Conjunctival lymphangiectasia and retinal angiopathy in hereditary transthyretin amyloidosis

Abstract Background Hereditary transthyretin amyloidosis (ATTR amyloidosis) is a rare condition where a mutation in the transthyretin gene leads to systemic deposition of amyloid. The manifestations and prognosis of ATTR amyloidosis depends on the specific ATTR mutation, with over 100 mutations reported in the literature. The manifestations of many rare forms of ATTR amyloidosis have not been well described, particularly the late-onset ophthalmic findings. Case presentation We present the case of a 43-year-old Caucasian male with a diagnosis of ATTRD18E amyloidosis confirmed by fat pad biopsy. He had diffuse systemic involvement, including cardiovascular, pulmonary, and gastrointestinal symptoms. He also had significant ocular involvement including vitreous opacities, retinal angiopathy, and conjunctival lymphangiectasia. These ocular findings modestly progressed at 2-year follow-up. Discussion The ATTRD18E mutation is a rare variant, with few described cases. To our knowledge, this is the first documented case of ATTRD18E amyloidosis with significant ocular involvement. These ocular findings may serve as a relevant biomarker for severe disease prognosis in ATTRD18E amyloidosis. With improving treatments addressing the systemic symptoms of ATTR amyloidosis, a better understanding of the late-onset ocular symptoms is becoming increasingly relevant.

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Tetraparesis and sensorimotor axonal polyneuropathy due to co-occurrence of Pompe disease and hereditary ATTR amyloidosis

Neurological Sciences ◽

10.1007/s10072-020-04896-3 ◽

2020 ◽

Author(s):

Milan Zimmermann ◽

Natalie Deininger ◽

Sophia Willikens ◽

Tobias B. Haack ◽

Kathrin Grundmann-Hauser ◽

...

Keyword(s):

Clinical Features ◽

Muscle Weakness ◽

Pompe Disease ◽

Late Onset ◽

Single Gene ◽

Lower Limbs ◽

Sensory Loss ◽

Motor Neuropathy ◽

Transthyretin Amyloidosis ◽

Attr Amyloidosis

Abstract Introduction/aims Hereditary transthyretin amyloidosis with polyneuropathy (hATTRPN) is an autosomal dominant multi-organ disorder manifesting in the third to fifth decade with the key clinical features of distal and painful sensory loss of the lower limbs and autonomic dysregulation. Motor neuropathy and cardiomyopathy evolve in the course of the disease. Pompe disease is an autosomal recessive disease leading to decreased levels of lysosomal enzyme acid α-glucosidase and proximal muscle weakness. We report the clinical features and diagnostic workup in the rare case of a patient with ATTR amyloidosis and late-onset Pompe disease, both genetically confirmed. Methods We performed a detailed clinical assessment, exome sequencing, and biochemical measurements. Results The patient presented with a distal, painful hypaesthesia of both legs, a cardiomyopathy, and a muscle weakness in the form of a girdle-type pattern of the arms and legs at the beginning and a spreading to distal muscle groups in the course of disease. Discussion This study highlights the importance of searching for co-occurrence of rare monogenetic neuromuscular diseases, especially in cases in which all clinical features can be readily explained by a single gene defect.

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CNS Involvement in Hereditary Transthyretin Amyloidosis

Neurology ◽

10.1212/wnl.0000000000012965 ◽

2021 ◽

Vol 97 (24) ◽

pp. 1111-1119

Author(s):

Luísa Sousa ◽

Teresa Coelho ◽

Ricardo Taipa

Keyword(s):

Case Reports ◽

Late Complication ◽

Amyloid Angiopathy ◽

Cns Involvement ◽

Transthyretin Amyloidosis ◽

Systemic Involvement ◽

Cranial Nerve Dysfunction ◽

V30m Mutation ◽

Cns Dysfunction ◽

Hereditary Transthyretin Amyloidosis

Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is predominantly a disease of the peripheral nerves, heart, kidney, and eye. CNS involvement has been a marginal issue in research and the clinical setting until recently. Growing evidence shows that leptomeningeal amyloid accumulation is frequent and present from early stages of ATTRv amyloidosis. Several recent studies show CNS symptoms arise as a common late complication in patients with the V30M mutation after at least 14 years of symptomatic peripheral nerve disease. Conversely, in non-V30M patients, there are several descriptions, mostly case reports, of patients presenting with severe phenotypes of ocular and CNS dysfunction (oculoleptomeningeal amyloidosis), with little systemic involvement. This phenotype is found in rare families worldwide, associated with at least 14 mutations. In both patients with late and early onset CNS dysfunction, symptoms include transient focal neurologic episodes, hemorrhagic and ischemic stroke, cognitive decline, and cranial nerve dysfunction. Pathologically, there is severe amyloid deposition in the leptomeninges and cerebral amyloid angiopathy of leptomeningeal and penetrating vessels. These amyloid aggregates are formed mostly by CSF-produced transthyretin (TTR) and seem resistant to the available ATTRv therapies that increase the stability or reduce the production of plasma TTR. This indicates that CNS involvement will become a meaningful issue in patient management in upcoming years.

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High-resolution ultrasound of peripheral nerves in late-onset hereditary transthyretin amyloidosis with polyneuropathy: similarities and differences with CIDP

Neurological Sciences ◽

10.1007/s10072-021-05749-3 ◽

2021 ◽

Author(s):

Luca Leonardi ◽

Giuseppe Di Pietro ◽

Antonella Di Pasquale ◽

Fiammetta Vanoli ◽

Laura Fionda ◽

...

