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VPS4A – de novo mutation (CIMDAG-Syndrome)
VPS4A-mutations (MIM:609982) cause a congenital ataxic multisystemic disorder with irregular neurodevelopment. This monogenetic de novo mutation can lead to structural brain abnormalities, severe neurodevelopmental delay, epilepsy, cataracts, growth impairment, and anemia.

Signs and symptoms
The first sign of a VPS4A-mutation is a severe microcephaly (typically with Z scores <-5) followed by gross motor delays in early infancy, general neurodevelopmental delays with lack of developmental milestones (head control, turning, sitting, walking), intellectual disability, epileptic seizure onset, growth deficiency, and language impairment. Severe intellectual or developmental disabilities are present in all known patients. All signs of infantile cerebral palsy like dystonia, dyskinesia, spasticity, ataxia, with profound neonatal onset of hypotonia can be observed. Persisting extrapyramidal symptoms with an ongoing plantar reflex (Babinsky sign) and Moro reflex. Integration disorder and sleep disorder (somnipathy) are also common. Patients may also suffer from significant feeding issues (needing a feeding tube) and constipation. Some patients experience nystagmus, strabismus, congenital cataracts, retinal dystrophy (Leber amaurosis), visual dysfunction or full blindness (nervus opticus atrophy). Hearing seems to be less affected, although sensorineural deafness was observed. Hip dysplasia, scoliosis and talipes are also common due to lack of mobility and spasticity. Some patients also develop hematologic problems, congenital dyserythropoietic anemia (CDA), hepatosplenomegaly or hepatosteatosis.

Brain abnormalities

 * cerebellar and/or vermal aplasia, hypoplasia and/or dysplasia
 * pontocerebral or cerebellar atrophy
 * bilateral polymicrogyria
 * thin and/or dysplastic corpus callosum
 * thickened calvarial vault
 * brainstem hypoplasia
 * base of the skull can display abnormal signal hypointensity in relation with high proliferative hematopoiesis
 * myelinization abnormalities or delay

VPS4A
The VPS4A-gene encodes the Vacuolar Protein Sorting-associated protein 4A ( VPS4A). This VPS4A protein belongs to the AAA-protein family (ATPases associated) with diverse cellular activities. VPS4A is involved in lysosomal/ endosomal membrane trafficking. It also holds a key role in cytokinesis (midbody during abscission, concentrating at the spindle poles in the metaphase) and reticulocyte maturation through exosome biogenesis. Cells lacking VPS4 (and/or its complex partner ESCRT-III) proteins develop aberrant nuclei, composed of fragmented or interconnected micronuclei, an increased number of centrosomes, multipolar spindles, and abnormal chromosome alignment during metaphase.

Cause
The affected gene is located at the 16th Chromosome: 16q22.1; The actually known multiple heterozygous VPS4A loss-of-function mutations are present in general population databases. To the actual knowledge a haploinsufficiency mechanism is not considered to cause the type of severe early childhood condition.

Missense variants
The VPS4A protein is a long molecule composed of a chain of 437 amino acids (aa). All genes have some amount of harmless variations in the general population, alike VPS4A, but in the middle of the VPS4A gene the background variation is reduced (~100aa-300aa). This area is relatively intolerant to genetic variation. Five of the probands published by Rodgers et al. had de novo heterozygous missense variants at amino acid (aa) position 284 (four cases c.850A>T (p.Arg284Trp) substitution and one case with a c.850A>G (p.Arg284Gly)) change. One WES diagnosed a variant at c.616G>A (p.Glu206Lys).

Not published is one case with a variant at position 284 c.605T>C Leu202Pro) in Germany, and one in England with a variant at position 116 (p.Ala116Thr). Further information is provided by the NCBI database.

Diagnosis
Diagnosis is based on genetic testing, with the recommended testing approach being whole exome sequencing (Trio-Exom-Analysis, WES and WGS). EEG monitoring frequently shows generalized epilepsy. Seizure onset usually occurs within the 1st year of age. MRI points out the previously described brain abnormalities.

Seizure types
Seizure types most commonly follow the classification proposed by the International League Against Epilepsy (ILAE) in 1981.


 * Atonic seizures
 * Eyelid myoclonia
 * Absence seizure
 * Myoclonic jerks
 * Tonic-clonic seizures
 * Grand mal seizure

Treatment
There is currently no cure (e.g. gene therapy) or causative treatment. Epilepsy may be controlled by the use of one or more anti-epileptic drugs, vagus nerve stimulation, or a ketogenic diet. At the actual state patients have seizures that are pharmacoresistant. Patients with significant feeding issues may require the use of a nasogastric, nasojejunal or gastric feeding tube. Communication may be supported with the use of an Augmentative and Alternative Communication device. Patients require the use of wheelchairs, adaptive strollers or Ankle Foot Orthoses. Supportive treatments can include:


 * Occupational Therapy
 * Physical Therapy
 * Speech Therapy
 * Equine-assisted Therapy
 * Aquatic Therapy or Hydrotherapy
 * Music Therapy
 * Light Therapy

Prognosis
Two affected individuals died in childhood or early adult life. The oldest known patient is 30 years of age.

Epidemiology
Actually 10 patients are known by the author of this article (6 published in the study by Rodgers et al. 2020, 2 in England, 1 in Germany, 1 in Canada).

Recommendations for parents
Facebook group: VPS4A mutation

Unique

The Undiagnosed Patients Program

The Adeli Medical Center

Napa Center London

CIMDAG -Syndrome
As proposed by Rodgers et al. the “acronym CIMDAG (cerebellar hypoplasia and cataracts, intellectual disability, congenital microcephaly, dystonia and dyserythropoeitic anemia, growth retardation; MIM: 619273) may highlight the main clinical features of this syndrome, which may also include other structural brain abnormalities, retinal dystrophy, hepatosplenomegaly, and sensorineural deafness”.