What is the cause of progressive limb weakness and muscle atrophy for 10 years?

*For medical professionals only

Most patients begin at the age of 10 to 20 years

The patient, a 38-year-old woman, was admitted to the hospital

In the first 10 years of admission, the patient had no obvious precipitating effect of left upper limb weakness, difficulty lifting, laborious combing of hair and washing of face, gradual involvement of right lower limb weakness, performance of climbing the ladder, squatting and laborious, symptoms persisted, slowly worsened, no morning twilight weight and volatility

Similar symptoms develop in the right upper and left lower extremities after 4 to 5 years, with atrophy

2 years before admission, both upper limbs are difficult to lift over the top of the head, bending difficulties, climbing the ladder needs to be supported, can still walk on their own, no muscle pain and swallowing difficulties, no special diagnosis and treatment, normal

Family history: 1 sister has similar symptoms, the current condition is mild, parents and 1 sister and 2 brothers have no similar medical history

Physical examination: P 82 beats/minute, R 20 times/minute, BP 112/75 mmHg, emaciated appearance, cardiopulmonary and abdominal abnormalities

Routine EEG: no significant abnormalities
.

ECG: incomplete right bundle branch block
.

ELECTROMY: muscle-induced damage
.

Pulmonary function measurement: mild restrictive pulmonary ventilation dysfunction, slightly decreased
lung diffuse function.

Muscular (left biceps) pathological examination: mild myogenic lesions, insufficient morphological basis for muscular dystrophy, please confirm the diagnosis with genetic testing; Embromic electron microscopy is diagnostic of myogenic amyotrophy
.

Molecular diagnosis: the presence of a chromosome 4q35 in a 4qA type EcoRI/p13E-11 fragment smaller than 38 kb suggests FSHD
.

▌ Final diagnosis: FSHD

Positioning, qualitative diagnosis? ▌ Localization diagnosis:
patients have progressive limb and facial muscle weakness, with muscle atrophy, mild elevation of muscle enzymes, electromyography and muscular pathology suggest muscle-induced damage, which can be localized as a disease
of the skeletal muscle system.
▌ Qualitative diagnosis:
onset of disease in adulthood, chronic course, family history, suggesting hereditary myopathy, combined with molecular test results can confirm the diagnosis, so it is characterized as FSHD
.

Typical clinical manifestations of FSHD FSHD is autosomal dominant inheritance, most patients from 10-20 years of age, manifested as progressive facial muscles, scapula and upper arm muscles of muscle atrophy and muscle weakness, often asymmetrical development, can see "cat face", "fish mouth", "winged shoulder", "free shoulder" and other typical appearance, later can gradually invade the pelvic belt muscle, abdominal muscles, dorsal flexor muscles, etc.
, showing a "duck step" gait, about 20% of patients eventually need to use a wheelchair
.

FSHD differential diagnosis (1) limb-band muscular dystrophy: also predominantly limb band muscle involvement, mostly chronic and progressive course, accompanied by significant amyotrophic atrophy, significantly elevated creatine kinase, but less involvement of facial muscles, generally symmetrical development, often lower extremity muscle group first affected, recessive inheritance is more common
.
(2) Ankylosing muscular dystrophy: mostly adult disease, often facial expression muscle involvement and limb muscle weakness and muscle atrophy, but mostly distal type, with muscle rigidity, muscle stiffness, typical of the "axe face", "goose neck" and fist loosening movement delay, examination of the forearm and hand extensor muscles have percussion muscle balls, clinically accompanied by cataracts, baldness, basal metabolic rate decline, lung capacity reduction, sexual dysfunction and other multisystem manifestations, Typical myotropic discharges appear on emography, muscle pathology examination shows the central nuclear chain in muscle fibers, and the muscle nuclei of atrophic fibers accumulate to form nuclear bags, so they can be excluded
.
(3) Other myopathies: the patient has no obvious motor intolerance and symptom fluctuations, and there is no pathological development of glycogen, lipid droplet aggregation or broken red fiber, and genetic metabolic myopathy is not supported; Patients have a late age of onset, and there are no phenomena such as rods, central axial hollows, and central nuclei in pathology, and congenital myopathy is not supported; Patients have a long medical history, have a family history, are not accompanied by myalgia, and do not support inflammatory myopathy
.

What is the basis and pathogenesis of FSHD molecular detection? FSHD is a typical Mendelian genetic disease, the causative gene is located in the long-arm sub-telomere region of chromosome 4 (4q35.
2), its structure is highly specific and complex, and it is directly related to the 3.
3kb tandem repeat (D4Z4 sequence) multi-copy deletion inside a polymorphic EcoR I fragment in this region - the normal population D4Z4 copy number is 11-100, while the patient is usually reduced to 1-10, and the EcoRI fragment is shortened to less than 38kb.
Diagnosis at the molecular level can be made by detecting this shortened sequence of polymorphic satellites and their specific sequences upstream and downstream
.
At present, the "gold standard" molecular diagnosis is the application of pulsed electric field gel electrophoresis (PFGE) technology combined with restriction fragment length polymorphic analysis (RFLP)/specific probe (p13E-11, 4qA/4qB and B31) multi-site Southrren hybridization genetic testing, foreign countries may only be Leiden University in the Netherlands, Rochester University in the United States, Research carried out by scientific research institutions such as Cardiff University in the United Kingdom can rarely be carried out in China, and most of them are only for clinical diagnosis
.
In terms of pathogenesis, although the pathogenic gene of FSHD has been located, the pathogenic gene has not been cloned so far, and the effector gene after the deletion of D4Z4 is not clear, which does not follow the classical model
of the traditional pathogenic gene mutation leading to the coding protein mutation.
Therefore, researchers have been working to find possible candidate genes from upstream and downstream of D4Z4 and internally
.

"Epigenetic effects" have become an important theory
that explains the pathogenesis of FSHD.
Deletion of the D4Z4 sequence caused chromosomal conformation changes in the 4q35 sub-telomere region led to abnormal upstream multigene regulation, among which the FRG1 gene was associated with skeletal muscle growth and development, becoming an important candidate gene
for FSHD.
Recent studies have also found that the acquired high expression of the DUX4 gene within D4Z4 in patients has a muscle-damaging effect and may play a leading role
in the pathogenesis.


Therefore, at present, the key links of the pathogenesis of FSHD are unknown, and the effector gene and related protein function of D4Z4 deletion, and the methylation of D4Z4 sequence are the focus and hotspot
of research.
FSHD muscle weakness develops in a descending pattern, first involving the facial muscles, then moving down to the shoulder blade muscles, humerus muscles, and finally affecting the pelvic limb band muscles, but there is no significant effect on
the patient's lifespan.
Facial muscle weakness is often the first sign of FSHD, but it may not be noticed immediately by the patient, often when someone or doctor tells him or she has a problem
.
Therefore, it is expected that through the above summary, everyone will have a certain understanding of the disease and avoid misdiagnosis and missed diagnosis
.

References:

Luo Yayin, Wang Zhe, Liang Zhanhua, etc.
Facial shoulder humeral muscular dystrophy type 1 case 1 case.
Journal of Dalian Medical University.
2021,43(03).

Lin Xiaodan, He Junjie, Chen Wanjin, etc.
Advances in the molecular mechanisms of facial-shoulder-brachial muscular dystrophy.
Chinese Journal of Modern Neurological Diseases.
2017,17(08).

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