Inherited Neuropathies: Giant Axonal Neuropathy, Charcot-Marie-Tooth Disease, and Hereditary Transthyretin Amyloidosis

Inherited neuropathies are an important cause of peripheral neuropathy. Appropriate and timely diagnosis is important for management and prognostication. In this article, we discuss 3 different neuropathy groups for which targeted therapies are under investigation: giant axonal neuropathy (GAN), Charcot-Marie-Tooth disease (CMT), and hereditary transthyretin amyloidosis (ATTRv).

Giant Axonal Neuropathy

GAN is an inherited neurodegenerative disease of the peripheral and central nervous systems caused by sequence variations in the GAN gene.

Pathogenesis

GAN is caused by a variety of autosomal recessive alterations in the GAN gene, which encodes the protein gigaxonin.¹ More than 80 different sequence variations have been identified that lead to a loss of function of gigaxonin.² The role of gigaxonin is incompletely understood, but it is suspected to be an E3 ligase substrate adaptor that is involved in the turnover and regulation of intermediate filaments.³ Disorganization of the intermediate filament network leads to accumulation of neurofilaments in axons and Schwann cells. These accumulations damage the structural integrity of nerve cells, and the resulting distension of the axon produces the eponymous giant axons.⁴

Presentation

GAN has wide clinical heterogeneity in presentation. After meeting initial milestones, affected children will slowly lose motor milestones, typically by 3 years of age but variably between infancy and 10 years of age.⁵ People with GAN experience frequent falls attributable to both muscle weakness and ataxia, which progress over 4 to 6 years. People with GAN typically will require the use of a wheelchair by the end of their first decade, and a majority will die of respiratory failure by the end of their third decade of life.¹

Peripheral nervous system involvement manifests as predominantly distal weakness and areflexia attributable to a sensory-motor polyneuropathy. However, unlike in other inherited neuropathies, such as CMT, individuals also may have proximal muscle weakness, leading to winged scapula or a positive Gower sign. Autonomic involvement is present in a subset of cases, leading to constipation and other gastrointestinal symptoms.¹

In contrast to most other inherited neuropathies, GAN also presents with central nervous system involvement.⁵ Most common is a cerebellar ataxia that contributes to impaired balance and frequent falls. Involvement of the corticospinal tracts may lead to pyramidal signs such as spasticity. Individuals also may have bulbar involvement, with optic atrophy, ophthalmoparesis, facial weakness, and dysarthria having been reported. Intellectual delay also may be present.^1,2

Systemic symptoms include precocious puberty and diabetes.¹ Individuals have a characteristic appearance, with a high forehead, kinky hair, and long eyelashes. People with GAN who do not have kinky hair tend to have a milder phenotype.¹

Diagnosis

GAN is diagnosed by genetic testing.¹ Nerve conduction studies show an axonal sensory-motor polyneuropathy.² On teased nerve biopsies, neurofilament swellings have a characteristic beads-on-a-string appearance; axonal and nerve cell body loss also may be seen.² MRI of the brain may demonstrate nonspecific white matter changes; T2 hyperintensities also may be seen in the basal ganglia, internal capsule, thalamus, and brainstem.⁶

Management

There are no disease-specific therapies for GAN. Treatment is symptomatic. A current phase 1 clinical trial is investigating the intrathecal administration of gene transfer using an adeno-associated virus (AAV) vector (Intrathecal Administration of scAAV9/JeT-GAN for the Treatment of Giant Axonal Neuropathy, NCT02362438) that has been shown to restore intermediate filament configuration and reduce neurofilament aggregation both in vitro and in mouse models.^7,8

Charcot-Marie-Tooth Disease

CMT, also known as hereditary sensory and motor neuropathy, is a heterogeneous group of inherited neuropathies caused by sequence variations in genes responsible for peripheral nerve function, leading to a length-dependent motor and sensory neuropathy.

