Three Turkish families with different transthyretin mutations

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ScienceDirect Neuromuscular Disorders 25 (2015) 686–692 www.elsevier.com/locate/nmd

Three Turkish families with different transthyretin mutations Can Ebru Bekircan-Kurt a,*, Nalan Günes¸ b, Arda Yılmaz c, Sevim Erdem-Özdamar a, Ersin Tan a a

Hacettepe University Neuromuscular Disease Research Laboratory, Neurology Department, School of Medicine, Ankara, Turkey b Neurology Department, Ankara Training Hospital, Ankara, Turkey c Neurology Department, School of Medicine, Mersin University, Mersin, Turkey Received 4 February 2015; received in revised form 5 May 2015; accepted 22 May 2015

Abstract Transthyretin (TTR)-related hereditary amyloidosis, also called familial amyloid polyneuropathy (FAP), is a rare autosomal dominant systemic disorder that presents with progressive axonal sensory, autonomic and/or motor neuropathies. The present report describes three families with three different TTR mutations who were followed from 1995 to 2014. Only one of these families expressed the Val30Met mutation, which is the most common mutation in endemic regions; all members of this family had late disease onset but varied severities and clinical presentations of the disease. The second family expressed the Thr49Ser mutation, which has not been well documented previously. Our limited experience obtained from these patients indicates that this mutation presents with autonomic neuropathy but a greater degree of cardiac involvement, especially fatal heart failure. The third mutation, Glu54Lys, has been identified as a cause of severe familial amyloid polyneuropathy; the family members with this mutation exhibited severe motor and autonomic neuropathy, early vitreous opacity, and fatal heart failure. Three of the patients with the Val30Met mutation were treated with tafamidis for longer than one year and cessation of the polyneuropathy resulted. However, a short trial of tafamidis in two patients with the Glu54Lys mutation, who showed severe systemic and neurological involvement, did not gain any clinical benefits. © 2015 Elsevier B.V. All rights reserved. Keywords: Familial amyloid polyneuropathy; Transthyretin; Val30Met; Thr49Ser; Glu54Lys

1. Introduction Amyloidoses are a heterogeneous group of diseases characterized by the tissue deposition of amyloid proteins in multiple organs such as the liver, kidney, heart and nervous system [1]. The specific organ involvement depends on the mutated protein, and to date, more than 30 proteins have been identified in amyloid fibrils [2]. Among these proteins transthyretin (TTR) is associated with the most common form of amyloidosis, which can be hereditary (familial) or secondary to senile systemic amyloidosis [3]. TTR is a plasma transport protein for thyroxine and vitamin A that is primarily produced in the liver [4]. When TTR is misfolded and aggregated in various tissues, especially the peripheral nerves, it causes progressive, mainly axonal, sensory, motor and autonomic neuropathy called “Familial Amyloid Polyneuropathy (FAP)” [1,4].

* Corresponding author. Neurology Department, School of Medicine, Hacettepe University, Sıhhiye 06100 Ankara, Turkey. Tel.: +90 312 3051741; fax: +90 312 3093451. E-mail address: [email protected] (C.E. Bekircan-Kurt). http://dx.doi.org/10.1016/j.nmd.2015.05.010 0960-8966/© 2015 Elsevier B.V. All rights reserved.

This disorder was first described in a Portuguese family in 1952 by Andrade [5] and in 1978, TTR was shown to be a major component of amyloid fibrils in FAP patients [6]. The most common mutation of TTR-FAP; a substitution of methionine for valine at position 30 on chromosome 18 (Val30Met); was described by Saraiva et al. several years later [7]. Presently, more than 100 autosomal dominant mutations or deletions of the TTR gene have been reported [8–10]. FAP has an autosomal dominant inheritance [11] and is endemic in Portugal, Japan, Sweden and Brazil [1,12]. Distinct polyneuropathies including sensorimotor polyneuropathies, entrapment neuropathies (usually carpal tunnel syndrome), autonomic neuropathy and small fiber neuropathy can manifest in TTR-FAP patients [8,13,14]. The present report describes three families with defined TTR mutations who were followed in our department from 1995 to 2014. Although Val30Met is the most common FAP mutation in endemic regions [8–10], only one of the families in the present report expressed this mutation. The other two families expressed two different mutations that have not been previously reported in the Turkish population [15]. The present report summarizes the clinical observations associated with each of

