Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

Neuropathy is one of the most common referrals to neurologic clinics. Affected patients often undergo extensive testing for acquired etiologies (ie, diabetes, immune inflammatory, and others) without a specific cause found. Within this group, inherited cause is common. Increasingly, genetic causes are becoming known and commercial testing available. The rate of recent discovery has been rapid and relates to (1) the extent of single gene disorders of nerve; (2) the ease of peripheral nervous system functional examination, including bedside and electrophysiologic testing; and (3) readily accessible pathologic tissue. Foremost, however, in the rate of recent discoveries is the work and tools of, collectively termed, the human genome project. Normal and pathologically affected proteins have been chromosomally mapped, cloned, and functionally characterized in nerve. Many other proteins influencing nerve have been identified using the same molecular techniques. The rapidity of ongoing discovery requires clinicians to be familiar with molecular biologic discoveries and consider wisely which testing be performed, if any. Publicly sponsored internationally available and continually updated Web information is available via (1) certified laboratory contact information; (2) clinically relevant reviews for doctors and patients; (3) and research opportunities that are emphasized collectively in the Web sites for GENE TESTS, OMIM, and IPNMDB [1,2,3].

• Inherited neuropathies are common

Inherited neuropathies present with varied symptoms, signs, and temporal course. In one large prospective study, inherited cause was the diagnosis found most commonly in individuals who were previously unclassified and undergoing extensive evaluation [4]. Kindred evaluations were essential in the identification of those individuals. Neurologists greatly underappreciate this group of disorders. The reason inherited forms often are overlooked is complex. The apparent paradox that stagnant gene defects can produce illness in mid to late life likely is contributory. Painless indolent course in many also obscures earlier identification. Specifically, mild neurologic impairments often exist in childhood but handicaps may not be apparent until adulthood. Because patients link their handicaps to clinical onset, subacute course often is described, thereby leading to major consideration of acquired neuropathies. For similar reasons, other affected family members often are not known. Meeting with and examining families considered unaffected often is helpful. Conversely, because pain commonly is found in acquired neuropathies, extensive laboratory searches are performed without adequate consideration of painful inherited conditions. Positive testing for causes of acquired entities should not exclude consideration of inherited disease. Laboratory results must be reviewed critically, as inherited illness may be the primary neuropathic process or additive of impairments. High arches, hammer toes of the feet, subluxed hips, foot ulcers, and various bony abnormalities are nonspecific clues of inherited neuropathy. Other features may include refractory treatment of “acquired” disease, doctor-identified foot drop previously not apparent to patients and often associated with frequent ankle sprains, and sometimes the label of being “clumsy.”

• Complex pathogenesis in inherited neuropathies

Nerve is susceptible to diverse pathologic insults. In part, these susceptibilities relate to the length of axons. Single-celled axons and their cytoplasm may extend greater than 1 meter in humans, necessitating complex structural, metabolic, and dynamic interactions to preserve function. Consideration of the normal architecture of nerve and its molecular interactions is important in understanding pathogenesis. Subspecialized myelin axonal proteins have been localized and interact at various regions of nerve: (1) adaxonal membranes (K+ channels and Caspr); (2) paranodal myelin loops (NF155 and NF186); and (3) microvilli or perinodal astrocytes (NF155, NF-186, Nr-CAM, tenascin-C, actin, ezrin, radixin, moesin, spectrin ßIV?1, ankyrin, and Na+ channels) [5]. Proteins at the basal lamina interacting with myelin at juxtaparanodal areas also have been identified and include F-actin, L-periaxin, laminin-2, utrophin, Dp116, and dystrophin-related protein 2 [DRP2]). Such proteins are essential in nerve integrity and regeneration and provide important scaffolding function for axonal growth cones. Further necessitated by the axons’ length are important transport proteins, some of which are known and associated with disease: anterograde transport (dynactin); (2) fast transport (kinesin family member 1B [KIF1B] and heat shock protein 22 [HSP22]); (3) neurofilament scaffolding (filamin 1, neurofilament light [NFL], and gigaxonin [GAN]); (3) mictotubule interacting (spastin and spartin); (4) vesicular transport (ras-associated protein [RAB7]) and others (reviewed elsewhere) [6,7,8].

Some of the earliest pathogenic discoveries occurred within individuals classified as having Charcot-Marie-Tooth disease (CMT), also known as hereditary motor and sensory neuropathy (HMSN) (discussed later). Identified earliest were defects within structural proteins of myelin (peripheral myelin protein 22 [PMP22] and myelin protein zero [MPZ]). Now, however, many identified defects have been found in ubiquitously expressed proteins present in multiple extraneural tissues and are important in such basic cell maintenance as transcription (early growth response 2 [EGR2]), translation (glycine tRNA synthetase [GARS]), DNA maintenance (tyrosyl DNA phosphodiesterase 1 [TDP1]), mitochondrial fusion (mitofusin [MFN2]), apoptosis (serine palmitoyltransferase [SPTLC1]), and many others. The discoveries emphasize the susceptibility or fidelity of nerve to defects tolerated by other systems. Different pathologic localization is summarized in Box 1.

Box 1. Molecular pathogenesis of inherited neuropathies

• Molecular anatomy and clinical disability

Clinical disabilities arising in the peripheral nervous system relate most directly to axonal protein degenerations, malformations, or disturbances. Early clinical studies using histopathologic and phenotypic correlates of nerve conductions suggested the important, clinically relevant interactions between Schwann cell products (myelin) and axons [9,10]. Patients who have demyelinating hereditary phenotypes, such as occur in HMSN type 1 (HMSN1) and Dejerine-Sottas syndrome (DSS), are noted to have axonal atrophy, despite primary myelin protein defect [9]. Longitudinal study (15 years) of patients later identified as having PMP22 duplication and MPZ missense mutations show conduction velocity follows an independent course (slowly improving during maturation, plateauing, and then worsening). Greater reductions in motor nerve conduction velocities correlated with more rapid progression of declines in the amplitudes of compound muscle action potentials (CMAP) and neurologic disabilities [10]. The findings are consistent with the essential role of specific myelin proteins in sustaining axonal health through the identified molecular interactions (described previously). This information has relevance to many acquired neuropathies where more rapid disabilities are accrued with primary axonal injury: (1) systemic and nonsystemic vasculitis [11,12]; (2) forms of axonal Guillain-Barré with periaxonal macrophage invasion (ie, acute motor axonal neuropathy) [13,14,15]; and (3) many toxic forms [16].

