Table 1 Clinical features of patients harboring the ACER3 gene variants

Sex

Female

Male

Male

Female

Male

Male

Consanguinity

First cousin

First cousin

First cousin

Remotely consanguineous

Remotely consanguineous

First cousin

Head circumference (HC)

Normal HC at first but late-infantile-onset microcephaly

Normal HC

Normal HC at first but late-infantile-onset microcephaly

Late-onset macrocephaly

Late-onset macrocephaly

Normal (at 1 month), microcephaly (at 3 years old)

Pregnancy history

None

None

Preeclampsia

None

None

Not mentioned

Family history of additional affected sibling

−

−

−

+

+

−

Age at disease onset (M)

5–6 months

11 months

6 months

6–13 months

6–13 months

12 months

Condition/age at the end of the study (Y)

Died at 3 years old

3 years old

1.66 years

13 years old

11 years old

3 years old

The best speech ability

2–3 words

5–10 words

Less than 10 incomplete words

5–10 words

5–10 words

3–5 words

Neurologic examination

Generalized dystonia, limb spasticity, hyperreflexia, truncal hypotonia, upward plantar reflex, opisthotonus

Distal dystonia, limb spasticity, hyperreflexia, upward plantar reflex, tripod sitting position, clonus

Dystonia, limb spasticity, hyperreflexia, upward plantar reflex

Dystonia, appendicular spasticity, areflexia, truncal hypotonia

Dystonia, appendicular spasticity, areflexia, truncal hypotonia

Dystonia, spasticity without areflexia, truncal hypotonia, ankle clonus

Systemic examination

Low set ears, high arched palate, beaked nose, flat nasal bridge, thick eyebrows

Normal

Normal

Low set ear, thick eyebrows, sloping forehead, prominent nose, short stature, flat philtrum, prominent lower lip

Low set ear, thick eyebrows, sloping forehead, prominent nose, short stature, flat philtrum, prominent lower lip

Coarse facial appearance, mild hirsutism, low anterior hair line prominent forehead, elongated face, bilateral epicanthal folds long eyelashes, low set ears, short philtrum prominent lower lip

Feeding condition

Feeding with gastrostomy tube (PEG)

No problem in feeding

No problem in feeding

Feeding with gastrostomy tube (PEG)

Feeding with gastrostomy tube (PEG)

Not mentioned

Respiratory support

Mechanical ventilation

No problem in breathing

No problem in breathing

Mechanical ventilation

Mechanical ventilation

Not mentioned

Basic metabolic tests

All NL except for high lactate

All NL

All NL

All NL except for high lactate

Not available

Not available

EEG findings

Low-voltage background, generalized slowing, no epileptic discharge activity

Normal

Not available

Generalized slowing without epileptic activity

Not available

Not available

EMG-NCV findings

Not available

Not available

Generalized sensory polyneuropathy

Not available

Not available

Sensory neuropathy without any motor neuron conduction abnormality

Brain MRI

MRI at age 18 months:

Mild supratentorial atrophy, thinning of corpus callous, abnormal signal of posterior periventricular white matter, deep Sylvian fissure, ventriculomegaly

Second brain MRI at age 27 months: the same findings with progressive atrophy

MRI at age 18 months:

Increased signal intensity in white matter of the trigone area

MRI at 1 year old:

normal

MRI at age 18 months:

Delayed myelination

With posterior deep and periventricular white matter abnormalities

At 1 and 2 years: normal

At 7 years: diffuse supratentorial and infratentorial atrophy, thinning of corpus, abnormal white matter signal changes

Not available

At 7 months old: normal

At age 22 months:

increased white matter signals on periventricular and parietal deep white matter

At age 32 months:

widespread increase in white matter intensity, ventricular enlargement, thinning of corpus callosum, cerebral and cerebellar atrophy

Variant

c.53T>C

c.292>C

c.566G>A

c.98A>G

c.98A>G

c.233G>A

Amino acid change

p.leu18pro

p.Tyr98His

p.Trp189X

p.Glu33Gly

p.Glu33Gly

p.Trp78X