X-linked Charcot–Marie–Tooth disease is a group of

genetic disorders A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders are ...

and a type of

Charcot–Marie–Tooth disease Charcot-Marie-Tooth disease (CMT) is an inherited neurological disorder that affects the peripheral nerves responsible for transmitting signals between the brain, spinal cord, and the rest of the body. This is the most common inherited neuropath ...

characterized by sensory loss associated with muscle weakness and atrophy alongside many other symptoms.

Signs and symptoms

Symptoms vary between subtypes, but generally they can be condensed into a basic summary: individuals with this condition have symptoms that, once present, progress over time (severity increases over time), these include: muscle weakness and

atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), malnutrition, poor nourishment, poor circulatory system, circulation, loss of hormone, ...

of the distal extremities (mostly involving

feet The foot (: feet) is an anatomical structure found in many vertebrates. It is the terminal portion of a limb which bears weight and allows locomotion. In many animals with feet, the foot is an organ at the terminal part of the leg made up of ...

legs A leg is a weight-bearing and locomotive anatomical structure, usually having a columnar shape. During locomotion, legs function as "extensible struts". The combination of movements at all joints can be modeled as a single, linear element cap ...

, and the thenar eminence of the hands), loss of sensation of the distal limbs, loss of reflexes of the deep tendon, high-arched feet, and (less commonly)

scoliosis Scoliosis (: scolioses) is a condition in which a person's Vertebral column, spine has an irregular curve in the coronal plane. The curve is usually S- or C-shaped over three dimensions. In some, the degree of curve is stable, while in others ...

. Symptoms that are less frequent among X-linked CMT disease patients include dysfunctions of the transient central nervous system which are associated with

dysphagia Dysphagia is difficulty in swallowing. Although classified under " symptoms and signs" in ICD-10, in some contexts it is classified as a condition in its own right. It may be a sensation that suggests difficulty in the passage of solids or l ...

dysarthria Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. It is a condition in which problems effectively occur with the ...

ataxia Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...

, generalized body weakness,

aphasia Aphasia, also known as dysphasia, is an impairment in a person's ability to comprehend or formulate language because of dysfunction in specific brain regions. The major causes are stroke and head trauma; prevalence is hard to determine, but aph ...

, and

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...

. Severe cases might exhibit proximal muscle weakness.

Complications

There are various complications associated with this condition, they are associated with the symptoms. One example is the localized loss of sensation characteristic of this condition which also takes temperature sensation with it, this might be dangerous due to the fact that someone might accidentally injure themselves not knowing something is hot.

Types

Although this condition is a type of

in on itself, it also has various subtypes with different symptoms, the following list comprises the 6 types of X-linked CMT: *X-linked Charcot–Marie–Tooth disease type 1: This subtype is characterized by childhood-onset progressive severe muscle weakness and atrophy of the distal lower limbs and intrinsic hand muscles, bilateral

foot drop Foot drop is a gait abnormality in which the dropping of the forefoot happens out of weakness, irritation or damage to the deep fibular nerve (deep peroneal), including the sciatic nerve, or paralysis of the muscles in the anterior portion of th ...

, high-arched feet,

hyporeflexia Hyporeflexia is the reduction or absence of normal bodily reflexes. It can be detected through the use of a reflex hammer and is the opposite of hyperreflexia. Hyporeflexia is generally associated with a deficit in the lower motor neurons (at ...

areflexia Hyporeflexia is the reduction or absence of normal bodily reflexes. It can be detected through the use of a reflex hammer and is the opposite of hyperreflexia. Hyporeflexia is generally associated with a deficit in the lower motor neurons (at t ...

of the tendons, and variable sensory loss of the lower limbs. Symptoms slightly less common than these ones include sensorineural

deafness Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss that precludes a person from understanding spoken language, an audiological condition. In this context it is writte ...

and problems of the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

. It is inherited in an

X-linked dominant ''Main Article:'' Sex linkage X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome. As an inheritance pattern, it is less common tha ...

manner. *X-linked Charcot–Marie–Tooth disease type 2: This subtype is characterized by infancy/childhood-onset progressive distal muscle weakness with atrophy that affects both lower and upper extremities (although it affects the lower extremities the most), high-arched feet, and areflexia of the

tendons A tendon or sinew is a tough band of dense fibrous connective tissue that connects muscle to bone. It sends the mechanical forces of muscle contraction to the skeletal system, while withstanding tension. Tendons, like ligaments, are made of ...

