Late adult-onset Hereditary Sensory and Motor Neuropathy due to TECPR2 mutations

Objective: The description of a new genetic association with late-onset axonal Charcot-Marie-Tooth disease (CMT). Method. A 57-year-old Brazilian woman presented with a slowly progressive history of paresthesia, muscle wasting and weakness in her lower limbs since age 50 years. Examination disclosed peroneal amyotrophy, bilateral pes cavus, mild distal weakness, reduced vibration, pain and temperature sensation in the the lower limbs and brisk tendon reflexes. Results. Neurophysiological studies showed chronic sensorimotor axonal polyneuropathy. Whole-genome sequencing showed compound heterozygous pathogenic variants in the TECPR2 gene (14q32.31). Conclusion. This novel genetic presentation of late-onset axonal CMT with brisk tendon reflexes associated with TECPR2.

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Charcot-Marie-Tooth disease type 2CC due to NEFH variants causes a progressive, non-length-dependent, motor-predominant phenotype

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2021-327186 ◽

2021 ◽

pp. jnnp-2021-327186

Author(s):

Menelaos Pipis ◽

Andrea Cortese ◽

James M Polke ◽

Roy Poh ◽

Jana Vandrovcova ◽

...

Keyword(s):

Age Of Onset ◽

Muscular Atrophy ◽

Disease Type ◽

Lower Limbs ◽

Reading Frame ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Neurophysiological Studies ◽

History Of ◽

Tooth Disease

ObjectiveNeurofilaments are the major scaffolding proteins for the neuronal cytoskeleton, and variants in NEFH have recently been described to cause axonal Charcot-Marie-Tooth disease type 2CC (CMT2CC).MethodsIn this large observational study, we present phenotype–genotype correlations on 30 affected and 3 asymptomatic mutation carriers from eight families.ResultsThe majority of patients presented in adulthood with motor-predominant and lower limb-predominant symptoms and the average age of onset was 31.0±15.1 years. A prominent feature was the development of proximal weakness early in the course of the disease. The disease progressed rapidly, unlike other Charcot-Marie-Tooth disease (CMT) subtypes, and half of the patients (53%) needed to use a wheelchair on average 24.1 years after symptom onset. Furthermore, 40% of patients had evidence of early ankle plantarflexion weakness, a feature which is observed in only a handful of CMT subtypes. Neurophysiological studies and MRI of the lower limbs confirmed the presence of a non-length-dependent neuropathy in the majority of patients.All families harboured heterozygous frameshift variants in the last exon of NEFH, resulting in a reading frameshift to an alternate open reading frame and the translation of approximately 42 additional amino acids from the 3' untranslated region (3′-UTR).ConclusionsThis phenotype–genotype study highlights the unusual phenotype of CMT2CC, which is more akin to spinal muscular atrophy rather than classic CMT. Furthermore, the study will enable more informative discussions on the natural history of the disease and will aid in NEFH variant interpretation in the context of the disease’s unique molecular genetics.

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Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction

BMC Medical Genomics ◽

10.1186/s12920-021-01001-1 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Beatrice Berti ◽

Giovanna Longo ◽

Francesco Mari ◽

Stefano Doccini ◽

Ilaria Piccolo ◽

...

Keyword(s):

Intellectual Disability ◽

Mitochondrial Dysfunction ◽

Early Onset ◽

Integrated Approach ◽

Compound Heterozygous ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Pathogenic Variants ◽

