Journal of the Peripheral Nervous System 19:175–179 (2014)
CASE REPORT
A novel INF2 mutation in a Korean family with autosomal dominant intermediate Charcot-Marie-Tooth disease and focal segmental glomerulosclerosis Hyung J. Park1 , Hye J. Kim2 , Young B. Hong1 , Soo H. Nam2 , Ki W. Chung2 , and Byung-Ok Choi1 1
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; and 2 Department of Biological Science, Kongju National University, Gongju, South Korea
Abstract Mutations in the inverted formin-2 (INF2) gene were recently identified in patients with autosomal dominant intermediate Charcot-Marie-Tooth (DI-CMT) disease and focal segmental glomerulosclerosis (FSGS). Here, we identified a novel p.L132P INF2 mutation in a Korean family with DI-CMT and FSGS by whole-exome sequencing. This mutation was cosegregated with affected individuals in the family and was not found in the 300 controls. The two affected members exhibited juvenile onset sensorimotor polyneuropathy and FSGS. Nerve conduction studies showed an intermediate range of motor nerve conduction velocities. We report a novel INF2 mutation in a family with DI-CMT and FSGS as the first case in Koreans. The INF2 mutation appears to be a major cause of CMT with FSGS. Key words: Charcot-Marie-Tooth disease, focal segmental glomerulosclerosis, inverted formin-2 gene, whole-exome sequencing
Introduction
reduced or normal NCVs (Harding and Thomas, 1980). Patients with an intermediate type of CMT exhibit values for NCV that overlap the other two CMT groups (Nicholson and Myers, 2006). CMT generally shows a weak genotype–phenotype correlation and is associated with more than 60 genes (Rossor et al., 2013). Since 1967, reports have revealed a connection between CMT and nephropathy, especially focal segmental glomerulosclerosis (FSGS) (Lemieux and Neemeh 1967; Hara et al., 1984; Paul et al., 1990). FSGS is a cause of nephrotic syndrome and the most common primary glomerular disorder that causes end-stage renal disease; however, the reason for the association is unclear, as FSGS is associated with a variety of causes such as viral infection, genetic defects, and toxin exposure (D’Agati et al., 2011). Recent studies have identified mutations in the inverted formin-2 (INF2) gene as the major
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous disorder of inherited peripheral neuropathies characterized by distal muscle weakness, sensory loss, and areflexia. CMT is divided into a demyelinating form (CMT1), an axonal form (CMT2), and an intermediate form. CMT1 patients exhibit markedly reduced nerve conduction velocities (NCVs), whereas CMT2 patients show slightly
Address correspondence to: Byung-Ok Choi, MD, Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-Gu, Seoul 135-710, South Korea. Tel: +(82)2-3410-1296; Fax: +(82)3410-0052; E-mail: [email protected]. Ki Wha Chung, PhD, Department of Biological Science, Kongju National University, 56 Gongjudaehak-ro, Gongju, Chungnam 314-701, South Korea. Tel: +(82)41-850-8506; Fax: +(82)41-850-0957; E-mail: [email protected]. © 2014 Peripheral Nerve Society
175
Park et al.
