LGMD

• 肢帯型筋ジストロフィー limb-girdle muscular dystrophy

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/02/28 16:05:44」(JST)

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Limb-girdle muscular dystrophy
Classification and external resources
Specialty	neurology
ICD-10	G71.0
ICD-9-CM	359.1
OMIM	159000 159001 607801 603511 602067 608423 609115 253600 253601 253700 608099 604286 601287 601954 254110 607155 608807 609308 611307 611588 607439 606822
DiseasesDB	32189
MedlinePlus	000711
eMedicine	neuro/189
MeSH	D049288
GeneReviews	Limb-Girdle Muscular Dystrophy Overview Calpainopathy Dysferlinopathy

Limb-girdle muscular dystrophy (LGMD) or Erb's muscular dystrophy is a genetically and clinically heterogeneous group of rare muscular dystrophies. It is characterised by progressive muscle wasting which affects predominantly hip and shoulder muscles.

LGMD has an autosomal pattern of inheritance and currently has no known cure.

It is similar to but distinct from Duchenne muscular dystrophy and Becker's muscular dystrophy.

Presentation

The term limb-girdle is used to describe these disorders because the muscles most severely affected are generally those of the hips and shoulders—the limb girdle muscles.

Symptoms of limb-girdle muscular dystrophy vary widely, but most commonly are muscle weakness and atrophy, myoglobinuria, myotonia, elevated serum CK, and, in ~20% of cases, cardiomyopathy.

The disease inevitably gets worse over time, although progression is more rapid in some patients than others. Eventually the disease can affect other muscles such as the ones located in the face. The disease commonly leads to dependence on a wheelchair within twenty to thirty years of symptom onset, but there is high inter-patient variability, with some patients maintaining mobility.

The muscle weakness is generally symmetric, proximal, and slowly progressive.

In most cases, pain is not present with LGMD, and mental function is not affected.

LGMD can begin in childhood, adolescence, young adulthood or even later. The age of onset is usually between 10 and 30. Both genders are affected equally. When limb-girdle muscular dystrophy begins in childhood the progression appears to be faster and the disease more disabling. When the disorder begins in adolescence or adulthood the disease is generally not as severe and progresses more slowly.

There is no sensory neuropathy or autonomic or visceral dysfunction at presentation. The specific dermatomes affected can be demonstrated clinically, and although lower limb deep tendon reflexes and plantar reflex are lost, abdominal reflexes are preserved.

Symptoms

A person with LGMD generally has difficulty walking, going both up and down stairs and raising from a chair or a squatting position. Difficulty bending over and falling on a regular basis are also common. Difficulty lifting certain objects is also a common presentation of LGMD as well as difficulty holding your arms out or above your head. Eventually the ability to walk/run deteriorates. It is advised that someone with the disorder not put themselves in situations of potential peril. For example, walking on floors that have even the slightest incline can cause the individual to lose balance and fall. It is not recommended for someone with the disease to walk on terrain which is not stable such as ice or other slippery surfaces to avoid a severe injury. This is mainly due to the fact that LGMD weakens the leg muscles so an individual with LGMD would be more inclined to fall than someone who does not suffer from the disorder. At times, heart palpitation can occur.

Prognosis

The distal muscles are affected late in LGMD, if at all. The disease typically causes loss of mobility or dependence on a scooter/wheelchair within 20 to 30 years of symptom onset. The various forms of LGMD are highly variable, and can be variable even among persons with the same form of LGMD. In its most severe form, LGMD2C, the symptoms are usually similar to Duchenne Muscular Dystrophy, with individuals losing the ability to walk between ages 10 and 12. In its mildest form, affected individuals have near-normal muscle strength and function.

While LGMD isn't typically a fatal disease, it may eventually weaken the heart and respiratory muscles, leading to illness or death due to secondary disorders. In its most severe form, LGMD2C, lifespans are typically limited to the 20s or early 30s. The mildest forms do not significantly affect lifespan.

Diagnosis

A muscle biopsy will show the presence of muscular dystrophy, and genetic testing is used to determine which type of muscular dystrophy a patient has. A consortium of LGMD Family Foundations (http://www.lgmd-diagnosis.org/about-the-sponsors) are offering free genetic sequencing for patients in the United States with muscle weakness (http://lgmd-diagnosis.org). The Jain Foundation (http://www.jain-foundation.org/) is an organization that helps patients become genetically diagnosed and has created an online tool for physicians called "ALDA (http://jain-foundation.org/lgmd-subtyping-tool/)," which predicts the LGMD subtype, saving time and money by avoidance of sequencing each LGMD by suggesting which are the most likely. ALDA is also now connected to the LGMD-diagnosis.org program and physicians are automatically offered the chance to apply for free genetic sequencing for eligible patients.