First Case ◽

Spine Mri

Abstract Background Charcot-Marie-Tooth disease (CMT) type 4B3 (CMT4B3) is a rare form of genetic neuropathy associated with variants in the MTMR5/SBF1 gene. MTMR5/SBF1 is a pseudophosphatase predicted to regulate endo-lysosomal trafficking in tandem with other MTMRs. Although almost ubiquitously expressed, pathogenic variants primarily impact on the peripheral nervous system, corroborating the involvement of MTMR5/SBF1 and its molecular partners in Schwann cells-mediated myelinization. Case presentation We report a case of severe CMT4B3 characterized by early-onset motor and axonal polyneuropathy in an Italian child in absence of any evidence of brain and spine MRI abnormalities or intellectual disability and with a biochemical profile suggestive of mitochondrial disease. Using an integrated approach combining both NGS gene panels and WES analysis, we identified two novel compound heterozygous missense variants in MTMR5/SBF1 gene, p.R763H (c.2291G > A) and p.G1064E (c.3194G > A). Studies in muscle identified partial defects of oxidative metabolism. Conclusion We describe the first case of an early onset severe polyneuropathy with motor and axonal involvement, due to recessive variants in the MTMR5/SBF1 gene, with no evidence of brain and spine MRI abnormalities, intellectual disability, no clinical and neurophysiological evidences of distal sensory impairment, and rapid neuromuscular deterioration. This report suggests that MTMR5/SBF1 should be considered in cases of infantile-onset CMT with secondary mitochondrial dysfunction.

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Characterising the phenotype and mode of inheritance of patients with inherited peripheral neuropathies carrying MME mutations

Journal of Medical Genetics ◽

10.1136/jmedgenet-2018-105650 ◽

2018 ◽

Vol 55 (12) ◽

pp. 814-823 ◽

Cited By ~ 8

Author(s):

Vincenzo Lupo ◽

Marina Frasquet ◽

Ana Sánchez-Monteagudo ◽

Ana Lara Pelayo-Negro ◽

Tania García-Sobrino ◽

...

Keyword(s):

Autosomal Recessive ◽

Late Onset ◽

Axonal Neuropathy ◽

Genetic Diagnosis ◽

Hereditary Neuropathy ◽

Motor Neuropathy ◽

Charcot Marie Tooth Disease ◽

Hereditary Motor Neuropathy ◽

Index Cases ◽

Mode Of Inheritance

BackgroundMutations in the metalloendopeptidase (MME) gene were initially identified as a cause of autosomal recessive Charcot-Marie-Tooth disease type 2 (CMT2). Subsequently, variants in MME were linked to other late-onset autosomal dominant polyneuropathies. Thus, our goal was to define the phenotype and mode of inheritance of patients carrying changes in MME.MethodsWe screened 197 index cases with a hereditary neuropathy of the CMT type or distal hereditary motor neuropathy (dHMN) and 10 probands with familial amyotrophic lateral sclerosis (fALS) using a custom panel of 119 genes. In addition to the index case subjects, we also studied other clinically and/or genetically affected and unaffected family members.ResultsWe found 17 variants in MME in a total of 20 index cases, with biallelic MME mutations detected in 13 cases from nine families (three in homozygosis and six in compound heterozygosis) and heterozygous variants found in 11 families. All patients with biallelic variants had a similar phenotype, consistent with late-onset axonal neuropathy. Conversely, the phenotype of patients carrying heterozygous mutations was highly variable [CMT type 1 (CMT1), CMT2, dHMN and fALS] and mutations did not segregate with the disease.ConclusionMME mutations that segregate in an autosomal recessive pattern are associated with a late-onset CMT2 phenotype, yet we could not demonstrate that MME variants in heterozygosis cause neuropathy. Our data highlight the importance of establishing an accurate genetic diagnosis in patients carrying MME mutations, especially with a view to genetic counselling.

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Peripheral Nervous System Involvement in Late-Onset Cobalamin C Disease?

Frontiers in Neurology ◽

10.3389/fneur.2020.594905 ◽

2020 ◽

Vol 11 ◽

Author(s):

Xujun Chu ◽

Lingchao Meng ◽

Wei Zhang ◽

Jinjun Luo ◽

Zhaoxia Wang ◽

...

