MRI analysis on a patient with the V30M mutation is characteristic of leptomeningeal amyloid.

We report a characteristic finding in gadolinium-enhanced magnetic resonance images (MRIs) of the central nervous system (CNS) in a 61-year-old man with a homozygous transthyretin (TTR) Val30Met mutation. Although he presented with polyneuropathy accompanied by autonomic dysfunction and vitreous opacities in both eyes, he has shown no overt signs or symptoms of CNS involvement. Total protein level in the cerebrospinal fluid was moderately elevated. In the gadolinium-enhanced T1-weighted MRIs of the brain and spinal cord, leptomeningeal enhancement was seen along the surfaces of the brain stem and more clearly in the spinal cord, suggesting leptomeningeal TTR-related amyloid deposition. Our result indicates that gadolinium-enhanced MRI of the CNS may be a very sensitive and useful method for detecting leptomeningeal amyloid deposition, since abnormal findings can be detected even at a presymptomatic stage of CNS involvement.     

Familial amyloid with a transthyretin leucine 33 mutation presenting with ascites

A 65-year-old female presented with symptomatic ascites. Light and electron microscopy examination of omental and peritoneal tissue obtained at exploratory laparotomy revealed amyloidosis. Immunochemical studies of the amyloid tissue showed positive staining with antibodies to transthyretin. Polymerase chain reaction (PCR), single strand conformation polymorphism analysis, and direct DNA sequencing demonstrated a transthyretin phenylalanine to leucine substitution at codon 33. This is only the second reported case of a transthyretin leucine 33 mutation. Moreover, this patient is unique among cases of transthyretin-associated amyloidosis with the clinical presentation of ascites. Am. J. Hematol. 59:249–251, 1998. © 1998 Wiley-Liss, Inc.     

Postmortem findings in a familial amyloid polyneuropathy patient with homozygosity of the mutant Val30Met transthyretin gene

Autopsy findings in a 68-year-old FAP patient with a homozygous mutation of the Val30Met TTR gene were described. In addition to amyloid deposits on the visceral organs, peripheral nerves and the vitreous body, severe deposition of amyloid in the leptomeninges and subarachnoid vessels in the brain and spinal cord was present. A double dose of the mutant gene may accelerate amyloid deposition on the ocular and meningeal tissues.     

A case of biopsy-proven leptomeningeal amyloidosis and intravenous Ig-responsive polyneuropathy associated with the Ala25Thr transthyretin gene mutation

A growing body of literature has described familial leptomeningeal amyloidosis, a rare phenotype resulting from deposition of transthyretin (TTR) amyloid within the leptomeninges. We report herein the case of a patient with leptomeningeal amyloidosis presenting with hearing loss, asymmetrical polyneuropathy and sensory ataxia. This is the first Japanese case displaying TTR mutation at codon 25, replacing alanine with threonine. Neurophysiological examinations suggested demyelinating polyradiculoneuropathy, which improved dramatically after high-dose intravenous immunoglobulin treatment. Demyelinating polyneuropathy in our patient may be attributable to massive leptomeningeal amyloidosis, and no systemic organ involvement was identified. These characteristic clinical manifestations may have resulted from the Ala25Thr TTR gene mutation.     

Efficiency of silencing RNA for removal of transthyretin V30M in a TTR leptomeningeal animal model

Abstract

Some TTR mutants target the central nervous system (CNS). Familial amyloid polyneuropathy (FAP) with leptomeningeal involvement has been described in 9% of transthyretin (TTR) mutations and in valine for methionine at position 30 (V30M) patients. These individuals present dementia, ataxia, brain hemorrhages and focal neurological episodes (FNEs). FNEs occurred also in V30M FAP patients with longer disease duration, who have undergone liver transplant to remove the source of plasma mutant TTR as a form of treatment. It is thus to expect that as better treatments for FAP emerge and prolong survival, meningeal-vascular CNS deposition will increase and need special therapies. Recently, we detected TTR meningeal-vascular deposition in a V30M TTR transgenic mouse model, opening new avenues of research to investigate selective treatments of this condition. Since pre-clinical studies with TTR siRNA therapeutics were shown to promote clearance of TTR non-fibrillar deposits in several organs and tissues, we investigated its effect on TTR meningeal-vascular deposition. We show that systemically administered TTR siRNA promoted TTR clearance in the extracellular matrix of meninges and brain blood vessels. Surprisingly, despite the striking decline of blood TTR, cerebrospinal fluid TTR levels were unaffected. Though this is reassuring because siRNA will not interfere with the neuroprotective role of TTR in the CNS, it raises new questions on therapeutical approaches for CNS ATTR.     

