Inherited neuropathies: an update
In this review, progress in hereditary neuropathy research published in the Journal of Neurology over the last 18 months is summarised.
KeywordsCharcot-Marie-Tooth disease Familial amyloid polyneuropathy Mitochondrial disease Tangier disease Allgrove syndrome ARSACS
The ability to diagnose and better understand the pathophysiology of hereditary neuropathies has greatly increased over the last few years. This article reviews and summarises new findings in the field with particular reference to papers published in the Journal of Neurology over the last 18 months.
Charcot-Marie-Tooth disease and related neuropathies
Charcot-Marie-Tooth disease (CMT) and cognate disorders are the most prevalent hereditary neuropathies, affecting one individual in every 2,500. Almost 70 genes have been associated with this heterogeneous group of neuropathies, and many of them have been discovered during the last 3–4 years, thanks to next generation sequencing technology such as whole exome sequencing [1, 2].
In an original and practical approach, Fischer et al.  exploited and adapted single-nucleotide polymorphism (SNP) array-based whole genome homozygosity mapping as a first screening step in the investigation of a series of 24 CMT patients with sporadic or recessive presentation, and could detect a genetic mutation in CMT-related genes in 63 % of cases. In their series, the demyelinating recessive CMT4C associated with mutations in the SH3TC2 gene was the most common genetic subtype, followed by CMT4A related to GDAP1 mutations. They confirmed that HSPB1 mutations, associated with a dominant distal hereditary motor neuropathy (dHMN) or axonal CMT (CMT2), may be rarely associated with recessive CMT2/dHMN. They also found another instance of the rare recessive CMT related to Mitofusin 2 (MFN2) mutations, which usually cause dominantly inherited neuropathies.
Davidson and colleagues studied a very large series of 140 index patients with Hereditary Sensory and Autonomic Neuropathy (HSAN), a heterogeneous group of rare disorders characterised by pure or predominant sensory involvement, with at least five different forms recognised . The authors investigated by direct sequencing the frequency distribution of six HSAN genes: SPTCL1 associated with HSAN IA, RAB7 (CMT2B), WNK1/HSN2 (HSAN IIA), FAM134B (HSAN IIB), NTRK1 (HSAN IV or Congenital insensitivity to pain with anhidrosis), and NFGB (HSAN V). Two other HSAN genes were not investigated, as there was no indication to do this from their clinical presentation. The authors found a pathogenic mutation in at least 14 % of the cases (a rate similar to the 19 % of the previous series by Rotthier and coauthors ), a still low yield that indicates that further HSAN genes are to be identified, and indeed five genes have been recently uncovered after study completion . SPTLC1 was the most commonly mutated gene in UK patients (13 index cases) and the p.Cys133Trp founder mutation was the most prevalent. NTRK1 was the next commonly mutated gene (6 %), predominantly in patients of Saudi Arabian descent, while mutations in all the other genes were rare, accounting for < 2 % each. Only one patient had a mutation in RAB7, which conversely was the most common mutated gene in the series of Rotthier et al. , partly due to a founder mutation in Austria. Two patients had novel recessive mutations in WNK1/HSN2, associated with the rare early-onset recessive HSAN type IIA form, characterised by sensory loss to all modalities leading to ulcers, acromutilation and Charcot joints [7, 8]. HSAN IIA was initially thought to be related to mutations in the HSN2 gene, but it later became evident that, as Shekarabi and colleagues point out , HSN2 is only a coding exon of the larger Protein Kinase Lysine-Deficient 1 (WNK1) gene. The WNK1/HSN2 isoform is specific to the nervous system and the alternatively spliced HSN2 exon is expressed only in neurons .
Genetic testing has become important in everyday clinical practice and it is relevant even for late-onset neuropathies, as a genetic cause is recognised in an increasing number of such cases. This is well shown by the paper by Marttila and colleagues, who report one Finnish family and one German patient with late-onset predominantly axonal CMT associated with the same novel MPZ mutation (p.Arg106Cys) . MPZ mutations are commonly associated with early-onset demyelinating or hypomyelinating CMT1B, but they also lead to CMT2 of much later onset [1, 11]. In this report, age of onset ranged between 48 and 67 years; two patients had sensorineural hearing loss, possibly related to CMT. The genetic nature of the neuropathy is not obvious in sporadic cases and MPZ mutations need to be considered in the differential diagnosis of late-onset chronic axonal neuropathies .