Keyword(s):

Nervous System ◽

Peripheral Nervous System ◽

Methylenetetrahydrofolate Reductase ◽

Late Onset ◽

Hot Spot ◽

Axonal Neuropathy ◽

Methylmalonic Aciduria ◽

Lower Limbs ◽

Compound Heterozygous ◽

Limb Weakness

Background: Cobalamin C (cblC) has a fundamental role in both central and peripheral nervous system function at any age. Neurologic manifestations may be the earliest and often the only manifestation of hereditary or acquired cblC defect. Peripheral neuropathy remains a classical but underdiagnosed complication of cblC defect, especially in late-onset cblC disease caused by mutations in the methylmalonic aciduria type C and homocysteinemia (MMACHC) gene. So the clinical, electrophysiological, and pathological characteristics of late-onset cblC disease are not well-known.Methods: A retrospective study of patients with late-onset cblC disease was conducted at our hospital on a 3-year period. The neuropathy was confirmed by the nerve conduction study. Sural biopsies were performed in 2 patients.Results: Eight patients were identified, with a mean onset age of 16.25 ± 6.07 years. All patients had methylmalonic aciduria, homocysteinemia, compound heterozygous MMACHC gene mutations were detected in all patients, and 7/8 patients with c.482G>A mutation. One patient concomitant with homozygote c.665C>T mutation in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. All patients showed limb weakness and cognitive impairment. Five patients had possible sensorimotor axonal polyneuropathy predominantly in the distal lower limbs. Sural biopsies showed loss of myelinated and unmyelinated fibers. Electro microscopy revealed crystalline-like inclusions bodies in Schwann cells and axonal degeneration.Conclusion: Late-onset cblC disease had possible heterogeneous group of distal axonal neuropathy. c.482G>A mutation is a hot spot mutation in late-onset cblC disease.

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Tetraparesis and sensorimotor axonal polyneuropathy due to co-occurrence of Pompe disease and hereditary ATTR amyloidosis

Neurological Sciences ◽

10.1007/s10072-020-04896-3 ◽

2020 ◽

Author(s):

Milan Zimmermann ◽

Natalie Deininger ◽

Sophia Willikens ◽

Tobias B. Haack ◽

Kathrin Grundmann-Hauser ◽

...

Keyword(s):

Clinical Features ◽

Muscle Weakness ◽

Pompe Disease ◽

Late Onset ◽

Single Gene ◽

Lower Limbs ◽

Sensory Loss ◽

Motor Neuropathy ◽

Transthyretin Amyloidosis ◽

Attr Amyloidosis

Abstract Introduction/aims Hereditary transthyretin amyloidosis with polyneuropathy (hATTRPN) is an autosomal dominant multi-organ disorder manifesting in the third to fifth decade with the key clinical features of distal and painful sensory loss of the lower limbs and autonomic dysregulation. Motor neuropathy and cardiomyopathy evolve in the course of the disease. Pompe disease is an autosomal recessive disease leading to decreased levels of lysosomal enzyme acid α-glucosidase and proximal muscle weakness. We report the clinical features and diagnostic workup in the rare case of a patient with ATTR amyloidosis and late-onset Pompe disease, both genetically confirmed. Methods We performed a detailed clinical assessment, exome sequencing, and biochemical measurements. Results The patient presented with a distal, painful hypaesthesia of both legs, a cardiomyopathy, and a muscle weakness in the form of a girdle-type pattern of the arms and legs at the beginning and a spreading to distal muscle groups in the course of disease. Discussion This study highlights the importance of searching for co-occurrence of rare monogenetic neuromuscular diseases, especially in cases in which all clinical features can be readily explained by a single gene defect.

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Clinical, genetic and disability profile of pediatric distal hereditary motor neuropathy

Neurology ◽

10.1212/wnl.0000000000011054 ◽

2020 ◽

pp. 10.1212/WNL.0000000000011054

Author(s):

Herminia Argente-Escrig ◽

Joshua Burns ◽

Gabrielle Donlevy ◽

Marina Frasquet ◽

Kayla Cornett ◽

...

