Distal hereditary motor neuropathies (dHMN)

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Introduction

Hereditary motor neuropathies (dHMN) are predominantly characterized by the degeneration of lower motor neurons and are usually referred to as spinal muscular atrophies (SMA) [15]. According to the distribution of clinical symptoms, dHMN is classified as the proximal or the distal form. The proximal form is comprised mainly of typical SMA and will not be discussed further in this chapter, whereas distal dHMNs give rise to hereditary neuropathies and have been called progressive muscular atrophy or spinal forms of Charcot-Marie-Tooth disease (spinal CMT) [15]. dHMN accounts for about 10% of all cases of spinal muscular atrophy and is clinically and genetically heterogeneous [26]. Based on this heterogeneity, Harding (1993) proposed a classification into seven different subtypes (dHMN I±VII) [15]. Four of these are inherited autosomal dominantly and three autosomal recessively, whereas X-linked pedigrees have not been identified so far (Table 8.1).

Electrophysiologic investigations of patients with dHMN are most helpful to differentiate between HMSN and dHMN but do not allow for discrimina- tion between single dHMN subtypes. Sensory nerve conduction studies are normal with the exception of the dHMN V/CMT2D overlap type, in which sensory nerve conduction velocities (SNCV) and sensory nerve action potentials (SNAP) may be reduced [1, 8]. Motor NCV (MNCV) is usually within the normal range; in the presence of severe wasting it may be slightly reduced due to loss of large motor neurons [15]. Electromyography reveals signs of acute (spontaneous fibrillation and positive sharp waves) or chronic (large- amplitude motor unit potentials and polyphasic potentials) neurogenic al- terations. Laboratory investigations are usually normal, in some patients, plasma creatine kinase may be moderately high [15].

The pathophysiological concept of dHMN includes degeneration of lower motor neurons in the anterior horn of the spinal cord with neurogenic muscular atrophy suggesting dying-forward atrophy. Consistently, in dHMN VI autopsy specimens revealed neurogenic atrophy of skeletal muscle without re- innervation [14]. The diameter of the anterior spinal roots was reduced and the remaining motor neurons showed chromatolysis. Morphometric and ul- trastructural analyses of sural nerve biopsies are normal in most cases. Mild

(dHMN)

F. Stægbauer, G. Kuhlenbåumer

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Table8.1.Clinicalfeaturesofdistalhereditarymotorneuropathies TypeDistributionInheritanceAgeatonsetAgeunableto walkLifeexpectancy dHMNIlowerlimbpredominanceAD2±20yrarenormal dHMNIIlowerlimbpredominanceAD20±40yrarenormal dHMNIIIlowerlimbpredominanceAR2±10yrarenormal dHMNIVlowerlimbpredominanceAR0±20yabout30yunknown dHMNVupperlimbpredominanceAD5±20yrarenormal dHMNVIupperandlowerlimbs;withdiaphragmatic paralysisAR0±1ynever1y dHMNVIIaupperlimbpredominance;withvocalcord paralysisAD10±20yrareprobablynormal dHMNVIIbupperlimbpredominanceandfacialweakness; withvocalcordparalysisAD10±20yrareprobablynormal dHMNJerashtypelowerlimbpredominance;withpyramidal featuresAR5±10yrareprobablynormal

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loss of axons involving large and small myelinated fibers as well as minimal denervation in unmyelinated axons may be found. Muscle biopsy reveals signs of chronic denervation and mild secondary myopathy.

To date seven genes and two additional chromosomal loci have been identified in dHMN (Table 8.2).

8.1 dHMN I ± small heat-shock protein 27 (HSP27 or HSBP1) (OMIM 608634)

z Clinical features:The clinical presentation of dHMN I resembles classical HMSN with respect to muscle weakness and wasting but, in contrast, clinically apparent sensory loss is absent in nearly all cases [10, 16]. dHMN I is inherited autosomal dominantly and age at onset is before the age of twenty and usually in the first decade. Typically, the first clinical signs of dHMN I are distal weakness and wasting of the lower limbs, particularly of the anterior tibial and peroneal muscles. Pes cavus like foot deformity is frequently found and may be more prominent than in hereditary motor and sensory neuropathies (HMSN). About one quarter of the patients de- velop thoracolumbar scoliosis. Progression of motor symptoms to the proximal muscles of the lower limbs is not frequent. Involvement of the upper limbs is rare and can be found in about 20% of cases. Loss of deep tendon reflexes is less frequent than in HMSN, ankle jerks are absent in about Table 8.2. Genetic classification of distal hereditarymotor neuropathies

