Clinical and genetic aspects of Charcot-Marie- Tooth

Click here to load reader

  • date post

    29-Oct-2021
  • Category

    Documents

  • view

    3
  • download

    0

Embed Size (px)

Transcript of Clinical and genetic aspects of Charcot-Marie- Tooth

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/ by-nc/4.0/).
REVIEW ARTICLE
Clinical and genetic aspects of Charcot-Marie- Tooth disease subtypes
Soo Hyun Nam, Byung-Ok Choi Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
ABSTRACT Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neuropathies and is both genetically and clinically heterogeneous, with variable inheritance modes. With regard to clinical and genetic aspects, CMT is divided into several subtypes, includ- ing CMT1, CMT2, CMT3, CMT4, CMT5, CMT6, X-linked CMT, and intermediate CMT. Up to date, more than 90 causative genes for CMT have been identified. Furthermore, previ- ous animal studies reported some molecules to have therapeutic effects on specific CMT subtypes, depending on the underlying genetic cause. Therefore, accurate genetic diagnosis is of crucial importance when performing customized therapy. Finally, recent investigations on induced pluripotent stem cells expanded the possibility of both pa- tient-specific cell therapy and drug discovery. The current review focuses on the latest classification updates for accurate CMT diagnosis.
Keywords: Charcot-Marie-Tooth disease; Classification; Diagnosis; Genes; Mutation
Precision and Future Medicine 2019;3(2):43-68 https://doi.org/10.23838/pfm.2018.00163 pISSN: 2508-7940 · eISSN: 2508-7959
INTRODUCTION
Charcot-Marie-Tooth disease (CMT) is the most common form of inherited peripheral neuropa- thy, with a prevalence of one in 2,500 people [1]. CMT patients usually present muscle atrophy, sensory loss, foot deformities, and areflexia [2,3]. However, CMT is a clinically and genetically heterogeneous disease, and some subtypes reveal unusual clinical features, including pyrami- dal features, vocal cord paralysis, hearing loss, or optic atrophy [4]. Furthermore, CMT is divid- ed into three categories based on its pathology, namely demyelinating, axonal, and intermedi- ate neuropathy [5,6]. Intermediate CMT neuropathy was reported to be characterized by both demyelination and axonal degeneration in peripheral nerve biopsies [7]. Demyelinating and axonal CMT neuropathy can be generally distinguished by assessing the median motor nerve conduction velocity (NCV), which is lower and higher than 38 m/sec, respectively [5,6]. Inter- mediate neuropathy usually ranges from 30 to 40 m/sec [7]. As more than 90 causative genes for CMT were found up to date, this disease is categorized into numerous subtypes [8-10]. In this review, the latest updates on the CMT subtypes and their clinical and genetic aspects were described, including Charcot-Marie-Tooth disease type 1 (CMT1), type 2 (CMT2), type 3 (CMT3), type 4 (CMT4), type 5 (CMT5), type 6 (CMT6), X-linked CMT (CMTX), and intermediate CMT.
