شاركو ماري توث

[بوادري]

أرجو أن تشرحوا لنا بشكل مفصل عن مرض (شاركو ماري توث ) او الضمور العصبي الشظوي

 

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اسال الله العظيم رب العرش العظيم أن يشفيك

 

[خطيب]

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Background

Charcot-Marie-Tooth (CMT) disease was first recognized independently in France and Great Britain (Charcot and Marie, 1886; Tooth, 1886). A few years later, a more severe form of inherited neuropathy was described (Dejerine and Sottas, 1893). More recent nomenclature designated Charcot-Marie-Tooth disease as a hereditary motor and sensory neuropathy (HMSN). Recent advances in genetic research have identified several types of HMSN, which correspond with specific genetic mutations. In 1968, Dyck and Lambert created a broader classification system, which is as follows:

• HMSN types 1A and B (dominantly inherited hypertrophic neuropathies)
• HMSN type 2 (neuronal type of peroneal muscular atrophy)
• HMSN type 3 (hypertrophic neuropathy of infancy [Dejerine-Sottas])
• HMSN type 4 (hypertrophic neuropathy [Refsum] associated with phytanic acid excess)
• HMSN type 5 (associated with spatic paraplegia)
• HMSN type 6 (with optic atrophy)
• HMSN type 7

This article discusses only HMSN types 1, 2, and 3 because these are the most commonly occurring hereditary neuropathies. Other forms of HMSN are extremely rare.
Pathophysiology

HMSN 1 is the most common form of hereditary neuropathy. Severely and uniformly slowed nerve conduction velocities (NCVs) and primary hypertrophic myelin pathology with prominent onion bulbs and secondary axonal changes are the hallmarks of the disease.
HMSN 2, on the other hand, represents the nondemyelinating neuronal type with relatively normal NCVs and primary axonal pathology. Although nerves are not enlarged in the neuronal form, weakness often is less marked and onset of this neuropathy is delayed.
Frequency

United States

Estimates of the frequency of Charcot-Marie-Tooth disease vary widely. In 1974, Skre and colleagues reported a prevalence of 1 case per 2500 individuals, whereas another worldwide meta-analysis estimated a prevalence of 1 per 10,000 individuals (Emery, 1991). Charcot-Marie-Tooth disease type 1 accounts for about two thirds of cases and Charcot-Marie-Tooth disease type 2 accounts for about one third of cases, while other forms of Charcot-Marie-Tooth disease are very rare.
Mortality/Morbidity

• Usually, life expectancy is normal.
• Disability is highly variable and difficult to predict in young individuals. This is related, at least in part, to the variable genetic penetrance of the disorders.
• In general, Charcot-Marie-Tooth disease is a slowly progressive condition. If progression accelerates, other causes, such as acquired neuropathies or other inherited neuromuscular conditions, should be sought.

Race

No racial predilection is reported for Charcot-Marie-Tooth disease.
Sex

The male-to-female ratio is not established. Often, males are affected slightly more than females; however, this is possibly due to an increased likelihood of nerve trauma.
Age

• The onset of HMSN 1 in the first decade of life is typical, but disease develops in some patients in young or mid adulthood.
• Patients with HMSN 2 are usually asymptomatic until later in life, and the symptoms most commonly begin in the second decade of life.
• The onset of HMSN 3 is in early childhood.[/align]

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History

• Hereditary motor and sensory neuropathy type 1<LI class=plain>
  • Because of its insidious onset, some patients are unaware of their disease or seek medical attention only late in life. In contrast to acquired neuropathies in which pain in a prominent feature, patients with HMSN1 experience a relative lack of pain.
  • Motor symptoms predominate over sensory symptoms.
  • Often, patients report loss of balance, muscle weakness, and foot deformities.
  • Onset in the first decade of life is typical, but disease develops in some patients in young or mid adulthood.
  • Patients report tripping over objects because of foot drop. Ankle sprains and fractures are frequent.
  • Because of hammertoes and high arches, patients have difficulty finding well-fitting shoes or experience painful calluses.
  • Cold feet, often associated with hair loss or leg edema, is common.
  • Not infrequently, asymptomatic individuals are discovered during screening of families after one relative has been diagnosed.
• Hereditary motor and sensory neuropathy type 2: Not infrequently, asymptomatic individuals are discovered during screening of families after one relative has been diagnosed.
• Hereditary motor and sensory neuropathy type 3 (Dejerine-Sottas syndrome)
• • This is a rare hypertrophic neuropathy of infancy inherited as an autosomal recessive trait.
  • The clinical features are those of a severe neuropathy with onset in early childhood.
  • Motor development is delayed.
  • Jumping and running are impaired.
  • Muscular weakness is progressive, affecting legs and arms.