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these three mutations in terms of their distinct systemic and neurological involvements. 2. Family 1 2.1. Case 1 A 54 year-old man presented with complaints of numbness in his hands and feet over the previous 2 months. Although his routine laboratory tests were normal, the neurological examination revealed glove- and stocking sensation loss and diminished Achilles reflexes. The patient was examined again 3 months later; his examination showed bilateral weakness in hip flexion, knee flexion and feet dorsiflexion and his deep tendon reflexes and vibration sensation were lost in the lower extremities. An electrophysiological examination indicated a mixed neuropathy that was prominent in the sensory nerves. There was a slight increase in the cerebrospinal fluid (CSF) protein levels (48 mg/dL) and a nerve biopsy revealed mild fiber loss with scattered thinly myelinated fibers (Fig. 1). A Congo-red staining procedure failed to identify the presence of amyloid proteins, and because chronic inflammatory demyelinating polyneuropathy (CIDP) could not be ruled out, the patient began a regimen of corticosteroids and intravenous immunoglobulin (IVIg) at appropriate doses. Despite receiving these treatments, the patient developed bilateral weaknesses in shoulder abduction, elbow flexion and extension and finger flexion with thenar and hypothenar atrophy in addition to his neurological deficits. An amyloid polyneuropathy was always suspected but the genetic analysis was not available at that time. The patient died at 64 years of age.

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2.2. Index case The son of Case 1 was referred to our department at 50 years of age, which was 19 years after the death of the Case 1. The initial examination revealed glove- and stocking sensation loss of pain and light touch. An electroneuromyography (ENMG) test returned normal results but the patient’s heart rate variability (HRV) indicated parasympathetic system dysfunction. DNA sequencing analysis revealed the Val30Met mutation and thus treatment with tafamidis was initiated and his sensory symptoms improved. The patient has been followed up for 18 months and has not expressed any motor deficits but an echocardiography test revealed a retardation of diastolic relaxation. 2.3. Case 3 Case 3, the paternal cousin of Case 1, was admitted with complaints of burning in her feet at 69 years of age. A neurological examination revealed glove- and stocking sensation loss of pain and light touch in conjunction with the absence of deep tendon reflexes. An electrophysiological examination revealed severe motor and sensory axonal neuropathy and moderate right-sided carpal tunnel syndrome. Due to the patient’s family history, a genetic analysis was performed and the Val30Met mutation was detected. Treatment regimens with pregabalin and tafamidis were initiated and the patient’s neuropathic pain improved within one year of tafamidis treatment. Currently, the patient can walk independently and does not have any motor deficits, but an echocardiography showed left ventricular hypertrophy and left atrial enlargement. Additionally, an electrocardiography test revealed a left anterior fascicular block and brain natriuretic peptide (BNP) level was high (136 pg/mL; normal value: 0–100 pg/mL). Five of the patient’s family members died after presenting with a similar clinical profile (Fig. 2A, Table 1A and 1B). 3. Family 2 3.1. Index case A 36 year-old man suffering from abdominal pain and constipation was referred to our gastroenterology department. An endoscopic duodenal biopsy was compatible with amyloidosis (Fig. 3), and a genetic analysis revealed a Thr49Ser mutation in the TTR gene. Although the patient’s neurological examination was normal, an echocardiography test showed diastolic heart failure with left ventricular hypertrophy and an electrophysiological examination revealed bilateral carpal tunnel syndrome. The patient was followed up at our cardiology department as a heart transplantation candidate, but he died at the age of 38 years. 3.2. Case 2

Fig. 1. Epoxy resin-embedded semi-thin transverse section of sural nerve biopsy obtained from the index case of Family 1 demonstrating mild fiber loss with scattered thinly myelinated fibers (20x).