Marked biochemical difference in amyloid proportion between intra- and extraocular tissues in a liver-transplanted patient with hereditary ATTR amyloidosis

In order to elucidate the pathomechanism of ocular amyloid formation in a liver-transplanted patient with hereditary ATTR amyloidosis, we investigated detailed biochemical features of ocular amyloid. The patient was a 49-year-old woman with V30M transthyretin (TTR) variant (p.TTRV50M), who underwent ophthalmectomy due to corneal rupture 10 years after liver transplantation (LT). The amyloid was selectively isolated from several portions in intra- and extraocular tissues using a laser microdissection (LMD) system and analyzed by liquid chromatography–tandem mass spectrometry to determine the composition percentage of wild-type and variant TTR in the isolated amyloid. Biochemical analysis revealed that the amyloid consisted mainly of variant TTR in intraocular tissues with a percentage >?80%. On the contrary in the extraocular muscles, wild-type TTR was the main component of the amyloid with a percentage of ～70%. Our data indicate that intraocular amyloid formation strongly depends on locally synthesized variant TTR and the contribution of wild-type TTR to amyloid formation is quite limited.     

Transthyretin Val71Ala mutation in a Dutch family with familial amyloidotic polyneuropathy

A Dutch family with familial amyloidotic polyneuropathy associated with the transthyretin mutation VaUlAla is described. This is the third reported family with this mutation, causing at the protein level an unstable TTR monomer and at the clinical level progressive wasting, polyneuropathy, autonomic dysfunction and vitreous opacities.     

Hereditary cardiac amyloidosis associated with the transthyretin Ile122 mutation in a white man

An 83 year old white man with atrial fibrillation was admitted to hospital after a cerebral infarct. Echocardiography was characteristic of cardiac amyloid deposition and subsequent tests confirmed amyloidosis of transthyretin (TTR) type, in association with the Ile122 mutation of the TTR gene; this has only been reported previously in African Americans in whom it occurs with an allele frequency of 2%. Haplotype analysis did not suggest a different founder than for the African Ile122 mutation. Cardiac amyloidosis should be considered among elderly patients presenting with cardiac failure and/or arrhythmia, particularly if they are resistant to conventional treatment; if confirmed, it should be followed by precise characterisation of amyloid fibril type. The prevalence of autosomal dominant cardiac TTR amyloidosis in elderly white people is unknown but early diagnosis and supportive treatment may prevent complications among affected family members.


Keywords: amyloid; amyloidosis; transthyretin; hereditary amyloidosis; stroke     

Impact of liver transplantation on the natural history of oculopathy in Portuguese patients with transthyretin (V30M) amyloidosis

Purpose: Evaluation of the impact of liver transplantation in the natural history of ocular disorders in familial amyloidotic polyneuropathy (FAP) amyloidosis TTR V30M related (ATTR V30M) patients.

Design: A clinical, retrospective and cross-sectional study of 64 Portuguese FAP ATTR V30M patients was carried out between January 2005 and December 2011.

Methods: Thirty-two liver transplanted patients (both eyes) aged 39.6–53.8 years old, 32/32 male/female, were paired with an equal number of non-transplanted patients, matching for age, gender, age at onset, disease duration and gender of transmitting parent. Intervention or observation procedure: Routine ophthalmological observation. Main outcome measures: Slit-lamp observation for abnormal conjunctival vessels (ACV), tears break-up time, iris, lens; fundus observation for vitreous, retina and optic disc; Schirmer test.

Results: Liver transplantation had no influence on tears break-up time, deposition of amyloid on the iris and retinal amyloid angiopathy. Slight, non-statistically significant protective effects of liver transplantation were noted in the first years for some ocular manifestations (ACV and scalloped iris), except for the abnormal Schirmer test, which was significantly more prevalent in non-transplanted patients’ eyes (81% versus 56%, p?=?0.002). On the other hand, deposition of amyloid on the lens, vitreous amyloidosis and glaucoma were apparently more common in transplanted patients. Those differences tended to disappear with time.

Conclusions: Ocular manifestations of FAP were not influenced by liver transplantation in a meaningful way. Both transplanted and non-transplanted FAP patients need similar regular follow-up due to long-term risk of serious ocular disease.     

