HEREDITARY MOTOR AND SENSORY NEUROPATHY IB
CHARCOT-MARIE-TOOTH DISEASE, AUTOSOMAL DOMINANT, WITH FOCALLY FOLDED MYELIN SHEATHS, TYPE 1B
PERONEAL MUSCULAR ATROPHY
CHARCOT-MARIE-TOOTH DISEASE, SLOW NERVE CONDUCTION TYPE, LINKED TO DUFFY
HMSN IB
HEREDITARY MOTOR AND SENSORY NEUROPATHY I
HMSN I
CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 1B
HMSN1B
CMT1B
HMSN1
Charcot-Marie-Tooth disease is a sensorineural peripheral polyneuropathy. Affecting approximately 1 in 2,500 individuals, Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system (Skre, 1974). Autosomal dominant, autosomal recessive, and X-linked forms have been recognized. ... Charcot-Marie-Tooth disease is a sensorineural peripheral polyneuropathy. Affecting approximately 1 in 2,500 individuals, Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system (Skre, 1974). Autosomal dominant, autosomal recessive, and X-linked forms have been recognized. - Classification On the basis of electrophysiologic properties and histopathology, CMT has been divided into primary peripheral demyelinating (type 1, or HMSNI) and primary peripheral axonal (type 2, or HMSNII) neuropathies. The demyelinating neuropathies classified as CMT type 1 are characterized by severely reduced motor NCVs (less than 38 m/s) and segmental demyelination and remyelination with onion bulb formations on nerve biopsy. The axonal neuropathies classified as CMT type 2 are characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy (see CMT2A1; 118210). Distal hereditary motor neuropathy (dHMN) (see 158590), or spinal CMT, is characterized by exclusive motor involvement and sparing of sensory nerves (Pareyson, 1999). McAlpine (1989) proposed that the forms of CMT with very slow nerve conduction be given the gene symbol CMT1A (118220) and CMT1B, CMT1A being the gene on chromosome 17 and CMT1B being the gene on chromosome 1. CMT2 was the proposed symbol for the autosomal locus responsible for the moderately slow nerve conduction form of the disease (axonal). For a phenotypic description and discussion of genetic heterogeneity of the various subtypes of CMT, see CMTX1 (302800), CMT2A1 (118210), CMT3 (DSS; 145900), CMT4A (214400), and CMTDIB (606482). - Genetic Heterogeneity of Autosomal Dominant Demyelinating CMT1 Autosomal dominant demyelinating CMT1 is genetically heterogeneous disorder and can be caused by mutations in different genes (see CMT1A, 118220; CMT1C, 601098; CMT1D, 607678), CMT1E (607734), and CMT1F (607734). See also 608236 for a related phenotype characterized by isolated slowed nerve conduction velocities (NCVs).
Saporta et al. (2011) were able to find a molecular basis for 527 (67%) of 787 patients with a clinical diagnosis of CMT. The most common CMT subtypes were CMT1A (118220) in 55%, CMT1X (302800) in 15.2%, HNPP ... Saporta et al. (2011) were able to find a molecular basis for 527 (67%) of 787 patients with a clinical diagnosis of CMT. The most common CMT subtypes were CMT1A (118220) in 55%, CMT1X (302800) in 15.2%, HNPP (162500) in 9.1%, CMT1B in 8.5%, and CMT2A2 (609260) in 4.0%. All other subtypes accounted for less than 1% each. Eleven patients had more than 1 genetically identified subtype of CMT. Patients with genetically identified CMT were separable into specific groups based on age of onset and the degree of slowing of motor nerve conduction velocities. Saporta et al. (2011) concluded that combining features of the phenotype and physiology allowed for identification of patients with specific subtypes of CMT, and the authors proposed a strategy of focused genetic testing for CMT.
