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Haythum O Tayeb R3, Neurology Brief review of the genetics and molecular biology of CMT & HNPP with clinical correlation Introduction with a general view of clinical evaluation for a possible hereditary neuropathy Discerning the clinical and electrophysiologic phenotype Genes and proteins involved demyelinating hereditary neuropathies Genes and proteins involved in axonal CMT (CMT2) Conclusion heterogeneous group of diseases insidious onset and indolent course over years to decades. They are common eg CMT 1:2500 Classification (clinical vs molecular) Onset and progression long-standing Pattern Distribution (distal vs proximal, symmetry) Motor, Sensory, autonomic Medical, drug, dietary history Family history No systemic involvement inheritance(AD, AR, Xlined, sporadic) Onset in the first two decades of life (classic) Early onset, severe (dejerine sottas) Late onset, mild Severity, distribution, quality of motor/sensory involvement Inheritance: AD, AR, X-linked, sporadic Associated abnormalities: hints to particular (uncommon) forms Deafness Tremor CNS involvement Diaphragmatic paralysis Vocal cord paralysis Pupillary abnormalities Mental retartdation Hereditary Neuropathy CMT HNPP HSAN dHMN CMT1: demyelinating (NCV < 38) CMT2: axonal (NCV>38) “intermediate HNPP CMT” a small membrane glycoprotein in compact peripheral myelin Chromosome 17p11.2 Autosomal Dominant inheritance Function: unknown. “Dosage sensitive”. 1.5 megabase tandem duplication of the region containing the PMP-22 gene accounts for 70% CMT1A Takes place during meiosis Abnormal gain of function Heterozygous 1.5 fold overexpression Homozyogous 2 fold overexpression In transgenic mice: PMP22 forms protein aggregates in endosomes. Mis-sense mutations A minority of CMT1A with a severe hypomyelinating neuropathy phenotype. deletion of the same 1.5 megabase is found in 85% of HNPP The remaining: frame-shift or nonsense mutations causing functional changes in the protein the major peripheral myelin glycoprotein MPZ gene: chromosome 1q22-23 Function: adhesion molecule in the formation and compaction of peripheral myelin * gain (toxicity of the misfolded protein) or loss (reduced amounts) of-function divergent manifestations CMT1B DSS, and hypomyelination neuropathy CMT2 (axonal rather than demyelinating!) Mild CMT phenotype (axonal NCS) CMT2J (Thr 124 Met mutations): late onset, marked sensory loss, deafness, and pupillary abnormalities Mutations A gap junction protein found in noncompacted paranodal loops and Schmidt-Lantermann incisures. also in oligodendroglia (CNS). Gene: GJB1 on chromosome Xq X-linked dominant* CMTX mis-sense mutations (mild clinical phenotype) nonsense &frame-shift (more severe phenotypes) Loss of function Men affected more severely Phenotype maybe difficult to distinguish from CMT1 and CMT2 “Intermediate NCS” CNS involvement reported (ABER, MRI) lipopolysaccharide-induced tumor necrosis factor-α [TNF-α]): a lysosomal protein chromosome 16p13. Mutations Mis-sense mutations in CMT1C families Phenotype: classic CMT1 Autosomal dominant CMT1 families not linked to either CMT1A or CMT1B encodes a transcription factor expressed that regulates the expression of myelin proteins including PMP-22, P0, Cx32, and periaxin in Schwann cells Chromosome 10q21-q22 Mutations CMT1D DSS, congenital hypomyelination neuropathy Respiratory compromise, cranial nerve dysfunction • Severe childhood-onset, autosomal-recessive demyelinating neuropathies or CMT4 • myotubularin-related protein-2 (MTMR2), • N-myc downstream regulated gene-1 (NDRG1) • Ganglioside-induced differentiation-associated protein-1 (GDAP1) • Early growth response (EGR2) • Periaxin • Others CMT4F Periaxin Severe CMT/DSS Associated with mutations in genes affecting intracellular processes such as axonal transport, membrane trafficking, mitochondrial function and protein translation CMT2A1 (1p35) kinesin protein axonal transport of synaptic vesicles CMT2A2 (1p36) Most common CMT2 Mitofusin2 (mitochondrial) Early, more severe +/- optic atrophy CMT2B (3q13-22) prominent sensory ,foot ulcerations similar to HSN1 (no lancinating pain) CMT2C Vocal cord respiratory failure, shortened life expectancy CMT2D (12q24) (7p14) weakness and atrophy more severe in hands than feet HNs are heterogeneous clinically, electrophysiologically and genetically. The evaluation starts with discerning the phenotype. CMT can generally be classified to demyelinating (CMT1 and 4) and axonal (CMT2) . HNPP is hereditary liability to multiple compression neuropathies with a demyeinating neuropathy. Demyelinating HN result from a variety of mutations in gene encoding proteins related to myelin structure and function (e.g. PMP-22 in CMT1A and HNPP, MPZ in CMT1B, CX32 in CMTX). CMT2, axonal, results from mutations in genes encoding proteins involved in axonal transport, mitochondrial function and translation (e.g. kinesin, mitofusin) Inheritance is mostly AD except for CMTX and uncommon AR forms eg CMT4 and others. Neurology in clinical practice, 5th edition, Walter G. Bradly and others Sorting out the inherited neuropathies. Practical Neurology 2007; 7;93-105 The dominantly inherited motor and sensory neuropathies: clinical and molecular advances. Muscle and Neurve 2006; 33:589597 Questions or comments…?