathy in monozygotic Brazilian twins. Amyloid. 2009;16:38–41. 12. Long D, Zeng J, Wu LQ, et al. Vitreous amyloidosis in two large mainland Chinese kindreds resulting from transthyretin variant Lys35Thr and Leu55Arg. Ophthalmic Genet. 2012;33:28–33. 13. Soares ML, Coelho T, Sousa A, et al. Haplotypes and DNA sequence variation within and surrounding the transthyretin gene: genotype-phenotype correlations in familial amyloid polyneuropathy (V30M) in Portugal and Sweden. Eur J Hum Genet. 2004;12: 225–237.
Journal of
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Volume 16, Number 1 September 2014
Discordant Phenotype in Monozygotic Female Twins With Lys35Thr TTR Familial Amyloidotic Polyneuropathy Katherine Ruzhansky, MD, MS,* Jacqueline Scoon, MD,* Louis H. Weimer, MD,* Mathew S. Maurer, MD,† John L. Berk, MD,‡ and Thomas H. Brannagan, III, MD*
Abstract Familial amyloidotic polyneuropathy is the hereditary form of transthyretin amyloidosis that is rapidly progressive. Discordant expression of Val30Met transthyretin amyloid in monozygotic twins has been reported in the past, in Europe and Asia. We report the first case of discordant expression of Lys35Thr transthyretin amyloid in female monozygotic twins in North America with eye involvement and peripheral neuropathy. Key Words: TTR, FAP, discordant expression, monozygotic twins, Lys35Thr
( J Clin Neuromusc Dis 2014;16:1–6)
amilial amyloidotic polyneuropathy (FAP) is a lethal, autosomal dominant genetic disease mediated by misfolding of transthyretin (TTR). It is caused by mutations in the TTR protein, which are single amino acid substitutions that alter the secondary and tertiary structure of the protein to cause misaggregation and amyloid fibril formation.1 TTR is produced predominantly in the liver and can deposit in peripheral nerve, intestines, heart, and kidney. It is also synthesized in the retina and choroid plexus, which can lead to vitreal and leptomeningeal deposits.2 Peripheral nerves and the heart are the most common targets for amyloid deposition. More than 100 mutations in the TTR protein are known, with Val30Met being the most common neuropathic mutation. Most patients are heterozygous for the TTR mutations, and amyloid deposits consist of both mutant and nonmutant (wild-type) TTR.2
F
FAP is an adult-onset disease that can clinically manifest as early as the second decade of life, but usually after 30 years of age, depending on the mutation. Liver transplantation prolongs survival in Val30Met patients, but its role in nonVal30Met is less certain. In a Japanese study, the probability of survival in those with Val30Met at 10 years is 56.1% compared with 100% in those who have received liver transplant.3 Other treatments include kinetic stabilizers of the TTR tetramer, including tafamidis, which is approved in Europe, and diflunisal, which is found to reduce the rate of progression of neurological impairment after 2 years compared with placebo.4 Another type of anti-amyloid therapy is to inhibit production of mutant and nonmutant TTR by post-transcriptional gene silencing.3 ISIS-TTRRx is a second-generation antisense inhibitor of the molecular target TTR. It is proven to reduce the amount of mutant and wild-type TTR in both the mouse model and in healthy volunteers.5 ALN-TTR01 and ALNTTR02 is a systemically administered formulation of a small interfering RNA targeting wild-type and mutant types of TTR.2 Rapid dose-dependent and durable lowering of both mutant and nonmutant TTR levels is observed.2 These anti-amyloid therapies are currently undergoing further clinical trials.3 Twins and multiples have always intrigued humans and have been subject to many scientific analyses. An increasing number of reports are being published on
From the *Department of Neurology, Peripheral Neuropathy Center, Neurological Institute, College of Physicians and Surgeons, Columbia University, New York, NY; †Division of Cardiology, College of Physicians and Surgeons, Columbia University, New York, NY; and ‡Amyloidosis Center, Department of Medicine, Boston University Medical Center, Boston, MA. The authors report no conflicts of interest. Reprints: Katherine Ruzhansky, MD, MS, Peripheral Neuropathy Center, Neurological Institute, College of Physicians and Surgeons, Columbia University, 710 W 168th St, Box 163, New York, NY 10032 (e-mail: kr2517@ columbia.edu). Copyright © 2014 by Lippincott Williams & Wilkins
2