Keyword(s):

High Resolution ◽

Peripheral Nerves ◽

Late Onset ◽

Transthyretin Amyloidosis ◽

Similarities And Differences ◽

Hereditary Transthyretin Amyloidosis

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Clinicopathological and biochemical findings of late-onset hereditary transthyretin amyloidosis 16 years after liver transplantation: an autopsy case study

Amyloid ◽

10.1080/13506129.2017.1295941 ◽

2017 ◽

Vol 24 (sup1) ◽

pp. 122-122

Author(s):

Mayumi Mizukami ◽

Mitsuharu Ueda ◽

Masayoshi Tasaki ◽

Yohei Misumi ◽

Teruaki Masuda ◽

...

Keyword(s):

Liver Transplantation ◽

Late Onset ◽

Autopsy Case ◽

Transthyretin Amyloidosis ◽

Hereditary Transthyretin Amyloidosis

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Cardiovascular autonomic functions in late-onset hereditary transthyretin amyloidosis with Val30Met mutation

Amyloid ◽

10.1080/13506129.2019.1582018 ◽

2019 ◽

Vol 26 (sup1) ◽

pp. 6-6

Author(s):

Tomohiko Nakamura ◽

Haruki Koike ◽

Ryoji Nishi ◽

Shohei Ikeda ◽

Yuichi Kawagashira ◽

...

Keyword(s):

Late Onset ◽

Autonomic Functions ◽

Transthyretin Amyloidosis ◽

Hereditary Transthyretin Amyloidosis

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Ocular Involvement in Hereditary Amyloidosis

Genes ◽

10.3390/genes12070955 ◽

2021 ◽

Vol 12 (7) ◽

pp. 955

Author(s):

Angelo Maria Minnella ◽

Roberta Rissotto ◽

Elena Antoniazzi ◽

Marco Di Girolamo ◽

Marco Luigetti ◽

...

Keyword(s):

Local Level ◽

Retinal Pigment ◽

Diagnostic Delay ◽

Amyloid Deposition ◽

Retinal Pigment Epithelial Cells ◽

Ocular Involvement ◽

Transthyretin Amyloidosis ◽

Systemic Involvement ◽

Ocular Manifestations ◽

Eye Involvement

The term amyloidosis describes a group of rare diseases caused by protein conformation abnormalities resulting in extracellular deposition and accumulation of insoluble fibrillar aggregates. So far, 36 amyloid precursor proteins have been identified, and each one is responsible for a specific disease entity. Transthyretin amyloidosis (ATTRv) is one of the most common forms of systemic and ocular amyloidosis, due to the deposition of transthyretin (TTR), which is a transport protein mainly synthesized in the liver but also in the retinal pigment epithelial cells. ATTRv amyloidosis may be misdiagnosed with several other conditions, resulting in a significant diagnostic delay. Gelsolin and keratoepithelin are other proteins that, when mutated, are responsible for a systemic amyloid disease with significant ocular manifestations that not infrequently appear before systemic involvement. The main signs of ocular amyloid deposition are in the cornea, irido-corneal angle and vitreous, causing complications related to vasculopathy and neuropathy at the local level. This review aims at describing the main biochemical, histopathological and clinical features of systemic amyloidosis associated with eye involvement, with particular emphasis on the inherited forms. We discuss currently available treatments, focusing on ocular involvement and specific ophthalmologic management and highlighting the importance of a prompt treatment for the potential sight-threatening complications derived from amyloid deposition in ocular tissues.

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Ocular Involvement in Hereditary Transthyretin Amyloidosis: A Case Series Describing Novel Potential Biomarkers

Genes ◽

10.3390/genes12060927 ◽

2021 ◽

Vol 12 (6) ◽

pp. 927

Author(s):

Angelo Maria Minnella ◽

Roberta Rissotto ◽

Martina Maceroni ◽

Angela Romano ◽

Romina Fasciani ◽

...

Keyword(s):

Case Series ◽

Photopic Negative Response ◽

Fundus Photography ◽

Ocular Involvement ◽

Transthyretin Amyloidosis ◽

Functional Changes ◽

Ocular Manifestations ◽

Corneal Confocal Microscopy ◽

Corneal Nerve ◽

Hereditary Transthyretin Amyloidosis

Hereditary transthyretin amyloidosis (hATTR) is a rare disease caused by a point mutation in the transthyretin (TTR) gene and inherited in an autosomal dominant fashion. TTR is a plasma protein that functions as a carrier for thyroxine (T4) and retinol (vitamin A). Ophthalmological manifestations are due to both the hepatic and ocular production of mutated TTR. In this case series, we report the ocular manifestations of hATTR in eighteen eyes of nine consecutive patients. Corneal nerve abnormalities as well as morphological and functional changes in the retina were investigated. The study was a single-center, retrospective, observational, clinical case series. In all patients, corneal confocal microscopy (CCM), multimodal imaging of the retina, including fundus photography and Optical Coherence Tomography (OCT), as well as rod and cone electroretinography (ERG) were performed. Eight patients had active disease and one was an unaffected carrier. In all study eyes, corneal nerve plexa examined with CCM were poorly represented or absent. Mixed rod-cone and cone ERG b-wave amplitudes were reduced, and photopic b-wave responses were significantly delayed. Photopic Negative Response (PhNR) amplitude was significantly reduced, while PhNR latency was significantly augmented. In 13/18 eyes, vitreous opacities and abnormalities of vitreo-retinal interface were found. The current results highlight the presence of corneal nerve damage. Functional retinal abnormalities, detected by ERG, can be found even in the presence of minimal or absent structural retinal damage. These findings support the use of CCM and ERGs to detect early biomarkers for primary hATTR.

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