The relationship between inherited and dysimmune neuropathies is matter of investigation and debate. There are some reports suggesting possible superimposition of dysimmune neuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), on different CMT types [13, 14]. The X-linked CMT type, CMTX, is particularly liable to be misdiagnosed with CIDP, because it is characterised by non-homogeneous conduction slowing, sometimes accompanied by temporal dispersion and conduction blocks [1, 15]. Miki and colleagues reported a CMTX family carrying the novel p.Leu76Arg GJB1 mutation in which two hemizygous brothers had rather sudden progression of deficits in their upper limbs and seemed to improve after repeat intravenous administration of IgG (IVIg), at least on clinical grounds, as no electrophysiological follow-up was performed ; the mutation-carrier sister was also treated with IVIg, but only minimal, if any, improvement was observed. Sudden worsening occurs in CMT, and evidence of inflammation is sometimes found at nerve biopsy; it is absolutely unclear and far from established whether this really represents an immune-mediated phenomenon requiring immunomodulation. Therefore, caution is to be recommended in interpreting CMT fluctuations, and treatment with IVIg or immunosuppression must be avoided unless there are sure reasons for expecting definite and lasting improvement, and any claimed efficacy must be clearly objectively documented.
Among the techniques that can be helpful in distinguishing CMT from CIDP, ultrasonography of nerves and roots might have a role. Sugimoto and colleagues employed median and ulnar nerve and cervical root ultrasonography in ten demyelinating CMT and 16 CIDP patients in an attempt to differentiate the two diseases. Demyelinating CMT patients showed significant larger nerve size at all levels in median and ulnar nerves as compared to CIDP patients .
An interesting case of co-occurrence of CMTX and multiple sclerosis (MS) was described by Weishaupt and colleagues ; their case is the third instance of MS in CMTX patients and the authors discussed whether this is simply coincidental or if there is a predisposing role of abnormal GJB1 in oligodendrocytes. Notably, dramatic central nervous system dysfunction may rarely occur in CMTX males, but is transient and accompanying magnetic resonance imaging (MRI) abnormalities are widespread and usually resolve after clinical regression . In this patient, however, MRI and cerebrospinal fluid (CSF) abnormalities were typical of MS, so that treatment with natalizumab was started and appeared to be successful.
Schwannomas and inherited neuropathies
Improvement in techniques of neuroimaging for peripheral nerves is allowing for detailed morphological studies, and may be of help in clarifying the relationship between tumours of nerves and hereditary neuropathies. It is of interest that there are occasional reports of isolated or multiple schwannomas occurring in patients affected by hereditary neuropathies of different nature, i.e. CMT type 1A associated with the PMP22 duplication , Hereditary Neuropathy with liability to Pressure Palsies (HNPP) caused by the reciprocal PMP22 deletion , and CMT related to INF2 (Inverted Forming 2) mutations . Recently, Ohyagi and colleagues  described an HNPP patient who had two suspected schwannomas close to entrapment sites, namely the peroneal nerve below the fibular head and the radial nerve at the elbow. The authors hypothesised that up-regulation and down-regulation of PMP22, which is also involved in cell cycle regulation, induces not only hyperplasia (characteristic of CMT1), but also definite proliferation of Schwann cells.
A predisposition to develop peripheral and central nervous system tumours (meningiomas, gliomas, and schwannomas) is typical of Neurofibromatosis type 2 (NF2), an autosomal dominant disorder caused by mutations in the NF2 gene encoding merlin, a tumour suppressor protein associated with the cytoskeleton . Bilateral vestibular nerve schwannomas occur in 95 % of patients. A peripheral polyneuropathy is frequently seen and can cause substantial disability. It is not clear whether it happens as a separate phenomenon related to merlin dysfunction or as the result of compression of isolated or multiple schwannomas. Different patterns have been reported, i.e. symmetrical sensorimotor polyneuropathy, usually characterised by predominant axonal damage, asymmetric neuropathy with focal amyotrophy, and multiple mononeuropathy. Bäumer and colleagues  performed an accurate evaluation of eight NF2 patients (the second largest group reported in the literature) that included an MRI study with high-resolution large-coverage microstructural T2 sampling of upper and lower limbs. They classified nerve abnormalities in non-compressive fascicular microlesions (< 2 mm), intermediate lesions (2–5 mm), and compressive macrolesions (>5 mm). The first two categories were the most frequently found, and their overall burden strongly correlated with neuropathy severity, suggesting that this is the predominant basis of the peripheral nerve damage, i.e. the summation of several intra-nerve micro or intermediate lesions, rather than compression related to macrolesions. These results have an important impact on the decision as to when to undergo surgical removal of macrolesions, and this novel MRI technique offers new investigative possibilities for other diseases characterised by diffuse nerve lesions.
