Clinical and Genetic Survey for Charcot-Marie-Tooth Neuropathy Based on the Findings in Turkey, a Country with a High Rate of Consanguineous Marriages

Inherited peripheral neuropathies (IPNs) are a heterogeneous group of disorders of the peripheral nervous system. The most common type of IPN is Charcot-Marie-Tooth (CMT) disease, which constitutes an interesting research focus for neurologists and human geneticists alike. Most cases with CMT manifest with a slowly progressive symmetric distal weakness in the lower limbs that usually begin in the first to the third decade that causes atrophy and foot drop. Deep tendon reflexes are usually absent or reduced. A proven and efficient CMT therapy is yet available and may require different molecules and approaches due to its high clinical and genetic heterogeneity. Several ongoing clinical trials are promising and are mostly focused on the most frequent form, namely CMT Type 1A (CMT1A). Approximately, 60% of patients with CMT can be genetically diagnosed using the most advanced mutation screening techniques that cover approximately 100 IPN genes. Turkey has a 25% consanguineous marriage rate, and nearly 60% genetic diagnosis rate can still be reached when SH3 Domain and Tetratricopeptide Repeat Domain 2, Ganglioside-induced Differentiation-Associated Protein 1, and Histidine Triad Nucleotide Binding Protein 1 genes are also screened along with Myelin Protein Zero and Gap Junction Protein Beta-1 after exclusion of CMT1A duplication in families with probable recessive inheritance. The genetic diagnosis rates in different regions worldwide implicate that the most recent sequencing techniques should be more commonly used for both diagnosis and identification of further CMT genes. Herein, presented our 30 years of experience on genetic diagnosis and management strategies in CMT neuropathy in Turkey and review clinical and genetic features of this group of disorders

Case Report / Olgu Sunumu A Family with Vocal Cord Paralysis Associated with GDAP1 Mutation in Giresun, Turkey Türkiye'nin Giresun İlinde GDAP1 Mutasyonuna Bağlı Vokal Kord Paralizisi Sum mary Öz

A Turkish family living in northern Turkey with hereditary neuropathy is described herein. The current study presents two sisters with severe proximal and distal motor deficits, anatomic deformities, such as pes cavus and claw hand, dependency on wheelchairs, who were born to parents with fifth-degree consanguinity, and developed vocal cord paralysis in the follow-up. The genetic analysis revealed that the siblings were homozygous for p.Q38X (c.112C>T) mutation in the GDAP1 gene. There are rare reports of vocal cord paresis in patients with hereditary neuropathy, which may result in respiratory difficulty in the clinical course. The aim of the current study was to highlight the importance of genetic studies that predict the development of vocal cord paralysis, which could reduce the expected life span in patients with hereditary neuropathy, a condition commonly encountered in our region owing to consanguineous marriage. Keywords: Vocal cord paralysis, hereditary neuropathy, GDAP1 gene Türkiye'nin kuzeyinde yaşayan herediter nöropatisi olan bir Türk aile tanımlanmıştır. Ciddi proksimal ve distal motor defisitleri olan, pes cavus ve pençe el gibi deformiteleri bulunan, tekerlekli sandalyeye bağımlı, takiplerinde vokal kord paralizisi gelişen, anne ve babaları beşinci dereceden akraba olan iki kız kardeş sunulmuştur. Kardeşlerin genetik analizlerinde GDAP1 geninde p.Q38X (c.112C>T) homozigot mutasyonu taşıdıkları gösterilmiştir. Herediter nöropatili hastaların klinik seyirlerinde solunum zorluğuna neden olabilecek vokal kord paralizisinin nadir de olsa geliştiğini bildirmiş yayınlar mevcuttur. Biz bu yazımızla bölgemizde akraba evliliklerinin yaygın olması nedeni ile sık gördüğümüz herediter nöropatili olgularda beklenen yaşam süresini kısaltabilecek vokal kord paralizisinin gelişebileceği hakkında önceden fikir verebilecek genetik çalışmaların önemini vurgulamak istedik

Genotype-phenotype Correlation in Pelizaeus Merzbacher Disease and Pelizaeus Merzbacher-like Disease

