Neurology: Case of the Month

Check Your Diagnosis — Patient 67

Sudhakar Tummala, M.D.
Steven Lovitt, M.D.

Diagnosis

Familial amyloid polyneuropathy (type I), with transthyretin gene mutation

Clinical Summary

In this patient, early development of burning pain, with predominant impairment of pain and temperature sensation on examination, and clinical evidence of autonomic dysfunction suggested a predominantly small-fiber neuropathy. Nerve conduction studies and electromyography suggested an axonal polyneuropathy, and impaired sympathetic skin responses corroborated the clinical impression of autonomic dysfunction. Among the causes of small-fiber neuropathy, amyloid deposition disorders should be considered, and the family history of neuropathy accompanied by cardiac and renal involvement suggested that a familial amyloid polyneuropathy was likely. After screening for concomitant causes of peripheral neuropathy, we biopsied the sural nerve, documenting amyloid deposition in nerve fibers. A DNA assay detected a mutation in one allele of the gene coding for transthyretin, predicting a substitution of methionine for valine at position 30 (Val30Met), the most common disease-associated mutation found in patients of Portuguese background presenting with familial amyloid polyneuropathy.

Discussion

Familial amyloid polyneuropathies (FAP) form a group of autosomal dominant neuropathies associated with endoneurial and polyvisceral deposition of amyloid proteins. They share many clinical features with acquired amyloidoses, including:

  1. Polyneuropathy causing a predominance of small-fiber sensory loss, autonomic neuropathy and carpal tunnel syndromes;
  2. Systemic involvement causing myopathy, myelopathy, restrictive cardiomyopathy, eye involvement, and nephropathy.

The classical pathology found in the amyloid polyneuropathies is the Congo red-staining, extracellular deposits, which show red-green birefringence with polarized light. Mutations of the three serum proteins, transthyretin (TTR), apolipoprotein A-1 and gelsolin, are identified that cause amyloid deposition in familial amyloid polyneuropathy.

Transthyretin (TTR) Mutation-Associated Neuropathies

Transthyretin protein is a homotetrameric, soluble protein in its wild form, transporting thyroxine and retinol. It presents two binding sites for thyroxine inside a central channel and four binding sites for retinol binding protein (RBP) at the outer surface. Usually only one binding site for thyroxine and one binding site for RBP are occupied at a given time. Monomers are made of 127 amino acids with one cysteine at position 10 (cys 10) from the N-terminus. They are folded as one short alpha-helical structure and eight beta strands (A-H) arranged in two sheets which expand into those of a second monomer interface. Two dimers interact at separate dimer-dimer interfaces to form tetramers. Many investigators hypothesize that gene mutations causing tertiary and quaternary structural changes of transthyretin may lead to misassembly of this protein into amyloid. Also, the mutant monomer may have an increased propensity to adsorb onto forming amyloid deposits. Normal as well as mutant transthyretin can be incorporated into amyloid deposits. The mechanism(s) by which amyloid deposition leads to cell and tissue toxicity remain to be clarified.

The liver represents the main source of transthyretin synthesis. Choroid plexus and retina produce small amounts of this protein.

The TTR gene is small, encoding four exons, over 7 Kb. Exon 1 encodes a signal peptide and the first three amino acids of the mature protein. As many as 80 point mutations and one in-frame microdeletion have been identified in exons 2 - 4 of the TTR gene. Most of these mutations are pathogenic, although non-amyloidogenic mutations in the TTR gene have been reported. The mutation leading to theVal30Met substitution (Met30) is the most frequent mutation worldwide in patients with FAP, and is virtually the only pathogenic mutation identified in Portuguese and Swedish FAP patients. These FAP families share the same haplotype, suggesting a founder effect. One new TTR variant (Val28Met) has been reported in a Portuguese case with late-onset FAP. At least 15 different point mutations have been identified in Japan, and at least 12 are reported in France, along with the Met30 variant. In these groups, the Met 30 variant appears to have arisen independently.