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discordant twin pairs, including FAP,6 with epigenetic mechanisms being one possible explanation. Discordant expression of FAP in monozygotic twins is described in patients of Indonesian descent and patients from Majorca, Portugal, Japan, Sweden, and Brazil. A total of 7 cases have been reported to date; all identified with Val30Met mutation. We report monozygotic female twins of Ashkenazi Jewish descent with the first recognized case of discordant presentation of familial amyloid neuropathy associated with the Lys35Thr mutation. We report twin sisters born in New York City, New York, in 1947 who were seen at Columbia University Medical Center. The twins were born to a 42-year-old mother who was in good health of Ashkenazi (Russian and Romanian) Jewish descent. The sisters lived together until age 21. Neither one of the twins smoked, and both drank alcohol socially. No relatives had known amyloidosis; however, one sister reports that their father had trouble with his feet and kidney disease; he died of possible underlying heart disease at age 81. Their mother died of pancreatic cancer at age 90. A brother, 14 years their senior had end-stage renal disease and died of a myocardial infarction at age 48. Another brother, 10 years their senior, died suddenly at age 62, presumably of acute renal failure as a complication of diabetes. Twin A was first seen in our neuropathy clinic in 2011, when she was 63 years old. She initially presented with visual impairment and floaters in the left eye at age 58, in 2004. She underwent vitrectomy, and pathology from the vitrectomy confirmed protein aggregates documented as amyloid deposits on Congo Red staining. Neuropathy symptoms started in 2005 as numbness in the left small toe, which then moved to all toes and up her calf. She subsequently developed leg weakness and balance problems. In 2009 to 2011, numbness progressed to involve the hands. She denied orthostatic symptoms or decreased sweating. She was however diagnosed with cyclical vomiting syndrome in 2008. Examination in 2009, found decreased sensation below the © 2014 Lippincott Williams & Wilkins
knees and absent vibration at the toes. Sensorimotor polyneuropathy was diagnosed. Fat pad aspirates exhibited apple green birefringence under polarized light on Congo Red staining, and subsequent testing revealed Lys35Thr gene mutation. Alternate causes of neuropathy were investigated. Her HgA1c was 4.8%; and vitamin B12, B6, and thyroid stimulating hormone (TSH) levels were normal. She was enrolled in a diflunisal study for 18 months but during the trial, her neuropathy symptoms progressed and she suspected that she was on placebo. She was then started on diflunisal 250 mg twice a day regimen as part of the open-label extension of the clinical trial, and felt symptomatic improvement. She did, however, develop elevated creatinine, brain natriuretic peptide (BNP), and troponin. Additionally, she had paroxysmal atrial fibrillation. Because of toxicity concerns, diflunisal was ultimately stopped. She had not received any further anti-amyloid treatment. When she was evaluated at our neuropathy clinic in 2011, her upper extremity examination was notable for 4/5 left wrist extension, 4/5 bilateral interossei and opponens strength, and otherwise 5/5 in all other muscles tested. In the lower extremities, strength was 3+/5 in the tibialis anterior bilaterally, 3+/5 on the right, and 32/5 on the left extensor hallucis longus. Vibratory sensation using the Rydel–Seiffer tuning fork, was absent at the toes and ankles, and 4/8 on the left and 5/8 on the right fingers. Functionally, she was unable to stand on her heels and had trouble standing on her toes. Lower extremity reflexes were absent, and she swayed on Romberg testing, but did not fall. Electrodiagnostic testing revealed the presence of axonal neuropathy. Twin A had a steady decline with several hospitalizations for urinary tract infections secondary to urinary retention from neurogenic bladder. She lost her vision because of a combination of glaucoma, vitreous amyloidosis, and bleeding as a complication of therapeutic anticoagulation. From a neuropathy perspective, she had both weakness and imbalance and was dependent
TABLE 1. Cases of Monozygotic Twins With FAP Reported in the Literature Since 1981 Case Reports 7
Sack et al
MunarQues et al8
Holmgren et al10
www.jcnmd.com
Saporta et al11
Twin
Year of Age of Symptom Gene Birth Onset Mutation
Clinical Manifestations
AOD
NR
NR
N
41
N
48
N Y, 34
63 34