• Inherited system atrophies affecting nerve (HMSN, HSAN, HSP, SCA)

Recognizing that many inherited neuropathies are system atrophies is helpful in diagnosis, classification, and management. For instance, patients who have small sensory fiber abnormalities may be at greater risk for mutilating foot injuries, and early aggressive prophylactic foot care and occupational council are emphasized. Chronic symmetric progression of motor, sensory, or mixed deficits initially in lower extremities is the hallmark of presentation in most system atrophy neuropathies. Classes of neurons (or nerve fibers) are affected selectively and fail to develop or degenerate or have supporting cells that undergo similar process. The population of neurons or axons affected and the names of the disorders are: lower motor, primary sensory, and autonomic neurons (HMSN) and primary sensory and autonomic neurons (hereditary sensory and autonomic neuropathy [HSAN]). Other system degenerations include corticospinal tract (spastic paraplegia), lower motor neurons (progressive muscular atrophy) or hereditary motor neuropathy, and large-diameter primary sensory neurons and cerebellum (spinocerebellar degeneration). Other less common inherited neuropathies affect multiple tissues, whereas even rarer forms, such as hereditary brachial plexus neuropathy, affect asymmetric upper extremities without evidence of a more generalized process.

• HMSN

The understanding of HMSN has evolved with each new technologic discovery; The earliest clinical descriptions include those of Virchow [17] and Eichorst [18]. The subsequent work of Charcot and Marie in France [19] and Tooth in England [20] provides phenotypic understanding: (1) progressive muscular atrophy involving the feet and legs first; second, after many years, affecting the hands; and, later still, affecting the forearms; (2) contractions of atrophic muscles; (3) vasomotor abnormalities; (4) lack of joint contractures; (5) normal sensation (now known not typical [ie, most with sensory loss, but often mild]); (6) frequent cramps; (7) degenerations in atrophic muscles; (8) frequent onset in infancy (symptomatic onsets at later ages in most patients); and (9) occurrence of the disorder in the same generation and in succeeding generation. Additional descriptions included Achilles tendons exuberance, pes cavus, atrophy of leg and thigh muscles so that the lower limbs resembled an “inverted champagne bottle,” hammertoes and clawhand, steppage gait, and, in some persons, constant shuffling of feet when standing in one place to maintain balance. Davidenkow provided more elaborate descriptions of the patterns of inheritance [21].

More recent classifications of Dyck and Lambert [22] provide a framework for the current incorporation of molecular data with previous electrophysiologic and histopathologic descriptions that include (1) clinical features, (2) mode of inheritance, and (3) molecular localization. The terminology reflects the hereditary nature, localization, and system involvement (ie, HMSN). The first, dominantly inherited, was a hypertrophic neuropathy (HMSN1), which was associated with slow nerve conduction velocities (typically 20 m per second or less in ulnar forearm) with complex Schwann cell processes forming lamellae separated by longitudinally directed collagen fibrils (onion bulbs) on nerve biopsy. Although the symptoms predominately affected motor nerves, sensory and autonomic fibers also were affected. The second (HMSN2) also affected predominately motor nerves but with normal to borderline slow nerve conduction velocities with axonal atrophy on nerve biopsy. The third (HMSN3) now known with dominant inheritance is present in childhood or infancy with loss of ambulatory milestones and more generalized neurologic deficit (especially proximal and upper distal involvement of upper and lower limbs) and has extremely slow nerve conductions (typically in the single digits to low teens, ulnar forearm) and characteristic exaggerated generalized onion bulbs and axonal fiber degenerations early in disease. The fourth type (HMSN 4), initially described with phytanic acid disease (Refsum), does not include those patients currently but rather refers to those who have autosomal recessive inheritance where demyelinating nerve conductions are most common but not exclusive. Many in this group have childhood onset and often are from consanguineous marriages with extraneural features that include facial dysmorphism and scoliosis. Other initially described forms with spasticity (HMSN 5) have been overshadowed by detailed work in hereditary spastic paraparesis (discussed later). Lastly, two additional categories were created out of observation of patients who had peripheral neuronal degenerations with optic atrophy (HMSN 6) and retinitis pigmentosa (HMSN 7) without clear molecular discovery to date.

Complex observations from the molecular biologic discoveries emphasize the need for incorporation of the clinical expression and molecular localization in the classification. Considering whether or not molecular defects are positioned in myelin or neuronal elements is, in itself, inadequate in classification, as mutations in neuronal elements, such as NFL, may disrupt saltatory conduction and cause slow nerve conduction velocities and damaged axons. Other examples include myelin genes, such as PMP22 and MPZ, which can cause either HMSN 1 phenotype or severe congenital onset HMSN 3. Furthermore, abnormalities in GJB1 and MPZ produce variable nerve conductions and pathologic description with apparent primary axonal atrophy. Other examples, however, emphasize the genetic cause over clinical features in the diagnosis. For example, rare PMP22 micromutations may cause recessive inheritance compared with most mutations in this gene, which are dominantly inherited. By considering the clinical features and genetic mutations, the classification has been improved and is promoting better clinical practice and basic science discovery.

• HMSN demyelinating forms (HMSN types I, III, IV, and X-linked)

Motor greater then sensory fibers are affected in this demyelinating group with diverse inheritance patterns, severity, and associated clinical features. Associated with these varieties are different pathologic and specific electrophysiologic features: (1) HMSN1A-C and HMSN4A-F; (2) DSS, also referred to as congenital hypomyelinating neuropathies (CHN); and (4) hereditary neuropathy with pressure palsies (HNPP). Identified genes or specific chromosomal loci are known (summarized in Table 1).