Familial amyloid polyneuropathy
Amyloidoses are a heterogeneous group of diseases characterised by localised or systemic tissue deposition of insoluble proteins that form unbranched fibrillar aggregates of beta-pleated sheet structure termed “amyloid”. Almost 30 proteins are known to form amyloid fibrils with several clinical phenotypes that require different diagnostic and therapeutic approaches, depending also on the sites of synthesis of amyloidogenic proteins. In transthyretin-related (ATTR) amyloidosis, the most frequent form of autosomal dominant familial amyloid polyneuropathy (FAP), the deposition of amyloid fibrils is due to mutations in the transthyretin (TTR) gene coding for the corresponding protein synthesised by liver and, in small amounts, also by choroid plexuses and retina. ATTR amyloidosis usually manifests with a nerve length-dependent predominantly sensory and autonomic neuropathy, related to the early involvement of small fibres; cardiac involvement is frequent and some cases have an exclusive or mainly cardiac phenotype . The most common TTR mutation is p.Val30Met, but more than 100 different mutations are known. Liver transplantation, abolishing the main source of mutated amyloidogenic protein, should be an early consideration in patients with ATTR amyloidosis, especially if they are carrier of the p.Val30Met mutation. Tafamidis meglumine, a TTR stabiliser preventing amyloid deposition, is used for treating early stage symptomatic FAP. Recently, Coelho and colleagues  performed an open label extension study and concluded that long-term treatment with tafamidis was well tolerated and reduced the rate of neurologic deterioration over a 30-month period. Pharmacological studies with other TTR stabilisers (Diflusinal or a combination of Doxycycline and Taurodesoxy-cholic acid) are in progress; additionally, gene therapy with small interfering RNAs and antisense oligonucleotides is a new therapeutic perspective for ATTR amyloidosis [27, 28].
Briani and colleagues  emphasise the importance of a differential diagnosis between ATTR and other amyloidosis, considering the new promising therapeutic options. They also underline the difficulties in diagnosis of these diseases, while describing a patient with restrictive cardiomyopathy, mild IgG-lambda monoclonal gammopathy without neuropathic symptoms, affected by late-onset ATTR amyloidosis associated with the novel p.Glu62Lys TTR mutation. The patient was initially misdiagnosed as being affected by the light-chain (AL) amyloidosis. AL amyloidosis is characterised by systemic involvement and, in about 35 % of cases, peripheral and/or autonomic neuropathy; it is caused by an amyloidogenic accumulation of an immunoglobulin light chain produced by a clonal plasma cell population in the bone marrow.
Another important issue is when to start treatment for ATTR amyloidosis, as tissue amyloid deposition starts well before symptoms, and early therapy should allow a better outcome. It is therefore critical to identify early clinical or objective disease manifestations that show that the disease process is ongoing and treatment is warranted. Lefaucheur and coauthors  tried to identify early neurophysiological markers of FAP in TTR mutation carriers. In this study, 20 asymptomatic/paucisymptomatic carriers of pathogenic TTR mutations were submitted both to conventional nerve conduction study and small-fibre tests including laser evoked potentials, sympathetic skin responses, quantitative sensory testing (QST) with measurement of cold and warm detection thresholds, and heart-rate variability assessment. Abnormalities in small-fibre tests (more frequently in cold and warm detection thresholds and laser evoked potentials) were found in 11 of 20 patients (including two asymptomatic carriers), while conventional conduction studies did not show any sign of distal polyneuropathy. Based on their results and because in early TTR-FAP a selective or largely predominant alteration of small fibres is documented, the authors suggest that a larger neurophysiological study including combined small-fibre tests in TTR mutation carriers can lead to early detection of the first signs of neuropathy onset. Skin biopsy, by demonstrating decreased intraepidermic nerve fibre density, is another potential early marker of disease .