Received: November 18, 2018 Revised: January 1, 2019 Accepted: January 8, 2019 Corresponding author: Byung-Ok Choi Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-1296 E-mail: bochoi@skku.edu
CLASSIFICATION OF CHARCOT- MARIE-TOOTH DISEASE
Charcot-Marie-Tooth disease type 1 CMT1 is a group of autosomal dominant demyelinating pe- ripheral neuropathies characterized by distal weakness and atrophy, sensory loss, foot deformities, and slow NCV. The peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ), early growth response 2 (EGR2), lipopolysaccharide-in- duced tumor necrosis factor (TNF)-alpha factor (LITAF), and
neurofilament light (NEFL) are known as causative genes (Table 1). The age of onset of CMT1 greatly varies, ranging from infancy to the fourth or subsequent decades of life. Al- though patients usually have their first symptoms between their first and the second decade of life, the several other clinical manifestations may appear later. Furthermore, its clinical severity is also variable, fluctuating between an ex- tremely mild form of the disease, which remains unrecog- nized, to a considerably serious form, which is associated with weakness and disability. Affected individuals typically
Table 1. Mutations of the demyelinating Charcot-Marie-Tooth neuropathy subtypes
Subtype Gene Locus Heredity Protein
Charcot-Marie-Tooth disease type 1 (CMT1)
CMT1A PMP22 17p12 AD Peripheral myelin protein 22 (duplication)
CMT1B MPZ/P0 1q23.3 AD Myelin protein zero
CMT1C LITAF/SIMPLE 16p13 AD Lipopolysaccharide-induced tumor necrosis factor-alpha factor
CMT1D EGR2/Krox20 10q21.3 AD Early growth response 2
CMT1E PMP22 17p12 AD Peripheral myelin protein 22 (point mutation)
CMT1F NEFL 8p21.2 AD, AR Neurofilament light polypeptide
CMT1 PMP2 8q21.13 AD Peripheral myelin protein 2
Charcot-Marie-Tooth disease type 3 (CMT3)/ Dejerine-Sottas syndrome (DSS)
CMT3A PMP22 17p12 AD, AR Peripheral myelin protein 22
CMT3B MPZ/P0 1q23.3 AD, AR Myelin protein zero
CMT3C Unknown 8q23-q24 AD Unknown
CMT3D PRX 19q13.2 AD, AR Periaxin
DSS-EGR EGR2/Krox20 10q21.3 AD, AR Early growth response 2
Charcot-Marie-Tooth disease type 4 (CMT4)
CMT4A GDAP1 8q21.11 AR Ganglioside-induced differentiation-associated protein 1
CMT4B1 MTMR2 11q21 AR Myotubularin related protein 2
CMT4B2 SBF2/MTMR13 11p15.4 AR SET binding factor 2
CMT4B3 SBF1/MTMR5 22q13.33 AR SET binding factor 1
CMT4C SH3TC2/KIAA1985 5q32 AR SH3 domain and tetratricopeptide repeat-containing protein 2
CMT4D NDRG1 8q24.22 AR N-myc downstream regulated 1
CMT4E EGR2/Krox20 10q21.3 AD, AR Early growth response 2
CMT4F PRX 19q13.2 AR Periaxin
CMT4G HK1 10q22.1 AR Hexokinase 1
CMT4H FGD4 12p11.21 AR FYVE, RhoGEF, and PH domain-containing protein 4
CMT4J FIG4 6q21 AR Polyphosphoinositide phosphatase
CMT4K SURF1 9q34.2 AR Surfeit locus protein 1
AD, autosomal dominant; AR, autosomal recessive; EGR, early growth response.
45https://doi.org/10.23838/pfm.2018.00163
Soo Hyun Nam, et al.
develop distal weakness, symmetric atrophy of muscles (mainly peroneal), and reduced-to-absent tendon reflexes. Additionally, sensory deficits of position, vibration, and pain/ temperature commonly occur in patients’ feet and, at a later stage, hands. Finally, pes cavus with hammer toes is fre- quently present since childhood, and variable scoliosis may develop during adolescence.