The daughter of the index case was referred due to complaints of constipation and orthostatic hypotension at the age of 18 years. Her neurological examination showed vibration sensation lost below her wrists and ankles and her blood pressure was 110/60 mmHg while lying down and 90/50 mmHg while standing. The patient’s ENMG results were normal but her HRV

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Fig. 2. The family trees of Family 1 (A), Family 2 (B), Family 3 (C).

indicated sympathetic system dysfunction. Because her father was diagnosed with amyloidosis, a genetic analysis was performed and the Thr49Ser mutation was detected. The patient’s cardiological and ophthalmological examinations were normal but her ejection fraction was 70% with mild tricuspid insufficiency; Holter monitoring revealed paroxysmal

ventricular extrasystole, her heart rate varied 56–138 beats per min. Her BNP level was normal and because she does not exhibit the symptoms of sensory-motor neuropathy or lower extremity autonomic neuropathy [12], no treatment was initiated. The patient is currently being followed up regularly and has not exhibited any other symptoms for 3 years.

Fig. 3. Hematoxylin-eosin (A) and Amyloid P component (B) immunohistochemical stainings of the duodenal biopsy of Case 1 (Family 2) showing submucosal amyloid deposits (courtesy of Prof. Dr. Gökhan Gedikoglu, Hacettepe University Department of Pathology).

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Table 1A Demographic, neurological data and outcome for all patients. Family no.

Patient no.

Mutation

Age of onset

Gender

Delay for diagnosis (years)

Neuropathy type

PND

FAP stage

Treatment

SF36 (PCS/MCS)

Survival (years)

Outcome

1

1

Val30Met

54

M

N/Aa

S, M

3a

2

N/A

10

Death

1

2

Val30Met

50

M

0

S, A

1

1

1

3

Val30Met

69

F

2

1

1

1

4b

Val30Met

82

F

5

S, M CTS S, M

1

1

2 2 3 3

1 2 1 2

Thr49Ser Thr49Ser Glu54Lys Glu54Lys

36 18 28 30

M F F F

1 0 2 0

CTS A S, M, A S, M, A

0 0 4 4

0c 1 3 3

CS IVIg Tafamidis PGB Tafamidis PGB Tafamidis PGB No No No No

55.3/ 52.9

2

No symptoms

19.8/ 46.9

1

Neuropathic pain

14.2/ 63.5

1

Neuropathic pain

N/A 55.2/ 57.8 N/A 17.6/ 22.7

2 5 4 4

Death Orthostatic hypotension Death Loss of ambulation

a

The patient could not be diagnosed with FAP. The patient was not specified in the text. c The patient was asymptomatic for peripheral and autonomic neuropathies. Abbreviations: A: autonomic neuropathy, CS: corticosteroids, CTS: carpal tunnel syndrome, ECG: electrocardiogram, F: female, FAP: familial amyloid polyneuropathy, IVIg: intravenous, M: motor neuropathy, MCS: mental component score (range: 17–62), N/A: not available, PGB: pregabalin, PCS: physical component score (range: 20–58), PND: polyneuropathy disability score, S: sensory neuropathy, SF36: Short form 36. b

Table 1B Systemic features and laboratory findings of all patients. Family no.

Patient no.

Mutation

Cardiac involvement

Vitreous opacity

Renal dysfunction

BMI

N/A 10.2

No No

No No

N/A 22

136

No

No

27.24

58 N/A

No No

No No

27.5 N/A

11 N/A

No Yes

No Yes

18 N/A

212

Yes

Yes

17

ECG

Holter

Echocardiography

BNP

N/A DD Minimal MI, TI LVH LAE Minimal MI, TI LVH DD Mild TI LVH

AWT VWT DD Septal granulation

1 1

1 2

Val30Met Val30Met

NSR NSR

N/A NSR

1

3

Val30Met

LAFB

NSR

1 2

4 1

Val30Met Thr49Ser

NSR N/A

NSR N/A

2 3

2 1

Thr49Ser Glu54Lys

VES N/A

3

2

Glu54Lys

NSR NSR Inferolateral T negativity NSR

N/A

Abbreviations: AWT: atrial wall thickness, BNP: brain natriuretic peptide, BMI: body mass index, DD: diastolic dysfunction, ECG: electrocardiogram, LAE: left atrial enlargement, LAFB: left anterior fascicular block, LVH: left ventricular hypertrophy, MI: mitral insufficiency, N/A: not available, NSR: normal sinus rhythm, TI: tricuspid insufficiency, VES: ventricular extrasystole, VWT: ventricular wall thickness.

