Young female, 38 years old,
Chief complaint: gradually aggravated involuntary hyperactivity for 9 years, memory loss for 7 years.
Current medical history: 20 10 patients showed involuntary movements of their hands, with mild symptoms, good walking and normal language, which was ignored. On 20 12, the patient began to suffer from memory loss and slow response, and did not see a doctor. 20 13' s symptoms of involuntary movement of hands are aggravated, and there are involuntary twisting of limbs and trunk, unstable walking, abnormal posture, unstable mood and bad temper. Magnetic resonance imaging (MRI) was performed to reveal the medulla oblongata, pons midbrain, bilateral thalamus, internal and external capsule, and semi-oval center. After oral administration of haloperidol, Antan, Taibili and Sololo, the symptoms improved. 20 14 The above symptoms are aggravated and the language is unclear. Check the magnetic vibration of the head. From 2065438 to September 2004, lumbar puncture in local hospital showed that intracranial pressure was 60mmH 2 O, white blood cell count was 7 /ul, and chloride and protein were normal. Moderate abnormality in EEG. Evoked potentials indicate that brainstem auditory evoked potentials are normal, lower limb evoked potentials are abnormal, and upper limbs are normal. Cranial magnetic * * * vibration plain scan+enhancement indicates that the hemispheres of both sides have extensive abnormal signals in the center of semi-oval circle, basal ganglia, thalamus and pons, and cerebellum atrophy. Because of the unknown diagnosis, he went to Shanghai for medical treatment, and took orally tiapride, risperidone and topiramate to treat dystonia and leukoencephalopathy and improved the experiment. There was no abnormality in tandem mass spectrometry of amino acids and fatty acids in hematuria, and the symptoms improved after treatment.
In May of 20 15, the symptoms of involuntary movement of limbs became worse again. A hospital in Beijing was diagnosed with early Tourette's syndrome and leukodystrophy. After injecting nerve growth factor and ganglioside into rats. The symptoms have improved. In June of 20 10, the above symptoms became worse again, and involuntary movements of mouth and eyes appeared. After continuing to give the above treatment, the symptoms did not improve significantly. As of 20 16, he was hospitalized in several hospitals in Beijing, during which he was suspected to be positive for AQP4 antibody++cerebrospinal fluid OB. The immune indexes of other rheumatism were negative. Hb 108g/L, the normal range for detection of heavy metals in blood and urine. Echinococcus examination: 1000 red blood cells were classified and 10 red blood cells were found. Ceruloplasmin145mg/L/L. CT+ enhancement in the upper abdomen showed calcification of the right lobe of the liver, multiple high-density shadows at the edges of bilateral renal sinuses, and calcification of renal papillae. After diagnosis, the immune-mediated brain injury caused by leukoencephalopathy may be a large genetic metabolic disease to be discharged, such as liver calcification and renal papillary calcification. Dexamethasone 15mgqd intravenous drip, supplemented by improving circulation, nourishing nerves and symptomatic treatment, the symptoms of patients were obviously improved. Perfecting the screening of leukoencephalopathy-related genes shows that 3- methylpreneuria type 2 /Barth syndrome may be related to hereditary spastic paraplegia 1 1 type.
From 20 18, the patients' involuntary movements increased, they had difficulty in eating, and they could not take care of themselves and traveled in wheelchairs. The reexamination in the local hospital showed that MMSE 17, IQ 57, mild depression and anxiety, symptomatic treatment and poor curative effect. On 20/0/9, Kloc went to our hospital for outpatient treatment and was admitted to our hospital.
Past history: 20 13 menstrual period after ovarian teratoma operation. /kloc-married 0/2 years ago, G 1P 1.
Physical examination: clear thinking, listlessness, slurred speech, strong explosive language, basically to the point. Cranial nerve: Both pupils are equal in size and circle, reflecting light, the connection between eyes is slightly poor, the tongue extends to the middle, the pharyngeal reflex is poor, and bilateral palatal arches move. The neck is soft, the muscle strength of limbs is grade 5, the muscle tension is low, knee reflex exists, and bilateral Pap sign is positive. * * * Economic exercise: nose, fingers, heels, knees and calves are not stable enough to get out of bed, it is difficult to close your eyes and walk in a straight line. Involuntary movement can be seen in the mouth, and involuntary movement can also be seen when limbs move.