Currently a "CHIP" is being developed by an organization called "NMD CHIP".

The project is designing chips for the diagnosis of mutations already known to cause Duchenne / Becker muscular dystrophies (DMD/BMD), limb girdle muscular dystrophies (LGMD), congenital muscular dystrophies (CMD), and hereditary motor-sensory neuropathies or Charcot-Marie-Tooth neuropathies (CMT). These diagnostic chips are described as "known-gene chips".

Genetics

LGMD is typically an inherited disorder, though it may be inherited as a dominant or recessive genetic defect. The result of the defect is that the muscles cannot properly form certain proteins needed for normal muscle function. Several different proteins can be affected, and the specific protein that is absent or defective identifies the specific type of muscular dystrophy. Among the proteins affected in LGMD are α, β, γ and δ sarcoglycans. The sarcoglycanopathies could be possibly amenable to gene therapy.

Treatment

Although exercise and physical therapy are advised to maintain as much muscle strength and joint flexibility as possible, there are few studies corroborating the effectiveness of exercise. Physical therapy and exercise may prevent the rapid progression of the disease rather than halt or reverse it. Calipers may be used to maintain mobility and quality of life. Careful attention to lung and heart health is also required. IVIg may increase strength in some forms and prevent progression in others, possibly through the prevention of fibrosis and inflammation without the secondary weakening caused by corticosteroids.

Prevention

Because it is a hereditary disorder, there is nothing an individual can do to prevent getting the disease. Because the weakness can affect the heart muscle, it is recommended that a doctor be aware of any heart-related symptoms so a cardiac pacemaker can be implanted to reduce the risk of sudden death due to an abnormal heart rhythm caused from the disease.

Research

There is a variety of research under way targeted at various forms of LGMD. Methods thought to hold significant promise for an effective treatment include "exon skipping" and gene therapy. Several clinical trials are under way and seeking to apply these methodologies to various limb girdle dystrophies.

GENETHON - LGMD 2C(Gamma-sarcoglycanpathy)

The results of a Phase I clinical trial of gene therapy for limb-girdle muscular dystrophy type 2C were published in the journal Brain in January 2012. The trial started in December 2006 and has been sponsored by Généthon (the not-for-profit research lab created by the French Muscular Dystrophy Association (AFM) and which is funded almost exclusively by donations from France's annual Telethon). The trial at Pitié-Salpêtriere (AP-HP) is being led by principal investigators Professor Serge Herson (Head of the Department of Internal Medicine 1) and Professor Olivier Benveniste (Institute of Myology). The study's primary objective was to evaluate the safety of local injection of increasing doses of an adeno-associated virus (AAV) vector harboring a "healthy" copy of the gene for gamma-sarcoglycan (the defective protein in this disease). Secondary objectives included the assessment of local and systemic immune reactions and the quality of gene transfer in the injected muscles in terms of efficacy, expression and distribution. The trial's results have just been published and were encouraging. Above all, the injections were well tolerated and not associated with adverse physical or biological effects. Immunohistochemical analysis of injected-muscle biopsy specimens showed ?SGC expression in three out the three patients who received the highest dose. Furthermore, in one of these patients (who had received the highest dose of treatment), a western blot assay revealed that normal protein gamma-sarcoglycan was being expressed in the muscle fibers. Thanks to gene therapy, the missing gamma-sarcoglycan protein was being produced anew. In addition to confirming the treatment's lack of toxicity (the study's primary objective), we were able to make progress in other areas, such as trial logistics, immunological aspects and even the optimal dose for treating a set of muscles efficaciously. This result is especially interesting because it means that we have established the dose threshold above which the treatment becomes efficacious. That’s very rare in a Phase I trial".

JERRY MENDELL - LGMD 2D(alpha-sarcoglycanpathy)

Researchers in the US led by Prof. Jerry Mendell have published the results of a gene therapy trial for limb girdle muscular dystrophy type 2D (LGMD2D). Individuals affected by this condition have a fault in their 'alpha-sarcoglycan' gene which contains the instructions for a protein which is essential for muscle function. In this clinical trial three teenagers with LGMD2D had a virus containing a healthy copy of the alpha-sarcoglycan gene injected into a muscle in their foot. Not only was the gene therapy deemed to be safe, a significant amount of alpha-sarcoglycocan protein was produced which persisted for at least three months.

The researchers inserted a healthy copy of the human alpha-sarcoglycan gene into the AAV1 virus along with a molecular 'switch' that would only allow the alpha-sarcoglycan protein to be produced in muscle. This virus was injected into one small muscle in the foot. The same muscle in the other foot was injected with saline (salty water) as a control. Either six weeks (two patients) or 3 months (one patient) after the injection the production of alpha-sarcoglycan protein was assessed.