Keyword(s):

Functional Limitations ◽

Genetic Profile ◽

Motor Neuropathy ◽

Clinical Genetic ◽

Hereditary Motor ◽

Charcot Marie Tooth Disease ◽

Pathogenic Variants ◽

Hereditary Motor Neuropathy ◽

Long Jump ◽

One Year

Objective:To describe the clinical, genetic and disability profile of pediatric distal hereditary motor neuropathy (dHMN) and to determine the utility of an outcome measure validated for children with Charcot-Marie-Tooth disease (CMT) in assessing disability in this cohort.Methods:We reviewed the clinical, neurophysiologic, and disability data on individuals with dHMN, evaluated before the age of 20 years, at two tertiary neuromuscular clinics in Australia and Spain. Disability was assessed annually with the CMT Pediatric Scale (CMTPedS) in a subset of individuals.Results:Twenty-two children (13 females) from 19 families were included. 14 individuals were symptomatic in the first year of life. Intellectual disability was present in six individuals and upper motor neuron signs, in eight. Pathogenic variants were found in nine families, more frequently in BICD2 (BICD2-4, DYNC1H1-2, MFN2-2, GARS-1). A novel pathogenic variant in the GARS gene was detected and characterized phenotypically. Disability was moderate on the CMTPedS (mean [SD], 18.2 [6.3], n=16), with balance and long jump being the most affected and sensation items and grip strength, the least. Over one year the CMTPedS total score deteriorated, on average 1.5 points (SD 3.7) or 9% (n=12), with significant variability in the rate of progression within the cohort.Conclusions:The genetic profile of pediatric dHMN is different to that identified in adult cohorts. This study has identified distinct functional limitations on the CMTPedS in children and adolescents with dHMN.

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Loss-of-function mutations in Lysyl-tRNA synthetase cause various leukoencephalopathy phenotypes

Neurology Genetics ◽

10.1212/nxg.0000000000000316 ◽

2019 ◽

Vol 5 (2) ◽

pp. e565 ◽

Cited By ~ 2

Author(s):

Chong Sun ◽

Jie Song ◽

Yanjun Jiang ◽

Chongbo Zhao ◽

Jiahong Lu ◽

...

Keyword(s):

Missense Mutation ◽

Protein Function ◽

Trna Synthetase ◽

Insertion Mutation ◽

Compound Heterozygous ◽

Missense Mutations ◽

Loss Of Function ◽

Charcot Marie Tooth Disease ◽

Pathogenic Variants ◽

Whole Exome

ObjectiveTo expand the clinical spectrum of lysyl-tRNA synthetase (KARS) gene–related diseases, which so far includes Charcot-Marie-Tooth disease, congenital visual impairment and microcephaly, and nonsyndromic hearing impairment.MethodsWhole-exome sequencing was performed on index patients from 4 unrelated families with leukoencephalopathy. Candidate pathogenic variants and their cosegregation were confirmed by Sanger sequencing. Effects of mutations on KARS protein function were examined by aminoacylation assays and yeast complementation assays.ResultsCommon clinical features of the patients in this study included impaired cognitive ability, seizure, hypotonia, ataxia, and abnormal brain imaging, suggesting that the CNS involvement is the main clinical presentation. Six previously unreported and 1 known KARS mutations were identified and cosegregated in these families. Two patients are compound heterozygous for missense mutations, 1 patient is homozygous for a missense mutation, and 1 patient harbored an insertion mutation and a missense mutation. Functional and structural analyses revealed that these mutations impair aminoacylation activity of lysyl-tRNA synthetase, indicating that defective KARS function is responsible for the phenotypes in these individuals.ConclusionsOur results demonstrate that patients with loss-of-function KARS mutations can manifest CNS disorders, thus broadening the phenotypic spectrum associated with KARS-related disease.

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Childhood onset homozygous recessive GDAP1 (p.Pro231Leu) mutation in a 9-year-old puerto rican pediatric female with axonal Charcot-Marie-Tooth disease: A case report

Journal of Pediatric Rehabilitation Medicine ◽

10.3233/prm-200695 ◽

2021 ◽

pp. 1-5

Author(s):

Ana Ortiz-Santiago ◽

Edwardo Ramos

Keyword(s):