The magnetic resonance image of the patient is as follows:
Diagnosis and treatment process: clonazepam and primidone were given symptomatic treatment after admission, and the patient's condition was closely observed and relevant laboratory tests were improved. After taking the medicine, the patient's symptoms improved slightly, but his sleepiness was obvious, so he stopped using primidone and adjusted it to clonazepam 1 mg QN. Tests showed low hormone levels. There is no obvious abnormality in residual blood biochemistry. Pelvic ultrasound showed normal uterus, but bilateral ovaries were not shown. Brain magnetic resonance reexamination showed that there were many abnormal signals in the center of bilateral semi-oval, lateral ventricle, thalamus and brain stem, and the range was similar to before. During hospitalization, the patient developed fever and his body temperature increased by 39 degrees. Lung CT showed a small amount of inflammation in the lower lobes of both lungs. Considering that lung infection is related to the patient's eating and coughing, he was given a gastric tube and asked to consult the infection department for anti-infection treatment. After that, the patient's body temperature dropped to the normal range, and antibiotics were stopped after stabilization.
During hospitalization, ask the patient about the changes of his condition every day, carefully check his body and observe the changes of symptoms and signs. We found that the patient's speech was poetic and explosive, and he could not get out of bed to stand or walk independently, with obvious ataxia symptoms. Therefore, buspirone citicoline sodium tablets were added to improve walking instability and language function, and coenzyme Q 10 and vitamin E were added. After more than 20 days of observation and treatment, the patient's condition improved obviously and his speech was slurred. He can get out of bed and stand on the window railing beside the bed, and he can walk independently with the help of his family.
The patient has bickering and involuntary limb movements, but the symptoms of cerebellar ataxia are more prominent, and the response effect to buspirone and other ataxia drugs is more obvious. The patient's brain magnetic resonance signal showed a wide range of abnormal white matter signals and cerebellar atrophy, which also supported the symptoms and drug efficacy. Although the patient was screened for leukoencephalopathy-related genes in the past, it was found that 3- methylpentadienuria type 2 /Barth syndrome may be related to hereditary spastic paraplegia 1 1 type. According to the overall analysis of the patient's condition, the detected genes can not reasonably explain the patient's condition, but the patient's condition still tends to be gene-related, so after full communication with family members, an external analysis was made. The results showed that there was a heterozygous mutation in * * * ataxia-pancytopenia syndrome-related gene SAMD9L, and its pathogenicity could not be confirmed because the carrier rate of this locus in normal people was extremely low. There are homozygous deletion mutations in exon 2 and heterozygous deletion mutations in exon 3- 17 in RNF2 16, which are related to cerebellar ataxia and hypogonadism (qPCR detected heterozygous deletion mutations in exon 6 and 17).
The report of RNF2 16 gene is related to cerebellar ataxia and hypogonadism. It is reported as autosomal recessive inheritance (AR). Theoretically, it is possible to cause disease (homozygous or compound heterozygous mutation) only if there are pathogenic mutations on two alleles at the same time. This sample is suspected to have homozygous deletion variation in exon 2 of this gene, which is theoretically pathogenic.
RNF2 16 is one of the pathogenic genes of Gordon Holmes syndrome (GDHS). Because GDHS is extremely rare, foreign reports are only case reports, so today we will look at the characteristics of Gordon Holmes syndrome.
The classification of Gordon Holmes syndrome on the website is as follows: endocrine diseases, genetic diseases, mental diseases, metabolic diseases, nervous system diseases, rare diseases and reproductive diseases.
Gordon Holmes syndrome is a rare disease characterized by reproductive and nervous system problems. One of the main features is the decrease of hormone secretion that promotes sexual development (hypogonadism). Many affected individuals delay the development of typical features in adolescence, such as facial hair growth and voice changes in men, and delayed menstruation and breast development in women. Some patients have never experienced puberty. Some patients seem normal in adolescence, but other reproductive system problems will appear in later life.
