Seizures are often refractory to medical therapy . Growth failure microcephaly

90%

Microcephaly is typically acquired (postnatal).

Developmental delay/intellectual disability

90%

Typically in the profound range

Hypotonia

90%

Typically mild, beginning in infancy

Dystonia other movement disorders

90%

Dystonia other hyperkinetic movements are later manifestations.

Hearing impairment

80%

Most fail newborn hearing screening

Frequent otitis media pneumonia

80%

If present, typically occurs during infancy early childhood

Visual impairment

70%

Optic atrophy; Cortical blindness

May be underreported without rigorous testing Gastrointestinal issues

70%

GERD, constipation, emesis may be present.

Feeding difficulties

60%

Often presenting along w/severe irritability during infancy

Skin pigmentation anomalies

~50%

Not present at birth; Reportedly dynamic,

May be mistaken for freckling Scoliosis

30%-99%1

Almost universal in late childhood adolescence GERD = gastroesophageal reflux disease Some features may develop and/or progress over time, making the estimate of the number of affected individuals who have each feature dependent on age at the time of evaluation.

Multiple genes incl:ARXCDKL5DCXKCNQ2

Infantile epileptic spasms syndrome (IESS)

ADXL2

Seizures (infantile spasms), developmental stagnation/regression

Hypsarrhythmia, a cardinal feature of IESS, is not consistently reported in GM3 synthase deficiency.

CNTNAP2(CASPR2)

Pitt-Hopkins-like syndrome 1 (PTHSL1) (OMIM 610042)

AR

Old Order Amish founder variant; Seizures, DD

PTHSL1 is assoc w/focal cortical dysplasia on brain MRI relative macrocephaly.

FMR1

Fragile X syndrome (FXS) (See FMR1 Disorders.)

XL

DD, ID

Relative macrocephaly is seen in FXS, whereas GM3 synthase is assoc w/relative normal head size at birth followed by acquired microcephaly.

MECP2

Classic variant Rett syndrome (See MECP2 Disorders.)

XL

DD, seizures

Skin dyspigmentation, visual deficits, hearing impairment are not defining features of Rett syndrome.; Profound regression w/significant loss of acquired developmental skills is not often seen in GM3 synthase deficiency.

SAMHD1

SAMHD1-related Aicardi-Goutires syndrome (AGS)

AR

Old Order Amish founder variant4; Microcephaly, seizures, feeding intolerances, neonatal hypotonia, irritability

SAMHD1-related AGS is assoc w/thrombocytopenia, leukoencephalopathy, basal ganglia changes on brain MRI.; SAMHD1-related AGS is assoc w/dry, scaly skin chilblains w/o pigmentary changes seen in GM3 synthase deficiency.

ST3GAL3

Developmental epileptic encephalopathy 15 (DEE15) (OMIM 615006)

AR

Significant overlap, incl seizures, visual impairment, hypotonia, dystonia

Congenital hearing impairment acquired microcephaly are not reported in DEE15. AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorder of glycosylation; DD = developmental delay; MOI = mode of inheritance; XL = X-linked ...

Feeding

Gastroenterology/ nutrition/ feeding team eval

Consider eval for GERD.; Consider swallow eval of aspiration risk nutritional status.; Consider eval for gastrostomy tube placement in persons w/dysphagia /or aspiration risk.

Hearing

Audiologic eval

Assess for hearing impairment w/standard DPOAE /or AEP testing.

Eyes

Ophthalmologic eval

To assess for presence of optic atrophy

Skeletal

Physical exam for signs of scoliosis

If present, consider radiographs of spine referral to orthopedist

Genetic counseling

By genetics professionals1

To inform affected persons their families re nature, MOI, implications of GM3 synthase deficiency to facilitate medical personal decision making Family support resources

GM3 Synthase Deficiency: Treatment of Manifestations Manifestation/Concern

Treatment

Considerations/Other

Irritability

Treatment depends on underlying source of new-onset or worsening irritability .

Consider standard therapies such as proton pump inhibitors for GERD, motility agents for constipation, ASM for seizures, typical antibiotics for infections, as needed.; Off-label use of SSRIs may be considered when precipitating factors are not identified [Authors, personal observations].

Epilepsy

Standardized treatment w/ASM by experienced neurologist

No ASM has been demonstrated effective specifically for this disorder.; ASM treatment may be only partially effective multiple ASMs may be required.

Dystonia other hyperkinetic movement disorders

Consider standard therapies for dystonia per neurologist or rehabilitation medicine.

Developmental delay/

Intellectual disability

See .

Sleep disturbance