In general, CMT disease is characterized by an insidious onset and slowly progressive weakness and atrophy of the distal limb muscles usually beginning in the legs and feet (especially in the peroneal compartment). As a result, patients frequently ... In general, CMT disease is characterized by an insidious onset and slowly progressive weakness and atrophy of the distal limb muscles usually beginning in the legs and feet (especially in the peroneal compartment). As a result, patients frequently trip while walking, have foot drop, and steppage gait. As both motor and sensory nerve function are affected in CMT, other features include impaired sensation and absent or hypoactive deep tendon reflexes. Weakness in the intrinsic hand muscles may occur later. The onset of CMT is typically in the first or second decade of life, although it may be detected in infancy. Variation in clinical presentation is wide, ranging from patients with severe distal atrophy and marked hand and foot deformity to individuals whose only finding is pes cavus and minimal distal muscle weakness (Pareyson, 1999; Murakami et al., 1996). The specific autosomal dominant demyelinating form described here is a slow nerve conduction type. In the family with Charcot-Marie-Tooth disease reported first in the lay press by Verrill and followed up by England and Denny-Brown (1952), members had sensory and trophic changes in addition to classic peroneal muscular atrophy. Norstrand and Margulies (1958) observed affected members in 3 generations. Gastrointestinal symptoms in the form of chronic diarrhea, nausea, and vomiting were striking. Autopsy showed degeneration in the lateral horn area of the spinal cord. Stark (1958) described a large affected kindred. Alajouanine et al. (1967) reported the phenomenal case of a woman who was a patient in La Salpetriere, Paris, for 64 years. The diagnosis was made by Charcot in 1891. She died at age 80 years. Argyll-Robertson pupils and blindness from optic atrophy began 40 to 50 years after onset of other signs of disease. Bradley and Aguayo (1969) described a family in which persons in 3 generations had chronic sensorineural polyneuropathy. The observations of Dyck and Lambert (1968) made it clear that cases diagnosed as peroneal muscular atrophy on clinical grounds include more than one genetic entity. Affected persons in some families showed markedly reduced peripheral nerve conduction velocity, and nerve biopsy displayed extensive segmental demyelination combined with concentric proliferation of Schwann cells (hypertrophic neuropathy). In other families affected persons showed relatively normal peripheral nerve conduction velocity and no changes on nerve biopsy. They concluded that in the latter families the disorder was a neuronal degeneration affecting both anterior horn cells and cells in the dorsal root ganglia. Dyck and Lambert (1968) suggested the existence of at least 3 entities: (1) a 'hypertrophic' neuropathy showing segmental demyelination in the peripheral nerves with marked reduction in nerve conduction; (2) a 'neuronal' type, with axonal degeneration but normal nerve conduction; and (3) a progressive 'spinal' form with profound distal weakness and atrophy in the lower limbs with no sensory abnormality. The authors noted the clinical overlap with amyloid neuropathy, particularly of the Indiana or Rukavina type (see 176300), and with hypertrophic neuropathy of Dejerine-Sottas (145900). In a study of 17 families with autosomal dominant hereditary motor and sensory polyneuropathy, Thomas et al. (1974) pointed out the clinical overlap between Charcot-Marie-Tooth disease (peroneal muscular atrophy), Dejerine-Sottas syndrome (hereditary hypertrophic neuropathy), and Roussy-Levy syndrome (180800). They suggested 'hereditary motor and sensory polyneuropathy' as an adequate designation for this heterogeneous class. Kloepfer and Killian (1974) described an extensive kindred with CMT in Louisiana in which 66 persons were judged to be heterozygous. Two marriages between heterozygotes produced 5 persons judged to be homozygous. These had onset of symptoms in early childhood with crippling evident by age 10. Heterozygotes were usually asymptomatic until their 20s or 30s. Two living homozygotes had severe mixed sensory and motor polyneuropathy with involvement of the facial nerves (Killian and Kloepfer, 1979). Kyphoscoliosis, thickening of peripheral nerves, and pes cavus were striking. In one, cerebrospinal fluid protein was markedly elevated and peripheral nerve biopsy was consistent with hypertrophic interstitial neuritis of Dejerine and Sottas. Satya-Murti et al. (1979) presented evidence suggesting that the auditory nerves and spinal ganglia undergo the same pathologic process as do peripheral nerves. They referred to the condition as hereditary motor-sensory neuropathy. Harding and Thomas (1980) confirmed division into CMT type 1 with slow conduction and CMT type 2 with normal conduction (rate in the median nerve below or above 38 meters per tenth second, respectively). They studied 228 patients (120 index cases and 108 affected relatives). Type 1 cases numbered 173 and type 2 55; 26 of the type 1 cases and 15 of the type 2 cases were sporadic. Most cases of type 1 showed autosomal dominant inheritance (39 families) but 4 probable autosomal recessive families were observed. No X-linked recessive families were found. In both types, males tended to be more severely affected, whereas affected but asymptomatic family members