Familial amyloid polyneuropathy associated with TTRSer50Arg mutation in two Iberian families presenting a novel single base change in the mutant gene

We present two families, from Spain and Portugal, with familial amyloid polyneuropathy (FAP) associated with the mutation TTRSer50Arg. This mutation was first described in two Japanese patients from independent families and later in a French-Italian patient and a Vietnamese family. The two families presented here, are the first to be diagnosed with this mutation in the Iberian Peninsula. In the patients of both families, FAP was very aggressive as they rapidly developed multiple symptoms with progressive deterioration; we emphasize the presence of severe orthostatic hypotension in the Spanish proband which confined him to a wheelchair. This proband was the first patient with this mutation to have undergone liver transplantation and results were encouraging. The mutation was detected in four patients and one disease-free relative by DNA sequencing of exon 3 and induced mutation restriction analysis. The most outstanding feature was the single base transversion A to C in codon 50 (CGT instead of AGT), whereas in both Japanese patients and the French-Italian patient it was T to G (AGG instead of AGT). To our knowledge only six FAP mutations with more than one single nucleotide mutation for the same codon have been reported to date.     

Value of renal biopsy in the prognosis of liver transplantation in familial amyloid polyneuropathy ATTR Val30Met patients

Liver transplantation for familial amyloid polyneuropathy (FAP) patients has been carried out worldwide and the outcomes seem to be promising. To clarify the severity of amyloid deposits on visceral organs, we evaluated the histopathological findings of biopsied renal and sural nerve specimens in 13 FAP patients with ATTR Val30Met by quantitative analysis, and compared them with the outcome of transplantation. Renal dysfunction with proteinuria seemed to correlate with the degree of amyloid deposits in glomeruli, not with that in medullary tissues. The severity of renal amyloid deposition did not consistently parallel that of myelinated nerve fiber loss in sural nerve. Three patients with proteinuria and severe amyloid deposits in glomeruli were considered to be unsuitable for transplantation. Ten patients underwent living donor liver transplantation and three resulted in unfavorable outcomes. These three had heavy amyloid deposits on renal tissues, especially in glomerular areas, but the severity of myelinated nerve fiber loss in their sural nerves was very similar to that in patients who made a good recovery. The prognosis after operation might be closely related to the severity of amyloid deposits in renal glomeruli. Renal biopsy is, therefore, recommended when determining the indications and contraindications for liver transplantation in FAP patients, although this biopsy is not routinely required.     

Recurrent V75M mutation within the Wiskott-Aldrich syndrome protein: description of a homozygous female patient

The Wiskott-Aldrich syndrome is a rare genetic disorder due to mutations in the WAS gene situated on chromosome X. It is comprised of microthrombocytopenia, eczema and immunodeficiency. However, the phenotypical presentation may vary as to the number and intensity of its manifestations. A milder form of Wiskott-Aldrich syndrome is known as the X-linked thrombocytopenia. We independently found eight individual or familial cases with the V75M substitution (9.76%). This high incidence was partly accounted for by the fact that three cases turned out to be related. The V75M mutation is recurrent, however, due to a CpG island. A genuine homozygous female patient was found. She showed microthrombocytopenia and infections to the same degree as her hemizygous father and brother. The WAS protein was decreased in a comparable fashion in the hemizygotes and the homozygote as well. Its amount was about 10% and 15% of normal in platelets and mononucleated white cells, respectively. In all patients was the picture consistent with XLT.     

A case report of a patient with inoperable primary diffuse leptomeningeal melanomatosis treated with whole-brain radiotherapy and pembrolizumab

Rationale:Primary diffuse leptomeningeal melanomatosis (PDLM) is a rare disease that affects melanocytes in the leptomeninges. There is very limited data on the efficacy of immunotherapy in this setting.Patient concerns:A patient (23 years old) was diagnosed with PDLM. Histologically, atypical melanocytic cells were also observed.Diagnosis:Immunohistochemistry showed positivity for S100 protein, NKiC3, and vimentin, and negativity for Melan-A and HMB-45, with a proliferation index of 30%. Extracranial disease was excluded using dermatological and other examinations, including positron emission tomography/computed tomography with ¹⁸F-fluorodeoxyglucose.Interventions:The patient was treated with whole-brain radiotherapy (10 fractions to a total dose of 30 Gy) concomitantly with pembrolizumab and then continued with immunotherapy until disease progression with a maximum effect of partial remission on magnetic resonance imaging scans.Outcomes:Progression-free survival was 6.0 months and overall survival 6.5 months.Lessons:This is one of the few case reports of an adult patient with this rare malignancy being treated with a programmed death-1 inhibitor with partial response. Immunotherapy in metastatic PDLM may be a reasonable therapeutic option.     

Finding of vascular amyloid TTR in inferior nasal concha in a patient with FAP TTRVal30Met

We report the case of a female patient with familial amyloid polyneuropathy (FAP) who demonstrated TTR amyloid deposition in the inferior nasal conchal vessels.