Physical

• Hereditary motor and sensory neuropathy type 1<LI class=plain>
  • Roughly half of patients with CMT could be grouped into a classic phenotype associated with distal weakness, decreased tendon reflexes, foot deformities, with or without sensory loss. Weakness and muscle atrophy, which is dominant distally, affect the legs more severely and earlier than the arms.
  • Sensation may be normal until adulthood, but mild diffuse sensory loss is common.
  • Hyporeflexia or areflexia is the rule.
  • Foot deformities include high arches or flat feet, hammertoes, and tight Achilles tendons.
  • Enlargement and excessive firmness are found in the nerves of more than 25% of patients and are often visible in the superficial cervical nerves and palpable in the arms.
  • Tremor occurs in up to 25% of patients.
• Hereditary motor and sensory neuropathy type 2<LI class=plain>
  • Peripheral nerves are not enlarged clinically, and weakness of feet and leg muscles predominates; hands are less severely affected than the legs.
  • Patients experience sensory loss in the distal extremities, and foot deformities (ie, pes cavus) tend to be less marked than those of HMSN 1.
• Hereditary motor and sensory neuropathy type 3
• • General areflexia with prominent enlarged peripheral or cranial nerves is typical.
  • Patients experience a definite sensory loss, and some patients have marked sensory ataxia.

Causes

• Genetic defects in inherited demyelinating neuropathies. Current estimates indicate that up to 60% of patients with CMT1 have the chromosome 17 duplication.
• • HMSN type 1A - Duplication on chromosome 17 (region containing human peripheral myelin protein 22 [PMP22] gene), point mutation in PMP22 gene, autosomal dominant inheritance, with the HMSN 1 locus mapped on the short arm of chromosome 17 (p11.2-p12 band)
  • HMSN type 1B - Point mutation in the P0 gene (an important structural protein of peripheral nerve myelin) on the long arm of chromosome 1, linked to the Duffy blood group
  • HMSN type 2 - Gene localized to chromosome 1
  • HMSN type 3 (Dejerine-Sottas disease) - Missense and point mutation in PMP22 (recent genetic studies) and the P0 gene, other undetermined causes
  • HMSN type X
    • X-linked dominant HMSN is phenotypically similar to HMSN type 1. Male subjects tend to be more severely affected, whereas female subjects may have a mild neuropathy or be asymptomatic.
    • No male-to-male transmission occurs.
    • Linkage analysis localized the locus to the proximal long arm of the X chromosome; a recent study isolated a gap junction protein, connexin 32, as the candidate gene, which, if abnormal, can cause HMSN X.
• Lupski and coworkers reported that a segment band of chromosome 17 (17p11.2-p12) was duplicated in affected members of families with HMSN 1A. The PMP22 gene is found in the region of the duplication. PMP22 encodes for the synthesis of a peripheral nervous system myelin protein. Most patients with genetically defined HMSN 1A have either a gene dose effect (ie, duplication of 17p11.2-p12) or a mutation affecting the PMP22 gene on chromosome 17. Interestingly, the human PMP22 gene is deleted in patients with HSMN with liability to pressure palsies.[/align]

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Other Problems to be Considered


Charcot-Marie-Tooth disease type 1B
Charcot-Marie-Tooth disease type 1A
Charcot-Marie-Tooth disease type 10
Charcot-Marie-Tooth disease type 2
Dejerine-Sottas syndrome
Congenital hypomyelination neuropathy
Acquired neuropathies
Chronic inflammatory demyelinating polyneuropathy (CIDP)
[/align]

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Lab Studies

• The workup should include tests that address causes of neuropathies, such as endocrinologic, infectious, and immunologic abnormalities; vitamin and nutritional deficiencies; and nerve compression.
• On cerebrospinal fluid (CSF) analysis, CSF protein levels usually are within the reference range in patients with Charcot-Marie-Tooth disease type 1B, but they may be elevated above 100 mg/dL. By contrast, CSF protein is elevated in most but not all cases of Dejerine-Sottas syndrome.