Journal of the Peripheral Nervous System 19:175–179 (2014)
A
B
c.395T>C
I 1 T/T
2 T/T
Control II 1 T/T
2 T/C
1 T/C
2 T/T
3 T/T
4 T/T
Patient
III
C
p.L132P
Homo sapiens
R Q G I E Y I L S N Q G Y V R Q L S Q A L D T S N VMV K K Q V F E L L A A L C I
Mus musculus
Q Q G I E Y I L S N Q G Y V R Q L S Q A L D T S N VMV K K Q V F E L L A A L C I
Rattus norvegicus
Q Q G I E Y I L S N Q G Y V R Q L S Q A L D T S N VMV K K Q V F E L L A A L C I
Felis catus
Q R G I E Y I L S N Q A Y V R Q L S L A L D T S N VMV K K Q V F E L L A A L C I
Ovis aries
Q E G I R Y I L S N Q A Y V R Q L S L A L D T S N VMV K K Q V F E L L A A L C I
Gallus gallus
H R G I E Y I V S N E G Y V R K L F Q A L D T T N VMV K K Q V F E L L A A L C I
Xenopus laevis
H K G I E Y I V N N E G Y V R K L S Q A L D T S N VMV K K Q V F E L L A A L C I
Figure 1. Pedigree, sequencing chromatograms, and conservation in the FC640 family with a novel inverted formin-2 (INF2) gene mutation. (A) Pedigrees of the FC640 family with Charcot-Marie-Tooth (CMT) disease and renal disease. Arrow indicates proband whose DNA was used for whole-exome sequencing (WES) ( , : unaffected; : affected). (B) Sequencing chromatograms of the p.L132P (c.395T>C) mutation in INF2. A heterozygous p.L132P mutation completely cosegregated with affected individuals in this family. (C) Conservation analysis of amino acid sequences between different species. Analysis was conducted using MEGA5 ver 5.05. The mutation site and surrounding sequences were well conserved between vertebrate species Homo sapiens: NP_071934.3, Mus musculus: NP_940803.2, Rattus norvegicus: XP_001072750.1, Felis catus: XP_003988097.1, Ovis aries: XP_004018217.1, Gallus gallus: XP_421396.4, and Xenopus laevis: NP_001084562.1.
school health checkup. At the age of 20, she felt chronic fatigue and general edema and was diagnosed with FSGS. She did not respond to treatment with steroids and angiotensin-converting-enzyme inhibitors and received a kidney transplant at age 45. She denied other symptoms such as cognitive impairment or hearing loss. The daughter of patient 1 (an 18-year-old woman; Fig. 1A, III-1) first noticed gait disturbance at the age of 16. When we first examined her at age 18, she presented with distal muscle weakness, predominantly in the tibialis anterior muscles. Affected sense and tendon reflexes were similar to those of her mother. She was also diagnosed with isolated proteinuria (random urine protein/creatinine ratio: 1.69) without symptoms of renal disease at age 17. Plasma levels of albumin, blood urea nitrogen, and creatinine were normal. The patient had not yet undergone a renal biopsy. She did not complain of other symptoms such as cognitive impairment or hearing loss. The clinical presentations
cause of autosomal dominant intermediate CharcotMarie-Tooth disease (DI-CMT) and FSGS (Boyer et al., 2011; Mademan et al., 2013; Rodriguez et al., 2013). In this study, we identified a causative mutation in a Korean family with DI-CMT and FSGS.
Case Report The proband (a 45-year-old woman; Fig. 1A, II-2) in the FC640 family presented to our neurologic clinic with gait disturbance. She first noticed steppage gait at age 17, after which time her muscle weakness progressed slowly. When we first examined her at age 45, she displayed distal muscle weakness and atrophy affecting all four limbs. Pain sensation was preserved, but vibration sense was reduced, and deep tendon reflexes were reduced in all extremities. In addition to neurological deficits, she had end-stage renal disease. At age 18, proteinuria was first identified at an annual 176
Park et al.
Journal of the Peripheral Nervous System 19:175–179 (2014)
Table 1. Comparison of phenotypes between the present patients with INF2 p.L132P and previously reported patients with p.L132R. Amino acid change Nucleotide change Ethnicity Inheritance Age at last exam (years) Age at proteinuria onset (years) Age at ESRD onset (years) Age at neurological symptom onset (years) Symptoms at onset Muscle weakness Distal upper limb Proximal lower limb Distal lower limb Muscle atrophy Distal upper limb Distal lower limb Sensory loss Foot deformity Hearing loss Median MNCV (m/s) References
p.L132P
p.L132P
p.L132R
p.L132R
c.395T>C Korean De novo 45 18 45 17 Gait defect
c.395T>C Korean AD 18 17 – 16 Gait defect
c.395T>G French De novo 21 20 21 10 Gait defect
c.395T>G French AD 29 19 29 21 Gait defect
P A P
P A P
A A A
P ND P
P P P P A 44–45 This study
A P P P A 34–37 This study
A P ND P A 30–32 Boyer et al. (2011)
P P P P A 42 Boyer et al. (2011)
A, absent; AD, autosomal dominant; ESRD, end-stage renal disease; INF2, inverted formin-2; MNCV, motor nerve conduction velocity; ND, not described; P, present.
