Charcot-Marie-Tooth disease: a novel Tyr145Ser mutation in the myelin protein zero (MPZ,P0) gene causes different phenotypes in homozygous and heterozygous carriers within one family

Charcot-Marie-Tooth disease type 1B (CMT 1B) is caused by mutations in the gene coding for peripheral myelin protein zero (MPZ, P0) that plays a fundamental role in adhesion and compaction of peripheral myelin. Here we report a Costa Rican family with a hereditary peripheral neuropathy due to a novel Tyr145Ser MPZ mutation. Four family members were heterozygously affected; two siblings of two heterozygous carriers were homozygous for this mutation. On neurological examination the heterozygous parents and their homozygous children both showed distal sensory deficits. The mother and the siblings displayed impaired deep tendon reflexes and mild sensory ataxia. The homozygous individuals were more severely affected with an earlier age of onset, distal motor weakness, and pupillary abnormalities. Electrophysiological studies revealed both signs of demyelination and axonal nerve degeneration. The sural nerve biopsy of one sibling showed thinly myelinated nerve fibers, onion bulb formation, and clusters of regenerating fibers. On electron microscopy axonal degeneration and decompaction of inner myelin layers were found. This Costa Rican family shows phenotypic variability depending on the homozygous or heterozygous state of the Tyr145Ser mutation carriers.A. Leal and C. Berghoff contributed equally to this work.     

Muscle-nerve involvement in autosomal dominant progressive external ophthalmoplegia with hypogonadism

Sixteen members of a family with a history of autosomal dominant progressive external ophthalmoplegia (adPEO) with hypogonadism were examined. The muscular involvement commenced cranially and descended in relation to increasing disease duration. The neuromuscular signs were PEO, dysarthria, dysphonia, limb muscle weakness with wasting, absence of Achilles tendon reflexes, and distal vibration sensory loss. The electromyogram (EMG) was myopathic in facial and proximal limb muscles. Neurogenic involvement was suspected in a few tibial anterior muscles. Neurography showed signs of axonal neuropathy correlated to clinical signs. F-responses were reduced in number or absent in peroneal nerves, and did not correlate to clinical signs or disease duration. Muscle biopsies in advanced cases had structural abnormalities of mitochondria, ragged-red fibers, and focal cytochrome c oxidase deficiency. A combination of muscle-nerve involvement with PEO, Achilles tendon areflexia, distal vibration sensory impairment, myopathic EMG, and abnormally low sural nerve responses seems to be typical of this type of mitochondrial disorder. © 1996 John Wiley & Sons, Inc.     

A family with adult-onset myofibrillar myopathy with BAG3 mutation (P470S) presenting with axonal polyneuropathy

We report a family with adult-onset myofibrillar myopathy with BAG3 mutation who presented peroneal weakness and axonal polyneuropathy, mimicking axonal Charcot-Marie-Tooth disease. The male proband noticed difficulty in tiptoeing at age 34. At age 42, the examination showed muscle weakness and atrophy in distal lower extremities with diminished patellar and Achilles tendon reflexes. Thermal and vibration sensations were also impaired in both feet. The serum CK level was 659 U/L. On muscle imaging, predominant semitendinosus muscle atrophy coexisted with atrophies in the quadriceps, gastrocnemius and lumbar paraspinal muscles. The muscle biopsy showed myofibrillar myopathy with fiber type grouping. His 68-year-old mother also had suffered from distal leg weakness and sensory impairment since her forties. A heterozygous mutation in BAG3 (P470S) was identified in both patients. Clinical features of myofibrillar myopathy with axonal polyneuropathy were consistent with BAG3-related myopathy. Our patients showed remarkably mild presentations without cardiomyopathy, unlike the majorities of previously reported cases.     