Other Tests

• Genetic testing: Patients in whom the clinical phenotype, family history, and findings on electrodiagnostic studies suggest an inherited neuropathy should undergo genetic testing. Genotyping permits sound genetic and prognostic counseling and advances the scientific understanding of phenotypes.

Procedures

• Electrodiagnostic studies
• • Charcot-Marie-Tooth disease type 1 is characterized typically by diffuse and uniform motor conduction velocity slowing in virtually all the nerves tested. In 1980, Harding and Thomas proposed a criterion that motor conduction velocity less than 38 m/s be used as the cutoff value for HMSN 1, provided the compound muscle action potential (CMAP) is at least 0.5 mV in the nerve where the conduction velocity is tested. Recent multiple studies have shown that neurophysiologic testing on the median and peroneal nerves revealed mean motor NCVs of 20 m/s (range, 5 m/s to 34 m/s) and 17 m/s (range, 10 m/s to 22 m/s), respectively. If temporal dispersion of the CMAP or conduction block is found, an alternative diagnosis, such as CIDP, should be considered.
  • Motor NCVs are near normal or normal in patients with HMSN 2. Sensory nerve action potentials (SNAPs) are reduced uniformly or are absent.
  • Motor conduction velocities are reduced markedly, usually below 10 m/s in patients with HMSN 3 (ie, Dejerine-Sottas syndrome).

Histologic Findings

Most nerve biopsies from patients with Charcot-Marie-Tooth disease show evidence of a hypertrophic demyelinating neuropathy, with onion bulbs as evidence of chronic remyelination and loss of myelinated fibers, preferentially those of large diameter. Focally sausagelike thickenings of myelin sheath (tomacula) have been described in patients with Charcot-Marie-Tooth disease. Note that tomaculous neuropathy also is a hallmark of hereditary neuropathy with liability to pressure palsy resulting from a deletion of PMP22 at band 17p11.2 and rare PMP22 nonsense mutations. Dejerine-Sottas syndrome and congenital hypomyelination neuropathy are characterized by more severe hypomyelination and demyelination and axonal loss.
[/align]

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Medical Care

Prevention, recognition, and treatment of acquired neuropathies are particularly important if compression neuropathies are to be avoided. This may require adjustments in lifestyle and avoidance of job-related nerve injury. Patients, family members, and physicians must be aware of drugs that can affect the peripheral nervous system.

• Physical therapy is often required to prevent and treat joint deformities. Prosthetic devices, such as ankle-foot orthoses, can prevent Achilles tendon shortening and prolong near-normal ambulation. At times, boots can delay the need for such ankle braces. Thick-handled tools and cutlery can render certain activities of daily living easier.
• Pain may result from joint deformities or compensatory overuse of certain muscle groups. Some types of pain may respond to nonsteroidal anti-inflammatory drugs (NSAIDs). Dysesthetic pain may occur but is not typical; it responds to antidepressants, such as amitriptyline, desipramine, or paroxetine, and to anticonvulsants, such as gabapentin or carbamazepine.
• Recent research and updates proposed that the most common form of inherited peripheral neuropathy results from overexpression of a single gene. Simple application of an antiprogesterone drug can reduce gene expression and alleviate symptoms in a rat model. Sereda et al described the first successful treatment strategy in a rat model of Charcot-Marie-Tooth subtype 1A (CMT-1A), the most common variant of the inherited peripheral neuropathies. Their observations offer a glimpse of hope for patients, provided their strategy can be translated into clinical trials in humans.