CMT1A CMT1A is caused by a duplication of the PMP22 gene, which encodes the PMP22, or a mutation in such a gene. The inheri- tance is autosomal dominant [11,12]. PMP22, a 22 KDa pro- tein, constitutes 2% to 5% of the peripheral nervous system (PNS) myelin being initially produced by Schwann cells and it is expressed in the compact portion of all the PNS myelin- ated fibers. The CMT1A caused by the duplication of the 17p11.2 site with the PMP22 is the most common form of CMT and accounts for 60% to 70% of the demyelinating CMT patients (approximately 50% of all CMT cases). CMT1A usual- ly occurs before the age of 20. It usually begins in patients’ feet and legs, and upper limb involvement also follows at a later stage. CMT1A is characterized by a slow progression, in- sidious onset, variable severity, and genetic heterogeneity. Allelic disorders with overlapping phenotype include the De- jerine-Sottas syndrome (DSS), hereditary neuropathy with li- ability to pressure palsies (HNPPs), and CMT with deafness. The main symptoms comprise muscle weakness, muscle at- rophy, walking difficulties, and foot drop in distal limbs. Fur- thermore, muscle cramps, distal sensory impairment, hy- poreflexia, and areflexia may also appear. Pes cavus, ham- mer toes, foot deformities, and claw hand deformities may be observed in the lower and upper extremities, respectively, kyphoscoliosis of the spine may also be seen. Moreover, the motor NCV is reduced in CMT1A and hypertrophic nerve changes may occur. Finally, while onion bulb formation and segmental demyelination/remyelination are detected via nerve biopsy, myelinated fibers are reduced and some pa- tients experience myelin outfoldings.
CMT1B CMT1B is caused by a heterozygous mutation in the MPZ gene encoding MPZ. The inheritance is autosomal dominant. MPZ is the major structural protein of myelin [13,14]. CMT1B accounts for less than 5% of the CMT cases and develops be- fore the age of 20, mainly starting from patients’ feet and legs. However, upper limb involvement also occurs, usually at later stages. CMT1B is clinically and genetically heteroge-
neous and its progression is characterized by a slow, insidi- ous onset. Distal limb muscle weakness, muscle atrophy, steppage gait, and foot drop are the main symptoms. Addi- tionally, cold-induced muscle cramps, distal sensory impair- ment, hyporeflexia, and areflexia may be also observed. Similarly, pes cavus, hammer toes, foot deformities, and, in some cases, claw hand deformities, are found. Furthermore, kyphoscoliosis of the spine and either Adie pupils or tonically dilated pupils may appear in some patients. In this subtype, the motor NCV is also reduced and hypertrophic nerve changes may occur. Finally, while onion bulb formation and segmental demyelination/remyelination are observed through nerve biopsy, the number of myelinated fibers de- creases and some patients experience myelin outfoldings.
CMT1C CMT1C is caused by a heterozygous mutation in the LITAF gene (also referred to as SIMPLE) on chromosome 16p13 [15]. The inheritance is autosomal dominant. The LITAF gene was first identified as a regulator of the TNFα gene expres- sion and its product is an early endosomal membrane pro- tein enriched in peripheral nerves and Schwann cells. CMT1C develops mainly during childhood and is genetically hetero- geneous. It is characterized by pes cavus, muscle weakness, and atrophy in distal limbs and by distal sensory impairment and hyporeflexia. Similarly to the other CMT1 subtypes, the motor NCV is also reduced in CMT1C and hypertrophic nerve changes are found. Finally, onion bulb formation and seg- mental demyelination/remyelination are observed through nerve biopsy.
CMT1D This form of CMT1 is caused by a mutation in the EGR2 gene [16-18]. The inheritance is autosomal dominant. Symptoms are present from an early age, specifically between the first and second decade of life, and usually begin in patients’ feet and legs, while upper extremities may be affected at later stages. CMT1D is also both clinically and genetically hetero- geneous, and its phenotype overlaps, in part, with both con- genital hypomyelinating neuropathy (CHN) and discrete sub- aortic stenosis. Distal limb muscle weakness, muscle atro- phy, steppage gait, and foot drop are the main symptoms. The motor NCV is reduced.
CMT1E Similarly to CMT1A, CMT1E is, at least in some instances, caused by a mutation in the PMP22 gene [19]. The inheritance is au-
46 http://pfmjournal.org
Charcot-Marie-Tooth disease subtypes
tosomal dominant. It usually begins in patients’ feet and legs during childhood, whereas upper limb involvement may de- velop at later stages. Allelic disorders with overlapping phe- notypes include CMT1A, HNPP, and DSS. The main symptoms associated with CMT1E comprise sensorineural hearing loss, pes calcaneovarus, pes cavus, distal limb muscle weakness, muscle atrophy, steppage gait, foot drop, and poor balance. Furthermore, hammertoes, foot and claw hand deformities are also observed. Patients present distal sensory impair- ment, hyporeflexia, and areflexia. The motor NCV is reduced.