were more commonly female. Type 1 cases had a peak age of onset of symptoms in the first decade of life and in comparison with type 2 had a greater tendency to show weakness of the hands, upper limb tremors and ataxia, generalized tendon areflexia, and more extensive distal sensory loss, sometimes with acrodystrophic changes. Foot and spinal deformities were more frequent, probably because of the early age of onset. Nerve thickening was confined to type 1 cases. In type 2 cases, onset of symptoms was most often in the second decade. Most type 2 cases were autosomal dominant but 2 probable autosomal recessive and some sporadic cases were found. Streib et al. (1984) described a family in which the 42-year-old proposita and her 12-year-old son were typically affected, whereas the father of the proposita was asymptomatic and had a normal neurologic examination and normal foot arches but showed slowing of nerve conduction velocities limited to the peroneal nerves. Marker testing could not exclude paternity. Davis et al. (1978) reported a somewhat similar family in which 2 sisters were severely affected clinically and had nerve conduction velocities below 20 m/sec. The mother was normal and the father was asymptomatic but had mild pes cavus, slight peroneal weakness, and slow conduction (12 m/sec) in the peroneal nerve. Conduction velocities were normal for median and ulnar nerves. These may be examples of mosaicism in the father in each of these cases. In a kindred with presumed CMT1B because of linkage to 1q markers, Ionasescu et al. (1992) described unusually early onset (before age 3 years) and phrenic nerve involvement in the proposita, a 39-year-old woman who required nocturnal ventilator support. Umehara et al. (1993) described a 31-year-old Japanese woman and her 5-year-old son considered to have dominant hereditary motor and sensory neuropathy with excessive myelin outfolding, or globular neuropathy. The main histologic features of the sural nerve were segmental demyelination and remyelination with moderate to marked loss of myelinated fibers, and myelin folding complex along all of the large and small myelinated fibers. The parents of the woman and all of her 8 sibs showed no neuromuscular abnormality. Insidious weakness of her legs had begun at 12 years. On examination, deep tendon reflexes were absent in both the arms and the legs. Vibration sensation was impaired in the distal part of the arms and was severely impaired in the distal part of the legs. Touch and pain sensations were normal. Nerve conduction studies showed marked slowing and absence of evoked responses of both motor and sensory nerves. The cerebrospinal fluid showed increased protein (111 mg/ml). Neither duplication nor deletion of the peripheral myelin protein-22 gene (601097) was suggested by Southern blot analysis. Globular neuropathy in 4 patients in an autosomal dominant pattern was first described by Dayan et al. (1968). Hoff et al. (2005) compared obstetric outcomes of 108 births by 49 women with CMT to over 2 million births by mothers without CMT gathered from a Norwegian birth registry from 1967 to 2002. Patients with CMT had a higher occurrence of presentation anomalies (9.3% vs 4.5%) and postpartum bleeding (12% vs 5.8%). The rate of operative delivery was twice that of the reference group (29.6% vs 15.3%), and forceps were used 3 times as often in the CMT group (9.3% vs 2.7%). The majority of CMT cesarean sections were emergency procedures. Hoff et al. (2005) postulated that abnormal birth presentations may have reflected CMT in the fetus and that the high incidence of uterine atony in the mothers reflected CMT-mediated neuropathy of uterine adrenergic nerves. - Charcot-Marie-Tooth Associated with Other Conditions Littler (1970) described a family in which peroneal muscular atrophy was associated with heart block. Ten members of 3 generations were affected. Littler (1970) proposed at least 3 genetic explanations: 2 independently segregating dominant disorders, 2 linked genes, and pleiotropic effects of a single gene. Kay et al. (1972) studied a myocardial biopsy specimen from the proband of the family reported by Littler (1970). The ultrastructural changes were similar to those previously described in simple myocardial hypertrophy and hypertrophic obstructive cardiomyopathy (192600). These consisted of the formation of cardiac 'villi' crowded with mitochondria, enhanced micropinocytosis, and vacuolation of the subsarcolemmal cytoplasm. In a brother and sister with type 1 CMT disease and type II diabetes mellitus, Chan et al. (1987) found diaphragmatic impairment to be severe in the sister and mild in the brother. They suggested that nerve involvement may be part of the clinical picture when diabetes mellitus is present. Benko et al. (2008) reported an unusual case in which a 3-year-old boy had both Gaucher disease type III (231000), resulting from a homozygous mutation in the GBA gene (L444P; 606463.0001) on chromosome 1q22, and CMT1B, resulting from a homozygous mutation in the MPZ gene on chromosome 1q23.3. Additional neurologic features included pupillary abnormalities and hearing loss. Further genetic analysis showed that the father also carried the MPZ mutation and had CMT1B, and that the boy had complete paternal isodisomy of chromosome 1 with no evidence of the maternal chromosome 1. Benko et al. (2008) noted the atypical form of inheritance as well as the unique molecular mechanism of 2 concurrent mendelian disorders in this patient.