Congenital hypomyelination neuropathy in a newborn infant: unusual cause of diaphragmatic and vocal cord paralyses

We report a case of congenital hypomyelination neuropathy presenting at birth. The infant had generalized hypotonia and weakness. There was decreased respiratory effort along with a right phrenic nerve and left vocal cord paralyses. Tongue fasciculations were present. Deep tendon reflexes were absent in the upper extremities and hypoactive (1+) in the lower extremities. Magnetic resonance imaging of the head revealed no intracranial abnormalities, including normal cerebral myelination. Nerve conduction study showed absence of motor and sensory action potentials in the hands when the nerves in the upper limbs were stimulated. A motor response could be elicited only in the proximal leg muscles. Needle electromyography study was normal in the proximal limb muscles, but showed active denervation in the distal muscles of the arm and leg. These findings were thought to be consistent with a length‐dependent sensorimotor peripheral polyneuropathy of axonal type with greater denervation of the distal muscles. A biopsy of the quadriceps muscle showed mild variability in fiber diameter, but no group typing or group atrophy. The muscle fibers showed no intrinsic abnormalities. Biopsy of the sural nerve showed scattered axons with very thin myelin sheaths. There was also a nearly complete loss of large diameter myelinated fibers. No onion bulb formations were noted. These findings were thought to be consistent with congenital hypomyelination neuropathy with a component of axonopathy. DNA analysis for identification of previously characterized mutations in the genes MPZ, PMP22, and EGR2 was negative. Several attempts at extubation failed and the infant became increasingly ventilator‐dependent with increasing episodes of desaturation and hypercapnea. He also developed increasing weakness and decreased movement of all extremities. He underwent surgery at 2 months of age for placement of a gastrostomy tube and a tracheostomy. He was discharged from the hospital on a ventilator at 6 months of age. The infant was 13 months old at the time of submission of this report. Although he appears cognitively normal, he remains profoundly hypotonic and is on a home ventilator. There was no evidence of progressive weakness. Congenital hypomyelination neuropathy is a rare form of neonatal neuropathy that should be considered in the differential diagnosis of a newborn with profound hypotonia and weakness. It appears to be a heterogeneous disorder with some of the cases being caused by specific genetic mutations.     

An axonal form of Charcot-Marie-Tooth disease showing distinctive features in association with mutations in the peripheral myelin protein zero gene (Thr124Met or Asp75Val)

OBJECTIVES AND METHODS: Seven families were studied with an axonal form of Charcot-Marie-Tooth disease (CMT) associated with mutations in the peripheral myelin protein zero (MPZ) gene-Thr124Met or Asp75Val. RESULTS: Patients with these mutations commonly showed relatively late onset sensorimotor neuropathy predominantly involving the lower limbs. Sensory impairment typically was marked, and distal muscle atrophy and weakness were also present in the legs. Adie's pupil and deafness were often present, and serum creatine kinase concentrations were often raised irrespective of which MPZ mutation was present. Relatively well preserved motor and sensory nerve conduction velocities contrasted with reduced or absent compound muscle action potentials and sensory nerve action potentials. Axonal change with marked axonal sprouting was seen in sural nerve specimens. CONCLUSION: The similar associated clinical findings suggest that patients with axonal CMT with an MPZ gene mutation share distinctive clinical features.     

Inherited polyneuropathy in Leonberger dogs: A mixed or intermediate form of Charcot‐Marie‐Tooth disease?

A spontaneous distal, symmetrical polyneuropathy in related Leonberger dogs with onset between 1 to 9 years of age was characterized clinically, electrophysiologically, histologically, and morphometrically. Exercise intolerance and weakness was associated with a high-steppage pelvic-limb gait, a loss or change in the pitch of the bark, and dyspnea. Neurological examination revealed marked atrophy of the distal limb muscles, depressed spinal and cranial nerve reflexes, and weak or absent movement of the laryngeal and pharyngeal muscles. Electrophysiological evaluation was consistent with denervation and was characterized by loss or marked attenuation of compound muscle action potentials and slowed motor nerve conduction velocity. Muscle biopsy specimens showed neurogenic atrophy. Chronic nerve fiber loss associated with decreased myelinated fiber density and a shift of the axonal size-frequency distribution toward smaller fibers was the predominant finding in peripheral nerve specimens. Pedigree analysis of a large multigenerational family, including nine sibships with at least one affected individual, suggested X-linked inheritance. Mutational and linkage analysis of this family may aid in identification of the chromosomal loci and gene responsible for this inherited axonal neuropathy. Further characterization of this inherited axonal neuropathy may establish the Leonberger dog as a spontaneous animal model of inherited axonal neuropathy and possibly lead to the discovery of a new gene or genes associated with axonal variants.     