Table 1. Demyelinating hereditary motor sensory neuropathy

• Genetic mutations in demyelinating HMSN

• Peripheal myelin protein 22 (HMSN type 1A, hereditary neuropathy with pressure palsies, and Dejerine-Sottas syndrome)

Aberrant interaction between Schwann cells and their axons likely explain clinical progressions with mutation of PMP22. Worsening impairments correlate with severity of electromyograms and nerve conduction abnormality with resultant evolving axonal injury [7]. PMP22 provides 2% to 5% of the total protein content of compact myelin [23]. Its complete function remains unclear, but it may have a role in structural myelin development and neural cell growth and differentiation [24,25].

Diverse phenotypes exist with PMP22 mutations, including, most commonly, HMSN 1A, followed by HNPP, and, rarely, DSS or CHN. All are motor greater than sensory, length-dependent neuropathies with demyelinating nerve conductions. HNPP presents with episodic progressive focal mononeuropathies at sites of compression associated with mild length-dependant neuropathy [26]. CHN and DSS are severe neuropathies that are genetically heterogenous. Abnormalities of developmental milestone in ambulation are the hallmark of the disease. Nerve conduction velocities are often less then 7 m per second with thin myelin surrounded by interposed collagen creating a characteristic onion bulb appearance [27,28].

PMP22 mutations most commonly cause deletions and duplications. The mechanisms leading to duplication mutation explain why the disorder is so common (ie, 60% to 70% of demyelinating forms) [29,30]. Duplications account for HMSN1A phenotype, whereas deletions produce the phenotype of HNPP [31]. Homologous repeat sequences (CMT1A-REP) that flank the region at 17p11.2 are believed to promote misalignment and unequal DNA recombination [32]. Alternate sex-linked mechanisms exist for deletions and duplication at PMP22. Denovo macromutations from paternal origin seem to be duplications alone. Maternal origin mutations, however, produce duplications and deletions. The specific mutation mechanisms at PMP22 during oogenesis include unequal sister chromatid exchange and intrachromatidal loop excision [33]. These sex-dependant mechanisms may in part explain the relative infrequency of HNPP compared with HMSN1A. Ascertainment of the clinical phenotype also may play a role, as HNPP tends to be milder and, therefore, may not be diagnosed. Rare patients who have frameshift mutations within PMP22 are reported with HNPP phenotype [34,35]. Also rare are missense mutations resulting in the HMSN1A phenotype [36,37,38,39]. The existence of autosomal recessive PMP22 point mutation also has been seen [40,41,42].

PMP22 heterozygous micromutations (typically missense mutations) can produce the severe dysmyelinating phenotype of DSS [43,44,45,46]. Factors external to PMP22 may alter clinical expression as identical mutations, even within the same family, with PMP22 duplication producing markedly varied clinical severity [47]. Dosing phenomena are proposed as a possible explanation for the clinical difference between HNPP (deletions) and HMSN1A (duplication) phenotypes. PMP22 mRNA and protein levels are increased in HMSN1A and decreased in HNPP [48,49]. Rare exceptions are noted; for example, patients homozygous for PMP22 duplications are noted for severe and mild phenotypes, suggesting that gene dosing alone is not sufficient to explain clinical variability [50,51].

Despite the understanding of PMP22, treatment remains impractical. Sahenk and colleagues [52] have administered subcutaneous injections of recombinantly generated neurotrophin 3 (NT-3) to promote axonal health and regeneration in the primary Schwann cell disorder, CMT1A. Their work showed pathologic improvements in two different mice models with PMP22 mutation. They then undertook a clinical pilot study in double-blinded placebo-controlled (N = 4 treated, N = 4 placebo) fashion over 28 weeks. Statistical improvements in neuropathy impairments, number of small myelinated fiber regeneration units, and solitary myelinated fibers compared with controls were seen.

Other therapeutic molecular approaches are suggested from animal work, including study of progesterone antagonists and ascorbic acid, whereby rat and mice neuropathies, respectively, have been improved [53,54]. Complex factors are proposed for these benefits, but primary reduction of overexpressed PMP22 remains a potential avenue for targeted therapies.

• Myelin protein zero (HMSN type 1B, HMSN type 2, Dejerine-Sottas syndrome, and CH [congenital hypomyelinating])

Mutations of this glycoprotein, MPZ, are associated with a great diversity of phenotypes, including (1) most commonly demyelinating nerve conductions (HMSN1B) and axonal forms (HMSN2 I, J) both severe and mild clinically, with (2) Adie’s pupil, (3) hemifacial spasm, (4) restless legs, (5) acute onset, (6) hearing loss, and (7) even multiple sclerosis and other CNS manifestations.

MPZ or P-zero (P[0]) is a major structural protein of compact myelin accounting for more than 50% of myelin by weight [55]. It contains one extracellular domain, one transmembrane, and one intracellular domain [56]. It functions as a true myelin adhesion-compacting molecule via homophylic interaction and is expressed only in Schwann cells. Opposed tetramers of P(0) at the membrane surface hold together the intraperiod line, whereas intracellular C-terminals hold by electrostatic interactions the major dense line. MPZ consists of six exons. The extracellar domain has sequence homology with some immunoglobulins [57,58] and antibody directed against P(0) has been observed in chronic inflammatory demyelinating polyneuropathy (CIDP) [59]. Rare patients who have CIDP-like phenotypes are to benefit from immunosuppression [60].

Mutations in the extracelluar domain are noted for extremes of clinical severeity and demyelination and are reviewed elsewhere [61]. More commonly, mutations in the intracellular domain are associated with DSS. DSS phenotypes, however, are associated with all domains. Combinations of these observations have led to speculation that the more deleterious mutations result from a gain of toxic function related to disruption of the P(0) tetramer. Factors external to the loci, however, must influence phenotypic expression.

Consideration of the possibility that inflammatory immune mechanism may influence MPZ pathogenesis come from several observations: (1) acute onset cases typical of inflammatory immune mechanism [62,63]; (2) multiple sclerosis, an inflammatory immune disease in two kindreds with MPZ mutation and unusual presentation [63,64]; (3) CIDP-like polyneuropathy responsive to steroids in patients who have MPZ mutations [60]; and (4) heterozygous Mpz ± Mpz- mice that genetically are unable to generate an immune response develop minimal polyneuropathy compared with immune competent controls [65]. Practical application of this information in care remains distant.