The muscles injected with the virus strongly produced the alpha-sarcoglycan protein in up to 69% of muscle fibres and was correctly located in the muscle membrane. This in turn restored the structure of a cluster of proteins that is normally found in muscle cells but is missing in muscles that lack alpha-sarcoglycan. This protein cluster is vital for the structure of the muscle fibres.

The results of this phase I clinical trial of gene therapy for LGMD2D are very promising. However, delivery of the gene therapy to the whole body, for example via the blood stream, is required for an improvement in symptoms to be seen in patients. This will be the next step in the development of gene therapy for LGMD2D. Clinical trials will be needed to determine the optimal route of administration, dose and the long term safety of the treatment.

The success of the AAV1 virus to deliver the gene to the muscles in this trial also bodes well for the development of gene therapy for other neuromuscular conditions.

List of limb-girdle muscular dystrophies

The "LGMD1" family is autosomal dominant, and the "LGMD2" family is autosomal recessive.

Family	Inheritance	Type	OMIM	Gene	Locus	Characteristics
LGMD1	autosomal dominant	LGMD1A	159000	TTID
		LGMD1B	159001	LMNA
		LGMD1C	607801	CAV3
		LGMD1D	603511	DNAJB6
		LGMD1E	601419	DES
		LGMD1F	608423	TNPO3	7q32.1–q32.2
		LGMD1G	609115	HNRPDL	4q21
		LGMD1H	613530		3p25.1–p23
LGMD2	autosomal recessive	LGMD2A	253600	CAPN3
		LGMD2B	253601	DYSF
		LGMD2C	253700	SGCG
		LGMD2D	608099	SGCA
		LGMD2E	604286	SGCB
		LGMD2F	601287	SGCD
		LGMD2G	601954	TCAP
		LGMD2H	254110	TRIM32
		LGMD2I	607155	FKRP
		LGMD2J	608807	TTN
		LGMD2K	609308	POMT1
		LGMD2L	611307	ANO5
		LGMD2M	611588	FKTN
		LGMD2N	607439	POMT2
		LGMD2O	606822	POMGNT1
		LGMD2Q	613723	PLEC1

References

External links

• Muscular Dystrophy Association
• LGMD in MDA website
• GeneReviews/NCBI/NIH/UW entry on Limb-Girdle Muscular Dystrophy Overview
• GeneReviews/NCBI/NIH/UW entry on Calpainopathy
• GeneReviews/NCBI/NIH/UW entry on Dysferlinopathy including Miyoshi Distal Myopathy (Miyoshi Myopathy), Limb-Girdle Muscular Dystrophy Type 2A (LGMD2A)
• Dystrophy Type 2B (LGMD2B)
• Healthline for Patients
• Washington University in St. Louis Neuromuscular Section LGMD
• Duke University (Great Clinical Description of LGMD phenotypes
• Glenn Lopate MD for emedicine
• Jain Foundation Inc:Orchestrating a cure for Miyoshi/LGMD2B
• Kurt+Peter Foundation: Raising funds for a cure for LGMD2C
• LGMD2D Foundation: Foundation dedicated to the development of a therapy or cure for LGMD2D

UpToDate Contents

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• 1. 肢帯型筋ジストロフィー limb girdle muscular dystrophy
• 2. デュシェンヌ型およびベッカー型筋ジストロフィーの臨床的特徴および診断 clinical features and diagnosis of duchenne and becker muscular dystrophy
• 3. 代謝性ミオパチーへのアプローチ approach to the metabolic myopathies
• 4. エメリー‐ドレフェス型筋ジストロフィー emery dreifuss muscular dystrophy
• 5. 眼咽頭型、遠位型，および先天性筋ジストロフィー oculopharyngeal distal and congenital muscular dystrophies

English Journal

• Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy.

• Bello L, Melacini P, Pezzani R, D'Amico A, Piva L, Leonardi E, Torella A, Soraru G, Palmieri A, Smaniotto G, Gavassini BF, Vianello A, Nigro V, Bertini E, Angelini C, Tosatto SC, Pegoraro E.SourceDepartment of Neurosciences, University of Padova, Padova, Italy.
• European journal of human genetics : EJHG.Eur J Hum Genet.2012 Dec;20(12):1234-9. doi: 10.1038/ejhg.2012.71. Epub 2012 May 2.
• Protein-o-mannosyl transferase 1 (POMT1) is a glycosyltransferase involved in α-dystroglycan (α-DG) glycosylation. Clinical phenotype in POMT1-mutated patients ranges from congenital muscular dystrophy (CMD) with structural brain abnormalities, to limb-girdle muscular dystrophy (LGMD) with microce
• PMID 22549409

• Genetic variability and clinical spectrum of Chinese patients with limb-girdle muscular dystrophy type 2A.