Type Inheritance Chromosomal

locus Reference Gene Reference

dHMN II AD 12q24.3 Timmerman

et al. 1996 [31] unknown ±

dHMN IV AR 11q13 Viollet

dHMN V AD 7p15 Christodoulou

et al. 1995 [8] GARS Antonellis et al. 2003 [1]

dHMN VI AR 11q13-q21 Grohmann

et al. 1999 [14] IGHMBP2 Grohmann et al. 2001 [13]

dHMN VIIa AD 2q14 McEntagart

dHMN VIIb AD 2p13 Puls et al. 2003

[28] DCTN1 Puls et al. 2003

[28]

Jerash type AR 9p21.1-p12 Christodoulou

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30% of cases, but in over 60% knee jerks and upper limb reflexes are normal. The prognosis of dHMN I is generally good. The disorder is very slowly progressive and in some cases it appears to arrest in later stages.

Fewer than half of the patients are able to walk unaided in adult or later adult life.

z Genetics and pathomechanism: Very recently, missense mutations in the small heat-shock protein 27 gene (HSBP1 or HSP27) were identified in four families with clinical features matching the description of dHMN I ([12]

and V. Timmerman, personal communication). It is not yet known whether the original families published by Harding are caused by mutations in HSP27 [16]. Mutations in HSP27 cause also CMT2F. HSP27 is induced by stress, like elevated temperature. It has antiapoptotic and cytoprotective properties, e.g., by inhibiting caspases [5, 19]. Upregulation of HSP27 is required for the survival of injured neurons and is overexpressed in Cu,Zn superoxide dismutase 1 (SOD1) transgenic mice, which are a model for amyotrophic lateral sclerosis (ALS) [3, 34]. HSP27 is also a suppressor of polyglutamine-induced cell death and plays a role in the organization of the neurofilament network. Transfection of HSP27 carrying mutations found in the dHMN families into eukaryotic cell lines lead to increased cell death and disturbances of neurofilament assembly [12].

8.2 dHMN II ± small heat-shock protein 22 (HSP22 or HSBP8) (OMIM 158590)

z Clinical features: dHMN II is an autosomal dominantly inherited disease and is similar to dHMN I in terms of clinical expression, histological and electrophysiological features as well as prognosis. Both forms differ in the age at onset since dHMN II is the adult type with the development of clinical symptoms in the second to fourth decade [23]. The symptoms start in the extensor muscles of the great toe and later of the extensor muscles of the feet. The disease progresses rapidly and all distal muscles of the legs are completely paralyzed after five years.

z Genetics and pathomechanism: In a large Belgian pedigree, the chromosomal locus of dHMN II was mapped to chromosome 12q24.3 [23, 31]. Re- cruitment of further families and reduction of the candidate region to 1.7 kb allowed the identification of missense mutations in the small heat-shock protein 22 gene (HSP22 also called: HSBP8) in four families [18]. All mutations resulted in an amino acid change at position 141 from lysine to two different amino acids. The mutation locates to the highly conserved so called alpha-crystalline domain which is common to a number of heat- shock proteins. HSP22 interacts with HSP27 which is mutated in a form of

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HMN I discussed in the preceding paragraph. This interaction is strength- ened if HSP22 is mutated and leads to formation of intracellular aggre- gates, thereby reducing cell viability through an unknown mechanism [18].

8.3 dHMN III ± chromosomal location unknown

z Clinical features:In autosomal recessive dHMN III, clinical symptoms de- velop in the first decade. Patients are generally mildly affected and the course of the disease resembles dHMN I and dHMN II [16]. Based on electrophysiological and histological studies, these forms are not distinguishable definitely.

z Genetics and pathomechanism:There are no studies available that confirm linkage of dHMN III to a single chromosomal locus.