Pathogenesis and Classification

More than 100 genes have been implicated in CMT and associated conditions such as hereditary motor neuropathy, hereditary sensory and autonomic neuropathy, and hereditary neuropathy with liability to pressure palsies.⁹ These genes code for proteins involved in various functions of the peripheral nerve, including myelination, axonal transport, Schwann cell differentiation, and mitochondrial function.¹⁰ Alterations can be inherited in an autosomal dominant, autosomal recessive, or X-linked fashion, and cause either an axonal or demyelinating neuropathy. One-third of somatic single nucleotide variants and 5% to 24% of duplications occur de novo; therefore, a family history may not be evident.¹¹ Different alterations in the same gene can lead to varying pathologic and clinical phenotypes; for example, different sequence variations in the MPZ gene can lead to either an axonal or demyelinating neuropathy.

The nomenclature of CMT is evolving as genetic causes are replacing phenotypic descriptions. The original classification has been based on a numeric system, with the major subtypes being CMT1 through CMT7, and specific sequence variants assigned a letter. CMT1 is autosomal dominant and demyelinating; CMT2 is axonal (either autosomal dominant or recessive); CMT3 is an early-onset and severe demyelinating form known as Dejerine-Sottas disease, which is now commonly included in the CMT1 category; and CMT4 is autosomal recessive and demyelinating. CMT5 through CMT7 are associated with other symptoms: spastic paraplegia (CMT5), optic atrophy (CMT6), and retinitis pigmentosa (CMT7). However, this nomenclature has gone out of favor and been replaced by the names of the specific causative genes. CMTX is an X-linked form of the disease. Letters are added after the number to designate specific genes and phenotypes; for example, duplication in the PMP22 gene leading to a demyelinating neuropathy is called CMT1A.

Presentation

The prevalence of CMT is 1 in 2500 people.¹⁰ The hallmark of the disease is slowly progressive muscle weakness and atrophy initially affecting the distal extremities. Symptoms typically start in the feet and progress to involve the hands. Because of the lack of positive sensory symptoms in many cases, people come to medical attention when muscle weakness interferes with daily functioning. Characteristic foot and ankle deformities, such as hammertoes, pes cavus, pes planus, and shin and hand atrophy, can provide clues about the chronicity of symptoms.^10,12

Symptoms typically start within the first 2 or 3 decades of life, and then continue to progress slowly over the next decades. Some variants present in early childhood, sometimes manifesting as floppy baby syndrome or delayed motor milestones. Individuals may describe a history of clumsiness, frequent falls, or difficulty heel- or toe-walking. Autosomal recessive forms are more severe and tend to be of early onset; limb deformities, delayed motor milestones, rapid clinical progression, or a higher degree of bulbar and respiratory involvement than in dominant forms may be present.¹³

Some forms of CMT may present with distinct symptoms that can be helpful in diagnosis. TRPV4 and SORD alterations are 2 important causes of CMT2. TRPV4-associated CMT is unique because it can affect the vocal cord and diaphragm.¹⁴SORD variation results in sorbitol accumulation and therapeutic trials may inform treatment of diabetic neuropathy as well.¹⁵

Diagnosis

A family history of weakness or sensory changes is important to investigate when considering a diagnosis of CMT, but may be negative, given the high prevalence of de novo sequence variants. Examination of family members may be helpful, if feasible. Nerve conduction studies can help distinguish between inherited and acquired neuropathies; inherited demyelinating neuropathies cause uniform slowing in conduction velocity, whereas acquired demyelinating neuropathies will present with patchy slowing and partial conduction blocks. Autonomic testing can distinguish CMT from hereditary sensory and autonomic neuropathy.

Nerve biopsy typically is not needed, but can be useful to distinguish between acquired and inherited neuropathies. Chronic inflammatory demyelinating neuropathy will demonstrate multifocal onion bulbs and inflammation, whereas inherited demyelinating neuropathies cause diffuse onion bulbs without inflammation.

Genetic testing remains the standard for diagnosis. PMP22 duplication (CMT1A), GJB1 alterations (CMTX1), PMP22 deletion (hereditary neuropathy with liability to pressure palsies), MPZ alterations (CMT1B), and MFN2 alterations (CMT2A) are the most common variants, with CMT1A accounting for about 50% of all cases.¹⁶ In the absence of a known gene in the family or an obvious identifying feature, a comprehensive neuropathy panel can be used to test for many genes at the same time.