A case of adult T cell leukemia/lymphoma with motor and sensory polyneuropathy]

A 62-year-old man was admitted to our hospital because of two months continuing paresthesia and muscle weakness of distal portions of the four limbs. On general physical examination, skin lesions, lymphadenopathy and hepatosplenomegaly were not found. Neurological examination revealed moderate weakness in the bilateral distal muscles of the lower limbs and left distal muscles of the upper limbs, and slight weakness in the right distal muscles of the upper limbs and the bilateral proximal muscles of the four limbs. Hand grasping powers were 24 kg and 2 kg on the right and left, respectively. The biceps, triceps and radial reflexes were decreased on the right, but normal on the left. The Achilles tendon reflex was decreased on the right and absent on the left. Paresthesia and superficial sensory disturbance were observed with glove and stocking distribution, which was more severe on the left side. The vibration and position senses were slightly decreased in the distal part of the lower limbs. On the laboratory examinations, serum anti-HTLV-I antibody was positive and no abnormal lymphocytes were observed in peripheral blood. Cerebrospinal fluid findings were normal, and anti-HTLV-I antibody was negative. Motor and sensory conduction velocities were normal or slightly decreased in all of the limb nerves examined, but the amplitudes of the compound muscle action potentials and the sensory nerve action potentials were asymmetrically decreased. Needle EMG showed fibrillation potentials and giant spikes with a reduction in number of motor unit potentials. The histological examination of the biopsied sural nerve revealed severe axonal degeneration without evidence of vasculitis or infiltration of abnormal lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypocalcemic hyper-CK-emia in hypoparathyroidism

A 15-year-old boy with increased serum creatine kinase (hyper-CK-emia) due to hypocalcemia in turn caused by idiopathic hypoparathyroidism (HP) is presented. Hyper-CK-emia was incidentally noted while managing a patient, aged nine, with mental retardation, epilepsy and mild hypocalcemia. Neurological examination showed normal deep tendon reflexes and no muscle weakness; electromyogram was normal. The hyper-CK-emia normalized during treatment for the hypocalcemia. Previously reported patients with hypocalcemic hyper-CK-emia or myopathy together with HP are discussed, as well as the degree of hypocalcemia and the wide spectrum of the muscle dysfunction.     

A NOVEL MYELIN PROTEIN ZERO MUTATION ASSOCIATED WITH CHARCOT-MARIE-TOOTH TYPE II DISEASE

Charcot-Marie-Tooth type II disease (CMT2) is a typical peroneal muscular atrophy syndrome and is characterised by normal or slightly reduced nerve conduction velocities with signs of axonal degeneration. CMT2 is genetically heterogeneous: linkage to 1p35–p36 (CMT2A; KIF1B gene), 3q13–q22 (CMT2B), 7p14 (CMT2D) and 8p21 (CMT2E; NF-L gene) loci has been reported for the autosomal dominant disease; however, the majority of CMT2 families do not link to any of the reported loci. Mutations of the myelin protein zero (MPZ) gene were found associated with demyelinating forms of hereditary neuropathies such as CMT1B, Dejerine-Sottas syndrome and congenital hypomyelination. So far, few CMT2 cases (CMT2F) were found to be caused by point mutations in the MPZ (see CMT Mutation Database, http://molgen-www.uia.ac.be/CMTMutations/ ) in 1q22 region.
We report a family in which three members are affected with a late-onset peripheral neuropathy. The index patient is a 68-year-old male who presents with pronounced distal muscle weakness of inferior limbs, bilateral pes cavus and absence of deep tendon reflexes. Electrophysiological findings were suggestive of an axonal form of peripheral neuropathy, thus allowing the diagnosis of CMT type 2. At the clinical and electrophysiological examination, two other family members (first cousins of the proband) resulted to be affected. MPZ gene direct sequencing revealed a heterozygous T/A transversion in the exon 3 of the gene, predicting an Asp103Glu aminoacid substitution in the extracellular domain of the protein. This variant was not found in unaffected relatives and in 100 normal chromosomes. This finding confirms the role of protein zero in axonal neuropathies and the phenotypic heterogeneity associated with MPZ mutations.
(The laboratory is a member of the European CMT Consortium; partially granted by Ministero della Sanitá to PM, MURST to FA)     