Neuropathies in metabolic and neurodegenerative diseases
Peripheral neuropathy, along with other neurological or systemic symptoms, is a clinical feature of many inherited metabolic or neurodegenerative disorders, which are often misdiagnosed because of their rarity and phenotypic variability. The presence of neuropathy may allow an early diagnosis, which is particularly important because some of these diseases are treatable, e.g., Cerebrotendinous Xanthomatosis and Fabry disease. Furthermore, neuropathy may be a major cause of disability in patients affected by such inherited diseases.
Tangier disease (TD) is a rare autosomal recessive disorder caused by mutations in the ATP-Binding Cassette transporter A1 (ABCA1) gene on chromosome 9q31, which encodes the membrane transporter ABCA1 that plays a central role in the transport of cholesterol from peripheral cells to the liver . TD is characterised by intracellular accumulation of cholesterol leading to hepatosplenomegaly, lymphadenopathy, and enlarged yellow–orange tonsils, and by low levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I (apoA-I). Approximately 50 % of the patients have a peripheral neuropathy that may present as either a remitting-relapsing mono/polyneuropathy or a syringomyelia-like neuropathy. Zyss and colleagues  retrospectively analysed four patients with genetically confirmed TD; three of them had a typical pseudosyringomyelic neuropathy with predominant upper limb weakness together with facial diplegia; the fourth had an atypical asymmetrical onset mimicking Lewis–Sumner syndrome. The authors underscored the clinical variability of disease that, combined with a heterogeneous electrophysiological pattern showing both demyelination and axonal degeneration, may lead to diagnostic errors, especially in the early stages of disease; indeed, average time to diagnosis in this study was 12.5 years. The authors suggested that lipid profile, with HDL cholesterol and apoA-I measures, should be included in the screening of patients with possible chronic inflammatory demyelinating polyneuropathies.
Cerebrotendinous Xanthomatosis (CTX) is a rare autosomal recessive lipid storage disorder caused by mutations in CYP27A1, the gene encoding the sterol 27-hydroxylase involved in bile acid synthesis, resulting in tissue accumulation of cholestanol, an intermediate compound along the pathway of bile acid synthesis. CTX is characterised by a great variability in disease onset and symptom evolution, even in individuals from the same family. The most common systemic findings are tendon xanthomas, juvenile cataracts and chronic diarrhoea; neurological features usually occur after the second decade of life and include cognitive impairment, peripheral neuropathy, epilepsy, and cerebello-pyramidal signs. CTX is treatable with chenodeoxycholic acid (CDCA) replacement therapy . Ginanneschi and colleagues  examined a large CTX population of 35 patients and analysed the effects of CDCA therapy on polyneuropathy. They showed that the polyneuropathy occurred in 74 % of the cases; it was usually mild, with a sensorimotor or motor axonal polyneuropathy being the most frequent pattern. CDCA treatment improved NCV in all treated patients, by increasing conduction along the still excitable fibres; consequently, the authors hypothesised that the treatment promotes myelin synthesis in nerve fibres with surviving axons.
Fabry disease (FD) is an X-linked lysosomal storage disorder caused by α-galactosidase A gene mutations resulting in accumulation of glycosphingolipids with subsequent organ failure. The most common neuropathic pattern is a small-fibre neuropathy that can even be the first clinical manifestation with onset during childhood or adolescence; further neurological features include cerebrovascular accidents and autonomic dysfunction . Bertelsen and colleagues  have recently assessed the presence of small-fibre neuropathy in 15 FD patients (five hemizygous males and ten heterozygous females) with neuropathic pain, by performing clinical examination, QST, corneal confocal microscopy, and skin biopsy. By comparing results of the different methods, the authors concluded that the diagnosis of small-fibre neuropathy still relies mainly on clinical symptoms and findings, and that paraclinical tests can support the diagnosis and are useful for clinical follow-up, as they can document progression of small fibre loss.
POLG1-related neuropathy: MNGIE-like phenotype
A predominantly sensory neuropathy, with ataxia and loss of proprioception and vibration sense, is one of the possible presenting features of patients carrying mutations in POLG1, a nuclear gene encoding the mitochondrial DNA polymerase gamma-1. POLG1 mutations can result in different clinical pictures, including progressive external ophthalmoplegia (PEO), sensory ataxic neuropathy with ophthalmoplegia (SANDO), and Alpers syndrome, often with multiple mitochondrial DNA deletions or depletion . Tang and colleagues  reported an extremely rare presentation of recessive POLG1 mutations, namely a neurogastrointestinal phenotype, similar to mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). MNGIE is characterised by severe gastrointestinal manifestations, ophthalmoplegia, cachexia, peripheral neuropathy (typically demyelinating) and subclinical leukoencephalopathy, associated with TYMP (thymidine phosphorylase) gene mutations . Tang et al. , reviewing clinical features of 92 unrelated patients with recessive POLG1 mutations, noted that three had clinical features consistent with MNGIE, but without leukoencephalopathy. The authors suggest that in MNGIE-like phenotypes, the lack of leukoencephalopathy, in addition to normal plasma thymidine, is suggestive of POLG1 mutations as the responsible molecular defect. Notably, all three patients had a peripheral neuropathy.