To our knowledge this location has not been described previously in FAP; in addition, it was detected in a patient who had undergone successful liver transplantation (LTX) 4 years earlier.

The amyloid deposition was found incidentally during examination of a right nasal obstruction caused by a nonspecific inflammatory polyp. Small focal deposits of amyloid TTR were observed on deep thick walled vessels, contrasting with the massive deposition reported in neoformed vessels in amyloidomas. This amyloid was clearly deposited between the onset of FAP and LTX and had probably decreased since the graft.

If amyloid deposition is frequent in inferior nasal concha in FAP, this location could be a suitable biopsy site.     

Diagnosis of sporadic transthyretin Val30Met familial amyloid polyneuropathy: a practical analysis

Transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) is the most common form of FAP and is now prevalent in areas other than those seen within conventional endemic foci. We investigated 15 patients with FAP ATTR Val30Met without a family history of FAP who were referred for sural nerve biopsy. Initial symptoms included somatic neuropathy in all patients, while sensory dissociation and autonomic symptoms were apparent only in two and seven patients, respectively. Nonspecific neuropathic features and slight abnormalities in cerebrospinal fluid protein levels and in electrophysiological indices related to nerve conduction led clinicians to initially suspect chronic inflammatory demyelinating polyneuropathy (CIDP) in some patients. Small-fiber predominant loss was observed in a minority of patients. In terms of cardiac involvement, findings suggestive of subclinical cardiomyopathy due to amyloid deposition, such as cardiomegaly on chest X-ray, thickening of the interventricular septum, and granular sparkling echo on echocardiography, were seen alone or in combination in 11 of 14 examined patients. In conclusion, clinicians should consider the possibility of FAP ATTR Val30Met in patients presenting with neuropathy of undetermined etiology to avoid misdiagnosis. Detecting subclinical cardiac involvement may help to diagnose late-onset FAP ATTR Val30Met in those without a family history of the disease.     

Ophthalmological manifestations in hereditary transthyretin (ATTR V30M) carriers: a review of 513 cases

Purpose: Assessment of ocular involvement in transthyretin-related familial amyloidosis with polyneuropathy (FAP) in a large cohort of Portuguese patients.

Methods: We reviewed the medical records of 513 Portuguese FAP mutation carriers, at the Ophthalmology Service, Centro Hospitalar do Porto, between 1 January 2008 and 31 January 2013. Abnormal conjunctiva vessels (ACV), Schirmer test, tear break-up time (TBUT), amyloid deposition on the iris (DAI), scalloped iris, amyloid deposition on the anterior capsule of the lens (DAL), vitreous amyloidosis, retinal amyloid angiopathy and glaucoma were evaluated and registered.

Results: Of the 513 carriers, 477 (93%) had clinical systemic disease with a median duration of 9.3 (5.1–13.7) years and 247 were men. Of these, 343 (72%) had been liver transplanted, on median of 6.6 (3.3–10.8) years before inclusion in this study. No ocular abnormalities were identified in the asymptomatic carriers (7%). The abnormalities observed with decreasing frequency were abnormal TBUT (379 patients, 79.5%, 751 eyes), abnormal Schirmer test (320 patients, 67%, 635 eyes), DAI (183 patients, 38.4%, 350 eyes), DAL (157 patients, 32.9%, 308 eyes), scalloped iris (133 patients, 27.9%, 238 eyes), glaucoma (97 patients, 20%, 165 eyes), vitreous amyloidosis (83 patients, 17.4%, 139 eyes), ACV (68 patients, 14%, 136 eyes) and amyloidotic retinal angiopathy (21 patients, 4%, 32 eyes).

Patients with abnormal Schirmer test (p?<?0.001), scalloped iris (p?=?0.006) and vitreous amyloidosis (p?=?0.007) were significantly older than the others. According to their age of onset of systemic disease, the patients have been split into early-onset (<40 years old), intermediate-onset (40–50 years old), late onset (>50 years old) and asymptomatic carriers. We observed a statistically significant difference in the prevalence of ACV (p?=?0.045) and of an abnormal Schirmer test (p?=?0.004) between groups. Transplanted patients have a significantly higher prevalence of DAI (p?=?0.001), DAL (p?=?0.009) and vitreous amyloidosis (p?=?0.025) than non-transplanted patients. Of the 165 eyes with glaucoma, 92.1% had scalloped iris (p?<?0.001) and of 32 eyes with retinal amyloidotic angiopathy, 68.8% had vitreous amyloidosis (p?<?0.001). All prevalences increased with time of disease. The earliest ocular manifestations were abnormal Schirmer test and abnormal TBUT (12% and 17% at 5 years of clinical disease) and the least prevalent was retinal amyloid angiopathy (8% at 15 years of clinical disease).