• SIMPLE-small integral membrane protein of lysosome or LITAF-Lipopolysaccharide induced tumor necrosis factor alpha or (HMSN1C)

Patients identified as having typical HMSN1 phenotypes may have missense mutations in a gene localizing to 16p13 [66], which was predicted to encode two separate transcripts for lipopolysaccharide-induced tumor necrosis factor a (LITAF) and small integral membrane protein of lysosome (SIMPLE) [67]. Initial reports suggested the defective protein product was the tumor necrosis homolog (ie, LITAF) [67]; however, subsequent work points to the expressed abnormality as SIMPLE [68]. Although SIMPLE protein function is unknown, it may be important in protein degradation given its conserved regions with E3 ubiquitin ligases, which are important proteosome processing proteins. Saifi and collegues [68] suggested mutations in SIMPLE may play a role in demyelinating and axonal phenotypes when a screen of 192 unrelated HMSN cohorts identified base alterations among 16 who had different phenotypes. These changes were not seen in controls and occurred in axonal and demyelinating forms. The tracking of these base alterations with disease phenotypes was not established in most families and, therefore, causative nature remains unclear.

• Early growth response 2 (HMSN type 1D, HMSN type 3C, and HMSN type 4E [Dejerine-Sottas syndrome and congenital hypomyelination])

Mutations of EGR2 seem rare and are reported with dominant and recessive inheritance with varied severity and demyelination [69,70,71,72]. The protein, EGR2, is a zinc finger transcription factor, which binds DNA, and is encoded by two exons [73]. The pathophysiology probably relates to regulation of peripheral myelin pathways, including PMP22 and MPZ (P[0]). In part, the EGR2 knockout mouse (Krox20) has provided evidence to the pathology, as hypomyelination is noted in the peripheral nervous system of these animals [74,75].

• Neurofilament light chain (HMSN type 2E and HMSN type 1F)

This neuron-specific protein, when mutated, has accounted for rare axonal phenotypes [76,77,78]. One family had saltatory conduction disruption as evidenced by demyelinating nerve conductions [79]. An initially described mutation, Glu528del, in a Bulgarian patient subsequently was found to represent a simple polymorphism in Japanese populations [80]. Expression studies of several mutations leading to this disorder suggest disruption of neurofilament assembly and axonal transport of neurofilaments in cultured mammalian cells and neurons [81]. Neural mitochondrial localization also may be implicated.

• GJB1—connexin 32 Charcot-Marie-Tooth X (CMTX1)

The transmembrane protein, connexin 32, is a gap-junction molecule encoded by gene GJB1 and expressed at paranodal regions within the Schmidt-Lanterman incisures of peripheral nerve myelin [82]. In nerve, the protein has two extracelluar loops, one intracellular loop, and two intracellular terminal domains. It seems to form reflexive gap junctions. These pathways probably provide diffusion pathways to transport ions, metabolites, and second messenger molecules through intracellular channels between axons and myelin [83].

Families have an X-linked dominant pattern of inheritance with chromosomal localization to Xq13.2. Males in general tend to be affected more severely, probably the result of gene dosing. Other X-linked forms are described with recessive inheritance and separate localization CMTX2 (Xp22.2) and CMTX3 (Xq26) without gene identification to date [84]. In large kindreds, absence of male-to-male inheritance and disparity in clinical severity between the sexes should raise suspicion as to the diagnosis of CMTX. Affected males may have variably slowed conduction velocities (between HMSN I and II), whereas females may have conduction velocities in the range of HMSN II [85,86,87]. Other investigators, however, show that the females have intermediate slowing, whereas the men have normal conduction velocities [88]. Still other investigators describe nonuniform slowing when examining multiple nerves [89,90]. Other investigators describe clinical central nervous system (CNS) involvement [91,92]. Using strict electrophysiologic criteria, presenting patients more likely are classified as having an axonal form with mild demyelinating features. Together, the electrophysiology, pathologic description, and animal models [93] suggest that connexin 32 neuropathy is a Schwann cell disorder that leads to axonal loss, with maldevelopment and loss of myelin.

Genetic analysis for connexin 32 mutations has allowed for several important observations. This disorder is not rare and probably accounts for the second most common form of HMSN after HMSN1A [94]. Point mutations are the most common mutation by far, and more than 150 different mutations have been identified in more than 200 unrelated families [95]. These data have provided for speculation about genotype-phenotype correlations. Nonsense mutations (frameshift mutations) tend to produce more severe phenotypes with earlier presentation compared with missense mutations [86,88,94]. Exceptions are noted, however, including the most dramatic case in two male siblings who had complete deletion of the connexin 32 coding sequence [96]. These brothers were affected no more severely than others who have typical missense mutation. Such observations suggest that factors external to the loci influence clinical expression and confuse whether or not connexin mutations exert their affect by a primary loss of function or by a dominant negative affect [97]. Extensive ongoing work is attempting to answer such difficult questions [83].

• Ganglioside-induced differentiation-associated protein 1 (HMSN type 4A and HMSN type 2K)

The GDAP1 gene is expressed in brain and spinal cord more than in peripheral nerve [98]. The function of GDAP1 is unknown, but it may be involved in signal transduction pathways in neuronal development. This may suggest primary pathogenesis and the cell bodies. Patients who have this disorder typically accrue deficits in the first decade of life and, as with many recessive disorders, consangunity often is present with varied expression, including peroneal atrophy with or without (1) hand weakness, (2) vocal cord paresis, and (3) optic atrophy [98,99,100,101,102]. Axonal features can be seen rarely in patients, but demyelination is foremost [103].

• Myotubularin-related protein 2 (HMSN type 4B1)

By inference from other myotubularin proteins, this protein, myotubularin-related protein 2 (MTMR2), may be important in regulation of RNA transcription in nerve. Specific mutations are noted for reduced phosphatase active in nerve [104]. Patients meet infantile developmental milestones but typically, by 2 years of age, are clinically affected and are wheelchair bound by young adulthood with proximal weakness and abnormal auditory evoked potentials. Death may occur in the fourth to fifth decade from presumed respiratory failure proportionate to the severity of the neuropathy [105,106].