Vallet and colleagues , through a retrospective study of eight adult patients with Allgrove syndrome, described the neurological aspects of this autosomal recessive disease, also known as “Triple A syndrome”, characterised by achalasia, adrenal insufficiency, and alacrima. The authors illustrated the clinical variability of Allgrove syndrome and the diagnostic difficulties that arise if neurological symptoms predominate over systemic features, as may occur in late-onset cases. The neurological findings described in this study are consistent with the previous literature and characterised by pyramidal syndrome, chronic peripheral neuropathy, dysautonomic and bulbar symptoms, and mild cognitive dysfunction. The neuropathy is axonal, predominantly motor, with more severe involvement of ulnar than median nerves. Allgrove syndrome is caused by mutations of the AAAS (Achalasia–Addisonianism–Alacrima Syndrome) gene encoding ALADIN, a protein thought to be involved in molecular transport across the nuclear membrane where it is located . In a few individuals with otherwise typical Allgrove syndrome, no AAAS mutation is found, suggesting genetic heterogeneity.
Spastic ataxia of Charlevoix Saguenay
Peripheral neuropathy is a typical feature of the autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS), a neurodegenerative disorder characterised also by progressive cerebellar ataxia and lower limb spasticity. Although many patients showed the classical ARSACS triad, each of these findings may be missing and a few patients may present with a pure neuropathy. It is controversial whether the neuropathy is axonal or demyelinating, but all recent series describe a sensory-motor polyneuropathy with reduced nerve conduction velocity (NCV) values [43, 44, 45]. The underlying pathology appears to be a severe reduction of large myelinated fibres, which might account for the reduced NCV, notwithstanding the lack of clear signs of demyelination. ARSACS, first described in patients from Canadian Quebec, usually starts during early childhood, although adult-onset cases have been described. The disease is due to mutations of the SACS gene encoding sacsin, a protein widely expressed throughout the brain. Recently, it has been shown that SACS mutations alter the mitochondrial network and sacsin seems to be involved in mitochondrial fission by interacting with dynamin-related protein 1 .
Gazulla and coauthors  extensively evaluated five ARSACS patients and proposed a pathogenic mechanism different from neurodegeneration. MRI showed that all five patients had—beyond atrophy of the cerebellum, cerebral cortex, and upper cervical cord—a hypointense pontine linear striation, corresponding to an increased amount of pontocerebellar fibres that interrupt the pyramidal tracts. The authors interpreted these results as suggestive of a developmental origin of the disease with pontocerebellar fibres compressing the pyramidal tracts at the pons from the embryonic period, thereby causing spasticity from a very early age. The authors confirmed the increased thickness of the retinal nerve fibre layer and noticed a straight dorsal spine, elements supportive of a developmental defect. Prodi and coauthors  substantiated the MRI finding of hypointense pontine linear striation, but attributed the hypointensity to the cortico-spinal tract being ‘squeezed’ by the over-represented transverse pontine fibres, which are hyperintense on T2-weighted images. They also detected thinning of the corpus callosum, a rim of T2-hyperintensity around the thalami, and microstructural alterations in the supratentorial white matter of forceps, cingulum and superior longitudinal fasciculus in all ARSACS patients analysed, so they suggest that these MRI findings should be considered diagnostic of ARSACS.
Conflicts of interest
Dr. Davide Pareyson received research funding from ACMT-Rete and Pfizer Italia, and funded travels from Kedrion SpA and Pfizer Italia. He is a member of the Inherited Neuropathy Consortium Rare Disease Clinical Research Consortium funded by the US National Institutes of Health (NINDS/ORD), Muscular Dystrophy Association, and Charcot-Marie-Tooth Association (CMTA). Dr. Giuseppe Piscosquito received funded travels from Pfizer Italia.
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