WHAT IS CMT4B3?

 

ONE GENE CHANGES EVERYTHING

(SBF1, MTMR5, DENND7A)

WHAT IS CMT4B3?

CMT4B3 is an ultra-rare form of Charcot-Marie-Tooth Disease (CMT) that affects the peripheral nerves, leading to severe motor function deterioration. While there are around 100 different forms of CMT, most typically begin affecting individuals in their 30s or 40s. In the U.S., approximately 1 in 2,500 people have CMT, totaling about 150,000 individuals, and about 3 million worldwide. This makes CMT as prevalent as Multiple Sclerosis (MS) and more common than Lou Gehrig's Disease (ALS). Despite its prevalence, CMT is often unheard of.

Hunter’s type, CMT4B3, manifests early in life and poses significant challenges. With only 14 documented cases worldwide, the severity of this degenerative nerve disorder is profound. CMT4B3 causes the axons in peripheral nerves—the pathways connecting the brain and spinal cord to muscles and sensory organs—to break down, ultimately leading to nerve death and muscle atrophy. This condition results in progressive and irreversible muscle wasting, loss of function in the arms, hands, legs, and feet, and can lead to paralysis and potential blindness.

Discovered in 2013, CMT4B3 is caused by a genetic mutation in the SBF1 gene on chromosome 22, which is responsible for producing the MTMR5 protein. Mutations in genes encoding myotubularin proteins have been linked to various diseases, including CMT4B1 and CMT4B2. Unfortunately, little is known about CMT4B3 at this time.

KNOWN SYMPTOMS OF CMT4B3
The symptoms of CMT4B3 can vary among patients but may include:

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  • Microcephaly

  • Strabismus

  • Cognitive Delay

  • Brain Atrophy

  • Intellectual Impairment

  • Limb Weakness

  • Muscle Weakness

  • Sensory Loss

  • Loss of Deep Tendon Reflexes

  • Reduced Action Potential Amplitude

  • Decreased Nerve Conduction Velocity

  • Fibrillation

  • Depleted Myelinated Axons

  • Focally Folded Myelin Sheaths

  • Spine Disorders

  • Scoliosis

  • Lumbar Hyperlordosis

  • Kyphoscoliosis

  • Short Stature

  • Gait Difficulties

  • Pes Cavus

  • Pes Planus

  • Drop-foot

  • Joint Laxity / Thumb Sign

  • Syndactyly

  • Complex Cranial Nerve involvement

  • Astigmatism

  • Gynecomastia

  • Hearing Loss

  • Nystagmus

  • Strabismus

  • Ophthalmoparesis

  • Absent Pupil Reactivity

  • Facial Weakness

  • Tongue Weakness

  • Abnormal gag reflex

  • Dysarthria

  • Dysphagia

  • Oromandibular Dystonia

  • Gynecomastia

  • Elongated Face / Wide Philtrum

  • Respiratory Involvement

  • Urinary incontinence

HOW DO YOU GET CMT4B3?

CMT4B3 is inherited in an autosomal recessive pattern, meaning a child must inherit two copies of a mutated gene—one from each parent. Often, the biological parents show no symptoms as one functional gene can compensate for the defective one. If both parents are carriers, there’s a 25% chance of having an unaffected child with two normal genes, a 50% chance of an unaffected child who is also a carrier, and a 25% chance of having an affected child with two recessive genes.

 
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Our funding and grants will support scientists and labs researching the function and relationship between protein loss and Hunter’s disease. We hope that by learning more about CMT4B3, we can develop effective treatments not only for Hunter but for others affected by rare and peripheral nerve disorders.

SCIENTIFIC DETAILS

HGNC Approved Gene Symbol: SBF1
Cytogenetic location: 22q13.33
Genomic coordinates (GRCh38): 22:50,444,999-50,475,034 (from NCBI)

CMT4B3 is an autosomal recessive disease caused by homozygous or compound heterozygous mutation in the SBF1 gene (603560) on chromosome 22q. Some myotubular proteins (MTMR) members contain catalytically inactive phosphatase domains, and thus, they belong to a subgroup called “pseudophosphatases” (i.e. MTMR5 and MTMR13). Studies suggested that MTMR5 and MTMR13 interact with MTMR2 directly via their coiled-coil domains (between the phosphatase domain and the PH domain), increasing the phosphatase activity of MTMR2 as well as commanding its subcellular localization. MTMR5 is thought to regulate the autophagy rate in cells. Phosphatases; myotubular proteins (MTMRs) possess 3-phosphatase activity toward both PtdIns3P and PtdIns (3,5)P 2 poliphosphoinositides (PPIn).

In the grand scheme of CMT, these three MTMR proteins are important in the vesicle trafficking pathway within neuronal cells, and cells that create the myelin sheaths – Schwann cells and oligodendrocytes. The vesicle trafficking pathway is a vital process that helps move proteins within the cell, out of the cell, as well as taking in proteins and other things from the outside. MTMR5 and MTMR13 are homologues which share 59% overall sequence identity. As MTMR5 is the closest homologue of MTMR13, it is possible that the loss of function in MTMR5 could also induce dysfunction in neuronal or Schwann cells via a similar mechanism with the MTMR2/MTMR13 complex. This may explain the strikingly similar phenotypes of patients with recessive mutations in the MTMR2, SBF2, and SBF1 genes.