• N-myc downstream-regulated gene 1 (HMSN type 4D)

This gene, N-myc downstream-regulated gene 1 (NDRG1), is expressed ubiquitously in nerve with particularly high levels of RNA transcripts in Schwann cells. It has been proposed to function in growth arrest and differentiation of myelinated fibers and perhaps Schwann cell signaling essential in axonal survival [107]. Mutations within this gene have resulted in severe neuropathy inherited in autosomal recessive fashion. Intially, a single mutation producing a premature stop codon at position 148 was believed causative of a founder affect in divergent Romani (Gypsy) groups across Europe [107,108]. Subsequently, different mutations were identified [109]. Clinically, patients have early-onset neuropathy, muscle weakness, and wasting with skeletal and foot deformities, panmodality sensory loss, and marked conduction velocity slowing with axonal degenerations. Patients have neural deafness in the second or third decade of life with conduction slowing in central pathways.

• PRX—L-periaxin (HMSN type 4F)

The periaxin protein seems important in myelin development and its localization changes from fetal to adult age. The gene is spliced alternatively to encode L- and S-periaxin and is essential for maintenance of peripheral nerve myelin [110,111,112]. At the molecular level, L-periaxin associates with DRP2 and dystroglycan at the basal lamina or extracellular membrane and is important for the correct localization of the DRP2-dystroglycan complex in sciatic nerve. In the Schwann cells of embryos, it is found only in the nucleus, but perinatally it localizes to adaxonal or periaxonal space. In contrast, adults show localization away from the axon on the surface of extracellular myelin. Nerve biopsies from patients who have HMSN4F demonstrate paranodal abnormalities characterized by disruption of paranodal loops and separation of myelin stuctures from periaxonal structures. Autosomal recessive point mutations of PRX are demonstrated as causative for severe demyelinating neuropathies characteristic of the dominately inherited Dejerine-Sottas form [112,113,114,115,116].

• HMSN axonal forms (HMSN type II and others)

As in the primary demyelinating neuropathies, clinical spectrum and genetic abnormalities are diverse. Because indolent axonal disease may not be determined as easily with electrophysiology, many inherited forms go without gene localization. The varied clinical and pathologic discoveries in this form include (1) the diverse group of HMSN II, (2) rare individuals who have HMSN IV (3) HMSN X, (4) and others, including HMSN V, VI, and VII as ascertained by nerve conduction abnormalities (Table 2).

Table 2. Axonal and intermediate hereditary motor sensory neuropathy

• Kinesin family member 1ß (HMSN type 2A)

The kinesin superfamily motor protein isoform, KIF1Bß, is important in transporting synaptic vesicle precursors. Mutations result in a loss of microtuble binding and altered transport along the axon. A single family is demonstrated with such mutation [117]. Mice with inactivation of KIF1ß also have an axonal neuropathy. Other genes also may disrupt axonal transport and, therefore, cause axonal predominant neuropathies, namely NFL (see previous discussion) and likely gigaxonin [118]. The latter is associated with a rare autosomal recessive neuropathy not classified as HMSN with characteristic axonal swellings and CNS (mental retardation) and hair (kinky hair) abnormalities. Disorganization of intermediate filaments is noted in this condition, termed giant axonal neuropathy, and gigaxonin localizes to the cytoskeletal.

• Mitofusin 2 (HMSN type 2A2 and HMSN type VI)

Some families who have chromosomal localization to 1p36 do not have mutation in KIF1B. Recently, they have been found to have mutation in the gene mitofusin 2 (MFN2) localizing to 1p36 [119,120,121]. Some individuals also have optic atrophy and spastic paraparesis, designated HMSN VI [122,123]. This nuclear-encoded mitochondrial GTPase gene seems to account for most affected individuals who have abnormality colocalizing to 1p36. The gene seems important in the fusion of mitochondrial membranes. Of particular note is the lost ability of mitochondria with mutation in MFN2 to transport along actin or microtubule filaments. This likely is relevant in neuropathy whereby axonal transport is predicted to be defective and, therefore, a plausible specific pathogenesis in distal axonal neuroapthies. The extent of DNA polymorphisms still is being ascertained as are genotype-phenotype correlations. Careful correlation within families is emphasized to better understand expression and varied presentation versus polymorphisms. At the same time, penetrance and extent of variable clinical expression are important to study within and between different families.

• RAB7 (HMSN type 2B or HSAN type I)

The extent of sensory involvement in patients affected by mutations of this gene can be so severe as to qualify as a dominant form of HSAN (discussed later). The mutilating foot injuries are accompanied by significant ankle dorsi flexor weakness. The gene seems important in axonal vesicular transport. The protein localizes to endosomes and is important in retrograde tubular extensions. Active RAB7 on phagosomal membranes associates with the effector protein, RAB7-interacting lysosomal protein (RILP), which in turn bridges phagosomes with dynein-dynactin, a microtubule-associated motor complex [124,125]. Activation of RAB7 is important to allow recruitment of RILP and consequent association of phagosomes with microtubule-associated motors [126]. It is predicted, therefore, that mutations of RAB7 ultimately affect axonal transport. Disruption of other specific microtubule motor complex proteins in nerve disease is known. For example, mutations of dynactin are believed to be causative of a motor neuron disease described in one family who had associated vocal cord paralysis and facial and hand predominant weakness [127]. Patients are described who do not have sensory symptoms, but detailed sensory testing is not reported. The described mutation is predicted to distort the folding of dynactins microtubule-binding domain and, thereby, interfere with retrograde axonal transport. Because mutations of this gene are associated with infectious ulcerations of the feet and neuropathy, it is an intriguing possibility that in addition to disruption of axonal transport it has potential defect in the innate immune system through disruption of phagocytosis. Foot insensitivity alone may not be adequate to explain acromutilations with infectious ulceration.