Rare myelin protein zero sequence variant in late onset CMT1B

Myelin protein zero (MPZ) mutations cause demyelinating neuropathies that range from severe neonatal to milder adult forms. We report a 65-year-old woman with slowly progressive leg weakness starting at 47. Examination revealed distal weakness and atrophy in all extremities, impaired light touch in both feet and pin perception to proximal calves, absent leg reflexes, and unsteady gait. Electrodiagnostic studies revealed a severe sensorimotor polyneuropathy with conduction velocities of 25 m/s - to normal. The conduction velocities in the upper 20's were seen in lower extremities with severe reduction of the corresponding compound muscle action potential amplitudes. She had a MPZ mutation with A-C transversion (nucleotide: 116, codon: 10, histidine-to-proline). Her sister has an identical mutation, with high arches, distal leg weakness, decreased vibration sensation in toes and ankle areflexia. Nerve conduction studies revealed a moderate-severe sensorimotor polyneuropathy with nerve conduction velocities of 36 m/s - to normal. Their mother had an abnormal gait and conduction velocities of 29-30 m/s. A third sister is clinically and genetically unaffected. One report has previously described four patients with this mutation with similar clinical and electrodiagnostic features. In patients tested for possible CMT, the frequency of MPZ His-Pro codon 10 substitutions was 0.11% (27 of 24,076 alleles).     

CMT with pyramidal features. Charcot-Marie-Tooth

To determine whether Charcot-Marie-Tooth (CMT) with pyramidal features is genetically distinct from other dominantly inherited axonal neuropathies, the authors examined all chromosomal loci and genes for axonal CMT. Two families were identified with an axonal CMT phenotype with distal wasting, weakness, pes cavus, sensory loss, and mild pyramidal signs (including extensor plantar responses, mild increase in tone, and preserved or increased reflexes but no spastic gait). Linkage studies excluded CMT2A, 2B, 2D, 2E, and 2F; ALS4; and HMN2. There were no mutations in the PMP22, MPZ/Po, or EGR2 genes.     

Late-onset sporadic case of SPG4 (1726T>C mutant) accompanied by polyneuropathy with diabetes mellitus]

We report a 73-year-old man with SPG4. From aged 53 he had diabetes mellitus and at 64 he developed spastic paraparesis and urinary disturbance. At 70 years, he began to walk with a stick and noted abnormal sensations in bilateral feet. There was no relevant family history. Moderate spasticity with mild muscle weakness, markedly brisk tendon reflex with pathological reflexes, and mildly abnormal sensation in bilateral lower extremities, and markedly spastic gait were found. MRI showed mild C4-C7 spondylosis and L4-5 disk protrusion but no abnormality of the corpus callosum. Nerve conduction and needle EMG studies revealed various abnormalities in distal (MCV, SCV) and proximal (F-wave) peripheral nerves, but no neurogenic changes in limb muscles. We found a missense spastin gene mutation (1726T>C) that causes Leu534Pro substitution. This spastin gene mutation was novel in Japanese, but has been reported in an Italian family. The present case's neuropathy might be related to diabetes mellitus, because SPG4 is generally not associated with neuropathy. However, recent studies suggest that SPG4 patients sometimes have subclinical neuropathy, and longer disease duration may contribute to peripheral neuropathy. Further study of clinical characteristics associated with the Leu534Pro mutation will be necessary.     