Several modifiers for TTR gene mutation effects have been hypothesized. Non-pathogenic and pathogenic mutations can be associated in compound heterozygotes, apparently causing differences in the phenotype. Anticipation has been reported in some Portuguese and Japanese families. The same variant (Met30) produces an earlier age of onset in Portuguese and Japanese endemic foci, and a later onset in Swedish endemic foci and sporadic Japanese cases, also suggesting the presence of genetic or non-genetic modifiers. Two pairs of proven Val30Met monozygotic twins, from Portugal and Majorca (another European FAP focus) had discordant age of onset and clinical course, suggesting that non-genetic factors modify the disease presentation. Males are affected more than females in most reports. However, the nature of the genetic and non-genetic modifiers operating in FAP associated with TTR gene mutations is unknown.

FAP type I, presenting with early autonomic and small-fiber neuropathy, and associated with progressive cardiac and renal involvement, usually progresses to death in a few years (mean of about 10 years in some reports). In contrast, another transthyretin mutation-associated neuropathy, FAP type II, has a more benign course. FAP type II often presents late, with typical onset in the 5th decade. Carpal tunnel syndrome may be the only manifestation for 1 or 2 decades. Later, these patients develop a generalized polyneuropathy with pain and paresthesias, and autonomic neuropathy complicated by intestinal malabsorption and blood pressure dysregulation. There is typically no renal or ocular involvement in FAP type II, although a restrictive cardiomyopathy may develop. A serine substitution at position 84 and histidine substitution at position 58 are the two amino acid substitutions arising from the gene mutations seen most commonly in patients with FAP type II.

Unusually aggressive forms of the disease are reported in patients with TTR gene mutations causing substitutions in positions 54 and 55 of transthyretin. Isolated central nervous manifestations such as dementia, depression, seizures, cerebral infarction or hemorrhage, due to leptomeningeal amyloidosis, have been reported in families carrying newly identified TTR gene mutations causing substitutions such as Asp18Gly, Val30Gly or Tyrl14Cys. A Leu12Pro TTR variant has been identified in a patient with severe peripheral neuropathy and prominent central manifestations caused by systemic, neuropathic and leptomeningeal amyloidosis. These reports indicate that leptomeningeal deposits are part of the spectrum of the TTR-related FAP syndromes. As a consequence, the potential exists for confusion with amyloidoma, a manifestation of an acquired amyloid disorder that results from AL-producing B-cell clones along perivascular sheaths.

Apolipoprotein A-1 Associated Neuropathy

An autosomal dominant form of FAP has been linked to mutations in the gene coding for apolipoprotein A1 (Apo A1). Apo A1-associated FAP (FAP type III) shares many features with FAP type I, but typically manifests early renal amyloidosis and a high incidence of duodenal ulcers. The normal function of apolipoprotein A1 protein is transportation of cholesterol from tissue to the liver. It is a major plasma and chylomicron protein. However, disease does not appear to be caused by a loss of function of this protein. Accumulation in amyloid fibrils of N-terminal fragments derived from the mutant Apo A1 protein occurs in affected patients, although the exact mechanisms of this remain unclear. Recent reports have also documented specific binding of wild-type transthyretin to Apo A1, and co-localization of normal transthyretin with Apo A1 in amyloid fibrils from affected patients.

Gelsolin Associated Neuropathy

Although first described in Finnish kindreds, this familial amyloid polyneuropathy (FAP type IV) is now described in other countries. The amyloid fibril protein in this disease derives in part from an abnormal fragment of gelsolin, which was characterized biochemically over a decade ago, leading to identification of mutations in the gelsolin gene that segregate with clinical disease. Gelsolin is an actin-binding protein found in numerous cell and tissue types including skeletal muscle, vascular structures, leukocytes, and neurons. This disorder is autosomal dominant. Disease typically starts in the 3rd or 4th decade with corneal lattice dystrophy, followed by insidious development of progressive cranial neuropathies in the 5th to 6th decades. The facial nerve is commonly involved, with a preponderance of upper facial fibers. Other cranial nerves involved in FAP type IV include trigeminal, hypoglossal and vestibulocochlear nerves. The facial skin is thickened at first but with time it becomes lax. A mild sensory peripheral neuropathy and mild autonomic involvement may develop, although large-fiber loss appears to be more prominent than small-fiber loss. Gelsolin amyloid deposits may be found in blood vessels, and have been reported to involve nerve roots more than distal axons. There is no prominent cardiac involvement as in the other FAP syndromes.