8.4 dHMN IV ± chromosome 11q13 (OMIM 607088)

z Clinical features:Autosomal recessive dHMN IV is much more severe than dHMN III. Age at onset is in the first to second decade and weakness and wasting is predominantly in the lower legs but, in contrast to the other forms, extends to the proximal muscles of the legs [26]. Progressive wor- sening during childhood and relative stabilization into adulthood has been reported [32]. In two affected persons from a Lebanese family, diaphragmatic paralysis was noted but this seems to be less frequent as in dHMN VI (see below).

z Genetics and pathomechanism: Viollet et al. found linkage to markers on chromosome 11q13 in an inbred Lebanese family with the clinical characteristics of dHMN IV [32, 33]. dHMN IV was mapped to a region overlapping with the dHMN VI candidate region on chromosome 11q13. dHMN VI is caused by mutations in the immunoglobulin l-binding protein 2 gene (IGHMBP2) [13]. Mutations in this gene were not found in the dHMN IV family indicating that both diseases are caused by distinct genes located in the same chromosomal region.

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8.5 dHMN V a and b ± Va: glycyl tRNA synthetase gene (GARS) (OMIM 600749) ± Vb: Berardinelli Seip congenital muscular dystrophy gene (BSCL2) (OMIM 270685)

z Clinical features:In autosomal dominant dHMN Va, muscle weakness and wasting is predominantly confined to the distal upper limbs. Lower limbs are involved only to a minor degree. Besides sporadic cases, few families have been described in which the disease was autosomal dominantly inherited [1, 8]. Most patients showed symmetrical weakness, while in others the distribution was strikingly asymmetrical. When present, clinical sensory loss was only a minor feature and pes cavus was frequent. In addition in some families mild spastic paraplegia was found. Interestingly, a similar phenotype was described in a family from Iowa in which sensory loss was common [17]. This disease was classified as axonal Charcot-Marie-Tooth type 2 and subcategorized as CMT type 2D. In a large Mongolian kinship, patients with features of dHMN Va and CMT2D were observed within one family [29]. Genetic studies revealed that dHMN Va and CMT2D are allelic and caused by mutations in the glycyl tRNA synthase (GARS) gene [1]. In a large Austrian family, clinical characteristics of dHMN V were found to- gether with brisk tendon reflexes and slightly elevated muscle tone. This entity will be called dHMN Vb in this book [2].

z Genetics and pathomechanism: Despite clinical heterogeneity, dHMN Va and CMT2D have been mapped to a single locus on chromosome 7p15[1].

Further genetic analysis, revealed mutations in the glycyl tRNA synthetase (GARS) gene in five families with dHMN Va, CMT2D or an overlapping phenotype demonstrating that both diseases are allelic [1]. GARS is expressed in an ubiquitous fashion including brain and spinal cord and be- longs to the family of aminoacyl-tRNA synthetases that perform an essen- tial function in protein synthesis by catalyzing the esterification of an amino acid to its cognate tRNA. These enzymes are necessarily present in each cell and must properly recognize the tRNA and the amino acid in order to maintain fidelity of translation. The exact mechanism by which mutations in this ubiquitously expressed gene lead to the specific phenotype remains to be unraveled. dHMN 5b maps to chromosome 11q12-q24 and is caused by missense mutations in the Berardinelli-Seip congenital lipodystrophy gene (BSCL2) [35]. Silver syndrome is an entity which is usually classified as hereditary spastic paraplegia type 17 (SPG17) but it is clinically very similar if not identical to dHMN V b and is also caused by mutations in BSCL2 [25]. All mutations causing dHMN Vb known to date destroy a N- glycosylation site, most likely resulting in protein misfolding. The mutated protein localizes to so called aggresomes while wildtype protein is evenly distributed in the cytoplasm [35].

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8.6 dHMN VI ± immunoglobulin l-binding protein 2 (IGHMBP2) (OMIM 604320)

z Clinical features: dHMN VI is inherited autosomal recessive and the age of onset is in very early childhood (weeks to months) [4, 24]. The most prominent symptoms are severe respiratory distress resulting from diaphragmatic paralysis with eventration shown on chest X-ray and predomi- nant involvement of the distal upper limbs. Muscle weakness spreads to in- volve proximal muscles and death may occur before the age of one year.

Because of the diaphragmatic involvement, dHMN VI is also referred to as spinal muscular atrophy with respiratory distress (SMARD) [14].

z Genetics and pathomechanism: dHMN VI was mapped to chromosome 11q13-q21 in three families of Lebanese, German and Italian origin [13].

Subsequently mutations in the gene encoding immunoglobulin l-binding protein 2 (IGHMBP2) have been found in six families with dHMN VI [13].