• Glycyl tRNA synthetase (HMSN type 2D and dSMAV type V)

Patients who have mutations in this gene, glycyl tRNA synthetase (GARS), may or may not have sensory involvement. Those who do not have sensory loss are labeled as having distal spinal muscular atrophy type V (dSMAV) whereas those who have sensory loss are labeled as having HMSN2D.

The gene is expressed ubiquitously in neural and non-neural tissues and functions in attachment of tRNAs with appropriate glycyl amino acid. Earlier work in myositis suggested its potential role in pathogenesis of that muscle disease. Specifically, antibodies directed against this tRNA are identified in dermatomyositis [128]. The work provided emphasis of the potential role of GARS as an autoantigen. Why mutations in this gene lead to selective neuropathy or motor neuronopathy remains unclear [129,130,131,132].

• Heat shock protein 27 (HMSN type 2F)

The initially described mutation S135F occurs in a conserved a-crystallin domain of the protein, heat shock protein 27 (HSP27) [133]. In vitro expression of this mutant resulted in poor viability of neuronal cells and impaired neurofilament assembly. Other families from Asia [134], among the Han Chinese, are identified with possible founder mutation [135].

• Heat shock protein 22 (HMSN type 2L and dHMNII)

HSP22 chromosomally localizes to 12q24 [136], a region of many neuromuscular diseases [137]. Motor axonal symptoms are predominant with distal involvements hallmarked. Because motor symptoms are prominent, some classify this condition as distal hereditary motor neuropathy (dHMNII). The occurrence of variable sensory involvement in distal motor predominant processes is described previously and includes the genes GARS, RAB7, and HMSN2C localized to 12q23-24 [137].

• Dynamin 2 (HMSN DI type B)

Dynamin 2, a ubiquitously expressed protein, seems important in membrane vesicle formation in clatherin-coated membranes. Mutations of this gene may lead to a variety of phenotypes, including centronuclear myopathy [138], and neutropenia with intermediate conduction slowing [139].

• Tyrosyl-RNA transferase (HMSN DI type C)

A tRNA transferase for tyrosine, this protein, tyrosyl-RNA transferase (YARS), is expressed in spinal cord and brain. It is reported rarely in families and individuals who have a neuropathy with dominant inheritance. Unlike GARS (discussed previously), motor neuronopathy is not described but, rather, motor and sensory involvement [140].

• Lamin A/C—axonal autosomal recessive neuropathy (HMSN type 2B1)

Inherited as an axonal form, lamin A/C has autosomal recessive inheritance. Lamin A/C is a nuclear envelope protein. As a group, the lamins are a large constituent of the nuclear lamina within the nuclear membrane. Their function is believed related directly to the proper handling of DNA chromatin with functions of replicational organization in addition to stabilizing the nucleus and its envelope protein [141]. Mutations of this gene have led to a variety of clinical phenotypes, including, rarely, an autosomal recessive axonal neuropathy among Algerian families [142]. The other clinical phenotypes include (1) skeletal muscle (Emery-Dreifuss muscular dystrophy [dominant or recessive] [143,144] and limb-girdle muscular dystrophy, autosomal dominant [LGMD1B] [145]); (2) cardiac conduction defects and cardiomyopathy (Emery-Dreifuss muscular dystrophy [143], LGMD1B, and dilated cardiomyopathy (CMD1A) [146]; (3) bone (mandibuloacral dysplasia) [147]; and (4) fat (partial lipodystrophy) [148].

• HSAN

Like HMSN, this group (HSAN) is heterogenous (Table 3). The distinguishing features between different types of HSAN relate to age of onset, mode of inheritance, fiber type involvement and, increasingly, the molecular biologic cause. The clinical distinction between various forms often is possible only with specialized testing, including autonomic testing that looks at postganglionic small nerve fiber function and nerve pathology, with nerve morphometrics defining the specific sensory fiber involvements. It is important to understand that motor function need not be spared but is not the primary cause of disabilities; rather, sensory loss is foremost. Each condition should, however, include the following features: (1) having a genetic basis; (2) selective or predominant involvement of primary sensory with or without autonomic neurons (axons); and (3) small-diameter sensory and sudomotor function that often is impaired, affecting acral (distal limb) tissue injury.

Table 3.. Hereditary sensory and autonomic neuropathy

^a Many autosomal dominant forms without known genetic cause. ^b Typically Ashkenazi Jews. ^c A single patient reported.

• Gene defects in HSAN

• SPTLC1 (HSAN1)

Within this specific genetic group, a great deal has been learned. Dominantly inherited symptoms typically begin in the second, third, or later decades of life. Plantar ulcers are common. Some kinships have severe lancinating pains of the feet and legs, whereas others have only loss of sensation, often with painless foot injuries. Peroneal atrophy with ankle dorsiflexion weakness is typical, with sensory loss major in disability. Families who have burning feet alone without sensory deficits likely represent a distinct entity and in at least one family linkage has been excluded to 9q22.1 [149], where the identified gene, serine palmitoyltransferase long-chain 1 (SPTLC1), resides [150^,151]. SPTLC1 is believed to be the rate-limiting enzyme in the synthesis of sphingolipids, including ceramide and sphingomyelin [152^,153]. Ceramide is important in regulation of programmed cell death in several tissue types, including differentiating neuronal cells [154].

• HSN2 gene and theoretic protein (HS2 and HSN2)

The HSN2 gene is unique by residing within another gene’s (PRKWNK) intron. Mutations of PRKWNK cause autosomal dominant pseudohypoaldosteronism type II (PHAII), characterized by severe hypertension, hyperkalemia, and sensitivity to thiazide diuretics, which may result from a chloride shunt in the renal distal nephron [155]. The HSAN2 and PHAII phenotypes are discordant as are the mutations of either gene.