CMT1F CMT1F is caused by a mutation in the NEFL gene [20], which encodes a subunit of the type IV intermediate filament het- eropolymers, a major component of the neuronal cytoskele- ton. Although this CMT subtype is autosomal dominant in most cases, autosomal recessive inheritance was reported in two families. CMT1F onset occurs during either infancy or childhood, between 1 and 13 years of age, and usually begins from patients’ feet and legs, while upper limb involvement usually develops at a later stage. Furthermore, it presents varying severity and genetic heterogeneity. Among the main symptoms, delayed motor development, muscle weakness and muscle atrophy in distal limbs can be distinguished. Ad- ditionally, distal sensory impairment, hyporeflexia, areflexia, and pes cavus are also typically observed. Similarly to the previously mentioned subtypes, CMT1F is associated with a reduced motor NCV, segmental demyelination/remyelin- ation, onion bulb formation, loss of myelinated fibers, irregu- lar myelin folds, and clusters of axonal regeneration.
Other CMT1 Recent studies reported a dominant inheritance of PMP2 mutations in demyelinating CMT patients [21]. PMP2 is a ma- jor protein of the nerve compact myelin. It belongs to the fat- ty acid-binding protein family and is likely involved in intra- cellular trafficking of lipids. Its clinical and electrophysiologi- cal phenotype is similar to the CMT1A subtype.
Charcot-Marie-Tooth disease type 2 Although CMT2 presents normal-to-slightly slower motor NCV, it was associated with a smaller activity potential and damages to the axons in neurolytic studies. Furthermore, CMT2 was reported to occur less frequently than CMT1 and to represent about one-third of the total CMT cases. Howev- er, this estimate may be undervalued considering that family history is not well understood and is classified as nonspecific
axillary neuropathy. The age of onset greatly varies, even within families, ranging from childhood to older adulthood (>60 years of age). Several genes associated with CMT2 were identified and studies were conducted to identify its mutation frequencies and specific clinical types (Table 2). Although de- ducing some CMT2 causative genes from the clinical features is possible, most CMT2 require the examination of a large number of genes. Mutations in the mitofusin 2 (MFN2) gene, which plays an important role in mitochondrial function, ac- count for more than 33% of the CMT2 subtype [9].
CMT2A CMT2A1 CMT2A1 is caused by a heterozygous mutation in the kinesin family member 1B (KIF1B) gene on chromosome 1p36 [22]. The inheritance is autosomal dominant. One family was found with such a mutation. Disease development can occur be- tween childhood and 50 years of age. Symptoms begin from patients’ feet and legs, while they may be observed in the up- per limbs at a later stage. CMT2A1 progresses slowly and is ge- netically heterogeneous. The main signs of such a disease in- clude distal limb muscle weakness, muscle atrophy, steppage gait, and foot drop. Additionally, pes cavus, hammer toes, and foot deformities appear in patients’ lower limbs. Furthermore, distal sensory impairment, hyporeflexia, and areflexia also appear. Motor NCV is normal or mildly reduced. Finally, axonal atrophy and degeneration/regeneration are observed through nerve biopsy, while small onion bulb formation and a reduced number of myelinated fibers may be found.