4. Family 3 4.1. Index case A 30-year-old female was referred to our neurology department because she had been suffering from diarrhea and numbness in her distal extremities for two years. A neurological examination revealed slow saccadic eye movements, diminished visual acuity, reduced deep tendon reflexes and glove- and stocking hypoesthesia. A motor examination showed distal muscle weakness with a Medical Research Council (MRC) score of 4/5 and an ophthalmological examination showed severe vitreous opacity. A cranial magnetic resonance imaging did not reveal an organic pathology that could have explained the slow saccadic eye movements but her ENMG results were compatible with an axonal

polyneuropathy. The patient’s sympathetic skin responses indicated sympathetic dysfunction, and her HRV suggested sympathetic and parasympathetic dysfunction. A sural nerve biopsy demonstrated severe myelinated and unmyelinated fiber loss as well as amyloid deposits, which were also detected on rectal biopsy. An echocardiography showed left ventricular concentric hypertrophy. The genetic analysis was positive for the Glu54Lys mutation on TTR gene, and as a result, tafamidis treatment was initiated. Unfortunately the patient died of heart failure one year later. 4.2. Case 2 A 30-year-old female, the sister of the index case, was admitted with heart failure, progressive leg weakness,

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incontinence, and orthostatic hypotension. The patient’s MRC scores were as follows: her bilateral shoulder abduction was 4/5, her elbow flexion and extension were 4/5, her finger abduction, adduction, opposition were 1/5; her hip flexion was 4/5, her knee flexion and extension were 4-/5, and her foot dorsiflexion and plantar flexion were 2/5. The patient’s deep tendon reflexes were absent and a glove- and stocking sensation loss was observed in all modalities. The ENMG results revealed severe sensorimotor axonal polyneuropathy and her HRV was compatible with parasympathetic and sympathetic dysfunction. An echocardiography indicated atrial and ventricular wall thickness with septal granulation and left ventricular diastolic dysfunction. The genetic analysis detected the Glu54Lys mutation and even though the patient was in the late stages of the disease, tafamidis treatment was initiated. However the patient discontinued treatment after three months and no

benefits were observed after such a short period. Presently, the patient can only walk short distances with the aid of two canes. 5. Discussion The clinical features of the most common TTR mutation, Val30Met, greatly differ among various ethnic groups and within different families due to variable penetrance [16–18]. FAP may be categorized into two subgroups; early-onset disease in endemic areas and late-onset disease in non-endemic areas [12]. The early-onset disease generally presents with autonomic dysfunction, a selective loss of superficial sensations (including nociception and thermal sensation), and atrioventricular conduction block in the second and third decades [19]. In non-endemic areas, the disease typically manifests after the age of 50 years and is characterized by sensory and autonomic neuropathies and cardiac involvement [12]. Turkey is not an endemic region for FAP and, in accordance

Table 2 Clinical and laboratory findings of previous and present familial amyloid polyneuropathy patients with the Glu54Lys mutation. Family (ref)

Patient Origin

Age Sex First Duration Neurological of manifestation of disease manifestation onset (year) (years)

1 [23]

1

Japanese

29

2 [24]

1

2

Systemic involvement

M

Autonomic 3 (constipation and vomiting)

Motor and Cardiac autonomic Ophthalmological polyneuropathies (vitreous opacity)

Costa-Rican 27

F

Severe Unknown Sensorimotor paresthesia, and autonomic gait polyneuropathies disturbances

Cardiac Ophthalmological (vitreous opacity)

Costa-Rican 26

M

Leg weakness

2

Unknown

Unknown

3 (present 1 cases)

Turkish

28

F

Numbness in distal legs

4

2

Turkish

30

F

Leg 4 weakness, incontinence, orthostatic hypotension

Sensorimotor Cardiac and autonomic (fatal polyneuropathies heart failure) Ophthalmological (vitreous opacity) Renal Sensorimotor Cardiac and autonomic (heart polyneuropathies failure) Ophthalmological (vitreous opacity)

Abbreviations: ECG: electrocardiogram, F: female, M: male, NSR: normal sinus rhythm.