In 2 pedigrees with CMT type 1, Hayasaka et al. (1993) identified mutations in the MPZ gene (159440.0001).
In a family with CMT1B with focally folded myelin sheaths first reported by Umehara et al. (1993), Nakagawa ... In 2 pedigrees with CMT type 1, Hayasaka et al. (1993) identified mutations in the MPZ gene (159440.0001). In a family with CMT1B with focally folded myelin sheaths first reported by Umehara et al. (1993), Nakagawa et al. (1999) identified a heterozygous mutation in the MPZ gene (159440.0024). In 2 pedigrees with a late-onset, relatively mild form of CMT1B with focally folded myelin sheaths, Fabrizi et al. (2000) identified a heterozygous mutation in the MPZ gene (159440.0023). Pathology showed a characteristic demyelinating process, but also revealed irregular myelin outfoldings and infoldings and tomacula. Fabrizi et al. (2000) noted that myelin outfoldings have been described in other autosomal dominant CMT patients with mutations in MPZ, EGR2 (129010.0004), and PMP22 (601097.0016), and that the finding is not restricted to CMT4B (see CMT4B1; 601382). Pareyson (1999) and Berger et al. (2002) gave comprehensive reviews of the molecular cell biology of Charcot-Marie-Tooth disease. Hisama (2005) described a 7-generation family in which multiple members were affected with a complicated neurologic phenotype including variable features of neuropathy, myotonia, and periodic paralysis. The same family had been described in the medical literature since 1934. The proband had late-onset demyelinating CMT, muscle cramping, and myotonia. His sister had hyperkalemic periodic paralysis (HYPP; 170500), and his father had severe childhood-onset CMT and periodic paralysis. Multiple other relatives had similar features of 1 or both disorders. Molecular analysis identified a missense mutation in the MPZ gene in the proband and a missense mutation in the SCN4A gene (603967.0001) in the sister; the father was deceased. Of those tested, 1 other family member had the MPZ mutation, and 4 other family members had the SCN4A mutation. Hisama (2005) commented on the unusual occurrence of 2 genetically unlinked neurologic disorders in this family and emphasized the diagnostic difficulties.
Boerkoel et al. (2002) provided information on the relative frequency of mutations causing CMT or a related peripheral neuropathy. Among 153 unrelated patients with peripheral neuropathy, 79 had a 17p12 duplication (PMP22 duplication) (601097) causing CMT1A, 11 a ... Boerkoel et al. (2002) provided information on the relative frequency of mutations causing CMT or a related peripheral neuropathy. Among 153 unrelated patients with peripheral neuropathy, 79 had a 17p12 duplication (PMP22 duplication) (601097) causing CMT1A, 11 a connexin-32 (304040) mutation, 5 a myelin protein zero mutation, 5 a peripheral myelin protein-22 mutation, 1 an early growth response factor-2 mutation (129010), 1 a periaxin mutation (605725), and 1 a neurofilament light chain mutation (162280), whereas none had a myotubularin-related protein-2 mutation (603557); 50 had no identifiable mutation. The NMYC downstream-regulated gene-1 (605262) and the kinesin-1B gene (605995) were not screened for mutations. Because one-third of the mutations found in this study had arisen de novo and thereby caused chronic sporadic neuropathy, Boerkoel et al. (2002) concluded that the molecular diagnosis is a necessary adjunct for clinical diagnosis and management of inherited and sporadic neuropathy. Among 227 Japanese patients with demyelinating CMT, Abe et al. (2011) found that 20 (8.8%) carried mutations in the MPZ gene.