the INF2 mutation cosegregated completely with the two affected members (Figs. 1A and 1B). Paternity of the proband and her siblings was confirmed by genotyping of 15 microsatellites using a PowerPlex 16 System (Promega, Madison, WI, USA). This mutation was not detected in 300 healthy controls, dbSNP138, the 1000 Genomes Database (2011 October), or the Exome Variant Server. All in silico predictions (SIFT, PolyPhen2, MUpro, and GERP) yielded acceptable results (Table S3), and amino acid positions were well conserved throughout different vertebrate species (Fig. 1C). Thus, the p.L132P (c.395T>C) mutation in INF2 was defined as the underlying cause of CMT in the FC640 family.
of the two affected members in this study were similar to presentations of previously reported patients with a p.L132R mutation, also in codon 132 of INF2 (Table 1); however, the severity of nephropathy was quite mild for the patients in this study. Nerve conduction studies were performed for patient II-2 when she was 45 years old and patient III-1 when she was 18 years old (Table 2). The range of forearm motor NCVs was 34.1–56.8 m/s. The amplitudes of compound muscle action potentials (CMAPs) were not elicited in peroneal nerves, and were reduced in tibial nerves. Sensory nerve action potentials of the median, ulnar, and sural nerves were absent. These findings were consistent with intermediate sensorimotor polyneuropathy. Visual evoked potentials and brainstem auditory evoked potentials were normal in patient II-2. Lower limb magnetic resonance imaging (MRI) showed a predominance of distal fatty substitution (Fig. S1, Supporting information). At the level of the lower leg, patient II-2 showed almost complete fatty replacement and patient III-1 showed fatty infiltration and muscle atrophy along the anterior and lateral compartments, but not in the deep and superficial posterior compartments. Thigh MRI scans were nearly normal in both patients. From whole-exome sequencing (WES) in the proband (II-2), we identified a novel p.L132P (c.395T>C) de novo mutation in INF2 (Tables S1 and S2). DNA sequencing by capillary electrophoresis on samples from extended family members showed that
Discussion In this study, we used exome sequencing to identify a novel heterozygous INF2 mutation (p.L132P) in a Korean family with CMT and FSGS. We believe this novel mutation is the underlying cause of CMT in this family because the mutation completely cosegregated with affected status within the family and was not found in 300 healthy controls. The p.L132P (c.395T>C) mutation was located in exon 3, encoding the diaphanous-inhibitory domain (DID); all CMT causative mutations in the INF2 gene have been found in the DID (Boyer et al., 2011; Mademan et al., 2013; Rodriguez et al., 2013; Toyota et al., 2013). The protein encoded by INF2 is a member of the formin family and consists of a DID, the formin 177
Park et al.
Journal of the Peripheral Nervous System 19:175–179 (2014)
studies have indicated that INF2 mutations are a main cause of dual pathology in patients of different ethnic groups (Mademan et al., 2013; Rodriguez et al., 2013; Toyota et al., 2013). Clinically, patients with INF2 mutations show sensorimotor polyneuropathy and FSGS as well as sensorineural hearing loss and demyelinating brain lesions. Almost all patients show initial involvement of the anterior and lateral compartment muscles of the lower leg following disease progression lengthwise. Electrophysiological results include forearm motor NCVs in the demyelinating or intermediate range (Boyer et al., 2011; Mademan et al., 2013; Rodriguez et al., 2013; Toyota et al., 2013). This study demonstrated that the clinical and electrophysiological spectrum of results for Korean CMT patients with an INF2 mutation was compatible with the results of previous studies. Two patients had juvenile symptom onset and an intermediate type of slowed nerve conduction: an axonal range was measured in patient 1 and an unequivocal demyelinating range was measured in patient 2 in the same family. The patients in this study had phenotypes similar to previous reports on patients with a different mutation in the same codon of INF2, except for the severity of nephropathy. We first reported lower limb MRIs of patients with an INF2 mutation in our study. Lower limb MRIs demonstrated that the anterior and lateral compartments of the lower legs were the first to be impaired, and muscle fat changes progressed in a length-dependent pattern. These radiological findings correlated well with clinical disease progression seen in both the present and previous studies (Table S4). In conclusion, we identified a novel INF2 mutation in a family with DI-CMT and FSGS as the first case in Koreans. The INF2 mutation appears to be a major cause of CMT with FSGS.