ECG

Echocardiography Family history

Complete right bundle branch block

Massive thickness His mother also of left ventricular complained of wall severe diarrhea, ileus and died age 33 of heart failure. His maternal grandmother died at age 35 of pneumonia, cardiac failure.

Right bundle branch block, T-wave repolarization changes Unknown

Cardiac enlargement and dysfunction

Unknown

Inferolateral T-wave negativity

Left ventricular hypertrophy

NSR

Atrial and ventricular wall thickness with septal granulation Left ventricular diastolic dysfunction

The index case had three siblings (one of whom is Patient 2), two uncles and one aunt affected as well as her mother who died age 38 due to amyloidosis. See Fig. 2B

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with the literature, the present cases who expressed the Val30Met mutation were older than 50 years [19]. However, the disease severities and clinical presentations differed within the individual family. For example, Case 1 from Family 1 presented with a severe neuropathy, whereas the three other cases exhibited only a mild polyneuropathy with neuropathic pain. The initially affected member of Family 1 could not be diagnosed with FAP due to the absence of amyloid deposits on the sural nerve biopsy. Although nerve biopsies are useful for the diagnosis of FAP, they can sometimes fail to identify the amyloid deposits due to the random distribution of amyloid; in previous case series, the chance of detecting amyloid deposits on a sural nerve biopsy ranged from 67 to 87% [20–22]. To the best of our knowledge, the clinical features of FAP patients with Thr49Ser mutation have yet to be fully investigated. The present index case with the Thr49Ser mutation had carpal tunnel syndrome but no other neurological symptoms. He had a severe heart failure that HRV could not be relevant. The daughter of the index case exhibited cardiac involvement and a moderate autonomic neuropathy without any motor or sensory symptoms and signs. Based on our limited experience with this family, the present findings suggest that the Thr49Ser mutation causes a predominantly cardiac phenotype. The Glu54Lys mutation was first described in a Japanese family who presented with early autonomic symptoms (constipation, diarrhea and vomiting as the prominent symptoms), vitreous opacity, and heart failure [23] (Table 2). The second family with this mutation was from Costa Rica and exhibited severe motor, sensory and autonomic neuropathies, vitreous opacity, and cardiac failure [24]. As all reported patients died before the age of 40 years, the authors concluded that Glu54Lys causes severe FAP [23,24]. In line with previous findings, five of six affected members of the present family died before the age of 45 years. These patients demonstrated severe motor neuropathies that resulted in a loss of ambulation, autonomic dysfunction with diarrhea and severe early impairments in visual acuity due to vitreous opacity. The cause of death in these patients tended to be heart failure. Although the standard therapy for TTR-FAP patients is still liver transplantation [1,4], randomized clinical trials have shown that there is a lower risk of neurological impairments following treatment with two drugs, tafamidis [25] and diflunisal [26]. Tafamidis, which is a benzoxazole derivate, binds and stabilizes TTR and has been approved by the European Medicines Agency for early-stage disease treatment of TTR-FAP patients expressing the Val30Met and non-Val30Met mutations [4]. However, there are a lack of data regarding its use in TTR-FAP patients during later disease stages [4]. In the present report, three of the patients with the Val30Met mutation have been undergoing tafamidis treatment for more than one year and the progression of the polyneuropathy has ceased. In contrast, the short tafamidis trials in two of the patients with the Glu54Lys mutation, who had severe systemic and neurological impairments, did not have any benefits. In conclusion, our experience with these families suggests that Val30Met, the most common mutation in FAP patients, is not as frequent among the Turkish population as it is in endemic regions. The other two mutations, Glu54Lys and Thr49Ser, have not previously been reported in Turkish patients [15]. The members of

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