Isolated facial diplegia in Guillain–Barré syndrome: Bifacial weakness with paresthesias

Bifacial weakness with paresthesias (BFP) is a subtype of Guillain–Barré syndrome defined by rapidly progressive bilateral facial weakness in the absence of other cranial neuropathies, ataxia, or limb weakness. Many patients also complain of distal limb paresthesias and display diminished or absent deep tendon reflexes. BFP is a localized form of Guillain–Barré syndrome and is thought to be caused exclusively by demyelinating‐ rather than axonal‐type neuropathy. Patients with BFP do not display anti‐ganglioside IgG antibodies. Since it is rare, many physicians are unfamiliar with BFP, as bilateral facial weakness is more commonly associated with sarcoidosis, Lyme disease, or meningeal pathology. Many patients diagnosed with bilateral Bell palsy may instead have BFP. In this review, we highlight the clinical features of BFP and outline diagnostic criteria. Muscle Nerve 52 : 927–932, 2015     

Two families of Charcot-Marie-Tooth disease with Adie's pupil, axonal neuropahy and the Thr124Met mutation in the peripheral myelin protein zero gene]

We reported two families of Charcot-Marie-Tooth disease (CMT) with Thr124Met mutation in the peripheral myelin protein zero (MPZ). The clinical features of the proband patients of both families showed Adie's pupil, severe sensory dominant neuropathy in lower extremities, and axonal changes in sural nerve biopsies and nerve conduction studies. Muscle atrophy and weakness was mild in the lower legs, while sensory impairment was marked. The proband patient of family 1 had four symptomatic siblings and one of them showed Adie's pupil. The elderly daughter of the proband of family 2 showed Adie's pupil and younger daughter showed photophobia. The biopsied sural nerves of both proband patients revealed prominent axonal sprouting, and sub-perineurial edema and mild fascicular enlargement. Segmental demyelination was not frequent in teased fiber assessment. The present two family cases strongly suggest that this MPZ gene mutation (Thr124Met) could be present among the patients with CMT type 2, axonal form. Furthermore, the patients showing sensory neuropathy and Adie's pupil may need to be reexamined with this mutation. It is also necessary to reassess genotype-phenotype correlation in CMT patients particularly in reference to type 1 and type 2.     

A case of CIDP with horizontal gaze-evoked nystagmus and ataxia]

A 46-year-old man developed mild to moderate weakness in the distal muscles of lower limbs and then had gradually progressive weakness and sensory loss in four limbs. He subsequently developed difficulty in walking over a few months. Examination showed severe distal muscle weakness and atrophy, but mild proximal weakness in four limbs. Superficial sensation was decreased in both distal limbs and his vibratory sense was mildly decreased in bilateral feet. All tendon reflexes were absent. Furthermore, he showed four-limb and truncal ataxia with bilateral horizontal gaze-evoked nystagmus in both directions. Nerve conduction study revealed sensorimotor neuropathy, and sural nerve biopsy showed mixed axonal damage and demyelination. Cerebrospinal fluid protein levels were raised 212 mg/dl. Lumbar spine MRI showed marked cauda equina enhancement with gadolinium. Anti-ganglioside antibodies were negative but serum antineuronal antibodies without known antigen specificity were found. Neurootological findings indicated bilateral horizontal gaze-evoked nystagmus was caused by spinocerebellar damage. We diagnosed this case was CIDP with cerebellar ataxia. After administration of high dose steroid therapy, intravenous methylprednisolone 1000 mg/day, his symptoms including ataxia and polyneuropathy were apparently improved.     