CMT2A2A CMT2A2A is caused by a heterozygous mutation in the MFN2 gene on chromosome 1p36.2 [23-25]. The inheritance is au- tosomal dominant. Specifically, both mitochondrial size and arrangement differ with cell type, physiologic condition, and pathological state. In fact, mitofusins, including the MFN2, mediate mitochondrial fusion and contribute to their dy- namic balance. The onset of the disease greatly varies be- tween childhood and the age of 50, with an earlier onset be- ing associated with increased severity, usually beginning from patients’ feet and legs, and eventually progressing to the upper limbs. Therefore, CMT2A2A greatly varies in severi- ty, with the identification of family with a fatal subacute en- cephalopathy. However, it was found to progress at a slow pace. Additionally, up to 25% of patients are either asymp- tomatic or mildly affected, suggesting incomplete pene- trance. The main symptoms include distal limb muscle
47https://doi.org/10.23838/pfm.2018.00163
Table 2. Mutations of the axonal Charcot-Marie-Tooth neuropathy subtypes
Subtype Gene Locus Heredity Protein
Charcot-Marie-Tooth disease type 2 (CMT2)
CMT2A1 KIF1B 1p36.22 AD Kinesin family member 1B
CMT2A2A MFN2 1p36.22 AD Mitofusin 2
CMT2A2B MFN2 1p36.22 AR Mitofusin 2
CMT2B RAB7 3q21.3 AD Members RAS oncogene family
CMT2B1 LMNA 1q22 AR Lamin A/C
CMT2B2 MED25 19q13.33 AR Mediator complex subunit 25
CMT2C TRPV4 12q24.11 AD TRP superfamily of cation channels
CMT2CC NEFH 22q12.2 AD Neurofilament heavy polypeptide
CMT2D GARS 7p15 AD Glycyl-tRNA synthetase
CMT2DD ATP1A1 1p13.1 AD ATPase Na+/K+ transporting subunit alpha 1
CMT2E NEFL 8p21 AD Neurofilament light polypeptide
CMT2F HSPB1/HSP27 7q11.23 AD Heat shock 27-kD protein 1
CMT2H Unknown 8q13-q23 AR Unknown
CMT2I MPZ/P0 1q23.3 AD Myelin protein zero
CMT2J MPZ/P0 1q23.3 AD Myelin protein zero
CMT2K GDAP1 8q21.11 AD, AR Ganglioside-induced differentiation-associated protein 1
CMT2L HSPB8/HSP22 12q24.3 AD Heat-shock 22-KD protein 8
CMT2M DNM2 19p13.2 AD Dynamin 2
CMT2N AARS 16q22.1 AD Alanyl-tRNA synthetase
CMT2O DYNC1H1 14q32.31 AD Dynein cytoplasmic 1 heavy chain 1
CMT2P LRSAM1 9q33.3 AD, AR Leucine rich repeat and sterile alpha motif containing 1
CMT2Q DHTKD1 10p14 AD Dehydrogenase E1 and transketolase domain containing protein 1
CMT2R TRIM2 4q31.3 AR Tripartite motif containing protein 2
CMT2S IGHMBP2 11q13.3 AR Immunoglobulin mu DNA binding protein 2
CMT2T MME 3q25.2 AD, AR Membrane metalloendopeptidase
CMT2U MARS 12q13.3 AD Methionyl-tRNA synthetase
CMT2V NAGLU 17q21.2 AD N-acetyl-alpha-glucosaminidase
CMT2W HARS 5q31.3 AD Histidyl-tRNA synthetase
CMT2X SPG11 15q21.1 AR Spatacsin
CMT2Y VCP 9p13.3 AD Valosin containing protein
CMT2Z MORC2 22q12.2 AD MORC family CW-type zinc finger protein 2
HMSN-P TFG 3q12.2 AD Protein TFG (TRK-fused gene protein)
PNMHH MYH14 19q13.33 AD Myosin, heavy chain 14
Charcot-Marie-Tooth disease type 5 (CMT5)
CMT5 MFN2 1p36.22 AR Mitofusin 2
Charcot-Marie-Tooth disease type 6 (CMT6)
CMT6 MFN2 1p36.22 AR Mitofusin 2
AD, autosomal dominant; AR, autosomal recessive; HMSN, hereditary motor and sensory neuropathy; PNMHH, peripheral neuropathy, myopathy, hoarseness and hearing loss.