. Symptoms that are slightly less common than these ones include sensory loss and

intellectual disabilities Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...

. It is inherited in an

X-linked recessive ''Main Article'': Sex linkage X-linked recessive inheritance is a mode of Mendelian inheritance, inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily hemizygous for ...

manner. *X-linked Charcot–Marie–Tooth disease type 3: This subtype is characterized by childhood/adolescent-onset pain and

numbness Hypoesthesia or numbness is a common side effect of various medical conditions that manifests as a reduced sense of touch or sensation, or a partial loss of sensitivity to Sensory receptor, sensory stimuli. In everyday speech this is generally r ...

, progressive distal muscle weakness and atrophy which begins in the lower limbs and spreads to the upper limbs, distal upper and lower limb pain sensation loss, high-arched feet, and areflexia or hyporeflexia of the distal tendons.

Spastic paraparesis Hereditary spastic paraplegia (HSP) is a group of inherited diseases whose main feature is a progressive gait disorder. The disease presents with progressive stiffness (spasticity) and contraction in the lower limbs. HSP is also known as heredi ...

has also been reported. It is inherited in an X-linked recessive manner. *X-linked Charcot–Marie–Tooth disease type 4: This subtype is characterized by neonatal/early childhood-onset gradually progressive severe distal limb muscle weakness and atrophy (especially that affecting the peroneal muscles), sensory loss affecting upper and lower extremities (with the lower ones being affected the most), high-arched feet, generalized

, and

hammer toes A hammer toe, hammertoe or contracted toe is a deformity of the muscles and ligaments of the proximal interphalangeal joint of the second, third, fourth, or fifth toe, bending it into a shape resembling a hammer. In the early stage, a flexible ...

. Sensorineural deafness and cognitive disabilities have been reported. It is inherited in an X-linked recessive manner. *X-linked Charcot–Marie–Tooth disease type 5: This subtype is characterized by infancy/childhood-onset progressive distal limb muscle weakness and atrophy that affects both upper and lower extremities (although it is important noting that it appears and is more noticeable on the lower extremities),

, gait abnormalities, bilateral severe/profound

congenital hearing loss Congenital hearing loss is a hearing loss present at birth. It can include hereditary hearing loss or hearing loss due to other factors present either in-utero (prenatal) or at the time of birth. Genetic factors Genetic factors are thought to ...

and progressive

optic neuropathy Optic neuropathy is damage to the optic nerve from any cause. The optic nerve is a bundle of millions of fibers in the retina that sends visual signals to the brain. Damage and death of these nerve cells, or neurons, leads to characteristic featu ...

. It is inherited in an X-linked recessive manner. *X-linked Charcot–Marie–Tooth disease type 6: This subtype is characterized by childhood-onset gradual but progressive variable distal muscle weakness and atrophy affecting the lower extremities, distal limb panmodal sensorial anomalies, high-arched feet,

claw toes A hammer toe, hammertoe or contracted toe is a deformity of the muscles and ligaments of the Anatomical terms of location#Proximal and distal, proximal Interphalangeal articulations of foot, interphalangeal joint of the second, third, fourth, or ...

, ankle areflexia, and

steppage gait Steppage gait (high stepping, neuropathic gait) is a form of gait abnormality characterised by foot drop or ankle equinus due to loss of dorsiflexion. The foot hangs with the toes pointing down, causing the toes to scrape the ground while walking, ...

. It is inherited in an

manner.

Genetics

This condition's causative X-chromosome gene depends on what subtype of CMTX one has, they are generally the following: *Type 1:

GJB1 Gap junction beta-1 protein (GJB1), also known as connexin 32 (Cx32), is a transmembrane protein that in humans is encoded by the ''GJB1'' gene. Gap junction beta-1 protein is a member of the gap junction connexin family of proteins that regulat ...