A novel mutation of LRSAM1 in a Chinese family with Charcot‐Marie‐Tooth disease

Charcot‐Marie‐Tooth (CMT) disease is the most common inherited peripheral neuropathy characterized by progressive distal muscle weakness and atrophy with decreased or absent tendon reflexes. Mutations in LRSAM1 have been identified to cause CMT disease type 2P. We report a novel LRSAM1 mutation c.2021‐2024del (p.E674VfsX11) in a Chinese autosomal dominant CMT disease type 2 family. The phenotype was characterized by late onset and mild sensory impairment. Electrophysiological findings showed normal or mildly to moderately reduced motor and sensory nerve conduction velocities in lower and upper limb nerves.     

Myeloneuritis Due to Acute Organophosphate (DDVP) Intoxication

Given the importance of agriculture and widespread use of pesticides, intoxication due to organophosphate insecticides is common in Turkey. Organophosphorus compounds may cause late-onset distal polyneuropathy occurring 2 or more weeks after the acute exposure. An 18-year-old woman and a 22-year-old man were admitted to the hospital with weakness, paresthesia, and gait disturbances at 35 and 22 days, respectively, after ingesting dimethyl-2,2-dichloro vinyl phosphate (DDVP). Neurological examination revealed weakness, vibration sense loss, bilateral dropped foot, brisk deep tendon reflexes, and bilaterally positive Babinski sign. Electroneurography demonstrated distal motor polyneuropathy with segmental demyelination associated with axonal degeneration prominent in the distal parts of both lower extremities.     

腓骨肌萎缩症1A型的临床、神经电生理和疾病基因突变分析

目的　观察腓骨肌萎缩症 (CMT) 1A型的临床、神经电生理特点和疾病基因的突变分析。方法对一CMT家系中 9个成员进行详尽的临床检查、疾病基因突变分析 ,对先证者进行神经电生理检查和神经肌肉活检。结果　本家系中 5人发病 ,符合常染色体显性遗传模式 ,除 1例患者无临床症状外 ,其余 4例均在2 0岁前起病。临床特点为进行性四肢远端肌无力、肌萎缩 ,末梢型感觉障碍 ,腱反射减弱或消失 ,足部畸形(高弓足 )。神经电生理检查示运动和感觉神经传导速度减慢。基因突变分析发现 17号染色体短臂 11 2区(17p11 2 )包含周围髓鞘蛋白 (PMP) 2 2基因的正向串联重复突变。结论　CMT1A型是CMT最常见类型 ,多于儿童期或青少年期起病 ,表现为进行性四肢远端肌无力、肌萎缩 ,腱反射减弱或消失。神经电生理特点为运动神经传导速度均一性减低 (<38m/s)。 17p 11 2区包含PMP 2 2基因在内的 1 5Mb(偶尔 <1 5Mb)的正向串联重复突变是CMT 1A最主要的突变型。     

A pedigree of Charcot-Marie-Tooth disease type 4F (Periaxin mutation)]

We report a 51-year-old man genetically diagnosed as Charcot-Marie-Tooth disease type 4F. The patient was the first child of healthy, consanguineous parents. He had two sisters and one of them showed similar but milder symptoms. He had gait disturbance since childhood. Then he noticed muscle weakness of his hands at the age of early forties, and more difficulties in gait at the age of late forties. On examination at age 51, he showed absence of all deep tendon reflexes, weakness of the hand and distal leg muscles, pes cavus and decreased sensitivity to touch and vibration in the lower extremities. Electrophysiological studies of the median nerve showed delayed motor nerve conduction velocity and undetectable sensory nerve action potentials. The histology of his sural nerve revealed moderate loss of large myelinated fibers and the diameters of residual fibers shifted to small shown as size-frequency histogram. Many fibers are thinly myelinated and some of the Schwann cells looked as wrapping around the myelinate fibers with their processes. On gene analyses, we identified an Arg 1070 Stop homozygous mutation in the Periaxin, known to be a causative gene for CMT type 4F. Based on these observations, we emphasized that broad genetic analyses are necessary for diagnosis of CMT disease, including so far unidentified mutations among the Japanese populations.