Table 2. Electrophysiological features of patients with p.L132P INF2 mutation. II-2 Age at exam (years) 45 Side Rt Median nerve TL (ms) 4.7 CMAP (mV) 9.7 MNCV (m/s) 44.7 F-wave (ms) 37.8 Ulnar nerve TL (ms) 2.8 CMAP (mV) 16.3 MNCV (m/s) 56.8 F-wave (ms) 24.8 Peroneal nerve TL (ms) A CMAP (mV) A MNCV (m/s) A F-wave (ms) A Tibial nerve TL (ms) A CMAP (mV) A MNCV (m/s) A F-wave (ms) A Median sensory nerve SNAP (𝜇V) A SNCV (m/s) A Ulnar sensory nerve SNAP (𝜇V) A SNCV (m/s) A Sural nerve SNAP (𝜇V) A SNCV (m/s) A H-reflex (ms) A
III-1
Lt
18 Rt
Normal value
Lt
3.9 3.8 4.1 11.2 11.1 14.6 43.8 34.1 36.7 31.0 39.4 39.0
6.0 >50.5 51.1 41.2 41.1 8.8 >39.3
A A
A A
A A
>7.9 >37.5
A A A
5.4 3.7 27.3 23.9 A A
>6.0 >32.1 C) mutation. Table S4. Clinical and genetic features of CMT patients with INF2 gene mutations.
179
CASE REPORT
A novel INF2 mutation in a Korean family with autosomal dominant intermediate Charcot-Marie-Tooth disease and focal segmental glomerulosclerosis Hyung J. Park1 , Hye J. Kim2 , Young B. Hong1 , Soo H. Nam2 , Ki W. Chung2 , and Byung-Ok Choi1 1
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; and 2 Department of Biological Science, Kongju National University, Gongju, South Korea
Abstract Mutations in the inverted formin-2 (INF2) gene were recently identified in patients with autosomal dominant intermediate Charcot-Marie-Tooth (DI-CMT) disease and focal segmental glomerulosclerosis (FSGS). Here, we identified a novel p.L132P INF2 mutation in a Korean family with DI-CMT and FSGS by whole-exome sequencing. This mutation was cosegregated with affected individuals in the family and was not found in the 300 controls. The two affected members exhibited juvenile onset sensorimotor polyneuropathy and FSGS. Nerve conduction studies showed an intermediate range of motor nerve conduction velocities. We report a novel INF2 mutation in a family with DI-CMT and FSGS as the first case in Koreans. The INF2 mutation appears to be a major cause of CMT with FSGS. Key words: Charcot-Marie-Tooth disease, focal segmental glomerulosclerosis, inverted formin-2 gene, whole-exome sequencing
Introduction
reduced or normal NCVs (Harding and Thomas, 1980). Patients with an intermediate type of CMT exhibit values for NCV that overlap the other two CMT groups (Nicholson and Myers, 2006). CMT generally shows a weak genotype–phenotype correlation and is associated with more than 60 genes (Rossor et al., 2013). Since 1967, reports have revealed a connection between CMT and nephropathy, especially focal segmental glomerulosclerosis (FSGS) (Lemieux and Neemeh 1967; Hara et al., 1984; Paul et al., 1990). FSGS is a cause of nephrotic syndrome and the most common primary glomerular disorder that causes end-stage renal disease; however, the reason for the association is unclear, as FSGS is associated with a variety of causes such as viral infection, genetic defects, and toxin exposure (D’Agati et al., 2011). Recent studies have identified mutations in the inverted formin-2 (INF2) gene as the major
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous disorder of inherited peripheral neuropathies characterized by distal muscle weakness, sensory loss, and areflexia. CMT is divided into a demyelinating form (CMT1), an axonal form (CMT2), and an intermediate form. CMT1 patients exhibit markedly reduced nerve conduction velocities (NCVs), whereas CMT2 patients show slightly
Address correspondence to: Byung-Ok Choi, MD, Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Gangnam-Gu, Seoul 135-710, South Korea. Tel: +(82)2-3410-1296; Fax: +(82)3410-0052; E-mail: [email protected]. Ki Wha Chung, PhD, Department of Biological Science, Kongju National University, 56 Gongjudaehak-ro, Gongju, Chungnam 314-701, South Korea. Tel: +(82)41-850-8506; Fax: +(82)41-850-0957; E-mail: [email protected]. © 2014 Peripheral Nerve Society
175
Park et al.