Management

Management of CMT typically has focused on supportive measures. Shoe orthotics can help correct foot positioning and bracing may be necessary to maintain walking stability. For more severe cases of bony malformation, surgeries such as plantar fasciotomy, tendon transfers, or osteotomies can be beneficial to reduce pain and improve ambulation. Pain in people with CMT tends to be either musculoskeletal or neuropathic; treatment should focus on elucidating the type of pain and treating it appropriately.⁹

Much of the research into disease-specific treatment has focused on people with PMP22 overexpression, because this is the most prevalent form of CMT. Ascorbic acid and progesterone antagonists have been studied in the past, given their ability to reduce PMP22 levels; the former did not meet efficacy end points, and a progesterone antagonist studied for treatment of CMT had many side effects.⁹ A clinical trial investigating a combination of baclofen, sorbitol, and naltrexone for the treatment of CMT1A is in progress (Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients [PREMIER], NCT04762758). Another ongoing clinical trial is testing an aldose reductase inhibitor for SORD, which has shown promising results at a prespecified interim analysis (Pharmacodynamic Efficacy and Clinical Benefit of AT 007 in Patients With Sorbitol Dehydrogenase (SORD) Deficiency [INSPIRE], NCT05397665).

Gene therapy is another promising avenue of active research. Both antisense oligonucleotides and small interfering RNAs were shown to decrease PMP22 levels and improve motor function in a rat model.¹⁷ Gene therapy trials targeting CMT-associated alterations with loss-of-function sequence variations using AAV vectors in both GJB1 and MPZ mutated rat models also are underway.^18,19

Additional considerations for the use of gene therapy in CMT include the delivery of AAV vectors into Schwann cells and interactions between wild-type and mutant proteins.⁹

Hereditary Transthyretin Amyloidosis

ATTRv is a hereditary form of amyloidosis characterized by deposition of abnormal transthyretin (TTR) fibrils into target tissues, which leads to a variety of symptoms, including cardiomyopathy and peripheral neuropathy. In recent years, several medications have been approved by the Food and Drug Administration (FDA) for the treatment of ATTRv, with further clinical trials underway.

Pathogenesis and Genetics

TTR is a tetrameric protein involved in the transport of thyroid hormone and retinol. Autosomal dominant alterations in the TTR gene lead to instability of the tetrameric protein, causing the formation of pathogenic, insoluble amyloid fibrils. These fibrils give rise to end-organ damage by a variety of mechanisms, including compression/obstruction, deposition in tissue, and interference with cellular signalling pathways.²⁰

More than 130 variants have been identified in TTR, most of which are pathologic. The most common sequence variant worldwide is V30M (endemic in Portugal, Brazil, and Japan); in the United States, the most common reported sequence variant is V122I. Phenotypic heterogeneity exists, dependent on the genetic alteration implicated, with a variety of disease severities, ages at onset, and organ systems involved.

Presentation

The spectrum of symptoms associated with ATTRv is broad, and depends in large part on the underlying sequence variation. Common symptoms include carpal tunnel syndrome, cardiac manifestations such as restrictive cardiomyopathy or arrhythmias, ocular abnormalities caused by abnormal deposition in the vitreous or lens, and peripheral neuropathy. The peripheral neuropathy can involve both somatic nerves, causing prominent pain, sensory loss, and weakness, as well as autonomic nerves, leading to gastrointestinal dysmotility and orthostatic hypotension.

