Table 1.

Phenotypic Features in Individuals with NACC1 c.892C>T (p.Arg298Trp) Variant

	Individual 1	Individual 2	Individual 3	Individual 4	Individual 5	Individual 6	Individual 7	Total
Age	20 months	12 years	18 years	3 years	9 years	13 months	12 years
Gender	M	F	M	M	F	M	M
NACC1 c.892C>T (Arg298Trp) variant	constitutional, de novo	constitutional, de novo	constitutional, de novo	constitutional, de novo	constitutional, de novo	constitutional, de novo	mosaic, de novo	7/7
Postnatal microcephaly	yes	yes	yes	yes	yes	no	no	5/7
Intellectual/developmental disability	profound	profound	profound	profound	profound	profound	severe	7/7
Bilateral cataracts	lamellar, diagnosed at 7 months old	diagnosed at 10 and 11 years old	diagnosed at 6 weeks old	anterior subcapsular, congenital	nuclear, diagnosed at 11 and 12 months old	no	no	5/7
GI problems/feeding difficulties	feeding intolerance, failure to thrive, gastrostomy at 9 months	dysphagia	severe feeding problems, PEG at 6 years old	feeding intolerance, failure to thrive, gastrostomy at 9 months	feeding intolerance, cyclic vomiting, gastrostomy at 2.5 years old	dysphagia, failure to thrive	feeding difficulties, GERD	7/7
Hypotonia	present	present	present	present	present	present	no	6/7
Seizures	infantile spasms	focal seizures	generalized tonic	infantile spasms	infantile spasms, mixed generalized and multifocal epilepsy	infantile spasms, tonic seizures	single febrile seizure, nocturnal seizures	7/7
Irritability	very fussy, breath-holding spells	yes	tactile aversion, unable to tolerate being held, periods of inconsolability	bouts of irritability, breath-holding spells	cyclical bouts of severe irritability, breath-holding spells	yes	yes	7/7
Sleep disorder	yes	–	yes	yes	episodes of dysauto-nomia (tachycardia and insomnia)	–	obstructive sleep apnea	5/7
Stereotypic movements	repetitive movement bringing hands to midline and pulling shirt down	autistic features, Rett-like hand auto-matisms; hands always in her mouth	Rett-like stereotypic hand movements	repetitive hand movements	random choreiform movements of the hands	no	hand flapping, autistic features	6/7
Brain MRI findings	delayed myelination, mildly decreased brain volume, slight enlargement of ventricles	brain atrophy, temporal arachnoid cyst, MRS showed decreased NAA over basal ganglia	reduced white matter, delayed and incomplete myelination with temporal lobes most affected, mildly decreased brain volume, MRS showed decreased NAA levels	delayed myelination and volume loss	minimal volume loss, delayed myelination	volume loss	scattered areas of subcortical white matter T2/FLAIR hyperintensity	7/7