Indonesia
F
1
1947
25
Indonesia
F
2
1947
29
Majorca
M
J
1931
38
Orthostasis, diarrhea (age 33), dysphagia, headache, dizziness, orthostasis NR Sensorimotor syndrome, urinary incontinence, orthostasis, paraplegic by age 39 Val30Met Sensorimotor syndrome
Majorca Portugal
M M
G A
1931 1959
50 30
Val30Met Sensorimotor syndrome Val30Met Sensorimotor syndrome
Portugal Japan
M M
J 1
1959 1971
34 29
Japan
M
2
1971
29
Sweden
M
A1
1941
50
Sweden
M
A2
1941
NA
Sweden Sweden
M M
B1 B2
NR NR
Val30Met Paresthesia and pain in the legs Val30Met None
Y NA
Brazil
M
No symptoms age 63 34 No symptoms 3 years after the onset of brother’s disease 21
Val30Met Sensorimotor syndrome Val30Met Diarrhea, urinary difficulty, impotence, dysautonomia Val30Met Weakness, numbness, diarrhea, urinary disturbance Val30Met Axonal polyneuropathy, diarrhea, orthostatic hypotension, trouble with walking Val30Met None
Twin 1 1980
NR
LT
Val30Met Sensory impairment, steppage gait, urinary retention, sexual impotence, constipation, autonomic dysfunction
COD NR Escherichia coli sepsis NR
NR Peritoneal complications
No
Y
62
Urosepsis
Y
Discordant Phenotype of Lys35Thr FAP in Twins
Ando et al9
Country of Origin Sex
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AOD, age of death; COD, cause of death; LT, liver transplant; NR, not reported; Y, yes; N, no; NA, not applicable.
Lys35Thr Carpal tunnel syndrome, sensory complaints, although had vitrectomy age 64 without path evidence of amyloid 66 1947 F United States
B
57 1947 F Present Case 2014
United States
A
N
66 N
N. Awaiting at the time of case report
Val30Met Neuropathic pain, erectile dysfunction, but later on developed muscle atrophy, sensory impairment, neuropathic pain and episodes of diarrhea Lys35Thr Vitreous infiltration, severe sensorimotor syndrome, cardiac failure, gastroparesis 25 Twin 2 1980 Brazil
M
Twin Case Reports
Country of Origin Sex
Year of Age of Symptom Gene Birth Onset Mutation
Clinical Manifestations
LT
AOD
COD
Unknown
Volume 16, Number 1 September 2014
TABLE 1 (Continued )
4
on a walker for ambulation, but was not ambulatory, however, due to visual impairment and medical illness. She has evidence of heart failure. Her echocardiogram results in 2012 were consistent with advanced amyloid cardiomyopathy as evidenced by a normal chamber size (43 mm) but an increased septal and posterior wall thickness of 17 mm and 14 mm, respectively, reduced ejection fraction of 25% to 30%, low tissue Doppler velocities, right ventricular hypertrophy, and advanced diastolic dysfunction. There was also bilateral atrial enlargement and left ventricular hypokinesis. She had atrial fibrillation treated with dabigatran, which was discontinued 3 months prior to her death. Her troponin, pro-BNP, and BNP were elevated. She has never had a cardiac magnetic resonance imaging because of claustrophobia. Her cyclical vomiting syndrome diagnosis had been revised in the past year to gastroparesis, and she was being treated with botulinum toxin injections. Diflunisal was being considered for treatment, prior to death but with close monitoring due to elevated baseline creatinine. She died in her sleep at age 66, in 2014. Twin B presented to our neuropathy clinic at age 66 for evaluation of familial amyloid neuropathy given her sister’s medical history. She reported right hand tingling and pain at night for over 10 years. Additionally, she described having a leathery feeling on the bottom of her feet, as well as numbness that has developed a few months before presentation. On examination, she has mild interossei and toe extensor weakness, as well as mild distal sensory and vibratory loss. She denied shortness of breath or palpitations, but noted lightheadedness upon standing. She denied dry eyes or dry mouth. Of note, she had vitrectomy for ocular hypertension at age 64. Vitreous fluid had a lattice-like appearance but Congo Red staining of extracted vitreous aggregates did not document amyloid deposits. Electrodiagnostic testing revealed mild-to-moderate chronic axonal sensorimotor polyneuropathy and severe right and moderately severe left median mononeuropathies at the wrist
Discordant Phenotype of Lys35Thr FAP in Twins
Journal of
CLINICAL NEUROMUSCULAR DISEASE Volume 16, Number 1 September 2014
TABLE 2. Summary of Affected Individuals With Lys35Thr Mutation and Their Clinical Phenotypes Patient Age of Onset 1 2 3 4 5 6 7 8 Twin A Twin B
Mid-fourth decade Mid-fourth decade Mid-fourth decade 48 50 40 43 40 57 66