Cardiac involvement is present in in 97% of individuals with the V122I sequence variant, and more than half also will have carpal tunnel syndrome or neuropathy. The V30M sequence variant is more heavily associated with polyneuropathy, but many people also will have cardiac manifestations.²¹

The polyneuropathy of ATTRv tends to be chronic and progressive in nature. Age at onset is stratified into 2 categories: an early-onset, endemic form, and a late-onset form that predominates in nonendemic regions. In the United States, the average age at symptom onset is 68 years, whereas the median age at onset in endemic countries is 33 years.²¹

In early-onset disease, symptoms of small-fiber neuropathy predominate, with people reporting pain and dysautonomia. Large-fiber involvement develops over time. In late-onset disease, large fibers become preferentially involved early in the disease process, causing numbness, weakness, and gait difficulties.²² If left untreated, symptoms progress over 3 to 15 years, ultimately leading to death.²¹ The late-onset form of the disease tends to have faster progression than the early-onset form, with median survival of 7 years after symptom onset.²²

Diagnosis

ATTRv should be suspected in people presenting with neuropathy and a family history of cardiomyopathy or a progressive neuropathy of unknown etiology, or who have prominent small-fiber symptoms such as pain and dysautonomia. Autonomic testing with the quantitative sudomotor axon reflex test or skin biopsy can be helpful if a small-fiber neuropathy is suspected. In people with large-fiber involvement, nerve conduction studies demonstrate a predominantly sensory or sensory-motor distal symmetric axonal polyneuropathy.²²

Diagnosis is confirmed with genetic testing. Biopsy may be used to evaluate specific organ system involvement; for example, if there is concern for an alternate cause of neuropathy, biopsy with Congo red staining can be useful to demonstrate amyloid deposition in the nerve. Mass spectroscopy is important to confirm the TTR origin of the amyloidosis. Endomyocardial biopsy remains the standard for diagnosing cardiac involvement. Scintigraphy with 99MTc-PYP scans can help diagnose cardiac involvement in ATTR, especially in the presence of normal serum protein electrophoresis, immunofixation, and free light chains.^20,22

Management

The previous standard of care for ATTRv involved liver transplantation, which was associated with significant morbidity and mortality in the perioperative and chronic immunosuppressive periods.²³ Novel therapeutic options now target various stages of the amyloidogenic cascade. These are divided into gene silencers and protein stabilizers. Protein stabilizers bind to and stabilize tetrameric TTR, preventing degradation into pathogenic amyloid fibrils.²³ The 2 most commonly used stabilizers are tafamidis (Vyndamax; Pfizer, New York, NY) and diflunisal (Dolobid; Merck, Rahway, NJ). Tafamidis was approved by the FDA for treatment of ATTRv-associated cardiomyopathy in 2019 after a large clinical trial (Safety and Efficacy of Tafamidis in Patients with Transthyretin Cardiomyopathy [ATTR-ACT], NCT01994889) demonstrated improved all-cause mortality rate and rates of cardiovascular-related hospitalizations.²⁴ Diflunisal, an NSAID that has demonstrated in vitro TTR stabilizing properties, has been used off-label to treat both amyloid cardiomyopathy and neuropathy.²⁵ Inotersen (Tegsedi; Ionis Pharmaceuticals, Carlsbad, CA) is an antisense oligonucleotide inhibitor of hepatic production of transthyretin protein.²³ Patisiran (Onpattro; Alnylam Pharmaceuticals, Cambridge, MA) is an RNA interference agent that targets the 3’ untranslated region of transthyretin mRNA to reduce hepatic production.²³ Both were approved by the FDA for the treatment of ATTRv-associated neuropathy in 2018 after 2 large randomized controlled trials demonstrated benefit in reducing circulating levels of TTR and impairment from neuropathy, and leading to improvement in quality of life, compared with placebo.^26,27 Vutrisiran (Amvuttra; Alnylam Pharmaceuticals, Cambridge, MA), another RNA interference agent, which is administered subcutaneously every 3 months, was approved for treatment of ATTRv-associated peripheral neuropathy in 2022. Eplontersen (Ionis Pharmaceuticals, Carlsbad, CA), a once-monthly subcutaneous antisense oligonucleotide injection, has been shown to be effective in ATTRv treatment and has been granted a New Drug Application by the FDA.

Conclusions

Inherited neuropathies represent a heterogeneous group of conditions leading to a variety of distinct clinical phenotypes and caused by myriad pathologic sequence variations. Our ability to diagnose these conditions has improved greatly with advances in and availability of genetic testing. Treatment for many inherited neuropathies remains supportive, but promising results are being reported from targeted therapy trials, with multiple active avenues of ongoing research.