Apparently Sporadic Amyloid Disorders

Patients that appear to have sporadic, or acquired light-chain (AL) amyloidosis, who do not have light chains in serum or urine, may be difficult to distinguish from familial amyloidoses. Recent studies document that transthyretin and other amyloidogenic gene mutations are often found in such patients, some of whom may present with neurologic involvement. Accordingly, genetic testing may be appropriate even in the absence of a family history, if clear evidence of a plasma cell dyscrasia cannot be documented.

Treatment

As the liver is the main source of mutant transthyretin, and the mutant protein is felt to drive the process(es) of amyloid formation, orthotopic liver transplantation (LT) was proposed over a decade ago as treatment for FAP. LT decreases the concentration of mutant TTR in the serum, and is associated with a slower rate of loss of unmyelinated axons in biopsied nerves. Several series of cases have been reported, generally suggesting that LT results in improved general well-being, weight gain, subjective improvement of symptoms, and possibly a stabilization or slowing of progression of motor and sensory dysfunction. Patients with very early, relatively isolated neuropathic involvement appear to be the best candidates for LT, hence early detection and diagnosis of FAP is critical for the success of this approach. Although patients with FAP usually do not have the severe liver disease present in other candidates for liver transplantation, the concomitant autonomic neuropathy may pose difficulties of its own during surgery.

D. Adams et al. report a prospective study of 45 patients with a mean follow-up of four years after transplantation for FAP. All patients had clinical manifestations of polyneuropathy with autonomic disturbances, and all were ambulatory at the time of LT, some requiring aid. All had documented amyloid with positive immunolabeling by anti-TTR antibodies of endoneurial congophilic deposits in nerve biopsy specimens. All underwent orthotopic liver transplantation and two also had a kidney transplantation for severe amyloid nephropathy. The estimated survival rate after transplantation at 1 and 5 years was 82% and 60%. Eight patients died within six months, and six between 17 and 46 months after liver transplantation. Causes of death include severe systemic infection and/or multiorgan failure or cardiac arrest. There was one suicide. Factor significantly associated with higher post-transplantation death included severe sensorimotor neuropathy (Norris score below 55), permanent urinary incontinence, and postural hypotension with a fixed pulse rate.

At present, many groups recommend LT early in the clinical course of FAP, with the goal of preserving the patient's functional status or slowing progression. In published series, it is not clear that overall mortality is affected by LT, although the small numbers of patients treated may be insufficient to detect a difference in all-cause mortality. The main experience with LT is with patients carrying the transthyretin Val30Met substitution, and it is unclear whether FAP resulting from other mutations would respond similarly.

Pharmacologic and immunologic treatments aimed at reducing amyloid accumulation and preventing cell and tissue toxicity of amyloid are being developed and tested.

Clinical Course and Follow-up

Following her diagnosis, this patient underwent orthotopic liver transplantation at the Texas Medical Center. At three months post-operatively, mild progression of distal muscle strength in the legs was noted, with a slightly more wide-based gait. She remained ambulatory without any assistance. No significant autonomic symptoms had developed.

Editor's Note

We thank Drs. Stanley H. Appel and Yadollah Harati, of the Department of Neurology at Baylor College of Medicine, for their assistance with this patient's diagnosis and management. Dr. Lovitt has joined the faculty of the University of Texas at San Antonio, TX.

-- Dennis R. Mosier, M.D., Ph.D.

References

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  8. Mendes de Souza M, Vital C, Ostler D, et al. Apolipoprotein AI and transthyretin as components of amyloid fibrils in a kindred with apoAI Leu178His amyloidosis. Am J Pathol. 2000;156:1911-7.
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