The five Canadian kindreds initially identified as having mutations in the HSN2 gene [156] all originated from Newfoundland families and carried identical homozygous mutation, 594delA, causing a frameshift and truncation of the protein from 434 amino acids to 206 amino acids. A homozygous insertional mutation at 918-919insA, found in a Nova Scotian family, led to a truncation of the protein to 318 amino acids. The French Canadian kindreds had this conserved mutation but in heterozygote state and with an additional homozygous 943C to T nonsense mutation. Such mutations were not found in a large cohort of appropriate normals. Discordant mutations in the HSN2 gene have been identified in Japanese and Lebanese patients [157^,158]. Despite convincing studies, Northern blot assays looking for the predicted HSN2 transcript in multiple human tissues and more sensitive reverse transcription assays using polymerase chain reaction in various tissues, including dorsal root ganglion, fail to identify the predicted product conclusively. Further work is needed in expression studies of this predicted protein. It is likely, however, that the difficulties in isolation relate to the selective expression in nerve at low levels. A signaling peptide sequence is predicted from the known sequence of HSN2, and the investigators have speculated about the HSN2 protein product as potentially important in nerve growth [156].

• Inhibitor kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein (HSAN type 3, familial dysautonomia, and Riley-Day syndrome)

HSAN3 complex disorder has prominent autonomic involvement with (1) autosomal recessive inheritance; (2) congenital or infantile onset; (3) predominance in Ashkenazi Jews; (4) peripheral sensory (all classes), autonomic neurons (axons), lesser involvement of motor neurons (axons), and possibly other CNS neurons; (5) history of poor sucking, repeated episodes of fever; (6) blotchy skin; and (7) absence of fungiform papillae of the tongue [159^,160]. Mutations in the inhibitor kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein (IKBKAP) gene, located at 9q31, cause HSAN3. Two mutations are identified and both disrupt phosphorylation (IKBKAP, IVS20DS, T-C, + 6; ARG696PRO) [161]. Why such defects lead to a dysautonomia and sensory neuropathy is unknown. Genetic testing for the two mutations may allow for ease of carrier and affected assessment in the Ashkenazi Jew population, where a strong founder effect likely accounts for limited responsible mutation.

• Tyrosine receptor kinase A (HSAN type IV)

This disorder includes (1) autosomal recessive inheritance; (2) congenital or infantile onset; (3) repeated high fevers, which may cause death; (4) decreased pain sensation and absence of sweating; (5) mental retardation in some patients; and (6) virtual absence of unmyelinated fibers in sural nerve. Rare patients who have HSAN V are described with (1) probable autosomal recessive inheritance, (2) congenital or infant onset, (3) selective loss of small myelinated fibers and normal unmyelinated fibers, and (4) normal motor sensory and sudomotor examinations [162].

Mutations in the neurotrophin receptor, TrkA, are causative of this disorder. Central and peripheral nerve tissues rely on neurotrophins and their receptors for proper formation. The gene, TrkA, is believed important for inducing neurite outgrowth and promotion of embryonic sensory and sympathetic neurons. Multiple mutations, including deletion, splice-site mutations, and missense mutations—all in the tryosine kinase domain of TrkA, are found causative [163^,164].

• Spinocerebellar ataxias with neuropathy

These system atrophies affect the spinocerebellar tracts and are inherited as autosomal dominant and recessive disorders. Currently, there are more than 20 dominant syndromes described and fewer known recessive forms. Peripheral nerve studies among spinocerebellar ataxias are limited, and primary axonal pathology is believed to predominate. Patients have progressive central ataxia with spinocerebellar degeneration and varied degrees of cognitive, ocular, autonomic, and hyperkinetic dysfunction. The most common disorder is inherited as autosomal recessive spinocerebellar ataxias (ie, Friedreich’s ataxia, the most common spinocerebellar syndrome). Other recessive forms include spinocerebellar atrophy with peripheral axonal degeneration (SCAN1), vitamin E deficiency (resulting from a-tocopherol transfer protein deficiency or abetalipoproteinemia), ataxia telangiectasia, infantile-onset spinocerebellar ataxia, Marinesco-Sjögren syndrome, spastic ataxia of Charlevoix-Saguenay, Refsum disease, carbohydrate-deficiency ataxia, and Cayman Island ataxia, among others [165].

Friedreich’s ataxia is caused by expansion of a GAA triplet repeat located within the first intron of the frataxin gene [166]. The gene is believed to be a nuclear origin mitochondrial protein that plays a role in iron homeostasis. With deficiency of the gene product, there is an accumulation of iron in the mitochondria, poor mitochondrial enzymes function, enhanced sensitivity to oxidative stress, and eventually free radical–mediated cell death.

• Hereditary spastic paraplegias with neuropathy

As with the spinocerebellar syndromes, the lower motor neuron involvement for these primary central spastic disorders typically is not clinically primary in deficit and, therefore, is not as well studied as desired. Of the more than 10 autosomal dominant genetically characterized spastic paraplegias, several are noted for variable extremity weakness and atrophy (SPGSPG9-10q23.3-q24.2, SPG17-11q12-q14, and SPG10-12q13). The conduction velocities of nerves typically are normal in the upper extremities, and in the lower extremity, normal or low normal, with reduction in CMAP amplitudes. On needle examination, fibrillations and fasciculations often are seen distally with increased size of motor unit potentials. Detailed descriptions of the electrophysiology and nerve biopsy reports are lacking in these and other forms, including SPG3A, where specific genetic cause is known [167].

There are no fewer than seven autosomal recessive forms of spastic paraplegia with identified chromosomal location and four are noted with either distal amyotrophy or neuropathy. Specific genes are identified in SPG7-16q-paraplegian and SPG20-13q-spartin (Table 4) [168].

Table 4. Hereditary spastic paraplegias with neuropathy

• Miscellaneous hereditary neuropathies

Historical classifications of some forms of HMSN are discussed later. Among those in which spastic paraplegias are predominant, characterization as “complicated” hereditary spastic paraplegias may be more appropriate. There also exists a group of disorders in which motor features are so prominent that motor neuronopathy is most appropriate, and specific genetic causes are found in some. When distal weakness is predominant, they may be referred to as dHMNII (Table 5).