• Luo SS, Xi JY, Zhu WH, Zhao CB, Lu JH, Lin J, Wang Y, Lu J, Qiao K.SourceDepartment of Neurology, Huashan Hospital, Fudan University, No 12 Middle Wulumuqi Road, Shanghai 200040, China.
• Muscle & nerve.Muscle Nerve.2012 Nov;46(5):723-9. doi: 10.1002/mus.23381. Epub 2012 Aug 24.
• INTRODUCTION: Previous studies of limb-girdle muscular dystrophy type 2A (LGMD2A) patients in many countries have suggested a heterogeneous genetic and clinical spectrum, but the genotypes and phenotypes of Chinese LGMD2A patients remain unclear.METHODS: We directly screened calpain-3 (CAPN3) in 18
• PMID 22926650

Japanese Journal

• CAPN3 mRNA processing alteration caused by splicing mutation associated with novel genomic rearrangement of Alu elements

• Hadj Salem Ikhlass,Hsairi Ines,Mezghani Najla [他]
• Journal of human genetics 57(2), 92-100, 2012-02
• NAID 40019158469

• Rapid Screening for Japanese Dysferlinopathy by Fluorescent Primer Extension

• Hayashi Saori,Ohsawa Yutaka,Takahashi Toshiaki,Suzuki Naoki,Okada Tadashi,Rikimaru Mitsue,Murakami Tatsufumi,Aoki Masashi,Sunada Yoshihide
• Internal Medicine 49(24), 2693-2696, 2010
• … Objective Mutations in the dysferlin gene cause limb-girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy (MM), which are collectively named dysferlinopathy. … Dysferlinopathy is the most frequent type of LGMD in the Japanese population. … Using the developed screening method, we were able to detect mutations in these hot spots in 3 samples out of 8 clinically suspected LGMD2B/MM patients in only approximately 8 hours. …
• NAID 130000413429

Related Links

• LGMD～Let's Go My Dream

奈緒です。（メール：lgmd.nao@gmail.com）. 夢に向かってもう一歩。宇宙飛行士、向井 千秋さんの言葉が座右の銘です。 HPの名前の由来. 奈緒はLimb-Girdle Muscular Dystrophyっていう病気です。略すとLGMD。 大きな夢を持って前に突き進んで行きたい ...

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Related Pictures

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★リンクテーブル★

リンク元	「筋ジストロフィー」「肢帯型筋ジストロフィー」
関連記事	「LG」

「筋ジストロフィー」

　　[★]

英

muscular dystrophy MD

同

筋異栄養症

関

筋ジストロフィー症、筋ジストロフィ、筋ジス、進行性筋ジストロフィー

			遺伝
デュシェンヌ型筋ジストロフィー	Duchenne muscular dystrophy	DMD	XR
ベッカー型筋ジストロフィー	Becker's muscular dystrophy	BMD	XR
顔面肩甲上腕型筋ジストロフィー	facioscapulohumeral muscular dystrophy	FSHD	AD
肢帯型筋ジストロフィー	limb-girdle muscular dystrophy	LGMD	AR
筋強直性ジストロフィー	myotonic muscular dystrophy	MD	AD, triplet repeat disease
先天性筋ジストロフィー	congenital muscular dystrophy	CMD
福山型先天性筋ジストロフィー	Fukuyama congenital muscular dystrophy	FCMD	AR

「肢帯型筋ジストロフィー」

　　[★]

英

limb-girdle muscular dystrophy, LGMD

同

肢帯筋ジストロフィー

エルプ型筋ジストロフィー Erb muscular dystrophy

関

進行性筋ジストロフィー、筋疾患

• 発症：10-20歳
• 症状：

• 下肢帯及び上肢帯の筋力低下から始まり、徐々に四肢をも冒す。仮性肥大を認めることもあり末期になれば関節収縮を生じる。経過は緩徐で呼吸筋や心筋が冒される症例もあるが、心筋障害は少ない。知能障害は伴わない。血清CKは軽度～中程度上昇。(BET.437)
• 上下肢の筋力低下・萎縮、深部腱反射減弱・消失
• 顔面は侵されない。下腿肥大・関節拘縮を認める。
• Gowers徴候陽性

	皮膚筋炎	肢体型筋ジストロフィー
症状	近位筋の筋力低下・萎縮 筋痛 筋把握痛	上下肢の筋力低下・萎縮 深部腱反射減弱・消失 腓腹筋の仮性肥大 関節拘縮
Gowers徴候	陽性	陽性

「LG」

　　[★]

同

lateral geniculate body