In early adulthood, patients with Gordon-Holmes syndrome will have nervous system problems, which usually begin with language disorders (dysarthria). With the deterioration of the disease, patients have balance and coordination problems (cerebellar ataxia), which often leads to difficulties in daily activities and requires wheelchair assistance. Some patients will suffer from memory loss and mental retardation (dementia).
heritage
Gordon-Holmes syndrome is a rare disease. Its incidence and prevalence are still unknown.
The cause of disease
Gordon-Holmes syndrome can be caused by mutation of RNF2 16 or PNPLA6 gene. Some people with this disease do not have mutations in these genes, indicating that mutations in other genes may be related to this disease.
Protein produced by RNF2 16 gene participates in a cellular process called ubiquitination, through which unwanted protein is labeled by a molecule called ubiquitin. Ubiquitin tags are signals of protein decomposition. One of several protein labeled with RNF2 16 is a kind of protein in nerve cells, which plays a role in synaptic plasticity. Synaptic plasticity is the ability of the connections between neurons (synapses) to change and adapt in response to experience over time. This process is very important for learning and memory.
The mutation of RNF2 16 gene weakened the ability of RNF2 16 protein to mark unwanted proteins for decomposition. The damaged neuroprotein destroys the normal synaptic connection and plasticity, which may be the promoting factor of dementia in patients with Gordon Holmes syndrome. At present, it is not clear how the functional loss of RNF2 16 protein leads to gonadotropin dysfunction or cerebellar ataxia.
The PNPLA6 gene provides instructions for the production of protein called Neuropathic Target Esterase (NTE), which helps to regulate the amount of some fats (lipids) that constitute the extracellular membrane. The correct content level of these lipids is very important for the stability and function of cell membrane. The content of NTE is the highest in the nervous system, which is considered to help maintain the stability of the membrane around neurons. NTE is also considered to play an important role in pituitary hormone release, which requires special changes in cell membrane. The pituitary gland is located at the bottom of the brain and produces a variety of hormones, including hormones that promote the development and growth of sexual characteristics.
The mutation of PNPLA6 gene is considered to damage the function of NTE. The researchers speculated that this damage changed the balance of lipids in the cell membrane. This imbalance may damage neurons in the brain, cause cerebellar ataxia, and damage the pituitary gland to release hormones related to the development of sexual characteristics, leading to hypogonadism. It seems that patients with Gordon-Holmes syndrome caused by PNPLA6 gene mutation will not develop dementia.
heritage
The inheritance mode of Gordon-Holmes syndrome is autosomal recessive inheritance, that is, two copies of genes in each cell are mutated. Parents of individuals with autosomal recessive genetic diseases all carry a mutant gene, but they usually do not show symptoms of the disease.
Other names for this disease.
Cerebellar ataxia and hypogonadism; Luteinizing hormone releasing hormone deficiency with ataxia; LHRH deficiency and ataxia.
After literature review, combined with our patient's clinical manifestations, laboratory tests and genetic analysis, we believe that this patient is Gordon Holmes syndrome. It also gives a relatively reasonable explanation for families who have been rushing for 9 years to see a doctor at the current medical level.
At the end of the article, I would like to thank Sun Yiwei, Wang Min, Qian Fang, Pang Rui and other doctors and sisters in the nursing department for their hard work! At the same time, thank the patients and their families for their trust!
References: ellipsis
Reference website:
https://www.malacards.org/card/gordon_holmes_syndrome
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Adhere to popular science and hope that doctors and patients will take fewer detours and the disease will be diagnosed and treated as soon as possible!
Video number: Dr. Zhao, Department of Neurology
WeChat official account: Dr. Zhao Guixian: Cactus 20 150 10 1
Zhao Guixian, doctor of clinical medicine, graduated from Clinical Medical College of Xi Jiaotong University in 2000. I graduated from Fujian Medical University in 2008. Since 2008, he has worked in the neurology department of Huashan Hospital affiliated to Fudan University. He has worked in the clinical front line for a long time. He is good at "diagnosis and differential diagnosis of various diseases of the central nervous system", and is good at immune diseases of the central nervous system such as multiple sclerosis, neuromyelitis optica and demyelinating diseases of the central nervous system. At the same time, I have carried out clinical and scientific research work on multiple sclerosis (MS), and have some experience in peripheral neuropathy and neurogenetic degeneration.