Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability.

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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.

Objectives Autosomal recessive spastic ataxia of Charlevoix‐Saguenay (ARSACS) is caused by the SACS gene variants. Main clinical features include early‐onset and progressive cerebellar ataxia, spasticity, sensorimotor polyneuropathy. However, the phenotypic spectrum expanded with the increased availability of next‐generation sequencing methods. Materials and Methods Herein, we describe the clinical features of nine patients from seven unrelated families with SACS variants from the cohort of the Neuromuscular Disorders Unit of the Neurology Department of the Istanbul University, Istanbul Faculty of Medicine. Results Seven patients were male. Seven patients in our cohort had disease onset in the first decade of life. Eight patients were born to consanguineous marriages. Distal weakness in the lower limbs was a prominent feature in all of our patients. Seven patients had ataxia, and six patients had spasticity. Interestingly, one patient showed an isolated Charcot‐Marie‐Tooth‐like phenotype. Five patients showed sensorimotor demyelinating polyneuropathy in the nerve conduction studies. Linear pontine hypointensity was the most frequent cranial magnetic resonance imaging (MRI) abnormality. Two patients with a later disease onset had a homozygous c.11542_11544delATT (p.Ile3848del) variant. The rest of the identified variants were scattered throughout the SACS gene. Conclusions Atypical clinical features in our patients highlight that the phenotypic spectrum of ARSACS can be observed in a wide range.