What do you know about autosomal recessive cerebellar ataxia?

Ataxia is derived from the Greek "a taxis", a- lack of + taxis-order, which means "no order or coordination".

Ataxia refers to a disorder of motor coordination that occurs under normal muscle strength.
The clinical manifestation is disorder of the amplitude and coordination of voluntary movements of the limbs, and the inability to maintain body posture and balance.

Author: darkpigx Source: "I can still eat a small fish and worm" WeChat public account ataxia is mainly caused by the involvement of the cerebellum and/or the fiber structure connected with the cerebellum (especially the brain stem).

Typical ataxia manifestations are as follows: Ataxia (appendicular or axial) of the limbs or trunk, Dysmetria, poor coordination, Dyssynergia, rotation dyskinesia, Dysdiadochokinesia, rebound phenomenon, Rebound Phenomenon, Dysarthria, Tremor, postural and gait instability, Titubation and increased postural sway tension reduction Hypotonia weakness Asthenia nystagmus Nystagmus and other eye movement disorders autosomal recessive inherited cerebellar ataxia (ARCA) is a complex, heterogeneous and disabling neurogenetic degeneration Diseases are more common in children and early adult patients.

Patients with cerebellar ataxia (CA) may have both central and peripheral nervous system involvement, or they may have symptoms and signs outside of the nervous system.

Common neurological symptoms other than ataxia in patients with CA include: peripheral neuropathy, weakened or missing ankle reflexes, and loss of vibration (video 1) movement disorders, such as chorea and dystonia (video 2), abnormal eye movements (video 1, 2, 3 are visible) pyramidal tract signs, such as positive pathological signs, hyperreflexia, spasticity (video 1) mental retardation or cognitive dysfunction epilepsy ▲ Video 1: FRDA patients’ gait disorder is caused by cerebellar sex Ataxia and sensory ataxia are caused by a combination of non-imbalance, staggering and steering difficulties when walking.

Because it is difficult for the patient to walk in a straight line, he needs to hold on to the wall when walking to prevent falling.

The patient showed poor discrimination in the finger-to-nose test and the finger-to-finger test, and showed posture instability when standing with feet close together.

Due to the effect of sensory ataxia, after the patient closes his eyes, his posture becomes more unstable, loses his balance, and even falls.

The instability of fixation leads to nystagmus and square wave jerks induced by visual tracking saccades.
In addition, the loss of lower limb tendon reflexes and the positive Babinski sign can be seen.

Video 2: Choreographed movements of the hands and torso of patients with eyeball ataxia type 1 (AOA1), accompanied by cervical dystonia.

Video 3: Nystagmus and nasal/temporal conjunctival telangiectasia induced by right horizontal gaze in patients with ataxia telangiectasia (AT).

Video 4: The head-eye reflexes of AOA1 patients are separated.
During the patient's head turning, the delay of the eyeball following the head movement can be observed.

Except for a small number of inherited metabolic diseases (such as non-ketosis hyperglycemia, pyruvate dehydrogenase deficiency, etc.
).

In the acute onset of CA, first consideration should be given to cerebellar stroke, cerebellar abscess, meningitis, vitamin B1 deficiency and drug poisoning, and other diseases that urgently need diagnosis and treatment, as shown in Table 1.

Then through a comprehensive examination to rule out acquired, subacute or chronic CA, such as cerebellar tumor, paraneoplastic syndrome, Creutzfeldt-Jakob disease, Whipple disease, celiac disease, autoimmune thyroiditis and glutamate decarboxylase antibody-related After CA and other diseases, if CA is gradually aggravated, neurodegenerative diseases should be considered.

Table 1 Diagnosis and examination of acute cerebellar ataxia.
Preliminary treatment of alcoholism, history of alcoholism, elevated liver enzymes, abstinence from alcohol, supplementation of vitamin B1, vitamin B1 deficiency, serum vitamin B1 levels decreased, supplementation of vitamin B1 drugs (such as carbamazepine, phenytoin, phenobarbital) Relevant medication history of Bital, lithium, fluorouracil, cytarabine, metronidazole, amiodarone), abnormal blood concentration, withdrawal of toxic substances (mercury, thallium, lead, toluene, organic solvents, pesticides) exposure to poisons History of exposure to cerebellar ischemia or hemorrhagic stroke Neuroimaging examination Stroke unit treatment of multiple sclerosis Neuroimaging examination Immunomodulation basal ganglia meningitis (tuberculosis or Listeria) Neuroimaging examination, CSF cytology examination Antibiotic cerebellum Inflammation (VZV virus, measles, influenza, influenza, JC virus, pertussis) neuroimaging, CSF, serum virology antiviral, such as acyclovir for VZV infection cerebellar abscess neuroimaging antibiotics, surgical drainage is common Autosomal recessive hereditary cerebellar ataxia ➤Friedreich ataxia (FRDA) Friedreich ataxia (FRDA) is mostly caused by amplification of GAA repeats in the frataxin (FXN) gene on chromosome 9.

Disease progression and severity are related to the number of GAA repeats.

FRDA is the ARCA with the highest prevalence in Western countries, accounting for about 1/2.

It usually starts in adolescence, but the age of onset can range from 2 years old to over 70 years old.

Most patients rely on wheelchairs to move around at the age of 20, and heart failure is the most common cause of death.

Typical manifestations: Progressive neurological dysfunction (including cerebellar and sensory ataxia, dysarthria, nystagmus, weakened or disappeared tendon reflexes, weakness of the lower limbs, pathological signs, arched feet, such as video 1).

Other features: scoliosis, cardiomyopathy, diabetes.