Journal of the Peripheral Nervous System 19:175–179 (2014)
A
B
c.395T>C
I 1 T/T
2 T/T
Control II 1 T/T
2 T/C
1 T/C
2 T/T
3 T/T
4 T/T
Patient
III
C
p.L132P
Homo sapiens
R Q G I E Y I L S N Q G Y V R Q L S Q A L D T S N VMV K K Q V F E L L A A L C I
Mus musculus
Q Q G I E Y I L S N Q G Y V R Q L S Q A L D T S N VMV K K Q V F E L L A A L C I
Rattus norvegicus
Q Q G I E Y I L S N Q G Y V R Q L S Q A L D T S N VMV K K Q V F E L L A A L C I
Felis catus
Q R G I E Y I L S N Q A Y V R Q L S L A L D T S N VMV K K Q V F E L L A A L C I
Ovis aries
Q E G I R Y I L S N Q A Y V R Q L S L A L D T S N VMV K K Q V F E L L A A L C I
Gallus gallus
H R G I E Y I V S N E G Y V R K L F Q A L D T T N VMV K K Q V F E L L A A L C I
Xenopus laevis
H K G I E Y I V N N E G Y V R K L S Q A L D T S N VMV K K Q V F E L L A A L C I
Figure 1. Pedigree, sequencing chromatograms, and conservation in the FC640 family with a novel inverted formin-2 (INF2) gene mutation. (A) Pedigrees of the FC640 family with Charcot-Marie-Tooth (CMT) disease and renal disease. Arrow indicates proband whose DNA was used for whole-exome sequencing (WES) ( , : unaffected; : affected). (B) Sequencing chromatograms of the p.L132P (c.395T>C) mutation in INF2. A heterozygous p.L132P mutation completely cosegregated with affected individuals in this family. (C) Conservation analysis of amino acid sequences between different species. Analysis was conducted using MEGA5 ver 5.05. The mutation site and surrounding sequences were well conserved between vertebrate species Homo sapiens: NP_071934.3, Mus musculus: NP_940803.2, Rattus norvegicus: XP_001072750.1, Felis catus: XP_003988097.1, Ovis aries: XP_004018217.1, Gallus gallus: XP_421396.4, and Xenopus laevis: NP_001084562.1.
school health checkup. At the age of 20, she felt chronic fatigue and general edema and was diagnosed with FSGS. She did not respond to treatment with steroids and angiotensin-converting-enzyme inhibitors and received a kidney transplant at age 45. She denied other symptoms such as cognitive impairment or hearing loss. The daughter of patient 1 (an 18-year-old woman; Fig. 1A, III-1) first noticed gait disturbance at the age of 16. When we first examined her at age 18, she presented with distal muscle weakness, predominantly in the tibialis anterior muscles. Affected sense and tendon reflexes were similar to those of her mother. She was also diagnosed with isolated proteinuria (random urine protein/creatinine ratio: 1.69) without symptoms of renal disease at age 17. Plasma levels of albumin, blood urea nitrogen, and creatinine were normal. The patient had not yet undergone a renal biopsy. She did not complain of other symptoms such as cognitive impairment or hearing loss. The clinical presentations
cause of autosomal dominant intermediate CharcotMarie-Tooth disease (DI-CMT) and FSGS (Boyer et al., 2011; Mademan et al., 2013; Rodriguez et al., 2013). In this study, we identified a causative mutation in a Korean family with DI-CMT and FSGS.