Table 5. Miscellaneous hereditary neuropathies: hereditary motor sensory neuropathy and others

•  Hereditary brachial plexus neuropathy

Attacks of brachial plexus neuropathy associated with inflammation [169] have undergone recent gene discovery. Specifically, Kuhlenbaumer and colleagues [170] reported, in six European families, mutation in a septin-like molecule SEPT9 at chromosome position 17q25. Mutations were not seen in four American kindreds with shared haplotypes but in two separate American families of European descent. Of 12 American kindreds, I identified only one that carries mutation within the gene at R88W, also of European descent without conserved haplotype. The described mutations in this gene were not identified in 56 cases of sporadic brachial plexus neuropathy (Parsonage-Turner syndrome) [171]. The gene is one of several GTP-binding scaffold proteins and is implicated in membrane dynamics, vesicle trafficking, apoptosis, and cytoskeletal remodeling.

•  Multisystem inherited neuropathies, “metabolic”

These inherited neuropathies have neural and non-neural tissues involvement (Table 6) [172]. Diverse presenting symptoms and signs exist. As a group, these diseases are rare when neurofibromatosis type 1 is excluded. Neurofibromatosis type 1 rivals in frequency the HMSNs (approximately 1 in 2000 affected). Specific pathologic features on nerve biopsies are common, but metabolic or genetic testing may preclude the need for nerve or other tissue biopsies. Because treatments are available in some, their recognition becomes important. Detailed description of these disorders is beyond the scope of this review and is reviewed elsewhere (see Table 6).

Table 6. Hereditary multisystem disorders with neuropathy (partial list)

• Current genetic testing considerations

Ethical and practical issues have arisen with the availability of the new genetic testing [173]. Previously, identification of affected and unaffected persons was limited to neurologic examination and electrophysiologic testing of the kinship [4]. It is now more complex: multiple genetic tests are available, testing is costly, and results frequently have low sensitivity and often are of uncertain significance. These issues make it difficult to decide who and which genes should be tested. If a test is ordered, the physician needs to be in a position to provide proper interpretation and counsel to a patient. The pretest discussion needs to include (1) comment of the variable clinical severity or expression of the disease; (2) future potential for work; (3) insurance issues; (4) risk for emotional upset; and (5) specific implications for family planning. Sometimes, other unforeseen complications occur as a result of testing, such as a chance discovery of an individual’s illegitimate or adopted status. Because preventative or reversible treatments for gene abnormalities are not readily available, the decision to undergo genetic testing must be made carefully. For the rare disorders in which medical interventions are available, testing of asymptomatic family members seems reasonable. For the other inherited disorders, asymptomatic people probably should not be tested. In contrast, clinically affected individuals suspected of having a defined variety of inherited neuropathy should be tested, because testing can confirm a diagnosis and provide for improved counsel. By taking a detailed family history and telephoning or examining relatives, the need for genetic testing may be diminished [4].

Knowing the sensitivity and specificity of each genetic test is important. Among many of the axonal forms of hereditary motor and sensory neuropathies, the sensitivity of available genetic testing may be low compared with their demyelinating counterparts. A recent report, however, suggests the benefit of genetic testing in individuals who have axonal phenotypes and who do not have family history [174]. Specifically, from 153 stored and unrelated neuropathy DNA samples, Boerkoel and colleagues performed aggressive testing of multiple known causative genes of CMT and found 100 individuals who had an identified mutation. One third of those identified as having the mutation were reported to have de novo “sporadic” mutation and many had axonal phenotypes. Their experience suggests the usefulness of genetic testing beyond our own Mayo peripheral nerve group experience. An algorithm approach considering clinical phenotype with electrophysiology is helpful (see Fig. 1).

To avoid erroneous results, choose accredited facilities for testing [1]. In these laboratories, false-positive results can occur and generally are the result of chance discovery of polymorphisms. Polymorphisms represent normal DNA sequences occurring at different frequencies in different populations or races. These polymorphic base pair changes may or may not change amino acid. When the base pair change does not alter amino acid sequences, the results should be viewed skeptically. Rare mutations not predicted to change the protein might do so by producing alternative splicing. Such mutations occur at exon-intron boundaries. With indeterminate results, tracking base change with affected status is emphasized. Kindred studies, transcription assays, transcription expression, and functional assays typically are research based, however, and referral to tertiary care centers is emphasized. If the DNA sequence is ambiguous, studying the protein can be helpful. Protein assays typically are available commercially only for disorders characterized as inborn errors of metabolism.

• Practical council in inherited neuropathies

Practice-based gene replacement, gene product manipulation, or other molecular therapies currently are not available for most inherited neuropathies. Nevertheless, physicians can make meaningful treatment interventions. The mainstay of those interventions is supportive with special attention to:

1.Genetic counseling, including discussion of inheritance pattern and potential for predicted specific impairments depending on disease, relevant to vocational council and risk injury assessment

2.Care of acral appendage, especially in the varieties of HSAN in which mutilating injuries are preventable

3.Proper bracing and supportive devices where appropriate

4.Emphasis on routine health maintenance, including weight control, screening for early diabetes, thyroid disease, and alcoholism, all of which may make impairments worse

5.Council of increased risk for worsened neuropathy with certain chemotherapeutic agents, including platinum-based agents, vinca alkaloids, and, likely, paclitaxel, thalidomide, and bortezomib products

6.Reassurance that these disorders often are compatible with normal life expectancy and life enjoyment

• Future molecular directions

The increasing appreciation of complex factors in disease modification will emphasize further the need for clinical phenotypic and expression characterization. Understanding of nerve molecular architecture and function is predicted to improve and lead to more specific targeted approaches in diagnosis and treatment. Current DNA testing platforms for inherited neuropathies remain expensive, insensitive for many, and largely are limited to neuropathies with mendelian patterns of inheritance. Using mass spectrometry in the rapid identification of mutations leading to alteration of protein structure holds promise for some disorders in which the protein abnormality is expressed within blood [175]. Identification of complex susceptibility factors and modifiers of genetically defined neuropathies are predicted in the current “proteomic era.” These discoveries will have implications for inherited and acquired neuropathies.

Using the tools that have allowed for understanding and diagnosis of neuropathy, specific drug developments are possible. Specifically, implementation of computer software and protein modelling programs already allow for the development of small molecules that may facilitate treatment of toxic gain or loss of function diseases, including denervating neuromuscular junction diseases and other degenerative neurologic disorders [176,177,178].

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