Surgical Care

Depending on the degree of foot deformities, patients may benefit from Achilles tendon lengthening, tendon transfers, hammertoe correction, and release of the plantar fascia.
Diet

Patients should maintain a well-balanced diet and avoid obesity, which can contribute to spinal root diseases and certain entrapment neuropathies (eg, meralgia paresthetica).[/align]

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Complications

• Rare complications include radiculopathies due to enlarged nerve roots.

Prognosis

• Life expectancy is normal.
• Disability is highly variable and difficult to predict in young individuals, even among siblings[/align]

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Medical/Legal Pitfalls

• HMSN and its variants are uncommon disorders and can be difficult to diagnose and treat. Frequently, patients with this disorder require referral to a medical center specializing in neuropathic disorders.
• Associated conditions must be excluded and treated appropriately.

Special Concerns

• No particular complications are associated with pregnant women with Charcot-Marie-Tooth disease type 1B.
• As with surgical procedures, prolonged positioning of the body and limbs in particular postures can result in nerve compression, which could make any underlying neuropathy worse.
• Regional anesthesia is contraindicated in Charcot-Marie-Tooth disease.
• Because of the variability of clinical manifestations, couples who have symptomatic or asymptomatic Charcot-Marie-Tooth disease type 1B may have homozygous offspring with Dejerine-Sottas syndrome or congenital hypomyelination neuropathy.

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[salo_spain]

مرض شاركوت – ماري- توث }

مرض شاركوت – ماري- توث } ​

هو مرض شائع جدا" اذ تصل نسبته في الولايات المتحدة 1\2500
يرجع اسم المرض الى اسماء الاطباء الذين اوجدوه بالبداية جان مارتين شاركوت–عام 1886
و بيير ماري في فرنسا و هوارد هنري توث في جامعة كامبريدج
و يعرف هذا المرض ايظا" HERIDITARY MOTOR and SENSORY NEUROPATHY
اعتلال اعصاب وراثي حركي و حسي يصيب الاعصاب المحيطية و يؤدي الى ضمور عضلات ذات منشأ عصبي
الاعصاب المصابة خارج الدماغ و النخاع الشوكي اذ تصيب الاطراف فيحث خلل حسي و حركي بعضلات الاطرافو لذلك نسميه اعتلال اعصاب محيطي ​

ما هي اعراض هذا المرض؟
تتأثر الوضيفة الحسية و الحركية للاطراف المصابة
- ضعف بالقدم و عضلات الساق
- هبوط قدم احيانا"
- خلل في استقامة الجسم بالوقوف و السقوط المتكرر او التعثر
- تشوه بالقدم- تشوه بالقوس للقدم مع تشكل اصابع المطرقة بسبب ضعف العضلات بين العظام في القدم و ظمورها يؤدي لى انكماش و شد في السلاميات الوسطى لاصابع القدم تسمى القدم حسب شكلها بجسم زجاجة الشمبانيا المقلوبة
- ضمور و ضعف في وظيفة اليدين في مرحلة متأخرة ناجم عن صعبة في استخدام الحركات الدقيقة باليدين ​

تحدث هذه الاعراض عند البالغين او في سن المراهقة احيانا" في وسط سن الشباب
تختلف الاعراض من مريض لآخر حتى اذا كان المرضى من نفس الاسرة
يمكن ان يظهر الالم بشكل متدرج و يصبح المريض بحاجة الى تداخل جراحي عظمي او اجهزة للمشي ​

في الحالات الصعبة تصاب عضلات الصدر و تؤدي لى صعوبة في التنفس
هذا المرض لا يسبب الموت و يمكن ان يعيش المريض حياة طبيعية ​