Case Report The proband (a 45-year-old woman; Fig. 1A, II-2) in the FC640 family presented to our neurologic clinic with gait disturbance. She first noticed steppage gait at age 17, after which time her muscle weakness progressed slowly. When we first examined her at age 45, she displayed distal muscle weakness and atrophy affecting all four limbs. Pain sensation was preserved, but vibration sense was reduced, and deep tendon reflexes were reduced in all extremities. In addition to neurological deficits, she had end-stage renal disease. At age 18, proteinuria was first identified at an annual 176
Park et al.
Journal of the Peripheral Nervous System 19:175–179 (2014)
Table 1. Comparison of phenotypes between the present patients with INF2 p.L132P and previously reported patients with p.L132R. Amino acid change Nucleotide change Ethnicity Inheritance Age at last exam (years) Age at proteinuria onset (years) Age at ESRD onset (years) Age at neurological symptom onset (years) Symptoms at onset Muscle weakness Distal upper limb Proximal lower limb Distal lower limb Muscle atrophy Distal upper limb Distal lower limb Sensory loss Foot deformity Hearing loss Median MNCV (m/s) References
p.L132P
p.L132P
p.L132R
p.L132R
c.395T>C Korean De novo 45 18 45 17 Gait defect
c.395T>C Korean AD 18 17 – 16 Gait defect
c.395T>G French De novo 21 20 21 10 Gait defect
c.395T>G French AD 29 19 29 21 Gait defect
P A P
P A P
A A A
P ND P
P P P P A 44–45 This study
A P P P A 34–37 This study
A P ND P A 30–32 Boyer et al. (2011)
P P P P A 42 Boyer et al. (2011)
A, absent; AD, autosomal dominant; ESRD, end-stage renal disease; INF2, inverted formin-2; MNCV, motor nerve conduction velocity; ND, not described; P, present.
the INF2 mutation cosegregated completely with the two affected members (Figs. 1A and 1B). Paternity of the proband and her siblings was confirmed by genotyping of 15 microsatellites using a PowerPlex 16 System (Promega, Madison, WI, USA). This mutation was not detected in 300 healthy controls, dbSNP138, the 1000 Genomes Database (2011 October), or the Exome Variant Server. All in silico predictions (SIFT, PolyPhen2, MUpro, and GERP) yielded acceptable results (Table S3), and amino acid positions were well conserved throughout different vertebrate species (Fig. 1C). Thus, the p.L132P (c.395T>C) mutation in INF2 was defined as the underlying cause of CMT in the FC640 family.
of the two affected members in this study were similar to presentations of previously reported patients with a p.L132R mutation, also in codon 132 of INF2 (Table 1); however, the severity of nephropathy was quite mild for the patients in this study. Nerve conduction studies were performed for patient II-2 when she was 45 years old and patient III-1 when she was 18 years old (Table 2). The range of forearm motor NCVs was 34.1–56.8 m/s. The amplitudes of compound muscle action potentials (CMAPs) were not elicited in peroneal nerves, and were reduced in tibial nerves. Sensory nerve action potentials of the median, ulnar, and sural nerves were absent. These findings were consistent with intermediate sensorimotor polyneuropathy. Visual evoked potentials and brainstem auditory evoked potentials were normal in patient II-2. Lower limb magnetic resonance imaging (MRI) showed a predominance of distal fatty substitution (Fig. S1, Supporting information). At the level of the lower leg, patient II-2 showed almost complete fatty replacement and patient III-1 showed fatty infiltration and muscle atrophy along the anterior and lateral compartments, but not in the deep and superficial posterior compartments. Thigh MRI scans were nearly normal in both patients. From whole-exome sequencing (WES) in the proband (II-2), we identified a novel p.L132P (c.395T>C) de novo mutation in INF2 (Tables S1 and S2). DNA sequencing by capillary electrophoresis on samples from extended family members showed that
Discussion In this study, we used exome sequencing to identify a novel heterozygous INF2 mutation (p.L132P) in a Korean family with CMT and FSGS. We believe this novel mutation is the underlying cause of CMT in this family because the mutation completely cosegregated with affected status within the family and was not found in 300 healthy controls. The p.L132P (c.395T>C) mutation was located in exon 3, encoding the diaphanous-inhibitory domain (DID); all CMT causative mutations in the INF2 gene have been found in the DID (Boyer et al., 2011; Mademan et al., 2013; Rodriguez et al., 2013; Toyota et al., 2013). The protein encoded by INF2 is a member of the formin family and consists of a DID, the formin 177
Park et al.
