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Zpráva o onemocněních · Neurological

Congenital Myasthenic Syndrome

Whole genome sequencing evaluates all 30+ CMS genes (CHRNE, DOK7, RAPSN, COLQ, AGRN, SCN4A, and others), providing the gene-specific diagnosis that determines whether pyridostigmine, salbutamol, 3,4-DAP, or fluoxetine is the correct treatment.

Zpráva o onemocněních hledá vzácné varianty, o nichž je známo, že způsobují onemocnění, na něž se zpráva zaměřuje.

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O tomto condition

A group of rare, inherited disorders characterized by impaired transmission of nerve signals to muscles, leading to muscle weakness and fatigue, typically manifesting at or shortly after birth.

Congenital myasthenic syndromes (CMS) are a genetically heterogeneous group of inherited disorders of neuromuscular junction (NMJ) transmission caused by pathogenic variants in over 30 genes encoding presynaptic, synaptic cleft, and postsynaptic NMJ proteins. Unlike autoimmune myasthenia gravis (MG), which is caused by antibodies against acetylcholine receptors (AChR) or muscle-specific kinase (MuSK), CMS is genetic and present from birth or early childhood. CMS affects approximately 1 in 100,000 and is frequently misdiagnosed as seronegative autoimmune MG.

CMS subtypes are classified by the location of the NMJ defect: presynaptic (CHAT, SYT2), synaptic (COLQ, LAMB2), and postsynaptic (CHRNE, RAPSN, DOK7, AGRN, SCN4A). The most critical clinical distinction is that DOK7-CMS and COLQ-CMS are worsened by acetylcholinesterase inhibitors (pyridostigmine/Mestinon), the standard first-line treatment for autoimmune MG. Administering pyridostigmine to a DOK7 or COLQ patient based on an incorrect MG diagnosis produces clinical deterioration rather than improvement. Salbutamol (a β2-agonist) is the treatment of choice for DOK7-CMS.

Gene-specific CMS treatment represents one of the clearest examples of pharmacogenomic medicine in neurology: CHRNE (the most common CMS gene) responds to pyridostigmine and 3,4-DAP. RAPSN responds to pyridostigmine and salbutamol. DOK7 requires salbutamol and is worsened by pyridostigmine. COLQ requires ephedrine or salbutamol and is worsened by pyridostigmine. Slow-channel CMS (gain-of-function AChR variants) responds to fluoxetine or quinidine. Without molecular diagnosis, treatment is empirical, and the wrong empirical choice can cause life-threatening respiratory crisis.

DOK7-CMS and COLQ-CMS are actively WORSENED by pyridostigmine, the standard first-line myasthenia treatment. Misdiagnosis as autoimmune MG and treatment with pyridostigmine can cause respiratory failure in these patients.

Všech 6 onemocnění, která analyzujeme

Congenital Myasthenic Syndrome (All Types)

Umbrella term covering all congenital myasthenic syndromes, including the common CHRNE, RAPSN, DOK7 and MUSK forms.

Co se diagnózou změní

Many forms respond to specific medications such as pyridostigmine, salbutamol or ephedrine, and the right choice depends on the gene involved.

Analyzované geny

Známé také jako

CMS; congenital MG; congenital myasthenia; Congenital Myasthenic Syndromes; erb-Goldflam syndrome; myasthenia gravis congenital; myasthenia gravis pseudoparalytica

Zahrnuty jsou také specifické formy

  • Congenital Myasthenic Syndrome 4

    Autozomálně recesivní

    Any postsynaptic congenital myasthenic syndrome in which the cause of the disease is a mutation in the CHRNE gene.

    CHRNE

  • Congenital Myasthenic Syndrome 8

    Autozomálně recesivní

    Any congenital myasthenic syndrome in which the cause of the disease is a mutation in the AGRN gene.

    AGRN

  • Congenital Myasthenic Syndrome 5

    Autozomálně recesivní

    Congenital myasthenic syndrome caused by mutation(s) in the COLQ gene, encoding acetylcholinesterase collagenic tail peptide. It is inherited in an autosomal recessive manner.