Puerto Rican ◽

Mitochondrial Protein ◽

Motor Neuropathy ◽

Childhood Onset ◽

Charcot Marie Tooth ◽

Charcot Marie Tooth Disease ◽

Old Order ◽

Sensory Motor ◽

History Of ◽

Tooth Disease

Charcot-Marie-Tooth disease (CMT) is a progressive hereditary neuromuscular neuropathy with pathology in the myelin sheath or the axon. CMT caused by mutations in the Ganglioside-induced differentiation associated protein 1 (GDAP1) gene has been described by a spectrum of phenotypic presentations. GDAP1 is a mitochondrial protein responsible for protecting neuronal bodies from oxidative stress. It is associated with axonal and demyelinating pathophysiology with recessive and dominant modes of inheritance.We describe a case of a 9-year-old Puerto Rican female with clinical and electrodiagnostic results compatible with an axonal sensory-motor neuropathy where a genetic test describes a homozygous GDAP1 missense mutation at the c.692C>T (p.Pro231Leu), previously undetected in a pediatric Latino patient. Mutations in GDAP1 have been previously described in Tunisian, Old Order Amish, European and Japanese families with varying modes of inheritance. To our knowledge, this homozygous variant presentation of the GDAP1 gene is the first to be described in a pediatric Puerto Rican patient without a family history of hereditary sensory motor neuropathy.

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Very late-onset Friedreich’s ataxia with rapid course mimicking as possible multiple system atrophy cerebellar type

BMJ Case Reports ◽

10.1136/bcr-2021-242073 ◽

2021 ◽

Vol 14 (7) ◽

pp. e242073

Author(s):

Tushar Ashok Vidhale ◽

Hemant R Gupta ◽

Rohan PJ ◽

Charmi Gandhi

Keyword(s):

Late Onset ◽

Cerebellar Atrophy ◽

Friedreich’S Ataxia ◽

Left Ventricular ◽

Friedreich's Ataxia ◽

Lower Limbs ◽

Compound Heterozygous ◽

Truncal Ataxia ◽

Gaa Repeats ◽

Whole Spine

This 55-year-old man was admitted to the hospital with an insidious onset, progressive backward fall (due to severe truncal ataxia), dysarthria, stiffness in extremities, distal dominant muscle wasting along with behavioural changes and urinary incontinence. Clinical assessment indicated mild cognitive decline (Mini-Mental State Examination 22/27) with cerebellar, pyramidal and peripheral nerves involvement. On investigations, nerve conduction studies revealed symmetrical, sensorimotor peripheral neuropathy affecting both lower limbs. Brain and whole spine MRI revealed widespread cerebral and mild cerebellar atrophy, pons and medulla volume loss, and a normal spinal cord. Transthoracic echocardiography revealed concentric left ventricular hypertrophy. His gene analysis revealed eight GAA repeats on allele 1, and 37 GAA repeats on allele 2 in the first intron of the frataxin gene. Considering his clinical profile and genetic analysis, he was diagnosed as a case of very late-onset Friedreich’s ataxia with likely compound heterozygous genotype.

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MEVALONATE KINASE DEFICIENCY IN AN INFANT: KEY ASPECTS OF DIAGNOSIS AND TREATMENT

PEDIATRIA Journal named after G N SPERANSKY ◽

10.24110/0031-403x-2021-100-2-276-283 ◽

2021 ◽

Vol 100 (2) ◽

pp. 276-283

Author(s):

M.F. Dubko ◽

◽

R.K. Raupov ◽

M.A. Kaneva ◽

E.N. Suspitsyn ◽

...

Keyword(s):

Late Onset ◽

Interleukin 1 ◽

Clinical Manifestations ◽

Specific Treatment ◽

Autosomal Recessive Inheritance ◽

Compound Heterozygous ◽

Mevalonate Kinase Deficiency ◽

Mevalonate Kinase ◽

Pathogenic Variants ◽

Severe Type

Mevalonate kinase deficiency (MKD) is a rare autoinflammatory disease with an autosomal recessive inheritance. The severity of the disease is correlated with the residual enzyme activity. There are two types of mevalonate kinase deficiency: a less severe type called hyperimmunoglobulinemia D syndrome (HIDS) and a more severe type called mevalonic aciduria. A little more than 300 cases with MDK have been described worldwide. The rarity of this disease, and polymorphism of clinical manifestations lead to late diagnosis and late onset of specific treatment. We described the 7-month-old infant with pathogenic variants c.118C> T (p.R40W) and c.206_207del (p.S69fs) in the MVK gene in a compound heterozygous state with the successful use of an interleukin-1 blocker.

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