Journal of the Peripheral Nervous System 19:175–179 (2014)
studies have indicated that INF2 mutations are a main cause of dual pathology in patients of different ethnic groups (Mademan et al., 2013; Rodriguez et al., 2013; Toyota et al., 2013). Clinically, patients with INF2 mutations show sensorimotor polyneuropathy and FSGS as well as sensorineural hearing loss and demyelinating brain lesions. Almost all patients show initial involvement of the anterior and lateral compartment muscles of the lower leg following disease progression lengthwise. Electrophysiological results include forearm motor NCVs in the demyelinating or intermediate range (Boyer et al., 2011; Mademan et al., 2013; Rodriguez et al., 2013; Toyota et al., 2013). This study demonstrated that the clinical and electrophysiological spectrum of results for Korean CMT patients with an INF2 mutation was compatible with the results of previous studies. Two patients had juvenile symptom onset and an intermediate type of slowed nerve conduction: an axonal range was measured in patient 1 and an unequivocal demyelinating range was measured in patient 2 in the same family. The patients in this study had phenotypes similar to previous reports on patients with a different mutation in the same codon of INF2, except for the severity of nephropathy. We first reported lower limb MRIs of patients with an INF2 mutation in our study. Lower limb MRIs demonstrated that the anterior and lateral compartments of the lower legs were the first to be impaired, and muscle fat changes progressed in a length-dependent pattern. These radiological findings correlated well with clinical disease progression seen in both the present and previous studies (Table S4). In conclusion, we identified a novel INF2 mutation in a family with DI-CMT and FSGS as the first case in Koreans. The INF2 mutation appears to be a major cause of CMT with FSGS.
Table 2. Electrophysiological features of patients with p.L132P INF2 mutation. II-2 Age at exam (years) 45 Side Rt Median nerve TL (ms) 4.7 CMAP (mV) 9.7 MNCV (m/s) 44.7 F-wave (ms) 37.8 Ulnar nerve TL (ms) 2.8 CMAP (mV) 16.3 MNCV (m/s) 56.8 F-wave (ms) 24.8 Peroneal nerve TL (ms) A CMAP (mV) A MNCV (m/s) A F-wave (ms) A Tibial nerve TL (ms) A CMAP (mV) A MNCV (m/s) A F-wave (ms) A Median sensory nerve SNAP (𝜇V) A SNCV (m/s) A Ulnar sensory nerve SNAP (𝜇V) A SNCV (m/s) A Sural nerve SNAP (𝜇V) A SNCV (m/s) A H-reflex (ms) A
III-1
Lt
18 Rt
Normal value
Lt
3.9 3.8 4.1 11.2 11.1 14.6 43.8 34.1 36.7 31.0 39.4 39.0
6.0 >50.5 51.1 41.2 41.1 8.8 >39.3
A A
A A
A A
>7.9 >37.5
A A A
5.4 3.7 27.3 23.9 A A
>6.0 >32.1 C) mutation. Table S4. Clinical and genetic features of CMT patients with INF2 gene mutations.
179