, located in Xq13.1 *Type 2: Xp22.2 *Type 3: Rearragement of chromosome 8q24.3 and Xq27.1. *Type 4:

AIFM1 Apoptosis-inducing factor 1, mitochondrial is a protein that in humans is encoded by the ''AIFM1'' gene on the X chromosome. This protein localizes to the mitochondria, as well as the nucleus, where it carries out nuclear fragmentation as part of ...

, located in Xq26.1 *Type 5:

PRPS1 Ribose-phosphate diphosphokinase (or phosphoribosyl pyrophosphate synthetase or ribose-phosphate pyrophosphokinase) is an enzyme that converts ribose 5-phosphate into phosphoribosyl pyrophosphate (PRPP). It is classified under . The enzyme is i ...

, located in Xq22.3 *Type 6:

PDK3 Pyruvate dehydrogenase lipoamide kinase isozyme 3, mitochondrial is an enzyme that in humans is encoded by the ''PDK3'' gene. It codes for an isozyme of pyruvate dehydrogenase kinase.The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded m ...

, located in Xq22.11

Diagnosis

This condition can be diagnosed through nerve biopsy,

muscle biopsy In medicine, a muscle biopsy is a procedure in which a piece of muscle tissue is removed from an organism and examined microscopically. A muscle biopsy can lead to the discovery of problems with the nervous system, connective tissue, vascular s ...

whole genome sequencing Whole genome sequencing (WGS), also known as full genome sequencing or just genome sequencing, is the process of determining the entirety of the DNA sequence of an organism's genome at a single time. This entails sequencing all of an organism's ...

, alongside examination of symptoms exhibited by the patient.

Treatment

Although Charcot–Marie–Tooth disease has no cure, it can be treated and managed by doing the following: *

Physiotherapy Physical therapy (PT), also known as physiotherapy, is a healthcare profession, as well as the care provided by physical therapists who promote, maintain, or restore health through patient education, physical intervention, disease preventio ...

Occupational therapy Occupational therapy (OT), also known as ergotherapy, is a healthcare profession. Ergotherapy is derived from the Greek wiktionary:ergon, ergon which is allied to work, to act and to be active. Occupational therapy is based on the assumption t ...

Orthoses Orthotics () is a medical specialty that focuses on the design and application of orthoses, sometimes known as braces, calipers, or splints. An is "an externally applied device used to influence the structural and functional characteristics of ...

*Walking aids *Non-steroidal antiinflammatory medication *Tricylic antidepressants or anti-convulsants Treatment for physical deformities includes: *Osteotomy *Arthrodesis * Plantar fascia release *

Spinal surgery Neurosurgery or neurological surgery, known in common parlance as brain surgery, is the specialty (medicine), medical specialty that focuses on the surgical treatment or rehabilitation of disorders which affect any portion of the nervous system ...

Prognosis

Because of its X-linked nature, males with the condition tend to exhibit symptoms that are more severe than their female counterparts, who generally show very mild to no symptoms at all.

Prevalence

Overall, it is estimated that 10-15% of all cases of Charcot–Marie–Tooth disease come from X-linked Charcot–Marie–Tooth disease. It is the second most common type of Charcot–Marie–Tooth disease. According to OrphaNet, 1 out of every 100,000 people are affected by CMTX. The following information comes from the

OMIM Online Mendelian Inheritance in Man (OMIM) is a continuously updated catalog of human genes and genetic disorders and traits, with a particular focus on the gene-phenotype relationship. , approximately 9,000 of the over 25,000 entries in OMIM ...

pages for the 6 subtypes of CMTX *Type 1: 30-50 families *Type 2: 3 families *Type 3: 2 families *Type 4: 5 families *Type 5: 7 families *Type 6: 1 family

References

{{reflist, 35em X-linked dominant disorders Peripheral nervous system disorders Cytoskeletal defects Syndromes affecting the nervous system