Charcot–Marie–Tooths sygdom

Synonymer

CMT, neuropati, Charcot–Marie–Tooth disease, Charcot–Marie–Tooth neuropathy, hereditary motor and sensory neuropathy (HMSN), peroneal muscular atrophy (PMA)

Beskrivelse

Arvelig lidelse der rammer PNS med progressivt tab af muskelvæv og følesans

Forekomst

1:2500

Symptomer

Begynder som regel i den tidlige voksenalder men kan vente til 30-40 års alderen. Første symptom er som regel dropfod.

Årsag

Duplikation af en stor region på den korte arm af kromosom 17 (75% af CMT) som indeholder genet PMP22.

Klassifikation

CMT is a result of genetic mutations in a number of genes. Based on the affected gene, CMT can be categorized into types and subtypes.<ref name="Lupski2010" />

Clinical categories

Type	Name	Incidence	Notes
CMT1	Demyelinating type	Affects approximately 30% of CMT patients	Causes severe demyelination, thereby impairing nerve conduction velocity.
CMT2	Axonal type	Affects approximately 20–40% of CMT patients	Mainly affects axons. Tends to affect lower extremities more than upper extremities. Clinical symptoms are often less severe than in CMT1. As it is an axonopathy, average nerve conduction velocity is usually not affected (sometimes slightly below normal but mostly above 38 m/s).
CMT3	Dejerine-Sottas disease	Very rare	Does not impair nerve conduction velocity.
CMT4	Spinal type
CMT5	Pyramidal type
CMT6
CMTDI	Dominant intermediate type
CMTRI	Recessive intermediate type
CMTX	X-linked type	Affects approximately 10–20% of CMT patients	This type encompasses all CMT forms that are inherited in an X-linked manner. Average NCV: 25–40 m/s.