Conclusion: Ocular disorders in FAP patients are common, and their prevalence increases with disease duration. Prevalence is influenced by several factors, such as the age at onset of FAP and liver transplantation.     

Identification of a novel transthyretin Thr59Lys/Arg104His. A case of compound heterozygosity in a Chinese patient diagnosed with familial transthyretin amyloidosis

Transthyretin (TTR) is a 127-amino acid residue protein synthesized mainly in the liver and in several minor sites, including the choroid plexus and the eye. in plasma, TTR circulates as a homotetramer and transports the hormone thyroxine and the retinol-binding protein-vitamin A complex. It is hypothesized that amino acid substitutions in TTR destabilize the tetramer by causing each subunit to form intermediates that may self-associate into amyloid fibrils. Deposition of wild type TTR, its variants and/or fragments as amyloid fibrils in tissues and organs is associated with familial transthyretin amyloidosis (A TTR). Reported herein is the characterization of a novel TTR Thr59Lys/Arg104His in a patient of Chinese ancestry, who was diagnosed with A TTR. The two variant proteins and the double gene mutations in this compound heterozygous case were detected and identified using a multifaceted approach consisting of isoelectric focusing, electrospray ionization mass spectrometry (MS), matrix-assisted laser desorption/ionization time-of-flight MS in combination with enzymatic digestion, and direct DNA sequence analysis. Previous studies have shown that the TTR Arg104His variant is non-pathologic. It appeared to provide a protective effect in another compound heterozygous case (TTR VaBOMet/Arg104His). However. the TTR Arg104His variant when presented with the TTR Thr59Lys variant did not seem to have any protective role.     

Amyloid detection in the transverse carpal ligament of patients with hereditary ATTR V30M amyloidosis and carpal tunnel syndrome

Introduction: Carpal tunnel syndrome (CTS) is a nonspecific manifestation of hereditary ATTR amyloidosis (ATTRm). Amyloid deposition of wild-type TTR (WT-ATTR) has been found in transverse carpal ligament (TCL) in idiopathic CTS. We retrospectively studied a group of patients with ATTRm and CTS submitted to carpal tunnel release surgery (CTRS).

Methods: From the nerve conduction studies performed in our Clinical Unit dedicated to hereditary amyloidosis between July 2009 and October 2013, we selected patients who fulfilled neurophysiological criteria for CTS, had been submitted to CTRS and whose TCL was available for pathology. Clinical registries were reviewed and amyloid detection in the ligaments was performed using Congo-red staining.

Results: We included 16 patients: three males (18.8%), mean age?=?46.1?years old, all with V30M mutation. At the time of surgery, four patients were considered asymptomatic and 12 symptomatic carriers, five of them late-onset ATTRm (onset age >50?years old). In all but one patient, the CTS preceded the polyneuropathy. Amyloid detection in the TCL was positive in 14 patients (87.5%).

Discussion/conclusions: In most patients, CTS preceded or was contemporary to the polyneuropathy and amyloid detection in TCL was positive. The detection of amyloid in TCL may add specificity to CTS as an early manifestation of the disease but more studies are needed.     

Sulphonylurea therapy improves cognition in a patient with the V59M KCNJ11 mutation

Background KCNJ11 mutations are a common cause of diabetes diagnosed in the first 6 months of life, and approximately 25% of patients have neurological features. Sulphonylureas have been shown to improve glycaemic control and also motor function, but the impact on cognitive function has not been extensively addressed previously. Methods The patient had a low birth weight and was found to have diabetes at the age of 2 days. The patient was treated with insulin from diagnosis. The child also had marked developmental delay so that his average functional age was 2.5 years when he was 12 years old. A V59M mutation in KCNJ11 was found on sequencing, resulting in a diagnosis of intermediate developmental delay, epilepsy, neonatal diabetes (DEND) syndrome. Identification of a Kir6.2 mutation allowed insulin injections to be replaced by glibenclamide tablets. Results This resulted not only in improved glycaemic control (HbA_1c fell from 8.1 to 6.5%), but also an impressive improvement in many aspects of cognitive function, with the functional age increasing to 4 years within 6 months of treatment change. Conclusions This is the first clear report of cognitive function improving in a patient with the neurological features associated with a K_ATP channel mutation following transfer to sulphonylureas. The finding of cognitive improvement suggests that glibenclamide is likely to be acting directly on the brain and not just on nerve and muscle, improving muscle strength.