    COLQ

  • Congenital Myasthenic Syndrome 6

    Autozomálně recesivní

    Congenital myasthenic syndrome caused by mutation(s) in the CHAT gene, encoding choline O-acetyltransferase. It is inherited in an autosomal recessive manner.

    CHAT

  • Congenital Myasthenic Syndrome 1a

    Autozomálně dominantní

    Any congenital myasthenic syndrome in which the cause of the disease is a mutation in the CHRNA1 gene.

    CHRNA1

Zahrnuje 37 příbuzných podtypů ↓
  • congenital myasthenic syndrome 10
  • congenital myasthenic syndrome 11
  • congenital myasthenic syndrome 12
  • congenital myasthenic syndrome 13
  • congenital myasthenic syndrome 14
  • congenital myasthenic syndrome 15
  • congenital myasthenic syndrome 16
  • congenital myasthenic syndrome 17
  • congenital myasthenic syndrome 18
  • congenital myasthenic syndrome 19
  • congenital myasthenic syndrome 1A
  • congenital myasthenic syndrome 20
  • congenital myasthenic syndrome 21
  • congenital myasthenic syndrome 2A
  • congenital myasthenic syndrome 2C
  • congenital myasthenic syndrome 3A
  • congenital myasthenic syndrome 3B
  • congenital myasthenic syndrome 3C
  • congenital myasthenic syndrome 4
  • congenital myasthenic syndrome 4A
  • congenital myasthenic syndrome 4B
  • congenital myasthenic syndrome 4C
  • congenital myasthenic syndrome 5
  • congenital myasthenic syndrome 6
  • congenital myasthenic syndrome 7
  • congenital myasthenic syndrome 8
  • congenital myasthenic syndrome 9
  • congenital myasthenic syndrome with tubular aggregates
  • myasthenia, congenital, refractory to acetylcholinesterase inhibitors
  • myasthenic syndrome, congenital, 1B, fast-channel
  • myasthenic syndrome, congenital, 22
  • myasthenic syndrome, congenital, 23, presynaptic
  • myasthenic syndrome, congenital, 24, presynaptic
  • myasthenic syndrome, congenital, 25, presynaptic
  • myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive
  • postsynaptic congenital myasthenic syndrome
  • presynaptic congenital myasthenic syndrome
MONDO:0018940Orphanet 590MedGen 155650

Proč sekvenování celého genomu

CMS treatment is entirely gene-specific: one gene's cure is another gene's poison. Molecular diagnosis is not optional; it is the difference between the right drug and the wrong drug.

The wrong treatment causes respiratory crisis: DOK7 patients given pyridostigmine deteriorate rather than improve

DOK7-CMS produces NMJ failure through impaired agrin-MuSK signaling and endplate remodeling. Pyridostigmine, by increasing acetylcholine concentration at an already dysfunctional endplate, exacerbates the NMJ pathology. Multiple case reports document respiratory decompensation in DOK7 patients treated with pyridostigmine based on an incorrect autoimmune MG diagnosis. Molecular DOK7 diagnosis triggers immediate pyridostigmine discontinuation and initiation of salbutamol, producing dramatic clinical improvement. This gene-specific treatment reversal is only possible with molecular diagnosis.

CMS is present from birth but frequently misdiagnosed for years: neonatal hypotonia, feeding difficulty, and ptosis should trigger NMJ evaluation

CMS typically presents in infancy with hypotonia, poor feeding, ptosis, and fatigable weakness, features that overlap with many other neonatal conditions. The diagnosis is frequently delayed for years because infant weakness is attributed to 'floppy baby syndrome,' cerebral palsy, or congenital myopathy. AChR antibody testing is negative (because CMS is not autoimmune), and the patient may be labeled as 'seronegative MG' without receiving genetic testing. WGS performed for unexplained neonatal or infantile weakness evaluates all CMS genes alongside other neuromuscular genes, identifying the treatable NMJ defect.

Další neurological conditions

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Jedna souprava, zaslaná domů. Celý váš genom je sekvenován na klinickém standardu používaném pro diagnostická rozhodnutí. Zprávy připravené pro lékaře doručíme do vašeho Genome Manageru během 6–8 týdnů — trvale platné a průběžně aktualizované s vývojem vědy.

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