• ما هي انماط هذا المرض؟ ​

يوجد عدة انماط CMT1-CMT2-CMT 3-CMT 4- CMTX
CMT1 تختلف بحسب نسبة الاصابة في غمد النخاعين للاعصاب المحيطية
A- ذات مورثة غالبة و هو عبارة عن نسخة من المورث الطبيعي 17 و الذي يحمل خريطة تشكل غمد النخاعينPMP-22 protein
وجدت الدراسات ان الخلل في تشكل البروتين المذكور يؤدي في مرحلة متأخرة الى اصابة اليدين
CMT1B مورثة قاهرةجسمية تحمل مواصفات بناء البروتين الذي يصنع النخاع و اسمه بروتين زيروP0
تعتبر هذه البروتينان الكونات الاساسية للنخاعين و اي خلل يمكن ان يؤدي الى تكراره في التصنيع المستقبلي و الى زيادة المرض ايظا"CMTC
CMT2 خلل في تشكل الاكسون في الخلايا العصبية المحيطية اكثر من الغمد و هناك ايظا" عدة انماط
CMT3 –Dejerine-Sottas disease
اصابة شديدة في لنخاعين و تصيب الاطفال الرضع
يؤدي الى ضمور عضلات- ضعف بالحس الخلل الاساسي يكون بالبروتين زيرو
CMT4 له عدة انماط بحسب شدة اصابة النخاعين ذات مورثة متنحية يمكن ان تظهر عند الاقليات الدينية التي تتبع بكثرة زواج الاقارب
ضعف بالساق الى ان تصبح الحالة عجز كامل عن المشي في البلوغ
CMTX له علاقة بالمورثة الجنسيةX- conexin-32 gen on the X chromosome
هذا النوع من البروتين موجود في خلايا شوان و تؤدي الى فصل الوصل بين عصبونات الاعصاب لذلك يصيب الذكور بشكل شديد في اوخر سن الطفولة و في المراهقة ​

ما هي اسباب حدوث هذا المرض؟
يلعب غمد النخاعين حول خلايا شوان العصبية في الكسونات او العصبونات كدور الطبقة البلاستيكية العازلة حول سلك الكهرباء و عندما نزيل هذه الطبقة يحدث ضياع متفاوت للسيلة العصبية او الناقلية العصبية فلا تعد السيلة قادرة على الوصول الى الخلايا العضلية او تؤدي الى تأخر او بطئ في عمل العضلة او اصابتها بالكامل بحسب نسبة اذية غمد النخاعين
بعض الانماط كما ذكرت ذات صفة قاهرة و اخرى جنسية متنحية ​

- كيف يتم التشخيص؟
-
القصة المرضية- الامراض في الاسرة الوراثية و غيرها
-الفحص العصبي
- نشاط الطفل و تجاوبه مع الاسرة بالمنزل
يجب فحص العضلات
في الحالات الايجابية التشخيص_ ضعف بعضلات اليد و العضد و الساقين و القدمين
ضمور بالعضلات – ضعف في المنعكسات- ضياع بالحس
احيانا" يوجد ميلان بالطرف- خلع ورك ولادي و جنف
تضخم في الاعصاب و يمكن جسها في حالةCMT1 بسب ثخانة غمد النخاعين
في حال الشك يجب اجراء تخطيط عضلات و اعصاب
في حال ايجابية التخطيط نجري خزعة من العضلات المصابة مع استئصال جزء من العصب الخاص للعضلةCMT2- axon degenerations ​

- لا يوجد علاج لهذا المرض دوائي
- نحافظ على العضلات و عدم التشوه بالمراقبة و الاجهزة و المعالجة الفيزيئية تحت اشراف طبي
- جراحات تقويمية للاطراف للحفاظ على الوظيفة
- تقوية العضلات و التمطيط يمكن ان يبطئ من الاصابو و يحسن من الوظيفة
- تمرينات خاصة لتقوية عضلة القلب و التنفس
- السباحة مع المساعدة- المشي باستخدام جبائر و اجهزة خاصة
- التغذية الخاصة ​

تجري الابحاث على الهندسة الوراثية لدراسة اسباب حدوث هذا المرض
و تجري الدراسات على تطوير ادوية بتعديل الخريطة الوراثية ​

و انا بشكل خاص لا اؤمن بالهندسة الوراثية لانه يمكن ان نصلح مورثة معينة لكن بنفس الوقت يمكن ان نخلق مورثة مسؤولة عن خلل اكبر في البشرية
بعض الدراسات الواعدة على الحيوانات اعطت نتائج باستخدام العامل المنمي للعصبNerve growth factor مثل هرمون الندروجين ليحمي من زوال النخاعين ​

 

[القلب الحنون]

مشكوره على المعلومات

والله يشفي كل مريض

 

[بنت التحدي]

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