Objective: Among the hypomyelinating diseases of childhood, Pellizeus Merzhachcr disease (PMD) is caused by X-linked proteolipid protein (PLP) gene mutations, whereas patients without mutations of PLP gene-called Pelizaues Merzbacher-like disease (PMLD) have recessive gap junction protein alpha 12 (gap junction alpha-12/gap junction gamma-2) gene mutations. The aim of this study was to evaluate clinical severity and progression in time in patients with PMD and PMLD

Hereditary Neuropathy with Liability to Pressure Palsy: The Clinical and Electrophysiological Features of Four Families**

Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant disorder characterized by acute, painless and recurrent mononeuropathies that are secondary to minor trauma or compression. Diagnosis is often overlooked when detailed examinations are not performed. We discuss the features of our four HNPP patients and their close relatives in order to emphasize the importance of clinical and electrophysiological findings in the diagnosis of HNPP. Four patients and three members of the family underwent genetic testing and HBDN deletion was shown in all

The first biallelic missense mutation in the FXN gene in a consanguineous Turkish family with Charcot-Marie-Tooth-like phenotype

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuropathy with a prevalence of 1 in 2500 individuals worldwide. Here, we report three Turkish siblings from consanguineous parents presenting with a CMT-like phenotype who carry a homozygous c.493C>T, p.Arg165Cys mutation in the FXN gene that is the only known causative gene for Friedreich's ataxia (FRDA). The identified missense mutation has been reported previously in two FRDA cases in compound heterozygosity with the common GAA repeat expansion in the first intron of the FXN gene. Analysis of skin biopsy samples from our family indicated that the mutation does not affect the expression levels of the frataxin, pointing to functional impairment of the corresponding protein. The CMT phenotype in the siblings was associated with visual impairment, optic nerve atrophy, and dysarthria. To the best of our knowledge, this family represents the first FXN missense mutation in homozygosity and challenges the notion that missense mutations have not been reported yet due to their embryonic lethality. Furthermore, this finding poses an interesting genetic overlap between autosomal recessive CMT and FRDA that we believe may have important implications on understanding the pathogenesis of these neurological disorders

Clinical and genetic aspects of hereditary spastic paraplegia in patients from Turkey

Objectives. Hereditary spastic paraplegias (HSPs) are a heterogenous group of rare neurodegenerative disorders that present with lower limb spasticity. It is known as complicated HSP if spasticity is accompanied by additional features such as cognitive impairment, cerebellar syndrome, thin corpus callosum, or neuropathy. Most HSP families show autosomal dominant (AD) inheritance. On the other hand, autosomal recessive (AR) cases are also common because of the high frequency of consanguineous marriages in our country. This study aimed to investigate the clinical and genetic aetiology in a group of HSP patients

Clinical and genetic aspects of hereditary spastic paraplegia in patients from Turkey

Objectives. Hereditary spastic paraplegias (HSPs) are a heterogenous group of rare neurodegenerative disorders that present with lower limb spasticity. It is known as complicated HSP if spasticity is accompanied by additional features such as cognitive impairment, cerebellar syndrome, thin corpus callosum, or neuropathy. Most HSP families show autosomal dominant (AD) inheritance. On the other hand, autosomal recessive (AR) cases are also common because of the high frequency of consanguineous marriages in our country. This study aimed to investigate the clinical and genetic aetiology in a group of HSP patients.Patients and methods. We studied 21 patients from 17 families. Six of them presented with recessive inheritance. All index patients were screened for ATL1 and SPAST gene mutations to determine the prevalence of the most frequent types of HSP in our cohort. Whole exome sequencing was performed for an AD-HSP family, in combination with homozygosity mapping for five selected AR-HSP families.Results. Two novel causative variants were identified in PLP1 and SPG11 genes, respectively. Distribution of HSP mutations in our AD patients was found to be similar to European populations.Conclusion. Our genetic studies confirmed that clinical analysis can be misleading when defining HSP subtypes. Genetic testing is an important tool for diagnosis and genetic counselling. However, in the majority of AR HSP cases, a genetic diagnosis is not possible