Genetic subtypes

Type	Subtype	OMIM	Gene	Locus	Inheritance	Notes
CMT1	CMT1A	Skabelon:OMIM2	PMP22	17p11.2	Autosomal dominant	The most common form of the disease, 70–80% of Type 1 patients. Average NCV: 20–25 m/s. Allelic with subtype CMT1E. When associated with subtype CMT1B (causing essential tremor and ataxia), it is called Roussy–Lévy syndrome.
	CMT1B	Skabelon:OMIM2	MPZ	1q23.3	Autosomal dominant	Responsible for 5–10% of Type 1 patients. Average NCV: < 15 m/s
	CMT1C	Skabelon:OMIM2	LITAF	16p13.13	Autosomal dominant	Usually shows up in infancy. Average NCV: 26–42 m/s. Symptoms are identical to CMT1A.
	CMT1D	Skabelon:OMIM2	EGR2	10q21.3	Autosomal dominant	Average NCV: 15–20 m/s
	CMT1E	Skabelon:OMIM2	PMP22	17p11.2	Autosomal dominant	Characterised by demyelination and loss of hearing; allelic with subtype CMT1A
	CMT1F	Skabelon:OMIM2	NEFL	8p21.2	Autosomal dominant
CMT2	CMT2A1	Skabelon:OMIM2	KIF1B	1p36.22	Autosomal dominant
	CMT2A2	Skabelon:OMIM2	MFN2	1p36.22	Autosomal dominant
	CMT2B	Skabelon:OMIM2	RAB7A RAB7B	3q21.3	Autosomal dominant
	CMT2B1	Skabelon:OMIM2	LMNA	1q22	Autosomal recessive	A laminopathy
	CMT2B2	Skabelon:OMIM2	MED25	19q13.33	Autosomal dominant
	CMT2C	Skabelon:OMIM2	TRPV4	12q24.11	Autosomal dominant	May cause vocal cord, diaphragm, and distal weakness
	CMT2D	Skabelon:OMIM2	GARS	7p14.3	Autosomal dominant	Symptoms are more severe in the upper extremities (hands), which is atypical for CMT
	CMT2E	Skabelon:OMIM2	NEFL	8p21.2	Autosomal dominant
	CMT2F	Skabelon:OMIM2	HSPB1	7q11.23	Autosomal dominant
	CMT2G	Skabelon:OMIM2	?	12q12–q13.3	Autosomal dominant
	CMT2H	Skabelon:OMIM2	GDAP1	8q21.11	Autosomal dominant	Allelic with subtype CMT2K
	CMT2I	Skabelon:OMIM2	MPZ	1q23.3	Autosomal dominant	Allelic with subtype CMT2J and forms of CMT3
	CMT2J	Skabelon:OMIM2	MPZ	1q23.3	Autosomal dominant	Allelic with subtype CMT2I and forms of CMT3
	CMT2K	Skabelon:OMIM2	GDAP1	8q21.11	Autosomal dominant	Allelic with subtype CMT2H
	CMT2L	Skabelon:OMIM2	HSPB8	12q24.23	Autosomal dominant
	CMT2M	Skabelon:OMIM2	DNM2	19p13.2	Autosomal dominant	Full name: CMT2M, included; more commonly classified as subtype CMTDIB
	CMT2O	Skabelon:OMIM2	DYNC1H1	14q32.31	Autosomal dominant	Allelic with spinal muscular atrophy with lower extremity predominance
	CMT2P	Skabelon:OMIM2	LRSAM1	9q33.3	Autosomal dominant Autosomal recessive	Juvenile or adult onset, slowly progressive
CMT3	CMT3	Skabelon:OMIM2	MPZ EGR2 PMP22 PRX	1q23.3 10q21.3 17p12 19q13.2	Autosomal dominant Autosomal recessive	More commonly known as Dejerine–Sottas disease; subtype CMT4F sometimes included here
CMT4	CMT4A	Skabelon:OMIM2	GDAP1	8q21.11	Autosomal recessive	Allelic with subtype CMTRIA
	CMT4B1	Skabelon:OMIM2	MTMR2	11q21	Autosomal recessive
	CMT4B2	Skabelon:OMIM2	SBF2	11p15.4	Autosomal recessive
	CMT4B3	Skabelon:OMIM2	SBF1	22q13.33	Autosomal recessive
	CMT4C	Skabelon:OMIM2	SH3TC2	5q32	Autosomal recessive	May lead to respiratory compromise
	CMT4D	Skabelon:OMIM2	NDRG1	8q24.3	Autosomal recessive	Characterised by demyelination and loss of hearing
	CMT4E	Skabelon:OMIM2	MPZ EGR2	1q23.3 10q21.3	Autosomal recessive	Also known as congenital hypomyelinating neuropathy; phenotype largely overlapping with subtype CMT4F
	CMT4F	Skabelon:OMIM2	PRX	19q13.2	Autosomal recessive	Phenotype largely overlapping with subtype CMT4E; may be the same as CMT3
	CMT4G	Skabelon:OMIM2	HK1	10q22.1	Autosomal recessive	Also known as Russe-type hereditary motor and sensory neuropathy (HMSNR); second most common cause of CMT in the Spanish Roma population
	CMT4H	Skabelon:OMIM2	FGD4	12p11.21	Autosomal recessive
	CMT4J	Skabelon:OMIM2	FIG4	6q21	Autosomal recessive	Allelic to amyotrophic lateral sclerosis type 11
CMT5	CMT5	Skabelon:OMIM2	?	4q34.3–q35.2	Autosomal dominant	Also known as CMT with pyramidal features; onset in 2nd decade of life with distal muscle wasting, particularly in legs
CMT6	CMT6	Skabelon:OMIM2	MFN2	1p36.22	Autosomal dominant	Characterised by optic atrophy, hence known also as CMT with optic atrophy
CMTDI	CMTDIA	Skabelon:OMIM2	?	10q24.1–q25.1	Autosomal dominant
	CMTDIB	Skabelon:OMIM2	DNM2	19p13.2	Autosomal dominant	Also classified as subtype CMT2M
	CMTDIC	Skabelon:OMIM2	YARS	1p35.1	Autosomal dominant
	CMTDID	Skabelon:OMIM2	MPZ	1q23.3	Autosomal dominant
	CMTDIE	Skabelon:OMIM2	INF2	14q32.33	Autosomal dominant
CMTRI	CMTRIA	Skabelon:OMIM2	GDAP1	8q21.11	Autosomal recessive	Allelic with subtype CMT4A
	CMTRIB	Skabelon:OMIM2	KARS	16q23.1	Autosomal recessive
CMTX	CMTX1	Skabelon:OMIM2	GJB1	Xq13.1	X-linked dominant	Responsible for approximately 90% of CMTX patients; some studies put this number significantly higher.<ref>Skabelon:Cite journal</ref><ref>Skabelon:Cite book</ref>
	CMTX2	Skabelon:OMIM2	CMTX2	Xq22.2	X-linked recessive
	CMTX3	Skabelon:OMIM2	CMTX3	Xq26	X-linked recessive
	CMTX4	Skabelon:OMIM2	NAMSD	Xq24–q26.1	X-linked recessive	Also known as Cowchock syndrome
	CMTX5	Skabelon:OMIM2	PRPS1	Xq22.3	X-linked recessive	Also known as Rosenberg–Chutorian syndrome; signs include optic atrophy, polyneuropathy and deafness
Type	Subtype	OMIM	Gene	Locus	Inheritance	Notes

It has to be kept in mind that sometimes a particular patient diagnosed with CMT can exhibit a combination of any of the above gene mutations; thus, in these cases precise classification can be a little arbitrary.