➤Ataxia telangiectasia (AT) AT is a relatively rare recessive genetic disease with a single gene mutation in autosomes (the mutant gene is ATM gene).

The incidence rate is 1/4 million to 100,000, mostly in infants and toddlers (2-5 years old).

The clinical phenotype is related to the activity of ATM protein.
The higher the activity of ATM protein, the lighter the clinical symptoms. Because AT is a primary immunodeficiency disease involving nerves, blood vessels, skin, reticuloendothelial system, endocrine system, etc.
, due to tumor susceptibility (especially lymphoma and leukemia) and prone to repeated infections (such as otitis media, sinusitis, upper Respiratory tract infections, lungs) must be closely monitored for changes in the condition.

Usually accompanied by conjunctival telangiectasia (such as video 3), separation of head and eye reflexes (such as video 4), chorea, dystonia, or peripheral nerve axonal damage.

Laboratory examination: about 80% of patients lacked serum IgA, 75% lacked IgE, 50% IgG levels decreased, AFP increased, and some patients had increased CEA levels.

▲Conjunctival telangiectasia, upper arm skin telangiectasia, ear capillary telangiectasia ➤With ocular ataxia (AOA) type 1 and type 2 also known as "ataxia with apraxia" type 1 and 2 Type refers to early-onset ARCA or sporadic cerebellar ataxia with eye movement apraxia, chorea, facial and limb dystonia, sensorimotor polyneuropathy, and cognitive impairment.

These two types of AOA account for up to 20% of ARCA cases.

AOA1, also known as "early-onset AOA", usually develops within 10 years of age; AOA1 cognitive impairment is common, and blood biochemistry can manifest as hypercholesterolemia and hypoalbuminemia.

Caused by mutations in the APTX gene encoding aprataxin protein.

AOA2 is more common than AOA1, and the age of onset is later, onset between the ages of 20-60.

AOA2 rarely shows cognitive impairment, and only about 50% of patients have eye movement apraxia.

AOA2 is caused by mutations in the SETX gene.

Its typical manifestations are progressive cerebellar ataxia, sensorimotor axonal neuropathy (98%), ocular movement apraxia (50%), strabismus (12%), and other hyperkinesia dyskinesias.

98% of AOA2 patients have elevated AFP levels.

Hypogonadism (<5%).

▲Recent studies have found that on the SWI and FLAIR images of 3.
0 T magnetic resonance, the lack of low signal in the cerebellar dentate nucleus is a highly sensitive and specific AOA imaging diagnostic marker.

➤Autosomal recessive hereditary spastic ataxia Charlevoix-Saguenay type (ARSACS) Autosomal recessive hereditary spastic ataxia Charlevoix-Saguenay type is a special form of early-onset spastic ataxia, It is the progressive degeneration of the cerebellum and spinal cord caused by homozygous and compound heterozygous mutations in the SACS gene.

Found in the Charlevoix-Saguenay region of Quebec, Canada in the late 1970s, it is the second most common autosomal recessive genetic spastic ataxia syndrome (SACS mutations account for 37% of FRDA gene-negative cases).

The main clinical manifestations are the triad of childhood-onset cerebellar ataxia, positive pyramidal tract signs, and peripheral neuropathy (peripheral neuropathy can also appear later).

Auxiliary examination: Ophthalmology optical coherence tomography (OCT) examination revealed retinal nerve fiber hyperplasia; MRI examination of cerebellar atrophy (obvious supracerebellar vermis), symmetrical T2 low signal band sign at the base of the pons.

▲Pictures A and B: Symmetrical striped low signal on both sides of the pons.

Figure C: The pons enlarged, the upper cerebellar vermis atrophy, and the corpus callosum became thinner.

Figure D: Thralamus limbic hyperintensity (circle) ▲Video: Video data of a Thai ARSACS patient.
The heterogeneity of ARCA's phenotype and genotype.
Most ARCA's age of onset, severity of disease progression, and extracerebellar and global physical signs are different of.

ARCA of the same phenotype may be caused by different diseases (such as FRDA and vitamin E deficiency ataxia).

Conversely, mutations in the same gene may cause several different phenotypes (such as FXN, Polg, or ATM).

FRDA can manifest as early onset (<10 years old), late onset (>25 years old) and very late onset (>40 years old).

The speed and severity of disease progression also vary greatly.

Atypical clinical manifestations of FRDA: ➤ Late-onset FRDA (LOFA) and very late-onset FRDA (VLOFA) ➤ FRDA with preserved tendon reflexes (FARR) ➤ Acadians type FRDA ➤ Spastic paraplegia treatment except for vitamin E deficiency ataxia, In addition to targeted specific treatments such as vitamin B12 deficiency ataxia, coenzyme Q10 deficiency ataxia, tendon xanthomatosis, no β lipoproteinemia, paroxysmal ataxia, etc.
, most ataxia diseases are still symptomatic Treatment is the mainstay.

▲Empirical medicine, rehabilitation and physical therapy, occupational therapy, speech therapy, and individualized care ▲NGS has developed rapidly and is widely used in the diagnosis of genetic diseases.
For patients with complex phenotypes, whole exome sequencing can improve the diagnosis rate, Shorten the diagnosis time.

References: [1]Anheim Mathieu,et al, N Engl J Med, 2012, 366: 636-46.
[2]Biswas Asthik,et al .
Neurology, 2018, 90: e1271-e1272.
[3]Srikajon Jindapa, et al.
Tremor Other Hyperkinet Mov (NY), 2020, 10: 1.
[4]Ronsin Solène, et al.
Eur J Radiol, 2019, 110: 187-192.
[5]Chen Weicheng ,et al.
Mol Med Rep , 2019, 20: 1655-1662.