ATAD1-associated Encephalopathy – A Rare Cause of “Stiff Baby Syndrome”

Introduction: Hyperekplexia or stiff baby syndrome is characterized by generalized hypertonia, nocturnal myoclonus and an exaggerated, abnormal startle response to auditory, visual and tactile stimuli1. Afamilial hereditary form (autosomal dominant or recessive) and sporadic cases were reported. Mutations in the GLRA1 gene are found in about 30% of cases2. Mutations in other genes have also been reported. In 2017 a very rare disease was identified, theATAD1-related encephalopathy, whichclinically presents as stiff baby syndrome3.

Patient: Our patients are male twins. Directly after birth we noticed extreme hypertoniaandhyper-excitability which was followed by poor feeding, muscle tremor, little spontaneous movements, and inability to fixate. Attempted therapy with clobazam, baclofen and phenobarbital had no effect on the muscularhypertonia. Routine laboratory parameters, EEG, ultrasound and MRI of the brain, metabolic investigations, EMG and muscle biopsy were normal. Molecular genetic testing of the most frequent hyperekplexia-associated genes was also normal.

Results: A recent study reportedATAD1-related encephalopathy as a new neurological disorderwhich can also present as stiff baby syndrome. Based on this study we performed molecular genetic analysis of the ATAD1 gene and found the homozygous ATAD1 missensemutationc.794G>A/p.(Arg265Lys) in the twins. Both parents are heterozygous carriers of the ATAD1 mutation. After informed consent was obtained we started off-label treatment with perampanelwhich however could not prevent the twins’ death at the age of 4.5 months due to hypoxia attacks.

Discussion: ATAD1 encodes thorase, an AAA+ ATPase that controls the internalization ofpostsynaptic AMPA receptors. While biallelicloss-of-function mutations in ATAD1result in increased AMPA receptors at the cell surface of neurons3, the recently reported homozygous gain-of-functionATAD1 mutationp.(His357Argfs*15) causes a decrease in the amount of AMPA receptors4. The clinical picture associated with either gain- or loss-of-functionATAD1 mutationsis similar as affected infants show the stiff baby syndrome and hyperekplexia. We conclude thatATAD1-related encephalopathy is a possible differential diagnosis in neonates with muscular hypertonia. Since ATAD1 plays a role in AMPAreceptor trafficking a therapeutic trial with perampanelshould be considered in patients with a loss-of-function mutation in ATAD1 3,5.

References

1. Praveen V, Patole SK, Whitehall JS. Hyperekplexia in neonates. Postgrad Med J 2001;77(911):570–572

2. Hyperekplexie, hereditäre (o.D) abgerufen von https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=3197&lng=DE

3. Ahrens-Nicklas RC. Umana

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