Clinical Phenotype Radiculopathy, vitreous amyloid Radiculopathy, vitreous amyloid Radiculopathy, vitreous amyloid Vitreous amyloid, radiculopathy Vitreous amyloid, radiculopathy Vitreous amyloid Radiculopathy Normal Vitreous amyloid, severe sensorimotor syndrome, cardiac failure, gastroparesis Carpal tunnel syndrome, sensorimotor polyneuropathy, although had vitrectomy age 64 without path evidence of amyloid
Patients 1 through 8 as reported by Long et al.12
consistent with Carpal tunnel syndrome. Autonomic testing, which includes heart rate variability at rest and cyclic deep breathing, Valsalva maneuver blood pressure and heart rate response, and tilt-table testing revealed mild-to-moderate parasympathetic cardiovagal and minimal to no evidence of peripheral sympathetic vasoconstrictor dysfunction and no neurogenic orthostatic hypotension. Laboratory testing showed the presence of positive anti-nuclear antibody with a 1:160 titer speckled pattern, elevated Gliadin IgG antibodies and normal Gliadin IgA and transglutaminase IgA antibodies, low B6 level, and a borderline B12 and random urine protein. Myelin-associated glycoprotein, dsDNA, urine protein electrophoresis, serum protein electrophoresis, copper, quantitative immunoglobulins, and TSH levels were normal. She has no history of diabetes or impaired glucose tolerance, and her random glucose was 96 mg/dL and HgA1C 5.1%. Her troponin and BNP were normal. Echocardiography showed grade I diastolic dysfunction with a normal systolic and valve function and an EF of 60%. Genetic testing revealed the same Lys35Thr TTR mutation as twin A and fat pad aspirates exhibited apple green birefringence under polarized light. Although discordant presentation of TTR has been reported in monozygotic twins
in the past, this is the first case of TTR Lys35Thr in Ashkenazi Jewish sisters living in the United States and causing peripheral neuropathy as part of the phenotype. Table 1 outlines the findings of previously reported twin cases. Discordant presentation in twin pairs ranged from 4 to 13 years after the onset of symptoms of the more severely affected twin. Although initial symptoms varied, dysautonomia tended to be an initial presentation for many. Most of the twin pairs eventually developed neuropathy and dysautonomia, but the time to onset of symptoms varied. TTR Lys35Thr has been identified as a cause of radiculopathy and vitreous amyloid in a family in China.12 Of the 8 family members with the gene mutation, 7 had evidence of disease at the time of the report. The clinical phenotype was vitreous amyloid and radiculopathy in 5/8, vitreous amyloid in 1/8, and radiculopathy in 1/8. Peripheral neuropathy is not reported in the previously published cases. Our case is therefore atypical for this particular gene mutation. As in our case, the reported patients with this gene mutation have late-onset disease, mean age being between 40 and 50 years old for this mutation. Table 2 summarizes the clinical phenotype of the individuals reported by www.jcnmd.com
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Long et al and the clinical phenotype of twin A and twin B. Although it is conceivable that one of the twins’ brothers was affected with TTR given his early death, there is no definitive evidence that other family members were affected, and this could be a de novo mutation in these twins. Twin B had vitreous that did not stain for amyloid, but it was noted to be abnormal with a lattice-like appearance that could have been the initial TTR amyloid symptom in this patient, making the age of initial presentation 64, or 6 years after twin A’s presentation. Given the progression of twin A’s disease is much more rapid, other factors likely play a role in the clinical phenotype of the affected individual. It has been reported that in the case of the Val30Met mutation, the onset of symptoms may be modulated by an interval downstream of TTR on the accompanying noncarrier chromosome (microsatellites D18S457 and D18S456). It is possible that a similar mechanism has a role in the Lys35Thr.13 REFERENCES 1. Benson MD. Liver transplantation and transthyretin amyloidosis. Muscle Nerve. 2013;47:157–162. 2. Coelho T, Adams D, Silva A, et al. Safety and efficacy of RNAi therapy for transthyretin amyloidosis. N Engl J Med. 2013;369:819–829. 3. Adams D, Theaudin M, Cauquil C, et al. FAP neuropathy and emerging treatments. Curr Neurol Neurosci Rep. 2014;14:435.
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