IGHMBP2 was chosen as a candidate gene since the homologous gene in the mouse had been shown to be responsible for spinal muscular atrophy in the neuromuscular degeneration (pmn) mouse, whose phenotype resembles dHMN V [30]. IGHMBP2 is ubiquitously expressed with the highest levels in testis. The exact physiological function of IGHMBP2 is not known and its role in the development of dHMN VI remains to be clarified.

8.7 dHMN VIIa ± chromosome 2q14(OMIM 158580)

z Clinical features:dHMN VII was first reported in 1980 in a large Welsh kindred in which dHMN with vocal cord paralysis was inherited autosomal dominant [36]. Onset was most commonly in the second decade with weakness and wasting of the small hand muscles subsequently involving the distal muscles of the legs. Hoarseness was usually noted and laryngoscopy showed unilateral or bilateral vocal cord paralysis. Additional families were reported later [27]. Interestingly, there is a large overlap between dHMN VIIa and Charcot-Marie-Tooth syndrome type 2C (CMT2C). CMT2C is characterized by autosomal dominant inheritance, motor and sensory involvement of the limbs and progressive weakness of the vocal cords and the diaphragm and is distinguishable from dHMN VIIa by the sensory involvement [11].

z Genetics and pathomechanism: dHMN VIIa was mapped to chromosome 2q14 in the original Welsh and an additional family [22], while the pheno- typical similar CMT2C was mapped to chromosome 12q23-q24 [20]. The causative genetic defects have not yet been identified.

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8.8 dHMN VIIb ± dynactin (DCTN) (OMIM 607641)

z Clinical features:Recently a North American kindred with dHMN VII was reported in which additionally progressive facial weakness was observed [28]. This form is genetically different and should therefore be classified as dHMN VIIb, whereas the classic form should be termed dHMN VIIa.

z Genetics and pathomechanism:dHMN VIIb has been localized to chromosome 12q13. A mutation in the dynactin-1 (DCTN1) gene, which is located in the linkage region, has been detected in one dHMN VIIb family [28].

The dynactin complex is required for dynein mediated retrograde transport of vesicles and organelles along microtubules. In transgenic mice, overexpression of dynamitin disrupts the dynactin complex and leads to late onset progressive motor neuron disease [21].

8.9 dHMN pyramidal/amyotrophic lateral sclerosis 4(ALS4), senataxin (SETX) (OMIM 602433)

z Clinical features: dHMN pyramidal is characterized by a variable age of onset between less than six months to 21 years of age. The main features are distal muscle weakness and atrophy, hyperreflexia and in some patients pyramidal signs [6]. The progression is slow and patients often become wheelchair bound in the fifth decade. Bulbar and respiratory muscles are spared and the life expectancy is not grossly reduced.

z Genetics and pathomechanism:dHMN pyramidal was mapped to chromosome 9q34 and recently causative mutations were identified in the senataxin gene (SETX) [6, 7]. Senataxin contains a putative DNA/RNA helicase domain. DNA/RNA helicases are involved in DNA repair, replication as well as in transcription, transcript stability and translation initiation. Interest- ingly the IGHMBP2 gene which is mutated in dHMN VI also contains a DNA/RNA helicase domain and shows high homology to SETX. While missense mutations are causing dHMN pyramidal, homozygous nonsense mutations are responsible for the ataxia-oculomotor apraxia syndrome type 2 (AOA2, OMIM 606002). AOA2 is a complex syndrome involving cerebellar ataxia and atrophy, oculomotor apraxia, loss of tendon reflexes and a late onset peripheral neuropathy.

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8.10 dHMN Jerash type ± chromosome 9p21.1-p12 (OMIM 605726)

z Clinical features: In 2000, Christodoulou et al. described seven consanguineous families from the Jerash region of Jordan in which dHMN was inherited autosomal recessive and age at onset was five to ten years [9]. Pa- tients presented with symmetrical distal atrophy and weakness of the lower limbs and pyramidal features. Pes cavus was present in all affected persons.

During the course of the disease involvement of the distal upper limbs was noticed. Sensory loss was not found. The authors classified this form of dHMN as Jerash type.

z Genetics and pathomechanism:In the seven consanguineous families from Jordan, the Jerash type dHMN was mapped to chromosome 9p21.1-p12 [9].

This region includes the ciliary neurotrophic factor receptor (CNTFR) gene, which is expressed exclusively in the nervous system and skeletal muscle. Since mice lacking CNTFR display severe motor neuron deficits, this gene has been named as a functional candidate gene. Mutation analysis of CNTFR in the Jerash families has not been reported so far.

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