48 http://pfmjournal.org
Charcot-Marie-Tooth disease subtypes
weakness, muscle atrophy, steppage gait, foot drop, distal sensory impairment, loss of pain and temperature sensation, and less severe loss of vibration and position sensation. Ad- ditionally, while hyporeflexia and areflexia are common, py- ramidal signs, increased muscle tone, extensor plantar re- sponses or hyperreflexia are rarely observed. Other signs as- sociated with CMT2A2A are pes cavus, hammer toes, and foot deformities. In contrast, cognitive declines and spasticity are rarely seen in the central nervous system (CNS), while py- ramidal features, tremor, or fatal subacute encephalopathy were also reported. Moreover, pain, skeletal contractures and scoliosis may occur in patients with an early disease onset, whereas hearing loss and optic atrophy are less likely. Al- though CMT2A2A is typically correlated with either normal or mildly reduced motor NCV, an absence in such a velocity is seen in patients with an early disease onset. Finally, axonal atrophy, degeneration/regeneration, and mitochondrial ab- normalities are observed through nerve biopsy, while both decreases in myelinated fibers and small onion bulb forma- tion may be found.
CMT2A2B CMT2A2B is caused by either a homozygous or a compound heterozygous mutation in the MFN2 gene on chromosome 1p36.2. The inheritance is autosomal recessive [26]. Its onset is during the first years of life and it shows variable severity, although most patients become wheelchair-bound. Distal sensory impairment, hyporeflexia, pes cavus, walking diffi- culty, foot drop, and loss of ambulation are CMT2A2B typical features, although other symptoms may include distal mus- cle weakness and atrophy, and occasional proximal muscle weakness in both the upper and lower extremities. Frequent observations are delayed gross motor development in the CNS and scoliosis and kyphosis in the spine. Furthermore, hearing impairment may also occur in some patients. Addi- tionally, ophthalmologic features comprise optic atrophy and pale optic discs, while some patients develop either vi- sual impairment at a later age or respiratory insufficiency due to muscle weakness. Finally, sural nerve biopsy shows a loss of large myelinated fibers.
CMT2B CMT2B This form of CMT2 is caused by a heterozygous mutation in the RAB7A, member RAS oncogene family (RAB7A) gene on chromosome 3q21 [27], which encodes for small GTPases, ubiquitously expressed proteins that play a role in the regu-
lation of the trafficking, maturation, and fusion of endocytic and autophagic vesicles. The inheritance is autosomal domi- nant. The peak age of onset is the second decade, when symptoms usually start from patients’ feet and legs, eventu- ally progressing to their upper limbs. CMT2B phenotypically overlaps with hereditary sensory and autonomic neuropathy type I (HSAN1). The main symptoms include muscle weak- ness of the distal limb, muscle atrophy, steppage gait, foot drop, distant sensory impairment, hyporeflexia, and areflex- ia. Furthermore, pes cavus, pes planus, hammer toes, foot deformities, and foot callus appear in the lower libs. Addi- tionally, either osteomyelitis or necrosis may be present in patients due to distal sensory neuropathy, while autoampu- tation may also occur. Moreover, ulcers are found in the skin given the occurrence of sensory neuropathy at distal sites, often leading to infection and amputation. Dystrophic toe- nail changes may occur as well. While motor NCV is mildly re- duced, axonal atrophy and degeneration/regeneration are observed through nerve biopsy. Finally, small onion bulbs and decreased number of myelinated fibers may be found.
CMT2B1 CMT2B1 is caused by a homozygous mutation in the lamin A/ C (LMNA) gene on chromosome 1q22 [28]. The inheritance is autosomal recessive. The LMNA gene encodes laminin and laminin C. Lamins are the structural protein components of the nuclear lamina, a protein network underlying the inner nuclear membrane that determines nuclear shape and size. Lamins constitute a class of intermediate filaments and three types, namely A, B, and C, were described…